Conditions: Atopic Dermatitis
Keywords: Moderate-to-severe atopic dermatitis Etrasimod APD334
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 140
Healthy volunteers: no

Brief summary:
The purpose of this study is to determine whether etrasimod is a safe and effective treatment for moderate-to-severe atopic dermatitis (AD).

Detailed description:

Arms:
arm 1: None arm 2: None arm 3: None arm 4: None

Interventions: intervention 1: Etrasimod 1 mg intervention 2: Etrasimod 2 mg intervention 3: Etrasimod matching placebo
Intervention descriptions: intervention 1: Etrasimod 1 mg tablet taken by mouth, once daily intervention 2: Etrasimod 2 mg tablet taken by mouth, once daily. intervention 3: Etrasimod matching placebo tablet by mouth, once daily.

Protocol document:
Prot_000.pdf: 


















Clinical Study Protocol 
APD334-201 
Etrasimod Versus Placebo in Subjects with Atopic Dermatitis (ADVISE) 
Amendment 1.0 
Arena Pharmaceuticals, Inc. 
Confidential 
Page 10 of 102 
TABLE OF CONTENTS 
CLINICAL STUDY PROTOCOL ..................................................................................................1 
SYNOPSIS ......................................................................................................................................2 
TABLE OF CONTENTS ...............................................................................................................10 
LIST OF APPENDICES ................................................................................................................15 
LIST OF TABLES .........................................................................................................................15 
LIST OF FIGURES .......................................................................................................................15 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................16 
1. 
INTRODUCTION ......................................................................................................19 
1.1. 
Atopic Dermatitis ........................................................................................................19 
1.2. 
Etrasimod ....................................................................................................................20 
1.3. 
Benefit and Risk Assessment ......................................................................................20 
2. 
OBJECTIVES .............................................................................................................22 
3. 
STUDY DESIGN .......................................................................................................23 
3.1. 
Overall Design ............................................................................................................23 
3.2. 
Discussion and Rationale for Study Design ...............................................................24 
3.3. 
End of Study ...............................................................................................................25 
4. 
STUDY POPULATION .............................................................................................26 
4.1. 
Inclusion Criteria – Double-Blind Treatment Period .................................................26 
4.2. 
Exclusion Criteria – Double-Blind Treatment Period ................................................26 
 
 
5. 
SUBJECT ACTIVITIES AND RESTRICTIONS ......................................................31 
6. 
STUDY TREATMENT ..............................................................................................32 
6.1. 
Study Treatment(s) Administered ...............................................................................32 
6.2. 
Identity of Study Treatment ........................................................................................32 
6.2.1. 
Etrasimod ....................................................................................................................32 
6.2.2. 
Placebo ........................................................................................................................32 
6.3. 
Dosage and Administration ........................................................................................32 
6.3.1. 
Instructions for Missed Dose(s) ..................................................................................33 
6.3.2. 
Dose Interruptions ......................................................................................................33 
6.4. 
Method of Assigning Subjects to Treatment ..............................................................33 
6.5. 
Selection and Timing of Dose for Each Subject .........................................................33 


Clinical Study Protocol 
APD334-201 
Etrasimod Versus Placebo in Subjects with Atopic Dermatitis (ADVISE) 
Amendment 1.0 
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6.6. 
Blinding ......................................................................................................................34 
6.7. 
Treatment Compliance ................................................................................................34 
6.8. 
Concomitant Therapy .................................................................................................34 
6.8.1. 
Required Concomitant Therapy ..................................................................................34 
6.8.2. 
Allowed Concomitant Therapy and Rescue Therapy .................................................35 
6.8.3. 
Prohibited Concomitant Therapy and Procedures ......................................................35 
7.
STUDY TREATMENT AND MATERIALS MANAGEMENT ..............................38 
7.1. 
Packaging and Labeling ..............................................................................................38 
7.2. 
Storage and Handling .................................................................................................38 
7.3. 
Preparation ..................................................................................................................38 
7.4. 
Accountability .............................................................................................................38 
7.5. 
Retention and Disposal ...............................................................................................38 
8.
REMOVAL OF SUBJECTS FROM THERAPY OR ASSESSMENT .....................39 
8.1. 
Discontinuation of Study Treatment ...........................................................................39 
8.2. 
Discontinuation from the Study ..................................................................................39 
8.3. 
Lost to Follow-Up.......................................................................................................40 
8.4. 
Premature Termination of the Study or Study Site .....................................................40 
9.
STUDY PERIODS .....................................................................................................42 
9.1. 
Screening and Eligibility ............................................................................................42 
9.1.1. 
Discontinuation of AD Medications ...........................................................................42 
9.2. 
Treatment and Safety Follow-Up Periods ..................................................................42 
9.2.1. 
Double-Blind Treatment Period: Week 0/Day 1 (Pre-Randomization) .....................42 
9.2.2. 
Double-Blind Treatment Period: Randomization (Study Day 1) ...............................43 
9.2.3. 
Additional Study Visits (After Day 1) ........................................................................44 
9.2.4. 
Double-Blind Treatment Period Safety Follow-Up Visit ...........................................44 
9.2.5. 
Open-Label Extension (Week 16-Week 68) ...............................................................44 
9.2.6. 
Open-Label Extension Period Safety Follow-Up Visit ..............................................44 
9.3. 
Early Study Treatment Termination ...........................................................................45 
9.4. 
End of Study Visit ......................................................................................................45 
10.
STUDY ASSESSMENTS AND PROCEDURES ......................................................46 
10.1. 
Subject Informed Consent ..........................................................................................46 
10.2. 
Screening and Eligibility ............................................................................................46 
10.2.1. 
Rescreening .................................................................................................................46 




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10.5.7.6. 
Ophthalmic Symptom Monitoring ..............................................................................61 
10.5.8. 
Adverse Events ...........................................................................................................62 
10.5.8.1. 
Definitions ..................................................................................................................62 
10.5.8.2. 
Eliciting, Recording, and Reporting Adverse Events .................................................64 
10.5.8.3. 
Reporting Serious Adverse Events .............................................................................65 
10.5.9. 
Pregnancy ...................................................................................................................66 
10.6. 
Procedures for Overdose .............................................................................................66 
 
 
 
 
 
 
 
 
 
 
11. 
PLANNED STATISTICAL METHODS ...................................................................69 
11.1. 
General Considerations ...............................................................................................69 
11.2. 
Determination of Sample Size ....................................................................................69 
11.3. 
Analysis Sets ...............................................................................................................69 
11.4. 
Missing Data ...............................................................................................................70 
11.4.1. 
Primary Methods of Handling Missing Data and Rescue Medication Uses ..............70 
11.4.2. 
Sensitivity Analyses ....................................................................................................70 
11.5. 
Efficacy Analyses .......................................................................................................71 
11.5.1. 
Endpoint Definitions ...................................................................................................72 
11.5.2. 
Primary Efficacy Endpoint .........................................................................................72 
11.5.3. 
Key Secondary Efficacy Endpoints ............................................................................72 
11.5.4. 
Secondary Efficacy Endpoints ....................................................................................72 
 
 
11.5.6. 
Efficacy assessment during open-label extension: .....................................................73 
 
 
11.5.8. 
Subgroup Analyses .....................................................................................................73 
11.6. 
Testing Strategy ..........................................................................................................73 
11.7. 
Interim Analysis ..........................................................................................................74 
11.8. 
Safety Analyses ..........................................................................................................74 
11.8.1. 
Safety Endpoints .........................................................................................................74 


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11.8.2. 
Adverse Events ...........................................................................................................74 
11.8.3. 
Extent of Exposure .....................................................................................................74 
11.8.4. 
Clinical Laboratory Parameters ..................................................................................74 
 
 
11.8.6. 
Vital Signs ..................................................................................................................75 
11.8.7. 
Physical Examination .................................................................................................75 
11.9. 
Statistical Considerations for the Open-Label Extension Period ...............................75 
12. 
ETHICAL CONSIDERATIONS................................................................................77 
12.1. 
Ethical Conduct of the Study ......................................................................................77 
12.2. 
Institutional Review Board or Independent Ethics Committee Approval ..................77 
12.3. 
Informed Consent and Assent .....................................................................................77 
12.4. 
Confidentiality ............................................................................................................78 
12.5. 
Protocol Compliance ..................................................................................................78 
13. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................79 
13.1. 
Training of Study Site Personnel ................................................................................79 
13.2. 
Monitoring ..................................................................................................................79 
13.3. 
Audit ...........................................................................................................................79 
14. 
DATA HANDLING AND RECORD KEEPING ......................................................80 
14.1. 
Data Management .......................................................................................................80 
14.1.1. 
Case Report Forms .....................................................................................................80 
14.1.2. 
Source Documents ......................................................................................................80 
14.2. 
Study Documentation and Records Retention ............................................................80 
14.3. 
Clinical Study Report .................................................................................................81 
14.4. 
Disclosure of Study Results ........................................................................................81 
15. 
RESPONSIBILITIES .................................................................................................82 
15.1. 
Investigator Responsibilities .......................................................................................82 
15.2. 
Sponsor Responsibilities .............................................................................................82 
16. 
REFERENCES ...........................................................................................................83 
 
 




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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Explanation 
AD 
atopic dermatitis 
ADR 
adverse drug reaction 
AE 
adverse event 
ALC 
absolute lymphocyte count 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
AST 
aspartate aminotransferase 
AV 
atrioventricular  
β-hCG 
beta human chorionic gonadotropin 
BP 
blood pressure 
bpm 
beats per minute 
BSA 
body surface area 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CK 
creatine kinase 
CRO 
contract research organization 
CYP 
cytochrome P450 
 
 
DLQI 
Dermatology Life Quality Index 
DNA 
deoxyribonucleic acid 
EASI 
Eczema Area and Severity Index 
EASI-50/-75/-90 
50%/75%/90% reduction in Eczema Area and Severity Index 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EoT 
end of treatment 
FA 
fluorescein angiography 
FAS 
Full Analysis Set 
FEV1 
forced expiratory volume in the first second 
FVC 
forced vital capacity 
GCP 
Good Clinical Practice 
HBsAg 
Hepatitis B surface antigen 


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Etrasimod Versus Placebo in Subjects with Atopic Dermatitis (ADVISE) 
Amendment 1.0 
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Abbreviation 
Explanation 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
HR 
heart rate 
IB 
Investigator’s Brochure 
IAC 
independent adjudication committee 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IGA 
Investigator Global Assessment 
IgE 
immunoglobulin E 
IGRA 
interferon-gamma release assay 
IMID 
immune-mediated inflammatory disorder 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
IUD 
intrauterine device 
IV 
intravenous 
IWRS 
Interactive Web Response System 
JAK 
Janus kinase 
LDH 
lactate dehydrogenase 
LFT 
liver function test 
LS 
least square 
mFAS 
modified Full Analysis Set 
MI 
multiple imputation 
MMRM 
mixed effects model with repeated measures 
NA 
not applicable 
NRS 
numerical rating scale 
 
 
OLE 
Open-Label Extension 
 
 
PGA 
Patient Global Assessment 
 
 
 
 




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1. 
INTRODUCTION 
1.1. 
Atopic Dermatitis 
Skin diseases are the fourth largest cause of disability worldwide (Karimkhani 2017). Atopic 
dermatitis (AD, also known as atopic eczema) is the most common chronic relapsing, 
inflammatory skin disease. The lifetime prevalence of AD is 10% to 20% in developed nations, 
and appears to be increasing (Weidinger 2016, Heratizadeh 2017). 
AD is more common in children. It is estimated that 90% of individuals with AD develop their 
first symptoms by age 5, and in approximately 60% of cases it manifests during the first year of 
life (Weidinger 2016, Boguniewicz 2017). The nature of AD is relapsing and remitting and 
patients diagnosed as children may even experience spontaneous disease remission later in 
adolescence (Bieber 2008, Eichenfield 2014). However, AD can remain a chronic and lifelong 
condition, with prevalence in adults ranging from 7% to 10% (Boguniewicz 2017). In a clinical 
study population, it was found that 50% of AD patients had been living with active disease for 
more than 27 years (Simpson 2016b). 
AD is characterized by systemic cutaneous inflammation and perturbed epidermal-barrier 
function resulting in dry, red, skin and intense itch (Bieber 2008, Weidinger 2016). Essential 
features for diagnosis of AD are pruritus, eczematous dermatitis, and a chronic or relapsing 
history of disease (Weidinger 2016, Boguniewicz 2017). Patients with AD are more likely to 
have other allergic or atopic conditions. In a 2016 study of 380 adults with moderate-to-severe 
AD, 51.3% had allergic rhinitis, 40.3% had asthma, 24.2% had allergic conjunctivitis, and 60.5% 
had other allergies. The disease burden of those with AD significantly impacts quality of life and 
patients report that their condition affects social and leisure activities (43.9%), work or studying 
(41.8%), and even clothing choice (57.9%) (Simpson 2016a). 
A combination of genetic, environmental, and immunologic factors appears to determine disease 
predisposition, while the pathogenesis of AD is thought to stem from the mutually reinforcing 
interaction between a disrupted epidermal barrier and an inappropriate immune response in the 
skin (Weidinger 2016, Heratizadeh 2017). Epidermal barrier disruption in AD facilitates 
penetration by allergens, immunoglobulin E (IgE) sensitization, and bacterial colonization 
(particularly Staphylococcus aureus), which induce persistent type 2 helper T cell responses 
(Salava 2014, Zhu 2018). 
There are currently various topical and systemic therapeutic options that are used for the 
treatment and symptomatic relief of AD, including corticosteroids, moisturizers, and systemic 
immunosuppressants. However, these current therapies are limited by poor compliance, safety 
profiles that prohibit long-term use, limited efficacy that provides only transient or marginal 
symptomatic relief, invasive administration procedures, or off-label use. Thus, there remains a 
great unmet medical need for an effective, safe, and orally administered treatment. 
 
 
 






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Amendment 1.0 
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2. 
OBJECTIVES 
Primary Objective 
• To assess the efficacy of etrasimod monotherapy (1 or 2 mg) in subjects with 
moderate-to-severe AD during the Double-Blind Treatment Period. 
Safety Objective 
• To assess the safety and tolerability of etrasimod monotherapy (1 or 2 mg) in subjects 
with moderate-to-severe AD during the Double-Blind Treatment Period. 
Open-Label Extension Objective 
• To assess the long-term safety, tolerability, and efficacy of etrasimod monotherapy 
(2 mg) in subjects with moderate-to-severe AD. 


















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Amendment 1.0 
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5. 
SUBJECT ACTIVITIES AND RESTRICTIONS 
For dosing requirements, including holding the dose prior to the study visit on study visit days, 
see Dosage and Administration, Section 6.3. Rescue therapies and prohibited 
medications/procedures are located in Section 6.8.2 and Section 6.8.3, respectively. 
Optimized skin care is expected to be followed prior to and maintained throughout the study as 
per current guidelines and recommendations for AD (Eichenfield 2014, Eichenfield 2017). 
Subjects are expected to continue their usual skin care routine and basic skin care regimen 
without notable changes for the course of the study treatment and follow-up periods. This 
includes frequency and length of showering or bathing, including bleach baths, the use of 
emollients, topical anesthetics, antihistamines, and topical and systemic anti-infective 
medications. 
Subjects must be willing to apply topical emollient or moisturizer at least once daily for 
≥ 1 week prior to the Baseline Visit and willing to continue daily application over the course of 
the study without change (ie, type, frequency, application). 
On visit days during the study, subjects should not apply any topical emollient or moisturizer 
prior to attending clinic and completing their visit. Study treatment should also be held the day of 
clinic visits. Subjects will take their daily dose at the study site on study visit days. 
 
 




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Amendment 1.0 
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completed. Subjects will take their daily dose at the study site on study visit days. The time of 
 sample collection and subsequent dosing should be documented. 
6.3.1. 
Instructions for Missed Dose(s) 
Subjects should be instructed that if they forget to take a dose, they can take the dose within 
8 hours of the normal dosing time; otherwise, they should take their next dose at the regular time 
on the following day. If the subject vomits the tablet, he/she should be instructed not to take 
another tablet on the same day, but to take the next dose at the regular time on the following day. 
Subjects should be instructed to contact the investigator if they miss more than 2 consecutive 
doses.  
6.3.2. 
Dose Interruptions 
If the investigator deems it necessary to withhold study treatment, temporary withholding is 
permitted for up to 3 days without obtaining prior approval from the Sponsor. If study treatment 
interruption ≥ 7 days is required for a medical reason, the investigator must contact the medical 
monitor as soon as this is anticipated. 
The procedure for first-dose cardiac monitoring as outlined in Section 10.5.7.4 should be 
performed and/or discussed with the medical monitor any time a subject misses a study treatment 
as follows: 
• ≥ 2 consecutive days within the first week of study treatment  
• ≥ 7 consecutive days after the first week of study treatment 
If these doses of study treatment are missed, subjects must contact the Investigator to discuss 
treatment re-initiation and are required to return to the study site before taking their next dose of 
study treatment. The subject must take the next dose of study treatment at the study site, and the 
in-clinic cardiac monitoring as outlined in Section 10.5.7.4 should be performed. 
6.4. 
Method of Assigning Subjects to Treatment 
For the Double-Blind Treatment Period, subjects will be centrally assigned to randomized study 
treatment using an Interactive Web Response System (IWRS). Details of the randomization 
methodology are provided in the statistical analysis plan (SAP). 
During the Open-Label Extension Period, all eligible subjects will receive the same treatment (no 
randomization). 
6.5. 
Selection and Timing of Dose for Each Subject 
Subjects will self-administer 1 tablet once daily (with water, either with or without food). The 
tablet should be taken at approximately the same time each day, preferably in the morning. On 
visit days during the study, subjects should not apply any topical emollient or moisturizer prior to 
attending clinic and completing their visit. Additionally, on study visit days, subjects should wait 
and take their dose at the study site after blood draws 
 and after all pre-dose 
assessments have been completed.  


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6.6. 
Blinding 
This study includes a Double-Blind Treatment Period with limited access to the randomization 
code. The investigational drug and placebo tablets are identical in physical appearance. The 
treatment each subject receives will not be disclosed to the investigator, study site staff, subject, 
Sponsor personnel involved with the conduct of the study (with the exception of the clinical 
supply staff and designated safety staff), or study vendors. The IWRS will hold treatment codes 
for study treatment. 
The IWRS will be programmed with blind-breaking instructions. In the case of an emergency, 
the investigator has the sole responsibility for determining if unblinding of a subject’s treatment 
assignment is warranted based upon medical necessity. Subject safety must always be the first 
consideration in making such a determination. If a subject’s treatment assignment is unblinded, 
the medical monitor or Sponsor delegate must be notified within 24 hours after breaking the 
blind. The date and reason the blind was broken must be recorded in the source documentation 
and electronic case report form (eCRF), as applicable. 
Unblinding may occur after all subjects have completed the Double-Blind Treatment Period, 
including the Safety Follow-Up Visit. 
6.7. 
Treatment Compliance 
The investigator is responsible for ensuring that subjects are correctly instructed on how to take 
their study treatment and that each subject is fully compliant with their assigned treatment 
regimen. Subject compliance will be based on tablet counts at specified study visits (Section 7.4 
and Appendix 1; Table 8 and Table 9). 
6.8. 
Concomitant Therapy 
Any medication (including over-the-counter or prescription medicines, vitamins, and/or herbal 
supplements) or vaccine that a subject receives from Day 1 through the end of study must be 
recorded along with the following: 
• Reason for use 
• Dates of administration including start and end dates 
• Dosage information including dose and frequency 
The medical monitor should be contacted if there are any questions regarding concomitant 
therapy. 
6.8.1. 
Required Concomitant Therapy 
Subjects are required to apply topical moisturizers at least once daily for at least 1 week before 
randomization and throughout the study without change (ie, type, frequency, application). 
Topical moisturizers are generally permitted, except for new prescription moisturizers or 
moisturizers containing additives (including ceramide, hyaluronic acid, urea, or filaggrin 
degradation products) during the Screening Period or during the study. Subjects may continue 
using stable doses of such moisturizers if initiated before the Screening Visit. 






Clinical Study Protocol 
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Amendment 1.0 
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• Subjects may not donate sperm, or oocytes during the study and for 4 weeks after the 
last dose of study treatment 


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7. 
STUDY TREATMENT AND MATERIALS MANAGEMENT 
7.1. 
Packaging and Labeling 
Tablets are packaged in induction-sealed, high-density polyethylene bottles with child-resistant 
screw caps and desiccant canisters. Each bottle will be labeled as required per country 
requirements. 
7.2. 
Storage and Handling 
 
7.3. 
Preparation 
No preparation by study site personnel is required. 
7.4. 
Accountability 
At specified study visits, previously dispensed study treatment tablets will be collected by the 
investigator or qualified staff to assess subject compliance (Appendix 1; Table 8 and Table 9). 
The investigator must maintain adequate records documenting the receipt, use, loss, or other 
disposition of study treatment tablets. To ensure adequate records, all drug supplies will be 
accounted for in the drug accountability inventory forms and will be monitored by counting of 
unused study treatment tablets. 
7.5. 
Retention and Disposal 
All study treatment will be reconciled by the study monitor and unused study treatment will be 
returned or destroyed according to applicable country regulations. On-site destruction following 
all local regulations and in accordance with applicable site standard operating procedures (SOPs) 
is permitted. Prior to any action being taken with study treatment, the investigator will contact 
the Sponsor (or contract research organization [CRO] for approval of such action). Final 
reconciliation will be performed at study completion.  


Clinical Study Protocol 
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8. 
REMOVAL OF SUBJECTS FROM THERAPY OR ASSESSMENT 
8.1. 
Discontinuation of Study Treatment 
A subject’s treatment with study drug may be discontinued for any of the following reasons: 
• AE 
• Death 
• Pregnancy (Section 10.5.9) 
• Protocol deviation 
• Physician decision 
• Withdrawal by subject 
• Lost to follow-up 
• Study terminated by Sponsor 
• Criteria met from cardiac heart rate monitoring to discontinue study treatment 
(Section 10.5.7.4) 
• Other 
8.2. 
Discontinuation from the Study 
Subjects may discontinue from the study at any time for any of the following reasons: 
• AE 
• Death 
• Pregnancy (Section 10.5.9) 
• Protocol deviation 
• Physician decision 
• Withdrawal by subject 
• Lost to follow-up 
• Study terminated by Sponsor 
• Criteria met from cardiac heart rate monitoring to discontinue study treatment 
(Section 10.5.7.4) 
• Other 
A subject may elect to discontinue study participation at any time for any reason without 
prejudice to their future medical care by the physician or at the institution. Subjects who 
discontinue study treatment during the Double-Blind Study Period but who consent to remain in 
the study will continue to comply with study visits and assessments.  


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If a subject withdraws consent, no further evaluations should be performed, and no additional 
data should be collected. The Sponsor may retain and continue to use any data collected before 
such withdrawal of consent. The investigator should make a reasonable attempt to document the 
specific reason why consent was withdrawn. 
An end of treatment (EoT) visit should be completed within 1 week of when study treatment has 
been terminated and a Safety Follow-Up Visit 4 weeks after the last dose of study treatment. 
Whenever possible, subjects should continue on study even when study treatment has been 
discontinued during the Double-Blind Treatment Period.  
8.3. 
Lost to Follow-Up 
A subject will be considered lost to follow-up if the subject repeatedly fails to return for 
scheduled visits and cannot be contacted by the study site. 
The following actions must be taken if a subject fails to return to the clinic for a required study 
visit: 
• The site must attempt to contact the subject and reschedule the missed visit as soon as 
possible and counsel the subject on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the subject wishes to and/or should continue in 
the study. 
• Before a subject is deemed lost to follow-up, the investigator or designee must make 
every effort to regain contact with the subject (this would include telephone calls and 
if necessary, a certified letter to the subject’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the subject’s 
medical record. 
Should the subject continue to be unreachable, he/she will be considered to have withdrawn from 
the study. 
8.4. 
Premature Termination of the Study or Study Site 
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 subjects 
• Subject enrollment is unsatisfactory 
• Upon request of Health Authorities 
The Sponsor will notify the investigator if the study is placed on hold or if the Sponsor decides to 
discontinue the study. Health authorities and (Independent Ethics Committee[s]) IECs/ 
(Institutional Review Board[s]) IRBs will be informed about the termination of the study in 
accordance with applicable regulations. 
The Sponsor has the right to replace a study site at any time. Reasons for replacing a study site 
may include, but are not limited to: 
• Excessively slow recruitment 


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• Poor protocol adherence 
• Inaccurate or incomplete data recording 
• Non-compliance with International Conference on Harmonization (ICH) guidelines 
for Good Clinical Practice (GCP) 








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Subjects who terminate the study treatment early in the Open-Label Extension Period, should 
have an EoT Visit (Section 9.3) and a Safety Follow-Up Visit 4 weeks after the last dose of study 
treatment. 
The Open-Label Extension Period Safety Follow-Up Visit will also be the End of Study Visit 
(Section 9.4). 
9.3. 
Early Study Treatment Termination 
Subjects who stop taking their study treatment before the end of the Double-Blind Treatment or 
Open-Label Extension Periods will return to the study site for an EoT Visit within 1 week of the 
last study treatment administration. Subjects who stop taking their study treatment before the end 
of the Double-Blind Treatment Period are not eligible to participate in the Open-Label Extension 
Period. Visit assessments are detailed in the 
 
. Study site staff will work with subjects who withdraw early to obtain as much 
follow-up data as possible. Lymphocyte counts should be monitored until returned to 
approximately baseline or stable. In the Double-Blind Treatment Period, whenever possible, 
subjects should continue in the study even if study treatment has been discontinued. Subjects 
who discontinue study treatment, but who consent to remain in the study will continue to comply 
with study visits and assessments. 
9.4. 
End of Study Visit 
The End of Study Visit for an individual subject is defined as the date of the final study contact 
(eg, Safety Follow-Up Visit) when assessments or procedures are done. 


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10. 
STUDY ASSESSMENTS AND PROCEDURES 
10.1. 
Subject Informed Consent 
The investigator, or a person designated by the investigator, will obtain written informed consent 
from each subject before any study-specific activities are performed. 
10.2. 
Screening and Eligibility 
Subject eligibility will be assessed based on protocol inclusion and exclusion criteria. All 
screening evaluations must be completed and reviewed to confirm that potential subjects meet all 
eligibility criteria. Screening procedures must be completed within 4 weeks prior to receiving the 
first dose of study treatment (Appendix 1; Table 8). 
Additional eligibility assessment will be performed at Week 16 to determine eligibility to 
continue into the Open-Label Extension Period, as outlined in Section 4.3. 
10.2.1. 
Rescreening 
If a subject fails ≥ 1 screening laboratory (or other) assessment criteria, the assessment(s) may be 
repeated once at the discretion of the investigator, and the subject may be enrolled if criteria are 
then met, provided the assessments are completed within the Screening Period. Any rescreening 
laboratory assessments beyond 1 time will need to be discussed with the medical monitor before 
proceeding. If a subject fails screening, then 1 re-screening attempt during a new Screening 
Period may be made, if appropriate. Each subject must be reconsented prior to each screening 
attempt. 
10.2.2. 
Demography and Other Subject Characteristics 
Demographics including year of birth, sex at birth, Hispanic ethnicity, and race as described by 
the subject, will be collected at Screening. 
10.2.3. 
Medical History/Atopic Dermatitis History 
A complete medical history of each subject will be collected and documented during Screening 
to determine subject eligibility. The history should include illnesses, hospitalizations, and 
participation in other investigational drug studies. 
The diagnosis of AD by Hanifin and Rajka criteria (
) will be recorded, and the 
duration of AD. 
10.2.4. 
Prior and Ongoing Therapies 
Prior therapies related to the treatment of AD will be collected during Screening. Documentation 
should include the rationale for prior treatment failure. All ongoing medications will be recorded 
at Screening and updated as needed throughout the entire study.  
10.2.5. 
Social History 
A social history including the amount and duration of tobacco and alcohol use will be collected 
at Screening. 




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10.3. 
Efficacy Assessments 
Multiple parameters will be collected during the study to assess efficacy/effectiveness of 
etrasimod including measures of AD severity, and patient-reported measures of AD symptoms 
and quality of life. Questionnaires and PRO assessments should be administered prior to 
obtaining investigator assessments, safety and laboratory assessments, and study treatment 
administration. Refer to the study manual for instructions on the administration and use of all 
patient-reported instruments (including POEM and DLQI). 
Wherever possible, to maintain consistency, the same individual at the site should administer the 
investigator assessments for the duration of the study. 
10.3.1. 
Eczema Area and Severity Index 
The EASI is a validated scoring system that grades the severity and extent of AD (Tofte 1998, 
Hanifin 2001). EASI is the core outcome measure for the clinical signs of AD, which has been 
used extensively in clinical studies. The EASI is a composite index with scores ranging from 
0 to 72. The EASI scoring assessment multiplies the percentage of the affected area in 4 specific 
disease characteristics (erythema, thickness [induration, papulation, edema], scratching 
[excoriation], and lichenification), which will each be assessed for severity by the investigator or 
designee on a scale of “0” (absent) through “3” (severe). 
The EASI Area Score is documented for 4 regions of the body. Region 1: head and neck; 
Region 2: trunk (including genital area); Region 3: upper limbs; and Region 4: lower limbs 
(including buttocks), with the area of AD involvement assessed as a percentage by body area and 


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converted to a score of 0 to 6. In each body region, the area is expressed as 0, 1 (1% to 9%), 
2 (10% to 29%), 3 (30% to 49%), 4 (50% to 69%), 5 (70% to 89%), or 6 (90% to 100%). 
The EASI will be collected at time points according to the 
 
. 
10.3.2. 
SCORing Atopic Dermatitis 
The SCORAD is a validated measure of the extent and severity of AD. There are 3 components 
to the assessment: A = extent or affected BSA, B = severity, and C = subjective symptoms. The 
extent of AD is assessed as a percentage of each defined body area and reported as the sum of all 
areas, with a maximum score of 100% (assigned as “A” in the overall SCORAD calculation). 
The severity of 6 specific symptoms of AD (redness, swelling, oozing/crusting, excoriation, skin 
thickening/lichenification, dryness) is assessed using the following scale: none (0), mild (1), 
moderate (2), or severe (3) (for a maximum of 18 total points, assigned as “B” in the overall 
SCORAD calculation). Subjective assessment of itch and sleeplessness is recorded for each 
symptom by the subject or relative on a Visual Analogue Scale, where 0 is no itch (or 
sleeplessness) and 10 is the worst imaginable itch (or sleeplessness), with a maximum possible 
score of 20. This parameter is assigned as “C” in the overall SCORAD calculation. The 
SCORAD is calculated as: A/5 + 7B/2 + C where the maximum is 103 (European-Task-Force-
on-Atopic-Dermatitis 1993).  
The SCORAD will be performed at time points according to the 
 
. 
10.3.3. 
Validated Investigator’s Global Assessment 
The vIGA scale for AD is a 5-point scale to measure disease severity. The IGA score is selected 
using descriptors that best describe the overall appearance of skin lesions at a given time point 
using the following scoring: 0 = clear (no inflammatory signs of AD); 1 = almost clear (barely 
perceptible erythema and papulation); 2 = mild (slight but definite erythema and papulation); 
3 = moderate (clearly perceptible erythema and papulation); and 4 = severe (marked erythema 
papulation) (vIGA-ADTM 2017).The vIGA will be performed at time points according to the 
. 
10.3.4. 
Atopic Dermatitis Body Surface Area Involvement 
Body surface area affected by AD will be assessed for each section of the body. The possible 
highest score for each region is: head and neck (9%), anterior trunk (18%), back (18%), upper 
limbs (18%), lower limbs (36%), and genitals (1%) and will be reported as a percentage of all 
major body sections combined. 
The BSA assessment will be performed at time points according to the 
 
. 


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10.3.5. 
Patient-Reported Outcomes 
10.3.5.1. Pruritus Numeric Rating Scale 
The pruritus NRS is a simple assessment tool that subjects will use to report the intensity of their 
pruritus (itch). The scale for the pruritus NRS is from 0 to 10 with 0 being “no itch” and 10 being 
“the worst itch imaginable.” 
At Baseline and subsequent visits, subjects will be asked to rate the intensity of their itch 
(maximum/peak and average) over the previous 7 days. Subjects will also be asked to rate their 
average itch intensity over the previous 24 hours and their maximum itch intensity in a daily 
diary (Stander 2013, PruritusResources 2019). 
The pruritus NRS will be assessed at time points according to the 
 
. 
10.3.5.2. Dermatology Life Quality Index 
The DLQI is a validated 10-item questionnaire designed to measure the impact of skin disease on 
the quality of life (QoL) of an affected individual (Finlay 1994). The format is a simple response 
to 10 items, which assess QoL over the past week. For each item, the scale is rated as follows: 
0 = “not at all”; 1 = “a little”; 2 = “a lot”; 3 = “very much,” with an overall scoring system of 
0 to 30; a high score is indicative of a poor QoL. For general inflammatory skin conditions a 
change in DLQI score of at least 4 points is considered clinically important (Basra 2015). 
The DLQI will be assessed at time points according to the 
 
. 
10.3.5.3. Patient Global Assessment of Disease 
Two questions will be included for subjects to rate their disease and their disease severity. 
Subjects will rate their overall well-being based on a 5-point Likert scale from poor to excellent. 
Subjects will be asked, “Considering all the ways in which your eczema affects you, indicate 
how well you are doing.” Response choices are: ‘Poor’, ‘Fair’, ‘Good’, ‘Very Good,’ or 
‘Excellent’. 
Subjects will also be asked to best describe the overall appearance of skin lesions at a given time 
point using the vIGA scale (Section 10.3.3). The vIGA scale has been adapted for patients to 
complete. The scale has been modified for easier understanding for subjects, to exclude medical 
terminology (eg, lichenification has been adapted to thickening and erythema to redness). 
Subjects will complete these assessments at time points according to the 
 
. 
10.3.5.4. Patient Oriented Eczema Measure 
The Patient Oriented Eczema Measure (POEM) is a patient-derived validated tool used for 
monitoring atopic eczema severity. The POEM consists of 7 questions asking patients to rank 
how many days over the past 7 days they have experienced specific AD-related symptoms  
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values return to normal or baseline or are no longer considered clinically significant by the 
investigator. If such values do not return to normal or baseline, or otherwise resolve to a 
non-clinically significant value within a reasonable period of time, as judged by the investigator, 
the etiology should be identified, and the Sponsor should be notified. Relevant local laboratory 
results and non-protocol specified assessments that are performed at a local laboratory and result 
in a change in subject management or are considered clinically significant by the investigator 
(eg, AE or dose modification) should be recorded in the eCRF.  
Information on the grading and management of laboratory abnormalities according to assessed 
severity is provided in Appendix 2 and Appendix 3. 


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Table 3: 
Clinical Laboratory Tests 
Infectious Disease 
Drugs of Abuse 
Human immunodeficiency virus (HIV), hepatitis B 
surface antigen (HBsAg), and hepatitis C virus (HCV) 
antibody (with reflex PCR) 
TB with interferon-gamma release assay (IGRA; 
preferably, QuantiFERON-TB Gold In-Tube).  
Urine drug screen: amphetamine, cocaine, 
methamphetamine, methylenedioxymethamphetamine, 
or phencyclidine  
Pregnancy Testing 
Coagulation 
Serum pregnancy test human chorionic gonadotropin 
(β-hCG- [only for females of child-bearing potential 
with positive urine β-hCG]) 
Urine β-hCG (only for females of child-bearing 
potential) 
Prothrombin time (PT) 
Activated partial thromboplastin time (PTT) 
International Normalized Ratio (INR) 
Urinalysis 
Hematology 
Appearance 
Bilirubin 
Color 
Glucose 
Ketones 
Microscopic examination of sediment 
Nitrite 
Occult blood 
pH 
Protein 
Specific gravity 
Urobilinogen 
Hematocrit 
Hemoglobin 
Mean corpuscular hemoglobin (MCH) 
Mean corpuscular hemoglobin concentration (MCHC) 
Mean corpuscular volume (MCV) 
Platelet count 
Red blood cell (RBC) count  
White blood cell (WBC) count with differential  
 
 
Serum Chemistry 
 
Albumin 
Alkaline phosphatase (ALP) 
Alanine aminotransferase (ALT) 
Aspartate aminotransferase (AST) 
Bicarbonate  
Blood urea nitrogen (BUN) 
Calcium 
Chloride 
Creatinine with eGFR by CKD-EPI 
Creatine kinase 
Gamma-glutamyl transferase (GGT) 
Glucose 
Lactate dehydrogenase (LDH) 
Lipase 
Magnesium 
Phosphorus 
Potassium 
Sodium 
Thyroid-stimulating hormone (TSH) with reflex free T4 
and free T3 if abnormal 
Total bilirubin 
Direct bilirubin 
Total cholesterol 
Total protein 
Triglycerides 
Uric acid 
Other Tests 
 
  
 
















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10.5.8. 
Adverse Events 
10.5.8.1. Definitions 
10.5.8.1.1. Adverse Event 
An AE is any untoward medical occurrence that does not necessarily have a causal relationship 
with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or 
disease temporally associated with the use of a medicinal product, whether or not considered 
related to the medicinal product. 
AEs can include, but are not limited to, 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 over the course of the 
study 
• Pre-existing conditions that worsen in severity, increase in frequency, or have new 
signs/symptoms 
Information on the grading and management of laboratory abnormalities according to assessment 
severity is provided in Appendix 2 and Appendix 3, respectively. 
10.5.8.1.2. Serious Adverse Event 
An AE should be classified as a serious adverse event (SAE) if it meets 1 of the following 
criteria: 
Fatal: 
The AE resulted in death. 
Life-threatening: 
The AE placed the subject at immediate risk of death. This 
classification does not apply to an AE that hypothetically might cause 
death if it were more severe. 
Hospitalization: 
The AE required or prolonged an existing inpatient hospitalization. 
Hospitalizations for elective medical or surgical procedures or 
treatments planned before the signing of informed consent in the study 
or routine check-ups are not SAEs by this definition. 
Disabling/ 
incapacitating: 
The AE resulted in a persistent or significant incapacity or substantial 
disruption of the subject’s ability to conduct normal life functions. 
Congenital anomaly 
or birth defect: 
An adverse outcome in a child or fetus of a subject exposed to the 
study treatment before conception or during pregnancy. 
Medically significant: The AE did not meet any of the above criteria but could have 
jeopardized the subject and might have required medical or surgical 
intervention to prevent one of the outcomes listed above or involves 
suspected transmission via a medicinal product of an infectious agent. 


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10.5.8.1.3. Adverse Drug Reaction 
An adverse drug reaction (ADR) in the pre-approval clinical experience with a new medicinal 
product or its new usages, particularly as the therapeutic dose(s) may not be established, is any 
noxious and unintended response to a medicinal product related to any dose. The phrase 
“responses to a medicinal product” means that a causal relationship between a medicinal product 
and an AE is at least a reasonable possibility (ie, the relationship cannot be ruled out). 
10.5.8.1.4. Events of Interest 
Based on the mechanism of action of etrasimod and prior experience with other agents acting via 
a similar mechanism, as well as known comorbid conditions with AD, potential events of interest 
may be identified. In addition to appropriate reporting of these events as an AE or an SAE, 
supplementary detailed information may be collected. 
10.5.8.1.5. Severity 
The severity of each AE will be assessed at the onset by a nurse/or physician. When recording 
the outcome of the AE, the maximum severity of the AE experienced will also be recorded. The 
severity of each AE will be graded according to the Common Terminology Criteria for Adverse 
Events: 
Grade 1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated. 
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living. 
Grade 3 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling, 
limiting self-care activities of daily living (eg, preparing meals, 
shopping for groceries or clothes, using the telephone, managing 
money). 
Grade 4 
Life-threatening consequences, urgent intervention indicated. 
Grade 5 
Death related to an AE. 
Additional information on CTCAE grading of AEs is provided in Appendix 2. 
10.5.8.1.6. Relationship 
The investigator is obligated to assess the relationship between the study treatment and each 
occurrence of each AE. The AE relationship to study treatment must be characterized as 1 of the 
following categories: 
Not Related: 
The AE does not follow a reasonable temporal sequence from 
administration of the drug, does not abate upon discontinuation of the 
drug, does not follow a known or hypothesized cause-effect 
relationship, and (if applicable) does not reappear when the drug is 
reintroduced, furthermore, there may exist a clear alternative medical 


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explanation (e.g., underlying disease state) or association with study 
procedure or study conduct.  
Unlikely Related: 
The temporal association between the AE and the drug is such that the 
drug is not likely to have any reasonable association with the AE.  
Probably Related: 
The AE follows a reasonable temporal sequence from administration of 
the drug and cannot be reasonably explained by the known 
characteristics of the subject’s clinical state, environmental or toxic 
factors, or other modes of therapy administered to the subject.  
Related: 
The AE follows a reasonable temporal sequence from administration of 
the drug, abates upon discontinuation of the drug, follows a known or 
hypothesized cause-effect relationship, and (if appropriate) reappears 
when the drug is reintroduced.  
The investigator will use clinical judgment to determine the relationship. Alternative causes, 
such as underlying disease(s), concomitant therapy, and other risk factors, as well as the 
temporal relationship of the event to the study treatment administration should be considered and 
investigated. The investigator should consult the IB and the Product Information of marketed 
products within the drug class, when applicable. For each AE, the investigator must document in 
the medical notes that he/she has reviewed the AE and has provided an assessment of causality. 
There may be situations in which an SAE has occurred, and the investigator has minimal 
information to include in the initial report to the Sponsor; however, the investigator should 
always make an initial assessment of causality for every event before the initial transmission of 
the SAE to the Sponsor. The investigator may change his/her opinion of causality based on 
subsequent receipt of information and send an SAE follow-up report with the updated causality 
assessment. The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. 
10.5.8.2. Eliciting, Recording, and Reporting Adverse Events 
10.5.8.2.1. Eliciting Adverse Events 
Subjects will be instructed that they may report AEs at any time. An open-ended or nondirected 
method of questioning should be used at each study visit to elicit the reporting of AEs. 
10.5.8.2.2. Recording Adverse Events 
The AE reporting period for safety surveillance begins when the subject is initially included in 
the study (date of first signature of informed consent) and continues up to 30 days after the last 
study treatment administration. If 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 closeout 
the event in the database if no further follow-up is necessary. 
Any SAE suspected to be related to the study treatment must be reported whenever it occurs, 
irrespective of the time elapsed since the last administration. 
Investigator and study personnel will record all AEs and SAEs whether received through an 
unsolicited report by a subject, elicited during subject questioning, discovered during physical 


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examination, laboratory testing, and/or other means by recording them on the eCRF and SAE 
Report Form, as appropriate. The following information should be recorded on the AE eCRF: 
• Description including onset and resolution dates 
• Whether it met SAE criteria 
• Severity 
• Relationship to study treatment or other causality 
• Outcome 
For SAEs, events occurring secondary to the primary event should be described on the eCRF in 
the narrative description field.  
The following should be considered when recording SAEs: 
• Death is an outcome of an event. The event that resulted in the death should be 
recorded and reported on the eCRF. 
• For hospitalizations, surgical, or diagnostic procedures, the illness leading to the 
surgical or diagnostic procedure should be recorded as the SAE, not the procedure 
itself. The procedure should be captured in the narrative as part of the action taken in 
response to the illness. 
10.5.8.2.3. Diagnosis Versus Signs or Symptoms 
In general, the use of a unifying diagnosis is preferred to the listing out of individual symptoms. 
Grouping of symptoms into a diagnosis should only be done if each component sign and/or 
symptom is a medically confirmed component of a diagnosis as evidenced by standard medical 
textbooks. If any aspect of a sign or symptom does not fit into a classic pattern of the diagnosis, 
report the individual symptom as a separate AE. 
10.5.8.3. Reporting Serious Adverse Events 
All SAEs are subject to reporting requirements. 
10.5.8.3.1. Serious Adverse Events 
All SAEs, whether or not considered related to study treatment, must be reported to the Sponsor 
Contact within 24 hours of becoming aware of the event. Enter the SAE information on the 
eCRF, and send other available pertinent information (eg, hospital records, laboratory results) to 
the designated Sponsor contact:  
IQVIA Pharmacovigilance 
 
 
 
If additional follow-up information is required or becomes available for a previously reported 
SAE, entry of the new information on the eCRF should be completed within 24 hours of 
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Elective hospitalization and/or surgery for clearly preexisting conditions (eg, a surgery that has 
been scheduled prior to the subject’s entry into the study) will not be reported as an SAE. All 
other hospitalizations, including elective hospitalizations for any condition that was not 
preexisting, will be reported as an SAE. 
Any SAE that is ongoing when the subject completes the study or discontinues the study will be 
followed by the investigator until the event resolves, stabilizes or returns to baseline status. 
10.5.8.3.2. Serious, Unexpected Adverse Drug Reactions 
All ADRs that are both serious and unexpected are subject to expedited reporting to regulatory 
agencies. An unexpected ADR is one for which the nature or severity is not consistent with 
information in the relevant source documents. 
The following documents or circumstances will be used to determine whether an AE/ADR is 
expected: 
1. For a medicinal product not yet approved for marketing in a country, the RSI of the 
company’s IB will serve as the source document in that country. 
2. Reports that add significant information on specificity or severity of a known, already 
documented serious ADR constitute unexpected events. For example, an event more 
specific or more severe than described in the RSI of the IB would be considered 
“unexpected.” 
10.5.9. 
Pregnancy 
If at any point any pregnancy test is confirmed positive, the subject will be withdrawn from the 
study treatment. 
Details of all pregnancies in female subjects and female partners of male subjects will be 
collected after the start of study treatment and until 30 days after the last dose. 
Pregnancy (during maternal or paternal exposure to study treatment) does not meet the definition 
of an AE; however, to fulfill regulatory requirements, any pregnancy and/or pregnancy outcome 
should be reported via the Pregnancy Report Form to the designated Sponsor Contact within 
24 hours of awareness. 
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs and should be reported as such even if 
outside the SAE reporting period. 
10.6. 
Procedures for Overdose 
See the IB for additional information. 
There is no established overdose threshold for this clinical study, nor is there any recommended 
specific treatment for an overdose but to provide supportive care if clinically indicated. 
In the event of a suspected overdose, the investigator and/or treating physician should: 
1. Closely monitor the subject for any AE/SAE and laboratory abnormalities and provide 
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11. 
PLANNED STATISTICAL METHODS 
11.1. 
General Considerations 
Statistical considerations will be discussed in Sections 11.2 to 11.8 for the Double-Blind 
Treatment Period, and in Section 11.9 for the Open-Label Extension Period. Details regarding 
the statistical analyses will be provided in the SAP, which will be finalized prior to database lock 
of the Double-Blind portion of the study. 
Continuous variables will be summarized using the number of observations, mean, standard 
deviation (SD), median, minimum, and maximum. Categorical variables will be summarized 
using frequency counts and percentages. 
11.2. 
Determination of Sample Size 
It is assumed that the percent change in EASI from Baseline to Week 12 will be normally 
distributed with a SD of 41%. Assuming a 1:1:1 randomization, 120 subjects (40 subjects each in 
1 mg etrasimod, 2 mg etrasimod, or placebo groups) is sufficient to achieve at least 90% power 
to detect a difference of 35% in EASI from Baseline to Week 12 between each of the etrasimod 
treatment groups and placebo by a 2-sample t-test using a 1-sided significance level of 0.025 
with estimated SD at 41%. This sample size also accounts for an estimated drop-out rate up to 
25%. 
11.3. 
Analysis Sets 
For purposes of analysis, the following analysis sets are defined (Table 7). 
Table 7: 
Analysis Sets 
Analysis Set 
Description 
Full Analysis Set (FAS) 
The FAS includes all randomized subjects, irrespective of whether 
they received any study treatment. 
Modified Full Analysis Set 
(mFAS) 
The mFAS population consists of all randomized subjects who 
received at least 1 dose of study treatment, have a baseline 
measurement, and have at least 1 post-randomization measurement. 
The mFAS is endpoint specific, therefore subjects included in the 
analysis set for 1 endpoint may differ from another endpoint, based 
on the baseline and post-baseline data. 
Per Protocol Set 
The Per Protocol Set consists of all subjects in the FAS population 
who adhere to the protocol. The Per Protocol Set will be used in 
sensitivity analyses of the primary and key secondary endpoints to 
evaluate the influence of major protocol violators and protocol 
deviators on the primary results. Subjects may be excluded from 
this population if they violate the eligibility criteria or significantly 
deviate from the study plan. Specific reasons for warranting 
exclusion from this population will be documented prior to 
database lock and may include, but are not limited to, study 
treatment noncompliance, receiving incorrect study treatment, 
missing more than a defined number of visits while still on study, 




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• Percentage of change in EASI from Baseline to Week 12 will be analyzed in the 
mFAS set, data will be set to missing after rescue medication uses; all missing data 
will be imputed using post-baseline worst-case-carry-forward method. 
• Proportion of subjects achieved EASI-75 response at Week 12 will be analyzed in the 
mFAS set using EASI scores imputed by the MI method discussed in Section 11.4.1. 
• Observed data analyses in mFAS set, regardless of rescue medication uses and 
without missing data imputation: 
− For longitudinal continuous variables (eg, percentage of change in EASI from 
Baseline to Week 12), mixed effects model with repeated measures (MMRM) 
analysis will be performed and by visit results will be reported; 
− For longitudinal dichotomous measures (eg, EASI-75, vIGA 0 to 1), logistic 
regression analysis will be performed by visit. 
• Completers analyses of primary and secondary endpoints for subjects who complete 
12 weeks of study treatment. 
• Analyses of primary and key secondary endpoints in the Per Protocol set. 
11.5. 
Efficacy Analyses 
The primary endpoint of percentage change in EASI from Baseline to Week 12 will be analyzed 
in the FAS and using MI procedure with analysis of covariance (ANCOVA) model. The 
ANCOVA model will include treatment group as factor, Baseline EASI score and randomization 
factor as covariates. Multiple results of ANCOVA (least square [LS] means and LS mean 
difference from placebo) for each MI dataset will be analyzed and reported along with 95% 
confidence interval (CI) and p-value using Rubin’s method (
). 
Proportion-based key secondary endpoints (eg, EASI-75, vIGA 0 to 1) at Week 12 will be 
analyzed in the FAS using the Cochran-Mantel-Haenszel method adjusted for randomization 
stratification factor. The number and percentage of subjects achieving the goal and the difference 
in proportion between treatment groups achieving the goal, along with p-value and the 95% CIs 
will be reported. 
Other secondary endpoints (listed in Section 11.5.4) will be analyzed using the following 
methods in general and specific details will be discussed in the SAP. 
• Longitudinal continuous variables measured at scheduled visits up to Week 12 will be 
analyzed using a MMRM model. The MMRM model will include treatment group, 
visit, and interaction of treatment-by-visit as factors, and baseline measure and 
randomization stratification factor as covariates. An unstructured covariance matrix 
will be specified for the MMRM model. LS means at visit and LS mean differences 
between treatment group with p-values and corresponding 95% CIs will be reported. 
This method will also be applied to other score based or continuous measures. 
• Longitudinal dichotomous measures at scheduled visits will be analyzed using a 
logistic regression model. The model will include treatment group as a factor, 
Baseline EASI score and randomization stratification factor as covariates. The odds 
ratios and 95% CIs, and associated p-value will be reported. 


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Analysis methods for exploratory endpoints will be described in the SAP. 
In addition to between group analyses on the primary and secondary endpoints, dose response of 
key efficacy measures for the 2 etrasimod doses and placebo will be assessed as exploratory 
using appropriate analysis models, which will be specified in the SAP. 
Efficacy data will be analyzed by randomized treatment, while safety data will be analyzed by 
actual treatment. 
11.5.1. 
Endpoint Definitions 
Efficacy will be assessed by changes in AD severity using EASI, vIGA, SCORAD, and BSA. 
Symptoms of itch will be assessed using the pruritus NRS. Patient-reported outcomes will also 
be assessed using the DLQI, POEM, and PGA. 
The following definitions will be used to assess efficacy outcomes:  
11.5.2. 
Primary Efficacy Endpoint 
• Percent change in EASI from Baseline to Week 12. 
11.5.3. 
Key Secondary Efficacy Endpoints 
• Proportion of subjects achieving EASI-75, defined as a 75% reduction of EASI from 
Baseline to Week 12. 
• Proportion of subjects with a vIGA 0 to 1 (on a 5-point scale) score and a reduction 
from Baseline of ≥ 2 points at Week 12. 
11.5.4. 
Secondary Efficacy Endpoints 
• Percent change in peak pruritus NRS from an itch daily diary from Baseline to 
Week 12. 
• Proportion of subjects with improvement (reduction) in peak pruritus NRS ≥ 3 from 
an itch daily diary from Baseline to Week 12. 
• Proportion of subjects achieving EASI-50, defined as a ≥ 50% reduction of EASI 
from Baseline to Week 12. 
• Proportion of subjects achieving EASI-90, defined as a ≥ 90% reduction of EASI 
from Baseline to Week 12. 
• Change and percentage change in percent BSA AD involvement from Baseline to 
Week 12. 
11.5.5. 
Exploratory Efficacy Endpoints 
• Change in DLQI from Baseline to Week 12. 
• Change in POEM from Baseline to Week 12. 
• Percent change in SCORAD from Baseline to Week 12. 




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11.7. 
Interim Analysis 
No formal interim analysis of efficacy is planned. Periodic blinded assessments of the 
assumption regarding the SD of the percentage change in EASI from Baseline to Week 12 may 
be conducted. The planned sample size will not be reduced as a result of the SD assessments. 
11.8. 
Safety Analyses 
A detailed description of all safety analyses will be provided in the SAP. 
11.8.1. 
Safety Endpoints 
•
Incidence and severity of AEs.
•
Incidence and severity of laboratory abnormalities and change from Baseline in
laboratory values (to include hematology, serum chemistry, coagulation, and
urinalysis).
•
Incidence of clinically significant vital sign abnormalities and changes from Baseline.
May include 
 post-first-dose.
•
ECGs.
•
Physical examination findings.
11.8.2. 
Adverse Events 
All AEs will be coded using the Medical Dictionary for Regulatory Activities. 
For each treatment group, the proportion of subjects with treatment-emergent AEs (TEAEs) will 
be summarized overall, by severity, and by relationship to study treatment. SAEs will also be 
summarized by treatment group. A TEAE is defined as: 
•
An AE that occurs after initiation of study treatment that was not present at the time
of treatment start.
•
An AE that increases in severity after the initiation of study treatment, if the event
was present at the time of treatment start.
Any AE occurring before the first dose of study treatment will be summarized separately. 
11.8.3. 
Extent of Exposure 
The duration of time on study and time on study treatment will be summarized for each treatment 
using descriptive statistics. The number of subjects on study treatment for certain time intervals 
will also be summarized. The total subject-years and total subject-years on study will also be 
included in this summary. 
11.8.4. 
Clinical Laboratory Parameters 
Laboratory parameters will be summarized by treatment group at each scheduled assessment 
time point using descriptive statistics. Associated laboratory parameters such as hepatic 
enzymes, renal function, and hematology values will be grouped and presented together. 




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• change from baseline will be analyzed on change from Double-Blind Treatment 
Period baseline, and change from Open-Label Extension Period baseline, respectively 
Efficacy outcomes will be measured at scheduled visits in the Open-Label Extension Period: 
EASI, vIGA, SCORAD, BSA, Pruritus NRS, POEM, DLQI, and PGA (Table 9 of Appendix 1). 
Dichotomous response outcomes derived from specific scores will be assessed. Continuous 
variables will be summarized by visit using the number of observations, mean, SD, median, 
minimum, and maximum; and categorical variables will be summarized by visit using frequency 
counts and percentages, with following considerations. 
• 1 treatment group in the Open-Label Extension Period and 3 subgroups in the 
Double-Blind Treatment Period will be analyzed 
• change from baseline in continuous variables will be analyzed on change from 
Double-Blind Treatment Period baseline, and change from Open-Label Extension 
Period baseline, respectively 
• subgroup analyses of main efficacy outcomes will be performed in, but not limited to, 
the following categories: 
− Week 12 EASI-75 responders versus non-responders 
− Week 12 vIGA responders versus non-responders (responder is defined as vIGA 
0 to 1 [on a 5-point scale] score and a reduction from Double-Blind Treatment 
Period Baseline of ≥ 2 points) 
− EASI score at Double-Blind Treatment Period baseline (≤ or > median) 
− Percent BSA AD involvement at Double-Blind Treatment Period baseline (≤ or 
> median) 


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12. 
ETHICAL CONSIDERATIONS 
12.1. 
Ethical Conduct of the Study 
This study shall be conducted in accordance with the ethical principles that have their origin in 
the Declaration of Helsinki and that are consistent with GCP, ICH guidelines, other applicable 
regulatory requirements (eg, local requirements), the study protocol, and where applicable, 
Sponsor and/or CRO SOPs.  
12.2. 
Institutional Review Board or Independent Ethics Committee 
Approval 
Before initiating a study, the investigator must have written and dated approval from the 
IRB/IEC for the study protocol, written informed consent form (ICF), subject recruitment 
materials and procedures (eg, advertisements or websites), and any other written information to 
be provided to subjects. Approval from the committee must be documented in a letter to the 
investigator specifying the protocol number, protocol version, documents reviewed, and the date 
on which the committee met and granted approval. 
All documents subject to review during the study, including any modifications made to the 
protocol after receipt of IRB/IEC approval, must also be submitted to the committee for approval 
prior to implementation. The investigator must also provide periodic reports as required and 
promptly report important safety information (ie, SAEs) and protocol violations, as appropriate, 
to the IRB/IEC. 
As part of the investigator’s written application to the IRB/IEC, the investigator should provide 
the committee with a current copy of the IB. If the IB is updated during the study, the 
investigator should supply an updated copy to the committee. 
12.3. 
Informed Consent and Assent 
The investigator will fully inform the subject of all pertinent aspects of the study, including the 
approval of the study by the IRB/IEC. Before informed consent/assent may be obtained, the 
investigator should provide the subject ample time and opportunity to inquire about details of the 
study and to decide whether to participate. 
Prior to a subject’s participation in the study, the IRB/IEC-approved ICF must be signed and 
personally dated by the subject and by the person who conducted the informed consent 
discussion.  
The written ICF and any other written information to be provided to subjects should be revised 
whenever important new information becomes available that may be relevant to the subject’s 
consent. Any revised written ICF or study materials to be available and/or supplied to subjects 
should receive the IRB/IEC’s approval in advance of use. The subject will be informed in a 
timely manner if new information becomes available that may be relevant to the subject’s 
willingness to continue participation in the study. The communication of this information should 
be documented. 


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12.4. 
Confidentiality 
All information generated in this study is considered highly confidential and must not be 
disclosed to any person or entity not directly involved with the study unless prior written consent 
is provided from the Sponsor. 
Prior to study participation, the investigator shall inform the subject that the monitor(s), 
auditor(s), IRB/IEC, and the regulatory authorities will be granted direct access to the subject’s 
original medical records for verification of clinical study procedures and/or data, and that, by 
signing a written ICF, the subject is authorizing such access. 
In addition, prior to study participation, the subject must be informed that the records identifying 
the subject will not be made publicly available; if the results of the study are published, the 
subject’s identity will remain confidential. 
12.5. 
Protocol Compliance 
The investigator/institution will conduct the study in compliance with the protocol agreed to by 
the Sponsor and regulatory authorities (if applicable) and that was approved by the IRB/IEC. The 
investigator/institution and the Sponsor should sign the protocol, or an alternative contract, to 
confirm agreement. 
The investigator should not implement any deviation from, or changes to, the protocol without 
agreement by the Sponsor and prior review and documented approval from the IRB/IEC of an 
amendment, except where necessary to eliminate immediate hazard(s) to study subjects or when 
the change involves only logistical or administrative aspects of the study (eg, change in monitor, 
change of telephone number). 
When an important deviation from the protocol is deemed necessary for an individual subject, 
the investigator must contact the medical monitor for the study. Such contact must be made as 
soon as possible to permit a review by the Sponsor to determine the impact of the deviation on 
the subject’s participation and/or the assessment of safety or efficacy in the study. Any 
significant protocol deviations affecting subject eligibility and/or safety must be reported by 
investigator or site delegate to the IRB/IEC and regulatory authorities, as applicable, prior to 
implementation. 
The investigator should document and explain any deviation from the approved protocol. 


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13. 
QUALITY CONTROL AND QUALITY ASSURANCE 
Quality assurance and quality control systems shall be implemented and maintained with written 
SOPs to ensure that the study is conducted, and data are generated, documented (recorded), and 
reported in compliance with the protocol, GCP, and the applicable regulatory requirement(s). 
Quality control shall be applied to each stage of data handling to ensure that all data are reliable 
and have been processed correctly. 
An agreement must be secured from all involved parties to ensure direct access to all 
study-related sites, source documents, and reports for the purpose of monitoring and auditing by 
the Sponsor and inspection by regulatory authorities. 
13.1. 
Training of Study Site Personnel 
Prior to study activities being initiated at the study site, the Sponsor or designee will train study 
site personnel on the protocol and applicable procedures. Training should be documented. 
Note: If new study site personnel are assigned to the study after the initial training, study sites 
should contact the study monitor to coordinate training. Qualified study personnel may conduct 
training, as appropriate. Training of new study personnel should also be documented. 
13.2. 
Monitoring 
Study site monitoring is conducted to ensure the study is progressing as expected, the rights and 
well-being of human subjects are protected, the reported study data are accurate, complete, and 
verifiable, and the conduct of the study is in compliance with the currently approved protocol, 
with GCP and with applicable regulatory requirements. Protocol deviations identified will be 
documented.  
Details of study site monitoring are documented in the study Clinical Monitoring Plan or similar 
document. The Clinical Monitoring Plan describes in detail who will conduct the monitoring, at 
what frequency monitoring will be done, at what level of detail monitoring will be performed 
(eg, targeted and/or risk based), and the distribution of monitoring reports. Monitoring may 
include a study site selection visit, which may be conducted in person or via communication 
media (eg, teleconference, online meeting) or may be waived in accordance with policy and 
procedures being followed for the study, if appropriate. Monitoring will include a study site 
initiation visit, interim monitoring visit(s), and a study site closeout visit. An interim monitoring 
visit may be combined with a closeout visit, if applicable.  
13.3. 
Audit 
Audits of vendors contracted by Arena for this study may be performed. Audits of participating 
study investigator sites may also be performed independently of, and separately from, routine 
monitoring to evaluate clinical study conduct and compliance with the protocol, SOPs, GCP, and 
the applicable regulatory requirements. 


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14. 
DATA HANDLING AND RECORD KEEPING 
14.1. 
Data Management 
14.1.1. 
Case Report Forms 
An eCRF must be completed for each subject screened/enrolled in this study. These forms will 
be used to transmit information collected during the study to the Sponsor and regulatory 
authorities, as applicable. 
The documentation related to the validation of the eCRFs will be maintained in the Trial Master 
File. The Trial Master File will be maintained by the CRO and the Sponsor. 
The investigator will document subject data in his/her own subject files. These subject files will 
serve as source data for the study. All eCRF data required by this protocol will be recorded by 
study site personnel. All data entered into the eCRF will be supported by source documentation. 
The investigator or an authorized member of the investigator’s staff will make any necessary 
corrections to the eCRF. All changed information, including the date and person performing the 
corrections, will be available via the audit trail, which will be part of the electronic data capture 
system. For any correction, a reason for the alteration will be provided. The eCRFs will be 
reviewed periodically for completeness and acceptability by Sponsor personnel (or their 
representatives). The Sponsor (or their representatives) will also be allowed access to all source 
documents pertinent to the study in order to verify eCRF entries. The investigator will review the 
eCRFs for completeness and accuracy and provide his or her electronic signature and date to the 
eCRFs as evidence thereof. 
14.1.2. 
Source Documents 
Per regulatory requirements, the investigator or designee will maintain accurate and up-to-date 
study documentation, including source documentation for each study subject. Source documents 
are defined as original documents, data, and records. These may include, but are not limited to, 
hospital records, clinical and office charts, laboratory data/information, subject electronic diaries 
or evaluation checklists, pharmacy dispensing and other records, recorded data from automated 
instruments (eg, ECGs, X-rays). Data collected during this study must be recorded on the 
appropriate source documents. 
The investigator(s)/institution(s) will permit study-related monitoring, audits, IRB/IEC review, 
and regulatory inspection(s) and will provide direct access to the source data. 
14.2. 
Study Documentation and Records Retention 
The investigator 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 IRB/IEC, and 
regulatory authorities (ie, FDA or international regulatory authorities) at any time, and should 
consist of the following elements: 
• Subject files: containing the completed eCRFs (if applicable), supporting source 
documentation including medical records, laboratory data, and signed ICFs. 


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• Regulatory files: containing the protocol with all amendments and Investigator 
signature pages, copies of all other regulatory documentation, all correspondence 
between the study site and the IRB/IEC and Sponsor, and drug accountability files, 
including a complete account of the receipt, dispensation, return, and disposition of 
the study treatment. 
Records will 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 study 
treatment and the appropriate competent regulatory authorities are notified. The Sponsor will 
provide written notification when it is appropriate for the investigator to discard the 
study-specific documents referenced above.  
During the record retention period, the investigator or designee must inform the Sponsor or 
designee (eg, CRO) of the location of study documentation. During or after the record retention 
period, the investigator or designee must inform and seek the Sponsor’s approval in the 
following circumstances:  
• If the custody of documentation needs to be transferred or moved to another location. 
• If the investigator is unable to retain documentation for the specified period. 
The Sponsor retains the right to utilize a document storage location/facility other than the one 
suggested by the investigator. 
14.3. 
Clinical Study Report 
Whether the study is completed or prematurely terminated, a clinical study report will be 
prepared and provided to the regulatory agencies according to applicable regulatory 
requirement(s). 
14.4. 
Disclosure of Study Results 
The Sponsor will post the results of the study in a publicly accessible database in accordance 
with the applicable laws and regulations. 


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15. 
RESPONSIBILITIES 
15.1. 
Investigator Responsibilities 
The investigator must comply with this protocol and the conduct of all study procedures. The 
investigator will disclose to the Sponsor sufficient, accurate, financial information to allow the 
Sponsor to submit accurate disclosure statements to the US FDA per 21 Code of Federal 
Regulations (CFR) Part 54 (Financial Disclosure by Clinical Investigators). The investigator is 
responsible for compliance with applicable sections of 21 CFR Part 312, Subpart D, 
(Responsibilities of Investigators) and other ICH GCP requirements, federal, and local laws, 
applicable to conducting drug studies. 
The investigator is responsible for ensuring an investigation is conducted according to the signed 
investigator statement, the investigational plan, and applicable regulations; for protecting the 
rights, safety, and welfare of subjects under the investigator’s care; and for the control of drugs 
under investigation. An investigator shall, in accordance with the provisions of 21 CFR Part 50, 
obtain the informed consent of each human subject to whom the study treatment is administered. 
15.2. 
Sponsor Responsibilities 
The Sponsor is responsible for compliance with applicable sections of 21 CFR Part 312, 
Subpart D (Responsibilities of Sponsors). The Sponsor is responsible for selecting qualified 
investigators, providing them with the information they need to conduct an investigation 
properly, ensuring proper monitoring of the investigation(s), ensuring the investigation(s) is 
conducted in accordance with the general investigational plan and protocols contained in the 
Investigational New Drug (IND) application, maintaining an effective IND with respect to the 
investigations, and ensuring the FDA and all participating investigators are promptly informed of 
significant new adverse effects or risks with respect to the drug. 








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UON. Patient-Oriented Eczema Measure (POEM) for self-completion. The University of 
Nottingham. https://www.nottingham.ac.uk/research/groups/cebd/resources/poem.aspx. 
Published 2004. Accessed July 29, 2019. 
Vaclavkova A, Chimenti S, Arenberger P, et al. Oral ponesimod in patients with chronic plaque 
psoriasis: A randomised, double-blind, placebo-controlled phase 2 trial. Lancet. 
2014;384(9959):2036-2045.  
van Buuren S. Multiple imputation of discrete and continuous data by fully conditional 
specification. Stat Methods Med Res. 2007;16(3):219-242.  
vIGA-ADTM. Validated investigator global assessment scale for atopic dermatitis, vIGA-ADTM. 
International Eczema Council (IEC). http://www.eczemacouncil.org/research/investigator-
global-assessment-scale/. Published 2017. Accessed January 14, 2019. 
Weidinger S, Novak N. Atopic dermatitis. Lancet. 2016;387(10023):1109-1122.  
Zhu TH, Zhu TR, Tran KA, Sivamani RK, Shi VY. Epithelial barrier dysfunctions in atopic 
dermatitis: A skin-gut-lung model linking microbiome alteration and immune dysregulation. Br J 
Dermatol. 2018;179(3):570-581.  
 
 


 
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APPENDIX 2: GRADING OF CLINICAL AND LABORATORY ADVERSE 
EVENTS 
All clinical and clinically significant laboratory abnormalities will be graded according to the 
CTCAE Scale for Severity of Adverse Events and Laboratory Abnormalities (available at: 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/ctcae_v5_quick_refere
nce_5x7.pdf).  
Examples of CTCAE terms and grading are provided for clinical adverse events in Table 10 and 
for laboratory abnormalities in Table 11. 
Table 10: 
Example of CTCAE Terms and Grading for Clinical Adverse Events 
Respiratory, thoracic and mediastinal disorders 
CTCAE Term 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Cough 
Mild symptoms; 
nonprescription 
intervention 
indicated 
Moderate 
symptoms; 
medical 
intervention 
indicated; limiting 
instrumental ADL 
Severe symptoms; 
limiting self-care 
ADL 
− 
− 
Definition: A disorder characterized by sudden, often repetitive, spasmodic contraction of the thoracic cavity, resulting in 
violent release of air from the lungs and usually accompanied by a distinctive sound. 
Dyspnea 
Shortness of breath 
with moderate 
exertion 
Shortness of breath 
with minimal 
exertion; limiting 
instrumental ADL 
Shortness of breath 
at rest; limiting self-
care ADL 
Life-threatening 
consequences; 
urgent 
intervention 
indicated 
Death 
Definition: A disorder characterized by an uncomfortable sensation of difficulty breathing. 
Wheezing 
Detectable airway 
noise with minimal 
symptoms 
Moderate 
symptoms; 
medical 
intervention 
indicated; limiting 
instrumental ADL 
Severe respiratory 
symptoms limiting 
self-care ADL; 
oxygen therapy or 
hospitalization 
indicated 
Life-threatening 
consequences; 
urgent 
intervention 
indicated 
Death 
Definition: A disorder characterized by a high-pitched, whistling sound during breathing. It results from the narrowing or 
obstruction of the respiratory airways. 
Dizziness 
Mild unsteadiness 
or sensation of 
movement 
Moderate 
unsteadiness or 
sensation of 
movement; 
limiting 
instrumental ADL 
Severe unsteadiness 
or sensation of 
movement; limiting 
self-care ADL 
− 
− 
Definition: A disorder characterized by a disturbing sensation of lightheadedness, unsteadiness, giddiness, spinning or 
rocking. 
Blurred vision 
Intervention not 
indicated 
Symptomatic; 
moderate decrease 
in visual acuity 
(best corrected 
visual acuity 20/40 
and better or 3 
lines or less 
decreased vision 
from known 
baseline); limiting 
instrumental ADL 
Symptomatic with 
marked decrease in 
visual acuity (best 
corrected visual 
acuity worse than 
20/40 or more than 
3 lines of decreased 
vision from known 
baseline, up to 
20/200); limiting 
self-care ADL 
Best corrected 
visual acuity of 
20/200 or worse 
in the affected eye 
− 
Definition: A disorder characterized by visual perception of unclear or fuzzy images. 
ADL, activities of daily life; CTCAE, Common Terminology Criteria for Adverse Events 


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Table 11: 
Example of CTCAE Terms and Grading for Laboratory Abnormalities 
 
 
Investigations 
CTCAE Term 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Alanine 
aminotransferase 
increased 
> ULN-3.0 × ULN if 
baseline was normal; 
1.5-3.0 x baseline if 
baseline was 
abnormal 
> 3.0-5.0 × ULN if 
baseline was 
normal; > 3.0-5.0 × 
baseline if baseline 
was abnormal 
> 5.0-20.0 × ULN if 
baseline was 
normal; > 5.0-20.0 × 
baseline if baseline 
was abnormal 
> 20.0 × ULN if 
baseline was 
normal; > 20.0 × 
baseline if 
baseline was 
abnormal 
− 
Definition: A finding based on laboratory test results that indicate an increase in the level of alanine aminotransferase (ALT 
or SGPT) in the blood specimen. 
Navigational Note: Also consider Hepatobiliary disorders: Hepatic failure 
Aspartate 
aminotransferase 
increased 
> ULN-3.0 × ULN if 
baseline was normal; 
1.5-3.0 × baseline if 
baseline was 
abnormal 
> 3.0-5.0 × ULN if 
baseline was 
normal; > 3.0-5.0 × 
baseline if baseline 
was abnormal 
> 5.0-20.0 × ULN if 
baseline was 
normal; > 5.0-20.0 × 
baseline if baseline 
was abnormal 
> 20.0 × ULN if 
baseline was 
normal; > 20.0 × 
baseline if 
baseline was 
abnormal 
− 
Definition: A finding based on laboratory test results that indicate an increase in the level of aspartate aminotransferase (AST 
or SGOT) in a blood specimen. 
Navigational Note: Also consider Hepatobiliary disorders: Hepatic failure 
Forced expiratory 
volume decreased 
FEV1% (percentages 
of observed FEV1 
and FVC related to 
their respective 
predicted values) 
99-70% predicted 
FEV1 60%-69% 
50%-59% 
≤ 49% 
− 
Definition: A finding based on test results that indicate a relative decrease in the fraction of the forced vital capacity that is 
exhaled in a specific number of seconds. 
Navigational Note: Also consider Respiratory, thoracic and mediastinal disorders: Respiratory failure or Dyspnea 
Vital capacity 
abnormal 
90%-75% of 
predicted value 
< 75%-50% of 
predicted value; 
limiting 
instrumental ADL 
< 50% of predicted 
value; limiting 
self-care ADL 
− 
− 
Definition: A finding based on 
 test results that indicate an abnormal vital capacity (amount of exhaled 
after a maximum inhalation) when compared to the predicted value. 
Navigational Note: Also consider Investigations: Forced Expiratory Volume; Respiratory, thoracic and mediastinal disorders: 
Respiratory failure or Dyspnea 
Carbon monoxide 
diffusing capacity 
decreased 
3-5 units below 
LLN; for follow-up, 
a decrease of 3-5 
units 
(mL/min/mm Hg) 
below the baseline 
value; asymptomatic 
and intervention not 
indicated 
6-8 units below 
LLN; for follow-up, 
an asymptomatic 
decrease of 
> 5-8 units 
(mL/min/mm Hg) 
below the baseline 
value; symptomatic 
and intervention not 
indicated 
Asymptomatic 
decrease of > 8 units 
drop; > 5 units drop 
along with the 
presence of 
pulmonary 
symptoms (eg, 
> Grade 2 hypoxia 
or > Grade 2 
dyspnea); 
intervention 
indicated 
− 
− 
Definition: A finding based on lung function test results that indicate a decrease in the lung capacity to absorb carbon 
monoxide. 
Navigational Note: Also consider Respiratory, thoracic and mediastinal disorders: Respiratory failure or Dyspnea 
ADL, activities of daily life; ALT, Alanine aminotransferase; AST, Aspartate aminotransferase; FEV1, forced expiratory volume at 1 second; 
FVC, forced vital capacity; LLN, lower limit of normal; SGOT, serum glutamic-oxaloacetic transaminase; SGPT, serum glutamic-pyruvic 
transaminase; ULN, upper limit of normal 
 
 


Clinical Study Protocol 
APD334-201 
Etrasimod Versus Placebo in Subjects with Atopic Dermatitis (ADVISE) 
Amendment 1.0 
Arena Pharmaceuticals, Inc. 
Confidential 
Page 99 of 102 
APPENDIX 3: GUIDANCE FOR THE MANAGEMENT OF CLINICAL 
AND LABORATORY ADVERSE EVENTS 
Clinical AEs and abnormal results of laboratory tests and safety assessments considered to be an 
AE by the Investigator should be graded according to the severity scale of the CTCAE.  
Uniform guidance for the management of AEs is provided in Figure 2. 
Grade 3 and 4 clinically significant laboratory abnormalities should be confirmed by repeat 
testing within 3 calendar days of receipt of results and before study treatment discontinuation, 
unless such a delay is not consistent with good medical practice. 
A clinically significant Grade 4 laboratory abnormality that is not confirmed by repeat testing 
should be managed according to the algorithm for the new AE grade. 
Study treatment may be continued without dose interruption for a clinically non-significant 
Grade 4 laboratory abnormality (eg, Grade 4 creatinine kinase after strenuous exercise, or 
triglyceride elevation that is non-fasting or that can be medically managed) or a clinical event 
considered unrelated to investigational product. 
Any questions regarding adverse event management should be directed to the medical monitor. 
 


Clinical Study Protocol 
APD334-201 
Etrasimod Versus Placebo in Subjects with Atopic Dermatitis (ADVISE) 
Amendment 1.0 
Arena Pharmaceuticals, Inc. 
Confidential 
Page 100 of 102 


Clinical Study Protocol 
APD334-201 
Etrasimod Versus Placebo in Subjects with Atopic Dermatitis (ADVISE) 
Amendment 1.0 
Arena Pharmaceuticals, Inc. 
Confidential 
Page 101 of 102 
APPENDIX 5: 
INVESTIGATOR SIGNATURE 
 
Study title: A Multicenter, Randomized, Double-Blinded, Placebo-Controlled 16-Week Study 
(with a 52-Week Open-Label Extension) to Assess the Safety and Efficacy of 
Etrasimod in Subjects with Moderate-to-Severe Atopic Dermatitis 
 
I have read the protocol described above. I agree to comply with all applicable regulations and to 
conduct the study as described in the protocol. 
 
 
 
 
 
 
 
 
Investigator Signature 
 
Date 
 
 
 
 
 
 
Investigator Name and Credentials - Printed 
 
 
 
 
 
 
 
 
Institution Name - Printed 
 
 
 
 
 
 
 
 
 
 
 
 




 
This is a representation of an electronic record that was signed electronically, and this 
page is the manifestation of the electronic signature. 
 
UserName: 
 
Title:  EVP, R&D & CMO 
Date: Tuesday, 20 August 2019, 11:58 AM   Pacific Daylight Time 
Meaning: Author Approval 
================================================
UserName: 
 
Title:  EVP, R&D & CMO 
Date: Tuesday, 20 August 2019, 11:58 AM   Pacific Daylight Time 
Meaning: Approval 
================================================


 
CLINICAL STUDY PROTOCOL 
SUMMARY OF CHANGES 
 
Protocol title: 
A Multicenter, Randomized, Double-Blinded, Placebo-Controlled 
16-Week Study (with a 52-Week Open-Label Extension) to Assess the 
Safety and Efficacy of Etrasimod in Subjects with Moderate-to-Severe 
Atopic Dermatitis 
 
 
Protocol number: 
APD334-201 
Version: 
Amendment 1.0, dated 19 August 2019 
Replaces version: 
Original, dated 29 April 2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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 distributed, copied, 
or disclosed. 


Clinical Study Protocol - Summary of Changes 
APD334-201 
Etrasimod Versus Placebo in Subjects with Atopic Dermatitis (ADVISE) 
Amendment 1.0 
Arena Pharmaceuticals, Inc. 
Confidential 
Page 2 of 10 
PROTOCOL AMENDMENT SUMMARY OF CHANGES 
Amendment 1.0, 19 August 2019 
Overall Rationale for the Amendment 
The overall rationale for the changes implemented in this protocol amendment were to provide 
operational clarifications and instructions to the clinical sites and investigators. In addition, further 
information is provided to investigators on monitoring patient safety. Minor editorial and document 
formatting revisions were also made for consistency.   
 

















SAP_001.pdf: 
 
 
Statistical Analysis Plan 
 
 
Arena Pharmaceuticals, Inc. 
Protocol Number: APD334-201 
 
 
A Multicenter, Randomized, Double-Blinded, Placebo-
Controlled 16-Week Study (with a 52-Week Open-Label 
Extension) to Assess the Safety and Efficacy of Etrasimod in 
Subjects with Moderate-to-Severe Atopic Dermatitis 
 
 
 
Version 3.0 
Date: 05 November 2021 
 
 






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TABLE OF CONTENTS 
List of Tables ..........................................................................................................................6 
1.Introduction ..........................................................................................................................7 
2.Protocol Objectives ..............................................................................................................7 
A. Primary Objective .................................................................................................7 
B. Safety Objective ....................................................................................................7 
C. Open Label Extension Objective ..........................................................................7 
3.Study Endpoints ...................................................................................................................7 
A. Primary Efficacy Endpoint ...................................................................................7 
B. Key Secondary Efficacy Endpoints ......................................................................8 
C. Secondary Efficacy Endpoints ..............................................................................8 
D. Exploratory Efficacy Endpoints ............................................................................8 
E. Open Label Extension Efficacy Endpoints ...........................................................9 
F. Safety Endpoints ...................................................................................................9 
4.Study Design ........................................................................................................................9 
A. Design Overview ..................................................................................................9 
B. Study Population .................................................................................................10 
C. Sample Size Determination.................................................................................10 
D. Treatment Randomization ...................................................................................10 
E. Assessment Schedule ..........................................................................................10 
5.General Analytical Considerations ....................................................................................11 
A. Data Sources and General Rules .........................................................................11 
B. Definition of Baseline and Study Day ................................................................11 
C. Analysis Visit Window .......................................................................................12 
D. Covariate Adjustment in Primary Analysis ........................................................13 
E. Interim Analyses .................................................................................................13 
F. Multiple Comparisons and Multiplicity ..............................................................13 
G. Analysis Sets .......................................................................................................13 
H. Missing Data .......................................................................................................15 
I. Data Display Characteristics ...............................................................................15 
6.Subject Characteristics .......................................................................................................15 
A. Demographics and Baseline Characteristics .......................................................16 
B. Medical History/Atopic Dermatitis History........................................................16 
7.Subject Accountability .......................................................................................................16 
A. Disposition ..........................................................................................................16 
B. Analysis Set Inclusions .......................................................................................17 
C. Protocol Deviations .............................................................................................17 
8.Efficacy Analyses ..............................................................................................................17 
A. Efficacy Outcomes ..............................................................................................17 




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List of Tables 
 
 
 
Table 2 Analysis Sets .............................................................................................................. 14 
Table 3 Summary of Efficacy Analyses ................................................................................. 25 
 
 


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1. Introduction 
 
This statistical analysis plan (SAP) describes the statistical rationale, methods, rules 
and conventions to be used in the presentation and analysis of efficacy, safety, and 
 data for Protocol APD334-201. It describes the data to be 
summarized and analyzed, including specifics of the statistical analyses to be 
performed. This Statistical Analysis Plan (SAP) is based on study Protocol 
Amendment 1.0, dated 19 August 2019.  
 
This SAP provides additional details concerning the statistical analyses outlined in 
the protocol and reflects any changes to the protocol from any amendments. This plan 
will not repeat all the definitions given in the protocol but will provide further details 
of the summaries and analyses planned therein. 
 
This plan will cover the analyses for: 1) the primary database lock after the 
completion of the Double-Blind (DB) Treatment Period; 2) the final database lock 
after the completion of the Open-Label Extension (OLE) Period. The plan will be 
finalized before the time of primary database lock and treatment unblinding. After 
that, the SAP may be amended to accommodate ad hoc analyses before the final 
database lock. Ad hoc analyses will be labeled as such on the output and identified in the 
Clinical Study Report. 
 
2. Protocol Objectives 
 
A. Primary Objective 
 
To assess the efficacy of etrasimod monotherapy (1 or 2 mg) in subjects with 
moderate to severe atopic dermatitis (AD) during the DB Treatment Period. 
 
B. Safety Objective  
 
To assess the safety and tolerability of etrasimod monotherapy (1 or 2 mg) in 
subjects with moderate to severe AD during the DB Treatment Period. 
 
C. Open Label Extension Objective  
 
To assess the long-term safety, tolerability, and efficacy of etrasimod 
monotherapy (2 mg) in subjects with moderate to severe AD. 
 
3. Study Endpoints 
 
A. Primary Efficacy Endpoint 
 
Percent change in Eczema Area and Severity Index (EASI) from Baseline to 
Week 12. 
 






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symptoms at the discretion of the investigator based on an exacerbation of 
disease severity or subject self-reporting of worsened symptoms. 
B.
Study Population
Subjects with chronic AD defined by Hanifin and Rajka criteria (
)
that has been present for at least 1 year despite optimized skin care (i.e., use of
emollients, avoidance of irritants) whose disease is not adequately controlled
with topical therapies, or for whom those therapies are not advisable.
C.
Sample Size Determination
It is assumed that the percent change in EASI from Baseline to Week 12 will be
normally distributed with an estimated standard deviation (SD) of 41%.
Assuming a 1:1:1 randomization, 120 subjects (40 subjects each in 1 mg
etrasimod, 2 mg etrasimod, and  placebo groups) is sufficient to achieve at least
90% power to detect a difference of 35% in EASI from Baseline to Week 12
between each of the etrasimod treatment groups and placebo by a 2-sample t-test
using a 1-sided significance level of 0.025. This sample size also accounts for an
estimated drop-out rate up to 25%.
D.
Treatment Randomization
Randomization will be stratified by vIGA score at Baseline (3 versus 4) and
region 
E.
Assessment Schedule
For the statistical analysis, DB Treatment Period will include 12 weeks treatment
and 4 weeks safety follow-up; OLE Period will include 52 weeks treatment and 4
weeks safety follow-up. The date at which the subject is randomized will be
referred to as the “Baseline/Day 1”. Subjects will be requested to attend the
following scheduled visits for the DB Treatment Period from their Baseline/Day
1 visit: Week 1, 2, 4, 6, 8, 12 and Week 16/SFU visit. For the OLE Period, Week
16 (this will be same as Week 16 in the DB Treatment Period), Week 17, 18, 20,
24, 28, 32, 40, 48, 56, 68, and Week 72/ SFU. The acceptable visit window for
scheduled visits for the DB Treatment Period including Week 16, and Week 17
and 18 in OLE Period is ± 3 days, for all the other OLE visits, the scheduled visit
window is ± 7 days. Visits that subjects make to the clinic outside the visit
window are recorded as unscheduled visits.
Please refer to protocol 
 for details.


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5. General Analytical Considerations 
 
A. Data Sources and General Rules 
 
Data are recorded on electronic case report form (eCRF) for each subject 
screened/enrolled in this study. These forms will be used to transmit information 
collected during the study to the Sponsor and regulatory authorities, as 
applicable. Laboratory data, 
 blood samples and 
 data are 
collected separately by the selected vendors. Section 14 of the protocol provides 
additional details regarding data handling and record keeping.  
 
Statistical analysis will be performed following IQVIA Biotech standard 
operating procedures and on the IQVIA Biotech computer network. All statistical 
analysis will be performed using SAS Version 9.4 with program code prepared 
specifically for the project by qualified IQVIA Biotech statisticians and SAS 
programmers. 
 
All observed and derived variables (e.g., change from baseline, percentage 
change from baseline, and response status) that are analyzed or summarized will 
be listed by subject. Descriptive statistics will provide an overview of the 
efficacy and safety results. For categorical parameters, the number and 
percentage of subjects in each category will be presented. For continuous 
parameters, descriptive statistics will include number of subjects, mean, SD 
median, minimum, and maximum. 
 
B. Definition of Baseline and Study Day 
 
Study day will be defined separately for the DB Treatment Period and OLE 
Period. For all subjects, Day 1 is the date of first study drug administration in the 
DB Treatment Period. This will be referred to as the Overall Day 1. For those 
enrolling into the OLE Period, an OLE Day 1 will be additionally defined as the 
date of the first study drug administration in the OLE Period at Week 16. 
 
Study day will be calculated relative to the date of Overall Day 1. 
 
Similarly, Baseline will be defined separately for DB Treatment Period and OLE 
Period as follows:  
 
x DB Treatment Period: baseline will be defined as the last available 
measurement prior to the first dose of the study drug in DB Treatment Period. 
Specifically, for vital signs (resting heat rate (HR), blood pressure (BP), body 
temperature, and respiratory rate) and 
, the Day 1 pre-
randomization assessments will be used as baseline measurements. The lowest 
pre-dose HR measurement will be used for comparison to the post-dose HR 
measurement. This will be referred to as the DB baseline. 
 


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x OLE Period: for those enrolling into the OLE Period, an OLE baseline will 
be additionally defined as the last pre-dose measurement at Week 16at Week 
16. 
 
Change from baseline is defined for both DB Treatment Period and OLE Period 
as the post-baseline value minus the baseline value unless otherwise specified. 
Percent change from baseline is calculated as follows: Percent change = (Change 
from baseline / Baseline) x 100.   
 
C. Analysis Visit Window 
 
Efficacy and safety endpoints will be analyzed according to their windowed 
visits defined by actual overall study day (i.e. calculated relative to first dose 
date in the DB Treatment Period). If more than one visit occurs within a single 
visit window, then the analysis will take the one closest to the target day. If the 2 
visits are equidistant from the target day, the later visit will be used. Some 
efficacy or safety data are not scheduled to be assessed at each post-baseline 
visit. If the assessment date is not in the analysis visit window, the analysis will 
take the post-baseline scheduled visit closest to the assessment date. If there are 2 
scheduled visits equidistant from the assessment date, the later visit will be used. 
The below table provides details of each analysis visit window. 


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D. Covariate Adjustment in Primary Analysis 
 
The primary efficacy analyses will adjust for baseline EASI score, baseline vIGA 
score (3 versus 4) and region 
 Key 
secondary analyses will adjust for baseline vIGA score (3 versus 4) and region 
 as described in Section 8 Efficacy 
Analyses below.  
 
E. Interim Analyses 
 
No formal interim analysis of efficacy is planned. Periodic blinded assessments 
may be conducted to assess the assumption regarding the SD of the percentage 
change in EASI from Baseline to Week 12. The planned sample size will not be 
reduced as a result of the SD assessments. 
   
F. Multiple Comparisons and Multiplicity  
 
For DB Treatment Period: no formal testing strategy or adjustments of the Type I 
error will be employed for the primary and key secondary endpoints. Estimates 
and confidence intervals (CIs) for treatment groups and from pairwise 
comparisons will be reported in an exploratory manner.  
 
For the OLE Period: no formal statistical testing will be performed. Only 
descriptive statistics will be provided. 
 
G. Analysis Sets  
 
The following analysis sets will be defined for the DB Treatment Period and 
OLE Period separately: 
 
 
 






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A. Demographics and Baseline Characteristics  
 
x Age (years) 
x Sex  
x Race 
x Ethnicity 
x Region 
x Weight (kg) 
x Height (cm) 
x Body mass index BMI (kg/m2) 
x Baseline EASI score 
x Baseline vIGA 
x Baseline percent BSA AD involvement 
x Baseline SCORAD total score 
x Baseline peak pruritus NRS score from daily diary 
 
B. Medical History/Atopic Dermatitis History 
 
Medical history will be coded using Medical Dictionary for Regulatory Activities 
(MedDRA Version 23.0 March 2020) and summarized by system organ class 
(SOC) and preferred term (PT). 
 
The following will be summarized for AD history: 
x Time since AD diagnosis in years, calculated as the year of screening minus 
the year of first AD diagnosis 
x Time since AD symptom in years, calculated as the year of screening minus 
year of first AD symptom 
x Number of exacerbations in the last 12 months 
x Hospitalization for complications of AD or side effects of treatment (Y, N) 
x Prior use of AD therapy (Y, N), including phototherapy, biologics, Janus 
Kinase (JAK) inhibitors and other immunosuppressants 
x Participation in prior dermatology clinical studies (Y, N) 
 
7. Subject Accountability 
 
A. Disposition 
 
Subject disposition in the whole study (DB Treatment Period and OLE Period) 
will be summarized using frequency counts and percentages, including: subjects 


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who were screened, randomized, enrolled into OLE Period, completed treatment 
in DB Treatment Period, completed treatment in the DB Treatment Period and 
OLE Period, discontinued treatment (overall and by reason of discontinuation) 
and discontinued study (overall and by reason of discontinuation). Screen failures 
will be summarized for overall only and by reason of screen failure.  
 
B. Analysis Set Inclusions 
 
The numbers and percentages of FAS subjects included in SAF, any mFAS, PPS, 
TCS, 
 will be presented for each treatment group and overall. Reasons 
for exclusion from the PPS will be summarized. 
 
C. Protocol Deviations  
 
The major protocol deviations will be summarized for each category by treatment 
group and all protocol deviations will be presented in a by-subject listing. The 
protocol deviations that lead to subjects being excluded from PPS will also 
presented in the listing. 
 
 
8. Efficacy Analyses  
 
A. 
Efficacy Outcomes 
 
x EASI is a validated scoring system that grades the severity and extent of AD. It is 
a composite index with scores ranging from 0 to 72. Percent change (0 -100) in 
EASI from Baseline to Week 12 is the primary efficacy endpoint. 
x vIGA is a 5-point scale to measure disease severity: 0 = clear; 1 = almost clear; 2 
= mild; 3 = moderate; and 4 = severe. 
x SCORAD is a validated measure of the extent and severity of AD. There are 3 
components to the assessment: A = extent or affected BSA, B = severity, and C = 
subjective symptoms. BSA is described below in BSA AD section. The severity of 
6 specific symptoms of AD (redness, swelling, oozing/crusting, excoriation, skin 
thickening/lichenification dryness) is assessed using the following scale: none (0), 
mild (1), moderate (2), or severe (3) (for a maximum of 18 total points, assigned as 
“B” in the overall SCORAD calculation). Subjective assessment of itch and 
sleeplessness is recorded for each symptom by the subject or relative on a Visual 
Analogue Scale, where 0 is no itch (or sleeplessness) and 10 is the worst imaginable 
itch (or sleeplessness), with a maximum possible score of 20. This parameter is 
assigned as “C” in the overall SCORAD calculation. The SCORAD total score is 
calculated as: A/5 + 7B/2 + C where the maximum is 103. 


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x Pruritus NRS is a simple assessment tool of the intensity of pruritus (itch) from 0 
to 10 with 0 being “no itch” and 10 being “the worst itch imaginable.” Both 
maximum/peak and average NRS scores will be assessed.  
In a daily diary, subjects are asked to rate their worst itch and itch on average over 
the previous 24 hours. The weekly average NRS (peak and average) will be 
analyzed as efficacy endpoints, and derived as per the following schedule and 
rule:  
o For DB Treatment Period: Baseline (Day 1), Week 1 (Day 2 to 8), Week 2 
(Day 9 to 15), Week 3 (Day 16 to 22)…Week 12 (Day 79 to 85)… and 
Week 16 (Day 107 to Day 113 or  Day of Week 16 visit whichever comes 
first for subjects enrolled into OLE Period). 
o For OLE Period: Week 17 (Day of week 16 visit +1 to Day 120), Week 18 
(Day 121 to 127), Week 19 (Day 128 to 134)…Week 28 (Day 191 +).  
o Subjects must complete at least 3 NRS entries to calculate the weekly 
average. The weekly average will be considered missing if more than 4 
entries are missing for that weekly interval. The baseline for the analysis 
of diary data is Day 1. 
At each scheduled office visit, the subject is asked to rate their worst itch and itch 
on average in the past 7 days and these are recorded as office based peak and 
average NRS.  
x BSA AD will be assessed for each region of the body and combined. The region 
percent affected BSA is the affected percentage (0-100) at each body region. The 
total percent affected BSA is the sum of multiplying region percent affected BSA 
by the multiplication factor with a maximum of 100. 
Body Region 
Multiplication Factor 
Head and Neck 
9% 
Upper Limbs (right) 
9% 
Upper Limbs (left) 
9% 
Lower Limbs (right) 
18% 
Lower Limbs (left) 
18% 
Anterior Trunk 
18% 
Back 
18% 
Genitals 
1% 
x PGA includes 2 questions for wellness and appearance. Subjects will rate their 
overall well-being based on a 5-point Likert scale from poor to excellent. Response 
choices are: ‘Poor’, ‘Fair’, ‘Good’, ‘Very Good,’ or ‘Excellent’. 


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x POEM consists of 7 questions asking patients to rank how many days over the 
past 7 days they have experienced specific AD-related symptoms. Each of the 
seven questions carries equal weight and is scored from 0 to 4 as follows:  
No days 
Scored 0 
1-2 days 
Scored 1 
3-4 days 
Scored 2 
5-6 days 
Scored 3 
Every day 
Scored 4 
The scores from the 7 questions are added up to give an overall POEM score (0-
28). An overall POEM score of 0-2 = ‘clear/almost clear’, 3–7 = ‘mild’, 8–16 = 
‘moderate’, 17–24 = ‘severe’, and 25–28 = ‘very severe atopic eczema’. 
x DLQI is a 10-item patient-reported outcome (PRO) measure that assesses the 
extent to which the skin condition has affected the subject’s quality of life over the 
past week, including 6 domains (daily activities, personal relationships, symptoms 
and feelings, leisure, work/school, and treatment). Total score (0-30) will be 
calculated as the sum of 10 questions with each ranging from 0 to 3.  The scoring 
of each answer is as follows: 
Very much 
Scored 3 
A lot 
Scored 2 
A little 
Scored 1 
Not at all 
Scored 0 
Not relevant 
Scored 0 
Question unanswered  Scored 0 
 
Question 7 
Question 7A 
Score 
Yes 
Any response 
3 
No 
A lot 
2 
No 
A little 
1 
No 
Not at all 
0 
Not relevant 
Any response 
0 
 
If one question is left unanswered this is scored 0 and the scores are summed and 
expressed as usual out of a maximum of 30. If two or more questions are left 
unanswered the total DLQI score is missing. If question 7 is answered ‘yes’ or 
‘not relevant’, then the answer of 7a will be ignored.   
 
B. Primary Efficacy Outcome Analysis  
 
The primary endpoint of percentage change in EASI from Baseline to Week 12 
will be analyzed based on the FAS using an analysis of covariance (ANCOVA) 
model. The ANCOVA model will include treatment group as factors, Baseline 
EASI score and the two randomization factors of baseline vIGA (3 versus 4) and 


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region 
 as covariates. EASI scores after 
rescue medication use will be set to missing. All missing EASI scores at 
scheduled visits up to Week 12 will be imputed using a multiple imputation (MI) 
technique with a fully conditional specification (FCS) method and predictive 
mean matching (PMM) for EASI scores (Heitjan 1991, van Buuren 2007). The 
rescue medications considered for the purposes of efficacy analysis will include 
topical and systemic corticosteroids used during the DB Treatment Period of the 
study. 
 
For MI, 100 imputation models will be generated, including treatment, baseline 
vIGA (3 versus 4), region 
 baseline EASI 
score, and EASI scores at the previous scheduled visits. Percent change in EASI 
at Week 12 will be derived from the imputed EASI values. 
 
  
  
  
 
Multiple results of ANCOVA (least square [LS] means and LS mean difference 
between etrasimod and placebo) for each MI dataset will be combined and 
reported along with 95% CI and p-value and using Rubin’s method (
 
). 
 
All subjects are required to have a baseline EASI score upon randomization. In the 
unlikely event that a subject is missing baseline EASI, the baseline value will be 
imputed first using the above covariates. The imputation model will be modified as 
appropriate based on the actual data.   
 
In addition to the primary method for handling missing data and rescue 
medication use in the FAS, the following sensitivity analyses will be performed 
using alternative methods and/or in alternative analysis set:  
 
x FAS, MI tipping point analysis 
A tipping point analysis (Carpenter and Kenward 2013) will be performed 
to investigate the robustness of departures from the missing at random 
(MAR) assumption in the MI model by applying a specified sequence of 
shift parameters that modify the imputed EASI values, as follows:  
o Missing EASI values will be imputed 100 times, following the MI 
method described above, with adjustment to the imputed EASI by shift 


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parameter S1=0.5 in both etrasimod groups. A positive adjustment 
assumes a worsened outcome. The adjusted EASI value will be capped 
at 72. Imputed percent change in EASI will be derived accordingly. 
The MNAR statement with the ADJUST option in PROC MI will be 
used to apply the shift parameter. 
 
o Each of the 100 completed datasets applying the shift parameters will 
be analyzed using an ANCOVA model as described above. The results 
from the 100 completed datasets will be combined for inference using 
PROC MIANALYZE. 
 
o Repeat the above steps, with adjustment by shift parameter S2=1.0 in 
both etrasimod groups. Repeat the process for the following pre-
specified shift parameters: 0.5, 1.0, 1.5, 2.0…71.5, 72 
 
o The shift parameters that result in a reversed study conclusion (i.e., p-
value increases from <0.05 to ≥0.05) will be indicated. 
 
x mFAS, using OC (observed data regardless of rescue medication uses and 
without imputation) 
  
EASI values at scheduled visits up to Week 12 will be analyzed using a 
MMRM model. The MMRM model will include treatment group, visit, 
and interaction of treatment-by-visit as factors, baseline EASI and baseline 
vIGA (3 versus 4) and region 
 as 
covariates. An unstructured (UN) covariance matrix will be specified for 
the MMRM model. If the model does not converge using an unstructured 
covariance matrix, an auto-regressive AR(1) structure will be tested. If 
AR(1) fails to converge, a compound symmetric structure will be used. LS 
means and LS mean differences at each visit between treatment groups 
with p-values and corresponding 95% CIs will be reported. 
 
The same ANCOVA model as described above for the primary analysis will be 
performed, using the following: 
 
x Last Observation Carried Forward (LOCF): The primary endpoint will be 
analyzed in the modified FAS (mFAS), with assessments after the first use 
of rescue medication set to missing. All missing data will be imputed 
using post-baseline LOCF method.  
x Worst Case Carried Forward (WCCF): The primary endpoint will be 
analyzed in the mFAS, with assessments after the first use of rescue 
medication set to missing. All missing data will be imputed using post-
baseline WCRF method. 
x Observed Cases (OC) in mFAS: observed data analyses in mFAS, 
regardless of rescue medication uses and without missing data imputation, 


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will be performed using a mixed effects model with repeated measures 
(MMRM) including all scheduled visits up to Week 12.  
x OC in Per Protocol Set (PPS): observed data analysis will be performed 
among PPS, regardless of rescue medication uses and without missing 
data imputation.  
x OC in treatment completers (TCS): observed data analysis will be 
performed among mFAS subjects who have completed 12 weeks of study 
treatment, regardless of rescue medication uses and without missing data 
imputation. 
 
C. Key Secondary Efficacy Outcome Analyses 
 
The two proportion-based key secondary endpoints (EASI-75 at Week 12 and 
vIGA response status at Week 12) will be analyzed in the FAS using the 
Cochran-Mantel-Haenszel method (CMH) adjusted for randomization 
stratification factors of baseline vIGA score (3 versus 4) and region 
 
 Missing data will be imputed in the FAS using the NRI 
method: missing dichotomous response status at Week 12 (including those after 
use of rescue medication) will be imputed using the non-responder imputation 
(NRI) method, ie, “non-responders” or “failure” for missing response. The 
number, percentage of subjects achieving the goal and Clopper-Pearson exact 
95% confidence intervals will be reported. The differences in proportion between 
treatment groups, along with p-values and the 95% CIs will also be reported. 
 
The following sensitivity analyses will be performed:  
 
x FAS, MI 
 
Missing Week 12 EASI-75 response status will be derived based on the 
multiple imputed datasets for EASI values as described above. The same 
CMH test will then be performed for EASI-75 and combined using 
Rubin’s method. Combined proportion along with the 95% CI, and p-
value will be reported.  
 
x mFAS, using OC (observed data regardless of rescue medication uses and 
without imputation) 
 
Response endpoint at Week 12 will be analyzed using a logistic regression 
model including treatment group as factor, Baseline EASI score and the 
two randomization factors of baseline vIGA (3 versus 4) and region 
 as covariates. Odds ratio of etrasimod 
versus placebo along with the p-value and 95% CI will be reported.  
 
The same CMH test as described above will be performed for the key 
secondary endpoints, using the following: 
 


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x PPS, using OC 
x TCS, using OC 
 
 
D. Other Secondary Efficacy Outcome Analyses  
 
Secondary efficacy endpoints will be analyzed using the below methods: 
 
x Longitudinal continuous variables (percent change in weekly peak pruritus 
NRS, change and percentage change in %BSA) measured at visits (weeks) up 
to Week 12 will be analyzed with a MMRM model based on FAS using 
observed data. The MMRM model will include treatment group, visit (week), 
and interaction of treatment-by-visit (week) as factors, and baseline measure 
and randomization stratification factors as covariates. An unstructured 
covariance matrix will be specified for the MMRM model. If the model does 
not converge using an unstructured covariance matrix, an auto-regressive AR(1) 
structure will be tested. If AR(1) fails to converge, a compound symmetric 
structure will be used. LS means at visit (week) and LS mean differences at 
visit (week) between treatment group with p-values and corresponding 95% 
CIs will be reported.  
 
x Dichotomous measures (weekly peak NRS ≥ 3 reduction, EASI-50, and 
EASI-90) at Week 12 will be analyzed in the same way as for the key 
secondary endpoints based on FAS with CMH method adjusted for 
randomization stratification factors of baseline vIGA score (3 versus 4) and 
region 
 Missing data (including those 
after use of rescue medication) will be handled by NRI method. The number, 
percentage of subjects achieving the goal and Clopper-Pearson exact 95% 
confidence intervals will be reported. The differences in proportion between 
treatment groups, along with p-values and the 95% CIs will also be reported. 
Weekly peak NRS ≥ 3 reduction will be assessed among the subset of subjects 
whose baseline peak NRS is ≥ 3. 
 
Sensitivity analyses will be performed in the PPS and TCS using observed data. 
 
E. Exploratory Efficacy Outcome Analysis  
 
Below exploratory endpoints will be analyzed in a similar manner as the 
secondary continuous variables with the MMRM model based on FAS using 
observed data. 
 
x Change in DLQI from Baseline to Week 12. 
x Change in POEM from Baseline to Week 12. 
x Percent change in SCORAD total and individual symptom scores from 
Baseline to Week 12. 


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The primary and sensitivity analysis for all efficacy endpoints are summarized in 
Table 3. 
 






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x Continuous variables: observed value and change (percent) from Baseline in 
EASI, SCORAD, BSA, pruritus NRS, POEM, DLQI, and PGA 
x Dichotomous variables: EASI-75, vIGA   
 
The above variables will be summarized by visit using descriptive statistics based 
on the applicable analysis set, with following considerations: 
 
x Only observed cases will be used with no imputation of missing data 
x Summaries will be provided for 1 treatment group (“Total”) in OLE Period 
and also by  orignal treatment groups (“Etrasimod 1mg” , “Etrasimod 2mg” 
and “Placebo”) in DB Treatment Period  
x Change from baseline in continuous variables will be analyzed on change 
from DB baseline and change from OLE baseline, respectively 
 
For OLE Period, subgroup analyses of main efficacy outcomes (EASI, vIGA, 
NRS, BSA) will be performed in the following categories:  
 
x Week 12 EASI-75 responders versus non-responders 
x Week 12 vIGA responders versus non-responders  
x EASI score at DB baseline (≤ or > median) 
x Percent BSA AD involvement at DB baseline (≤ or > median) 
 
 
G. Efficacy Analysis on Subgroups of Subjects  
 
Subgroup analyses of primary and key secondary endpoints for the DB 
Treatment Period will be conducted for each of the following groups:  
 
x Sex (male, female) 
x Race (White, Other) 
x Age (≤ or > median) 
x Baseline vIGA (3 or 4) 
x Baseline EASI score (≤ or > median) 
x Baseline percent BSA AD involvement (≤ or > median) 
 
 
9. Safety Analyses 
 
Safety analyses will use data from the SAF for DB Treatment Period and OLE Safety 
Set for OLE Period. For the DB Treatment Period, summary will be done on the 3 
treatment groups; for the OLE Period, summary will be done on 1 treatment group in 
the OLE Period and 3 subgroups in the DB Treatment Period. Week 16 is the last 


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scheduled visit in DB Treatment Period and first scheduled visit in OLE Period. 
Overall (DB + OLE) summaries will be provided as detailed below. 
 
A. Exposure and Compliance 
 
The following exposure and compliance parameters will be defined and 
summarized for DB treatment and OLE Periods separately, and for overall using 
descriptive statistics: 
 
x The duration (days) on study, defined as date of last study visit minus date of 
first dose of study treatment plus 1. Total subject-years of duration on study 
will be summarized. 
 
x The time (days) on study treatment, defined as date of last dose of study 
treatment minus date of first dose of study treatment plus 1. Total subject-
years of time on study treatment will be summarized. The overall time on 
study treatment will be the sum of days a subject on treatment during DB and 
OLE periods. 
 
x Total number of tablets taken, defined as total number of tablets dispensed 
minus total number of tablets returned. Unreturned bottles will be assumed 
unused and will be included as 0 tablets in amount taken.  
 
x Percent compliance will be calculated for the DB Treatment Period, OLE 
Period and study overall as the number of tablets taken divided by the 
expected number of tablets (days on study treatment × 1 tablet/day), expressed 
as a percentage. 
 
x Subject compliance is defined as 80% - 120% (inclusive) in percent 
compliance. If the percentage of study medication compliance is unknown, the 
subject is assumed to be non-compliant with study medication.  
 
x Number and percent of subjects that have dose interruptions, as well as those 
with dose interruptions due to AEs  
 
B. Prior and Concomitant Medication/Therapy and Rescue Therapy 
 
Prior and concomitant medications will be coded using the WHODrug Version 
01 March 2020 (Global, B3 format). 
 
Prior (with start and stop dates prior to first dose of study drug) and concomitant 
(ongoing or with stop dates on or after first dose of study drug) medications will 
be presented in a by-subject listing. Rescue therapy medications will be 
presented in a separate listing. Non-drug treatment for AD will be presented in a 
separate listing. 


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For the determination of prior vs concomitant medications/therapies, the 
following rules regarding the stop date will be applied and Baseline below refers 
to baseline in DB Treatment Period:  
 
x If only year was recorded, and it is before Baseline, it is a prior 
medication; if year is same or after Baseline, it is assumed to be a 
concomitant medication.  
x If day is missing, but month and year are before Baseline, it is a prior 
medication; if month and year are the same as Baseline, it is assumed to 
be a concomitant medication; if month and year are after Baseline, it is a 
concomitant medication.  
x If start date is after Baseline, it is a concomitant medication regardless.  
x All medications that start in the OLE Period are considered as 
concomitant. 
 
Prior medications/therapies for DB Treatment Period will be summarized by 
treatment using WHO Drug Dictionary (WHO-DD) Anatomical-Therapeutic-
Chemical (ATC) classification and preferred term (PT). The highest available 
level of ATC among ATC 1-4 will be presented. For example, if ATC 1, ATC 2 
and ATC 3 are available, the summary table and subject listing will present ATC 
3. Concomitant medications/therapies will be summarized for DB Treatment 
Period, OLE Period and overall using ATC and PT. 
 
C. Adverse Events 
 
All AEs will be coded using MedDRA Version 23.0 March 2020. A treatment-
emergent AE (TEAE) is defined as: 
 
x Any reported AE that occurs after initiation of study treatment that was not 
present at the time of treatment start. 
x All AEs that occur in the OLE Period are considered as TEAEs. 
 
For the determination of TEAEs, the following rules regarding the partial start 
date will be applied and Baseline below refers to baseline in DB Treatment 
Period: 
 
x If only the year was recorded, and it is before Baseline, it is a non-TEAE; if 
year is the same or after Baseline, it is assumed to be a TEAE.  
x If the day is missing, but month and year are before Baseline, it is a non-
TEAE; if the month and year are the same as Baseline, it is assumed to be a 
TEAE; if the month and year are after Baseline, it is a TEAE.  
x If start date is after Baseline, it is a TEAE regardless. 
 
If the relationship to treatment is missing, the event will be conservatively 
considered as being related to study drug. If the severity is missing, a separate 


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category of missing severity will be included in the summary table, and no 
imputation of severity will be performed.  
 
AE profile will be provided (for DB Treatment Period, OLE Period, and overall), 
by treatment group and overall as follows: 
 
x All AEs 
x Non-TEAEs (for DB Treatment Period and overall) 
x All TEAEs 
x Serious AEs 
x Non-Serious TEAEs 
x TEAEs leading to study treatment discontinuation 
x TEAEs leading to study treatment interruptions   
x TEAEs related to study treatment. This will include TEAEs with a drug 
relationship of “Probably Related” and “Related” 
 
Summaries of the incidence of TEAEs (for DB Treatment Period, OLE Period, 
and overall), will be displayed by treatment according to the following: 
 
x TEAEs by SOC in alphabetical order and PT in descending order of frequency 
(in etrasimod 2mg, etrasimod 1mg, and then placebo)  
x SAEs by SOC and PT 
x TEAEs by SOC, PT, and maximum Common Terminology Criteria for 
Adverse Events (CTCAE) severity  
x TEAEs by SOC, PT, and maximum relationship to the study treatment  
x Non-serious TEAE by SOC and PT 
 
Targeted Medical Events by PT and Category will be summarized for DB 
Treatment Period, OLE Period, and overall. 
 
All AEs will be presented in a by-treatment, and by-subject listing, for the DB 
treatment and OLE Periods separately, detailing the verbatim term given by the 
investigator, the PT, SOC, onset date, end date, CTCAE grade, outcome, 
relationship to study treatment, action taken with study drug, other action taken, 
seriousness and criteria for seriousness. SAEs and AEs leading to study treatment 
discontinuation will also be presented in a separate listing.  
 
D.  Clinical Laboratory Results 
 
Laboratory parameters from the central laboratory will be summarized by 
treatment group at each scheduled assessment time point. For continuous lab 
parameters (hematology, serum chemistry, coagulation, and urinalysis), absolute 
values and change from Baseline will be summarized using descriptive statistics. 
For the OLE Period, change from Baseline will be calculated for the DB baseline 
and OLE baseline separately. Associated laboratory parameters (e.g., hepatic 










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C. Sensitivity Analysis for Percent Change in EASI 
Additional sensitivity analysis for percent change in EASI will be performed 
with observed cases in the FAS using the MMRM model described in section 8 
(subsection B) 
 
 
D. Additional Subgroup Analyses for EASI-75 and vIGA 
                   Prior Systemic Failure Subject (Yes, No) 
Prior Systemic Failure Subject are subjects who previously had 
ineffective/intolerant therapy in oral steroid, oral JAK and Dupilumab, or 
other conventional Systemic therapy: 
x 15 subjects in the 2mg etrasimod group: 
 
x 3 subjects in the 1mg etrasimod group: 
 
 
x 10 subjects in the placebo group:
 
EASI-75 and vIGA response rate by visit will be analyzed for the subgroups 
of Prior Systemic Failure Subject (Yes, No) and using the same CMH 
analysis described in section 8 (subsection C).