Clinical trial NCT02536404
Conditions: Ulcerative Colitis
Sponsor: Arena Pharmaceuticals
Start date: 2016-01-25; Completion date: 2018-11-01
Enrollment: 118 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to determine whether etrasimod (APD334) is a safe and effective treatment for ulcerative colitis after 52 weeks of treatment.

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: Etrasimod intervention 2: Placebo
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_000.pdf: 


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PROTOCOL AMENDMENT SUMMARY 
The following is a list of major changes made to the APD334-005 Protocol dated 20 October 
2016. Minor clarifications and corrections have been made throughout for consistency. These 
changes are incorporated in Protocol Amendment 04 dated 27 March 2017. 
Section(s) Amended 
Description of Changes Made 
Header/Footer, Title Page, and 
TOC 
Added “Amendment 04”, updated date to 
reflect finalization of amended protocol, 
updated sponsor contact, pagination and TOC 
Protocol Amendment Summary 
Updated table to include summary of major 
changes to the protocol 
Synopsis 
Updated Sponsor and medical monitor contact 
details 
Synopsis 
Updated Secondary Outcome to add proportion 
of patients who achieve clinical response 
Study Definitions 
Updated to reflect APD334-003 completers to 
be eligible for APD334-005 study  
3.1 Overall Study Design and Plan 
Updated to reflect APD334-003 completers to 
be eligible for APD334-005 study  
4.2 Inclusion Criteria #6 
Updated to reflect APD334-003 completers to 
be eligible for APD334-005 study 
5.3 Selection and Timing of Dose 
for Each Patient 
Updated to reflect APD334-003 completers to 
be eligible for APD334-005 study 
5.4 Method of Assigning Patients 
to Treatment Groups 
Updated to reflect APD334-003 completers to 
be eligible for APD334-005 study  
6.9.6 3-Component Mayo Score  
Updated to reflect APD334-003 completers to 
be eligible for APD334-005 study 
6.15 Study and Site 
Discontinuation  
Added section on reasons to terminate the 
study 
7.1 Extension Study Enrollment 
Activities  
Updated to reflect APD334-003 completers to 
be eligible for APD334-005 study  
7.2 Study Activities 
Updated to reflect APD334-003 completers to 
be eligible for APD334-005 study 
9.2 Sample Size and Power 
Calculation 
Updated to reflect APD334-003 completers to 
be eligible for APD334-005 study 
9.5 Efficacy Endpoints 
Updated Secondary Outcome to add proportion 
of patients who achieve clinical response 
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Section(s) Amended 
Description of Changes Made 
9.6 Statistical Methods 
Modified according to amended study design. 
 
 
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Study Design: APD334-003 and -005 (extension) 
 
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TABLE OF CONTENTS 
PROTOCOL AMENDMENT SUMMARY ..............................................................................2 
SYNOPSIS .................................................................................................................................4 
TABLE OF CONTENTS .........................................................................................................10 
LIST OF APPENDICES ..........................................................................................................14 
LIST OF ABBREVIATIONS ..................................................................................................15 
STUDY DEFINITIONS ..........................................................................................................18 
1 
INTRODUCTION ...........................................................................................................19 
1.1 
Background Information ........................................................................................20 
1.1.1 
Rationale for Proposed Clinical Study .........................................................20 
1.2 
Ethics and Regulatory Considerations ...................................................................23 
2 
STUDY OBJECTIVES ....................................................................................................25 
2.1 
Primary Objective ..................................................................................................25 
2.2 
Secondary Objective ..............................................................................................25 
3 
INVESTIGATIONAL PLAN ..........................................................................................26 
3.1 
Overall Study Design and Plan ..............................................................................26 
3.2 
Study Duration and Dates ......................................................................................26 
4 
STUDY POPULATION SELECTION ...........................................................................27 
4.1 
Study Population ....................................................................................................27 
4.2 
Inclusion Criteria ...................................................................................................27 
4.3 
Exclusion Criteria ..................................................................................................28 
5 
STUDY TREATMENT(S) ..............................................................................................29 
5.3 
Selection and Timing of Dose for Each Patient .....................................................29 
5.4 
Method of Assigning Patients to Treatment ..........................................................29 
5.5 
Randomization and Blinding .................................................................................30 
5.5.1 
Randomization .............................................................................................30 
5.5.2 
Blinding........................................................................................................30 
5.5.3 
Maintenance of Randomization Codes and Code-break Procedures ...........30 
5.6 
Concomitant Therapy.............................................................................................30 
5.7 
Restrictions ............................................................................................................30 
 
 
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9.3 
Analysis Populations ..............................................................................................53 
9.4 
Demographics and Baseline Characteristics ..........................................................53 
9.5 
Efficacy Endpoints .................................................................................................54 
9.5.1 
Efficacy Endpoints .......................................................................................54 
9.5.2 
Exploratory Efficacy Endpoints ...................................................................54 
9.6 
Statistical Methods .................................................................................................55 
9.6.1 
Data Analysis for Secondary Efficacy Endpoints ........................................55 
9.6.2 
Data Analysis for Exploratory Efficacy Endpoints .....................................56 
 
 
9.6.4 
Multiplicity ..................................................................................................57 
9.6.5 
Interim Analysis ...........................................................................................57 
9.6.6 
Data Safety Monitoring Board .....................................................................57 
 
 
9.8 
Safety Analysis ......................................................................................................57 
9.8.1 
Adverse Events ............................................................................................58 
9.8.2 
Physical Examinations .................................................................................58 
9.8.3 
Concomitant Medication ..............................................................................58 
9.8.4 
Vital Signs ....................................................................................................58 
9.8.5 
Clinical Laboratory Values ..........................................................................58 
 
 
 
 
10 REGULATORY REQUIREMENTS...............................................................................60 
10.1 
Pre-Study Documentation ......................................................................................60 
10.2 
Investigator Obligations .........................................................................................60 
10.3 
Patient Confidentiality ...........................................................................................60 
10.4 
Informed Consent...................................................................................................60 
10.5 
Institutional Review Board ....................................................................................61 
11 PROTOCOL MANAGEMENT AND ADMINISTRATIVE CONSIDERATIONS ......62 
11.1 
Study Documentation.............................................................................................62 
11.2 
Protocol Interpretation and Compliance ................................................................62 
11.3 
Study Monitoring ...................................................................................................62 
12 PRINCIPAL INVESTIGATOR SIGNATURE PAGE ...................................................63 
13 REFERENCE LIST .........................................................................................................65 
PROTOCOL SIGNATURE PAGE .........................................................................................67 
 
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LIST OF ABBREVIATIONS 
µg 
microgram 
ABPM 
ambulatory blood pressure monitor 
ADL 
Activities of Daily Living 
ALB 
albumin 
ALK-P 
alkaline phosphatase 
ALT 
alanine aminotransferase (SGPT) 
ANOVA 
analysis of variance 
AST 
aspartate aminotransferase (SGOT) 
bpm 
beats per minute 
BUN 
blood urea nitrogen 
Ca 
calcium 
CBC 
complete blood count (test) 
CFR 
Code of Federal Regulations 
CGMP 
Current Good Manufacturing Practice 
CI 
confidence interval 
CIA 
collagen-induced arthritis 
Cl 
chloride 
CL/F 
apparent oral clearance 
CLr 
renal clearance 
CRF 
case report form 
CRO 
contract research organization 
DSMB 
Data Safety Monitoring Board 
EAE 
experimental autoimmune encephalomyelitis 
ECG 
electrocardiogram 
eCRF 
electronic CRF 
ED50 
median effective dose 
ELISA 
enzyme-linked immunosorbent assay 
FDA 
Food and Drug Administration 
FEF25-75% 
mean forced expiratory flow between 25 and to 75% of FVC 
FEV1 
forced expiratory volume in the first second 
FVC 
forced vital capacity 
GCP 
Good Clinical Practice 
GGT 
gamma glutamyl transferase 
Hb 
hemoglobin 
HBsAg 
hepatitis B surface antigen 
hCG 
human chorionic gonadotropin 
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Hct 
hematocrit 
HCV 
hepatitis C virus 
HDPE 
High-density polyethylene 
HIV 
human immunodeficiency virus 
h 
hour 
HR 
heart rate 
 
 
ICH 
International Conference on Harmonisation  
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug  
IRB 
Institutional Review Board 
INR 
International Normalized Ratio 
kg 
kilogram 
LDH 
lactate dehydrogenase 
MCH 
mean corpuscular hemoglobin 
MCS 
Mayo Clinic Score 
MCV 
mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
milligram 
mL 
milliliter 
mm 
millimeter 
mmHg 
millimeters of mercury 
MMRM 
mixed-effect model repeated measures 
MRSD 
maximum recommended starting dose 
Na 
sodium 
NOAEL 
no observed adverse effect level 
OCT 
optical coherence tomography 
OTC 
over-the-counter 
PA 
posteroanterior 
PD 
pharmacodynamic 
PBL 
peripheral blood lymphocyte 
PFT 
pulmonary function test 
PI 
Principal Investigator 
 
 
PML 
progressive multifocal leukoencephalopathy 
PRO 
patient reported outcome 
PT 
prothrombin time  
PTT 
partial thromboplastin time 
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RBC 
red blood cell (count) 
RIBA 
recombinant immunoblot assay 
S1P(1-5) 
sphingosine 1-phosphate (1-5) receptor 
SAE 
serious adverse event 
SAS 
statistical analysis software 
SBP 
systolic blood pressure 
SD 
standard deviation 
sec 
second 
SOP(s) 
standard operating procedure(s) 
TEM 
T effector memory cells 
VICF 
Voluntary Informed Consent Form 
VS 
vital signs 
WBC 
white blood cell (count) 
WHO 
World Health Organization  
WHODRUG 
World Health Organization Drug Dictionary 
 
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 Lymphocyte trafficking agents such as the anti-
integrins natalizumab and vedolizumab, both administered intravenously, have demonstrated 
proof-of-concept in IBD indications and are approved for treatment of CD and both CD and 
UC, respectively. And more recently, RCP1063, an S1P1 oral receptor modulator showed 
promising results in a Phase 2 study for ulcerative colitis. The availability of oral lymphocyte 
trafficking agents such as APD334 would offer patients an additional, more convenient 
treatment for IBD. 
1.1 
Background Information 
1.1.1 
Rationale for Proposed Clinical Study 
UC is characterized by diffuse mucosal inflammation limited to the colon which involves the 
rectum in about 95% of cases and may extend proximally, typically in a symmetrical, 
circumferential, and uninterrupted pattern, to involve parts or all of the large intestine.13 
Symptoms for UC can vary, depending on the location and severity of inflammation, but 
some of the most common are diarrhea, abdominal cramps and rectal bleeding. The hallmark 
clinical symptom is bloody diarrhea often with prominent symptoms of rectal urgency and 
tenesmus.13 
S1P1 receptor signaling on lymphocytes allows their exit from lymph nodes along a S1P 
gradient. Functional antagonism of these S1P1 receptors through agonist-mediated cellular 
internalization results in retention of certain lymphocyte subpopulations in lymph nodes and 
prevents their egress to the periphery.  It is through this mechanism that APD334 may 
potentially reduce inflammation in inflammatory bowel disease.  Lymphocyte lowering has 
been correlated with clinical efficacy for S1P functional antagonists in multiple sclerosis, 
psoriasis, and ulcerative colitis. This same mechanism may also be useful in treating a variety 
of other inflammatory and autoimmune diseases. 
This study is designed to evaluate the long-term safety, tolerability and efficacy of APD334 
in UC patients who have completed the APD334-003 induction study. 
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1.2 
Ethics and Regulatory Considerations   
The study will be conducted in compliance with the International Conference on 
Harmonisation (ICH) Guidelines for Good Clinical Practice (GCP), Title 21 of the United 
States (US) Code of Federal Regulations (CFR) Part 50 (21CFR §50 (Protection of Human 
Subjects), 21 CFR §56 (Institutional Review Boards [IRB]), and 21 CFR §312 
(Investigational New Drug [IND]) and applicable regulatory requirements, the study 
protocol, and where applicable, sponsor and / or Contract Research Organization (CRO) 
Standard Operating Procedures (SOPs). The protocol and informed consent will be submitted 
for consideration by the appropriate IRB/IEC and written approval from the Chair or 
designated deputy of the IRB/IEC is required before clinical activities of the study can 
commence. 
The IRB/IEC must be notified promptly by the investigator of the following: 
• Deviations from, or changes in, the protocol to eliminate immediate hazards to the 
trial volunteers 
• Changes increasing the risk to volunteers and/or affecting significantly the conduct of 
the trial 
• All AEs that meet the definition of a SAE 
• New information that may adversely affect the safety of the volunteers or the conduct 
of the trial 
 
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Any changes to the protocol will be made by means of a formal written protocol amendment. 
All amendments will require IRB/IEC approval before implementation except when changes 
to the protocol are required immediately to eliminate hazards to the volunteer. 
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2 
STUDY OBJECTIVES 
2.1 
Primary Objective  
The primary objective of this study is to evaluate the long-term safety and tolerability of 
APD334 in patients with ulcerative colitis who have completed the APD334-003 study. 
2.2 
Secondary Objective  
The secondary objective of this study is to evaluate the effect of APD334 on achieving and 
maintaining clinical response and/or remission in patients with ulcerative colitis after 46 
weeks of treatment. 
 
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4 
STUDY POPULATION SELECTION 
4.1 
Study Population 
Patients with ulcerative colitis, who have completed the APD334-003 study as planned and 
who meet the eligibility criteria for APD334-005.  
4.2 
Inclusion Criteria 
Each patient must meet the following criteria to be enrolled in this study: 
6. Completion of the APD334-003 study  
 
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5 
STUDY TREATMENT(S) 
5.3 
Selection and Timing of Dose for Each Patient 
Investigational product will be dispensed to eligible patients under the supervision of the 
investigator or his/her designee at the week 12 visit of the APD334-003 study.  
5.4 
Method of Assigning Patients to Treatment 
After completing study APD334-003 and signing a voluntary informed consent form (VICF), 
eligible patients from study ADP334-003 will be assigned to receive 2 mg APD334 q.d. 
Treatment assignment and duration are as follows: 
• Open-label 2 mg APD334 x 34 weeks 
 
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monitor or contracted designee. The investigator agrees to provide sufficient access to study 
medication as required for the reconciliation process to be completed in a timely fashion. 
5.10 Investigational Product Retention at Study Site 
At completion of the study, all study medication will be reconciled by the Arena monitor or 
contracted designee and then returned at the direction of Arena to be retained or destroyed 
according to applicable country regulations. Prior to any action being taken with study 
medication after the study is completed, the investigator will contact Arena (or contracted 
CRO) for approval of such action. 
5.11 Data Safety Monitoring Board 
Not applicable. 
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6 
STUDY PROCEDURES 
6.1 
Informed Consent 
The investigator will obtain and document VICF for each patient screened for this study.  All 
patients will be informed in writing of the nature of the protocol and investigational therapy, 
their possible hazards, and their right to withdraw at any time, and will sign a form indicating 
their consent to participate prior to the initiation of study procedures. The patient’s medical 
record should contain written documentation indicating that informed consent was obtained. 
The VICF must be reviewed and approved by the investigator’s designated IRB/IEC and by 
the sponsor. The VICF should include all the elements as outlined in Section 4.8.10 of the 
ICH guideline for GCP (E6). 
6.2 
Medical and Social History 
At baseline, evaluations will include a medical and social history update, to include tobacco, 
alcohol and caffeine use. Concomitant medications, recent blood donations, illnesses, and 
participation in other investigational drug studies will also be recorded. 
6.3 
Physical and Neurological Examination 
The physical examination, which includes assessments of general appearance, skin, head 
(eyes, ears, nose, and throat), neck, thyroid, lungs, heart, abdomen, back, lymph nodes, 
extremities, height and body weight; and the neurological examination, which includes 
assessments of the neurological system (cranial nerves, motor and sensory function, 
coordination, and mental status) will be performed by the principal investigator or 
sub-investigator. The physical and neurological exams performed at the 
 visit of 
study APD334-003 will serve as baselines for the APD334-005 study.  
The physical examination will also include visual acuity and dilated ophthalmoscopy (by an 
ophthalmologist) and with OCT (where available) 
 (to rule out and 
monitor for any significant retinal disease, including macular edema). Retinal photos will be 
taken during the baseline visit
 
and any subsequent unscheduled ophthalmoscopy.  
6.4 
Progressive Multifocal Leukoencephalopathy (PML) Checklist 
Monitoring for progressive multifocal leukoencephalopathy (PML), a potential adverse effect 
of S1P1 agonists, will be performed at each site visit 
 using a 
subjective PML checklist. The investigator or subinvestigator will administer the subjective 
PML checklist. The subjective PML checklist will also be administered to probe for 
symptoms suggestive of PML. Any patients reporting signs and/or symptoms of PML will 
undergo objective testing and may be referred to a neurologist for a full evaluation.  
Additional information on PML is provided in Section 6.11.1.1 and a copy of the PML 
checklist is provided in Appendix 2. 
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6.8.1 
Laboratory Parameters 
Clinical safety laboratory tests will be conducted as outlined in Appendix 1. Laboratory tests 
will include the following. Results of the total white blood cell and lymphocyte counts will 
be reviewed and monitored per Section 5.5.2. 
Serum Chemistry 
Albumin (ALB) 
Alkaline phosphatase (ALK-P) 
Alanine aminotransferase (ALT; SGPT) 
Amylase 
Aspartate aminotransferase (AST; SGOT) 
Bicarbonate  
Blood urea nitrogen (BUN) 
Calcium (Ca) 
Chloride (Cl) 
Creatinine  
Creatine kinase and MB subtype (if elevated) (% 
and total MB) 
Gamma-glutamyl transferase (GGT) 
Glucose 
Lactate dehydrogenase (LDH) 
Lipase 
Magnesium 
Phosphate  
Potassium (K) 
Sodium (Na) 
Serum Chemistry (cont.) 
Total bilirubin  
Total cholesterol  
Total protein  
Triglycerides 
 
Hematology  
Hematocrit (Hct) 
Hemoglobin (Hb) 
Mean corpuscular hemoglobin (MCH) 
Mean corpuscular volume (MCV) 
Platelet count 
Red blood cell count (RBC) 
White blood cell count (WBC) with differential (% 
and absolute counts) 
 
Coagulation 
Prothrombin time (PT) 
Activated partial thromboplastin time (PTT) 
International Normalized Ratio (INR) 
 
6.8.2 
Urinalysis 
Urinalysis parameters for clinical laboratory tests include the following: 
• 
appearance 
• 
occult blood 
• 
bilirubin 
• 
pH 
• 
color 
• 
protein 
• 
glucose 
• 
specific gravity 
• 
ketones 
• 
urobilinogen 
• 
leukocyte esterase 
 
 
Microscopic urinalysis will be performed when there is a positive or abnormal macroscopic 
urinalysis result. 
6.8.3 
Sample Collection, Storage, and Shipping 
Blood samples for hematology, coagulation parameters, serum chemistry, will be collected 
according to the laboratory manual provided by the local or central laboratory and according 
to the schedules of procedures and visits (Appendix 1). 
6.8.4 
Blood Volume 
Total blood volume for clinical laboratory tests during study conduct is less than 150 mL. 
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6.10.2 
Hematologic Sampling 
Blood samples for CBC with differential and platelet count will be assessed 
 
.   
If the 
 
value at the 2-week follow-up, patients should return for weekly CBCs until the absolute 
peripheral lymphocyte count has returned to at least this value.  
All details regarding collection of blood samples for CBC with differential analysis will be 
collected and prepared according to that specified in the laboratory manual provided 
separately by the central laboratory.  The samples should be packed and shipped to the 
central laboratory, according to the directions in their laboratory manual, which will send 
them on to the bioanalytical laboratory for analysis. 
6.10.3 
Total Blood Volume 
Total blood volume collected for 
/hematologic samples is less than 120 mL during the 
study.   
6.11 Adverse Events Assessments 
Patients will be monitored from ICF signature to 30 days after the last dose of study drug for 
adverse reactions to the study drug and/or procedures. 
AEs will be recorded and reported in accordance with ICH GCP and 21 CFR§312.32. The 
definitions of AEs and SAEs will be as given in the ICH Topic E2A, ICH Guideline “Note 
for Guidance on Clinical Safety Data Management: Definitions and Standards for Expedited 
Reporting.”  The outcome of an AE will be defined according to ICH Topic E2B, ICH 
Guideline “Note for Guidance on Clinical Safety Data Management: Data Elements for 
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Transmission of Individual Case Safety Reports.” The relationship to investigational product 
will be classified using the World Health Organization (WHO) criteria. 
6.11.1 
Adverse Event Reporting 
Patients will be instructed that they may report AEs at any time. All events reported 
following study medication administration will be recorded as treatment emergent AEs 
(TEAEs). 
Monitoring of ongoing AEs will be continued up to 30 days after study medication 
administration. In the event that an AE is not resolved or stabilized by this time, the sponsor 
in consultation with the investigator will decide whether to continue to monitor the AE or 
close-out the event in the database if no further follow-up is necessary. 
For this study, an AE is defined as: “Any untoward medical occurrence in a study patient 
administered any dose of the study medication APD334 and which does not necessarily have 
to have a causal relationship with this treatment.” An AE can therefore be any unfavorable 
and unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of the study medication, whether or not related to the 
product. AEs can be any of the following: 
• Unfavorable changes in general condition 
• Subjective or objective signs/symptoms 
• Concomitant disease or accidents 
• Clinically relevant adverse changes in laboratory parameters observed in a patient 
in the course of a clinical study 
• Pre-existing conditions which worsen in severity or frequency or which have new 
signs/symptoms associated with them 
 
Adverse events will be elicited at the time indicated in the schedule by asking the question: 
“Since you were last asked, have you felt unwell or different from usual in any way?”  Any 
adverse or unexpected events, signs and symptoms, will be fully recorded on the Adverse 
Event Form including details of intensity, onset, duration, outcome and relationship to the 
drug as determined by the PI.  Whenever possible, a constellation of signs and symptoms 
should be recorded as a unifying diagnosis (e.g., self-limited fever, runny nose, cough, and 
scratchy throat should be captured as an upper respiratory infection rather than by the 
individual signs and symptoms). AEs may also be reported at any time. The type and 
duration of follow-up of patients after AEs will be documented. 
6.11.1.1 
Progressive Multifocal Leukoencephalopathy (PML) Checklist 
A patient with multiple sclerosis developed progressive multifocal leukoencephalopathy 
(PML) after nearly 8 months of treatment with another S1P1 agonist21, and enablement of the 
John Cunningham (JC) virus is therefore a potential adverse effect of this therapeutic class. 
Patients in this trial should therefore be monitored for any new onset or worsening of 
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neurological signs and symptoms. Signs and symptoms associated with PML are diverse, 
progress over days to weeks, and include progressive weakness on one side of the body or 
clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation 
leading to confusion and personality changes. The progression of deficits usually leads to 
death or severe disability over weeks or months. If PML is suspected, withhold dosing and 
refer to a neurologist; if confirmed, discontinue dosing permanently. 
The investigator or subinvestigator will administer the subjective PML checklist. The 
subjective PML checklist will be administered at each site visit to probe for symptoms 
suggestive of PML. Any patients reporting signs and/or symptoms of PML will undergo 
objective testing and may be referred to a neurologist for a full evaluation. 
A copy of the PML checklist is provided in Appendix 2. 
6.11.2 
Serious Adverse Events and Expedited Reporting of Adverse Events 
A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose results 
in the following outcomes: 
• Death 
• Is Life-Threatening 
• Required/Prolonged Hospitalization 
• Disability/Incapacity 
• Congenital Anomaly/Birth Defect 
• Important Medical Event 
SAEs will be captured from the time of ICF signature to 30 days after the last dose of study 
drug, and will be monitored until resolution or stabilization. 
An important medical event that may not result in death, be life-threatening, or require 
hospitalization may be considered a SAE when, based upon appropriate medical judgment, it 
may jeopardize the patient and may require medical or surgical intervention to prevent one of 
the outcomes listed in this definition. Examples of such a medical event includes allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias, or convulsions that do not result in in-patient hospitalization, or the development 
of drug dependency or drug abuse. 
Elective hospitalization and/or surgery for clearly pre-existing conditions (for example a 
surgery that has been scheduled prior to the patient’s entry into the study) will not be 
reported as a SAE. All other hospitalizations, including elective hospitalizations for any 
condition that was not pre-existing, will be reported as a SAE.   
Any AE considered serious by the investigator or which meets SAE criteria must be reported 
to PPD Pharmacovigilance (PVG) using the remote data capture (RDC) system within 
24 hours from the time study site personnel first learn about the event. The following contact 
information is to be used for SAE reporting: 
 
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• Grade 2:  Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental Activities of Daily Living (ADL)*. 
• Grade 3:  Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-
care ADL**. 
• Grade 4:  Life-threatening consequences; urgent intervention indicated. 
• Grade 5:  Death related to AE. 
 
Activities of Daily Living (ADL): 
*Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc. 
**Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, 
taking medications, and not bedridden. 
6.11.4 
Assessment of Adverse Event Relationship to Study Medication  
The relationship of an AE to investigational product(s) will be classified using modified 
WHO criteria (Edwards and Biriell, World Health Organization Collaborating Centre for 
International Drug Monitoring 1994) as follows. 
Related:  a clinical event, including laboratory test abnormality, with a reasonable time 
sequence to administration of the drug, unlikely to be attributed to concurrent disease or 
other drugs or chemicals, and which follows a clinically reasonable response on withdrawal 
(dechallenge). Rechallenge information is not required to fulfill this definition; or an event 
that could also be explained by concurrent disease or other drugs or chemicals where 
information on drug withdrawal may be lacking or unclear. 
Not related:  a clinical event, including laboratory test abnormality, with sufficient evidence 
to accept that there is no causal relationship to drug administration (e.g., no temporal 
relationship to drug administration, because the drug was administered after onset of event; 
investigation shows that the drug was not administered; proof of other cause; etc.); or an 
event with a temporal relationship to drug administration which makes a causal relationship 
improbable, and in which other drugs, chemicals or underlying disease provide plausible 
explanations. 
6.11.5 
Assessment of Adverse Event Outcome 
Outcome of AEs will be defined based on ICH Topic E2B, ICH Guideline. 
• Recovered/Resolved 
• Recovered/Resolved with Sequelae 
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• Recovering/Resolving 
• Not Recovered/Not Resolved 
• Fatal 
• Unknown 
 
6.11.6 
Action Taken for Adverse Event 
Action taken for AEs will be documented according to the following: 
• Concomitant medication or other treatment 
• Withdrawal from the study 
 
6.11.7 
Action Taken for Study Drug 
Any action taken with study drug will be defined based on ICH Topic E2B, ICH 
Guideline and documented in the CRF according to the following: 
• Drug Withdrawn 
• None (not changed) 
• Dose Interrupted 
• Unknown 
• Not Applicable 
 
6.11.8 
Collection of Extra Laboratory Samples/Investigations 
In the event of a clinically important AE, a suitable sample may be collected for drug assay 
or for additional laboratory tests. The investigator must ensure that the sample is properly 
labeled and stored. The investigator and others responsible for care of the patient should 
institute any supplementary investigations of significant AEs based on the clinical judgment 
of the likely causative factor. This may include seeking a further opinion from a specialist in 
the field of the AE. The company may suggest special tests based on expert advice. 
6.11.9 
Follow-up of Adverse Events Present at Last Scheduled Study Visit 
Adverse events present at the last study day 
 that require follow-up or a 
repeat laboratory test will be followed-up initially for 30 days according to the site’s standard 
practice for AE follow-up. AEs that have not resolved or stabilized at 30 days after the last 
patient’s last study dose, will be reviewed with the sponsor on an individual basis to 
determine whether the database will be locked and subsequently updated once the events of 
ongoing AEs are resolved or whether database lock will be held. 
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• Patient enrollment is unsatisfactory. 
• The Sponsor will notify the investigator if the study is placed on hold, or if the 
Sponsor decides to discontinue the study or development program.   
• The Sponsor has the right to replace a site at any time.  Reasons for replacing a site 
may include, but are not limited to, the following: 
• Excessively slow recruitment 
• Poor protocol adherence 
• Inaccurate or incomplete data recording 
• Non-compliance with the ICH guidelines for GCP 
 
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• 12-lead ECG (per Appendix 1) 
• Drug administration 
• Drug dispensation/accountability 
• Record adverse events 
• Record concomitant medications/procedures 
 
7.2.2.3 
Weeks 
 Procedures 
• PML checklist 
• Pulmonary function test (spirometry) 
 
• Urine pregnancy test (females only, not diagnosed as postmenopausal) 
 
 
• CBC with differential and platelets 
 
• Clinical laboratory tests (serum chemistry, hematology, coagulation parameters, 
urinalysis and CRP) 
 
• Stool Sample 
 
• Fecal calprotectin 
 
 
  
• Diary review 
• Vital signs 
 
  
• 12-lead ECG (per Appendix 1) 
 
• Drug administration 
• Drug dispensation/accountability 
• Record adverse events 
• Record concomitant medications/procedures 
 
7.2.2.4 
Week 46/End-of-Treatment (EOT) or Early Termination Procedures 
• Physical/ neurological exam 
• PML checklist 
• Urine pregnancy test (females only, not diagnosed as postmenopausal) 
• CBC with differential and platelets 
• Ophthalmoscopy with OCT (where available) and retinal photos 
• Clinical laboratory tests (serum chemistry, hematology, coagulation parameters, 
urinalysis and CRP)  
• Pulmonary function test (spirometry) 
• Stool Sample 
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8 
DATA MANAGEMENT 
8.1 
Data Collection 
All data (ECGs, clinical laboratory data, and all other study-related data) will be collected 
according to the sponsor or CRO’s SOPs. 
Upon database lock, which occurs after resolution of all queries, the CRO, if applicable, will 
provide statistical analysis software (SAS) transfer datasets to the sponsor and to the 
biostatistician for analysis using secure electronic data transfer per the sponsor’s 
specifications. 
8.2 
Data Coding 
8.2.1 
Adverse Events 
Adverse events will be coded using the most current Medical Dictionary for Regulatory 
Actvities (MedDRA) and tabulated, including categorical information of interest such as 
onset and resolution times, time of onset relative to dose, severity at onset, maximum 
severity, causal relationship to study medication, and action taken. Whenever possible, a 
constellation of signs and symptoms should be recorded as a unifying diagnosis (e.g., self-
limited fever, runny nose, cough, and scratchy throat should be captured as an upper 
respiratory infection rather than by the individual signs and symptoms). AEs that occur after 
the first dose of study medication will be considered to be ‘treatment-emergent’. 
8.2.2 
Concomitant Medications and Non-drug Treatments 
Due to the variability in how medications are recorded, a standard naming convention is 
required in order to tabulate this data effectively. A common method of standardization is to 
categorize medications by their Preferred Term. In order to do this, medications will be 
coded using the World Health Organization Drug Dictionary (WHODRUG). 
8.2.3 
Medical History 
Medical history will be coded using the most current MedDRA (version 18.0 or later).   
 
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9 
PLANNED STATISTICAL METHODS 
The statistical analysis of the data obtained from this study will be the responsibility of the 
CRO. Details of the statistical analyses will be included in a separate statistical analysis plan 
(SAP) which will be finalized prior to database lock. If after database lock changes are made 
to the pre-specified statistical analysis plan, the changes will be listed along with an 
explanation as to why they occurred in the Clinical Study Report. 
9.1 
Hypotheses and Objectives 
9.1.1 
Objectives 
9.1.1.1 
Primary Objective 
The primary objective of this extension study is to evaluate the long-term safety and 
tolerability of APD334 in patients with ulcerative colitis who have completed the 
APD334-003 study. 
9.1.1.2 
Secondary Objective(s) 
The secondary objectives of the study are to evaluate the effect of APD334 on achieving and 
maintaining clinical response and/or remission in patients with ulcerative colitis after 46 
weeks of treatment.  
9.1.1.3 
Exploratory Objectives 
The exploratory objectives of the study are to examine the effect of APD334 treatment in 
patients with ulcerative colitis on: 
 
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9.1.2 
Hypotheses 
There are no formal hypothesis tests specified in this study due to the lack of control 
treatment group. 
 
9.2 
Sample Size and Power Calculations  
Patient enrollment is limited by the number of patients who complete the  APD334-003 
study. Therefore sample size and power calculation is not needed. 
9.3 
Analysis Populations 
The analyses of all proportion based efficacy variables will use the Intent-to-Treat (ITT) 
population as primary. For other continuous efficacy endpoints, the Modified Intent-to-Treat 
(MITT) population will be used as primary. A completer’s population will be used as a 
secondary analysis population for the efficacy endpoints.   
INTENT-TO-TREAT POPULATION (ITT): 
This population consists of all enrolled patients, who received at least 1 dose of APD334 in 
the extension study. 
MODIFIED INTENT-TO-TREAT POPULATION (MITT): 
This population consists of all enrolled patients, who received at least 1 dose of APD334, 
have a baseline measurement, and have a post-enrollment measurement in the extension 
study for the specific efficacy endpoint being assessed. Note that MITT population can vary 
with endpoints since some patients may have the needed data for inclusion in the MITT 
population for some endpoints but not for others. 
COMPLETERS POPULATION (CP): 
This population consists of all patients who completed the extension study. No missing data 
will be imputed for this analysis. Any substantial differences between conclusions based on 
the ITT/MITT population and the completers’ population will be investigated. 
SAFETY POPULATION (SP): 
The Safety Population will include all enrolled patients who received study medication in the 
extension study. 
9.4 
Demographics and Baseline Characteristics 
All baseline patient characteristics of demographic data (age, height, weight, race), ulcerative 
colitis history, social history (smoking status, caffeine intake, alcohol intake), medical history 
(abnormalities only), physical examination (abnormalities only), and concomitant 
medications at study entry will be listed for all patients.   
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Demographic data will be summarized and tabulated for the overall population. Continuous 
variables will be summarized using number of observations (n), mean, standard deviation 
(SD), median, minimum, and maximum. Frequencies and percentages will be reported for all 
categorical data 
9.5 
Efficacy Endpoints 
9.5.1 
Efficacy Endpoints 
Secondary outcome measures are achievement, durability and maintenance of clinical 
response and/or clinical improvement. They include the following: 
• The proportion of patients who achieve or maintain clinical response [defined as a 
decrease in 3-component Mayo Clinic score of ≥ 2 points and at least 30% with either 
a decrease of rectal bleeding of ≥ 1 or rectal bleeding score of 0 or 1] at Week 46 
compared to APD334-003 baseline  
• The proportion of patients who achieve or maintain clinical remission [defined as 
individual subscores of the 3-component Mayo Clinic score as follows: an endoscopy 
score (using flexible proctosigmoidoscopy) of 0 or 1, a rectal bleeding score of 0, and 
a stool frequency score of 0 or 1 with a decrease of ≥ 1 point at Week 46 compared to 
APD334-003 baseline  
 
9.5.2 
Exploratory Efficacy Endpoints 
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9.8.1 
Adverse Events 
Adverse events will be coded using the most current Medical Dictionary for Regulatory 
Activities (MedDRA) and tabulated, including categorical information of interest such as 
onset and resolution times, time of onset relative to dose, severity at onset, maximum 
severity, causal relationship to study medication, and action taken. AEs will be regarded as 
‘pre-treatment’ if they occur between Screening and the time of administration of the first 
dose of APD334. All other AEs that occur after the first dose of study medication will be 
considered to be ‘treatment-emergent’. 
Treatment-emergent AEs (TEAE) will be listed by patients. They will be summarized and 
expressed in terms of maximum severity and relationship to study medication. The incidence 
of TEAEs classified according to system organ class will be summarized. TEAEs will also be 
summarized by maximum intensity (assessed according to the Common Terminology 
Criteria for Adverse Events v4.0313 definitions) and relatedness to study medication. 
Summaries of the number (%) of patients with at least 1 TEAE, classified according to 
MedDRA system organ class and preferred term, will also be provided for: 
• Drug-related TEAE 
• Treatment-emergent AEs leading to permanent discontinuation of study medication 
(study medication discontinued or withdrawal from study). 
• Serious adverse events (SAEs) 
Serious adverse events will be listed by patient. If there are no SAEs at the end of the study, 
the tables or listings will state that there are no SAEs in the study. 
9.8.2 
Physical Examinations 
Physical examination results (abnormalities only) at each study visit will be listed. 
9.8.3 
Concomitant Medication 
Pre-treatment and concomitant medication administered during the study will be listed. 
Concomitant medications will be coded using the WHODRUG Dictionary. 
9.8.4 
Vital Signs 
Individual vital sign measurements will be listed and summarized using descriptive statistics. 
Summary statistics will also be provided for change from baseline in vital sign 
measurements. Baseline is defined as the last pre-enrollment measurement. 
9.8.5 
Clinical Laboratory Values 
Individual lab values will be listed by visit, and summarized using descriptive statistics. 
Summary statistics will also be provided for change from baseline in lab values. Baseline is 
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10 REGULATORY REQUIREMENTS 
10.1 Pre-Study Documentation 
The sponsor must receive the following documentation prior to initiation of the trial: 
• Protocol signature page signed and dated by the principal investigator (PI) 
• FDA form 1572 signed and dated by the PI 
• Curriculum vitae of the PI and subinvestigators, updated within 2 years 
• Current medical licenses for the PI and all subinvestigators 
• Financial disclosure form signed by the PI and all subinvestigators listed on the FDA 
Form 1572 
• Copy of the IRB/IEC approval letter for the study and approved VICF 
• IRB/IEC Membership List 
 
Additional country specific documentation may be required per international regulatory 
authorities. Documents will be collected by the CRO per regulatory requirements. 
10.2 Investigator Obligations 
The PI is responsible for ensuring that all study site personnel, including subinvestigators and 
other study staff members, adhere to all FDA and other country specific regulations and 
guidelines regarding clinical trials, including guidelines for GCP (including the archiving of 
essential documents), both during and after study completion. The PI will be responsible for 
the patient’s compliance to the study protocol. The PI is responsible for providing the 
sponsor an adequate final report shortly after he/she completes participation in the study, in 
accordance with ICH Guidelines E6, E2A, and E8. 
10.3 Patient Confidentiality 
All information obtained during the conduct of the study with respect to the patients’ state of 
health will be regarded as confidential. This is detailed in the written information provided to 
the patient. An agreement for disclosure of any such information will be obtained in writing 
and is included in both copies of the VICF signed by the patient. The study data shall not be 
disclosed to a third party without the written consent of the sponsor.   
10.4 Informed Consent 
According to the ICH guideline for GCP (E6), the investigator will obtain and document 
informed consent for each patient screened for this study. All patients will be informed in 
writing of the nature of the protocol and investigational therapy, its possible hazards, and 
their right to withdraw at any time, and will sign a form indicating their consent to participate 
prior to the initiation of study procedures. The patient’s medical record should contain 
written documentation indicating that informed consent was obtained. The VICF must be 
reviewed and approved by the investigator’s designated IRB/IEC and by the sponsor. The 
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VICF should include all the elements as outlined in Section 4.8.10 of the ICH guideline for 
GCP (E6). 
10.5 Institutional Review Board 
This protocol and relevant supporting data are to be submitted to the appropriate IRB/IEC for 
review and approval before the study can be initiated. Amendments to the protocol will also 
be submitted to the IRB/IEC prior to implementation of the change. The sponsor must 
receive a letter documenting the IRB/IEC approval prior to initiation of the study. The PI is 
also responsible for informing the IRB/IEC of the progress of the study and for obtaining 
annual IRB/IEC renewal. The IRB must be informed at the time of completion of the study 
and should be provided with a summary of the results of the study by the PI. The PI must 
notify the IRB/IEC in writing of any SAE or any unexpected AE according to ICH 
guidelines. 
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11 PROTOCOL MANAGEMENT AND ADMINISTRATIVE 
CONSIDERATIONS 
11.1 Study Documentation 
The PI and study staff has the responsibility of maintaining a comprehensive and centralized 
filing system containing all study-related documentation. These files must be available for 
inspection by the sponsor, representatives of the sponsor, the IRB/IEC, and regulatory 
authorities (i.e., FDA or international regulatory authorities) at any time, and should consist 
of the following elements: 
Patient files, containing the completed case report forms (CRFs), supporting source 
documentation from the medical record including laboratory data and the VICF; 
Regulatory files, containing the protocol with all amendments and investigator signature 
pages, copies of all other regulatory documentation, and all correspondence between the site 
and the IRB/IEC and sponsor; and Drug accountability files, including a complete account of 
the receipt and disposition of the study medication (test article). 
Records are to be available for 2 years after marketing application approval, or if the 
application is not approved or never submitted, 2 years after the last shipment and delivery of 
the material and the appropriate competent regulatory authorities are notified. The sponsor 
will provide written notification when it is appropriate for the investigator(s) to discard the 
study-specific documents referenced above. 
11.2 Protocol Interpretation and Compliance 
To ensure accurate interpretation and implementation of the study, the procedures and 
endpoints defined in the protocol will be carefully reviewed by the PI and his or her staff 
prior to the time of study initiation. The sponsor and PI will follow all reasonable means to 
resolve any differences of opinion of matters of eligibility, toxicity and other endpoints.  In 
the event that a resolution cannot be reached then one or both parties may seek to terminate 
the study following the provisions outlined in the Clinical Trials Agreement. 
11.3 Study Monitoring 
The sponsor or a contracted monitor will visit the study center periodically to monitor 
adherence to the protocol, compliance with ICH guidelines, adherence to applicable FDA 
regulations, and the maintenance of adequate and accurate clinical records.  Case report 
forms will be reviewed to ensure that key safety and efficacy data are collected and recorded 
as specified by the protocol. The monitor will be permitted to access patients’ complete 
medical records, laboratory data, and other source documentation as needed to monitor the 
trial appropriately. 
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12 PRINCIPAL INVESTIGATOR SIGNATURE PAGE 
I agree to conduct the study as outlined in the protocol entitled, “An Extension Study of 
APD334-003 in Patients with Moderately to Severely Active Ulcerative Colitis” in 
accordance with the guidelines and all applicable government regulations including Part 54: 
Financial Disclosure by Clinical Investigators. These guidelines and regulations include, but 
are not limited to: 
• Permission to allow the sponsor, or designee, and the FDA or other country specific 
regulatory agencies to inspect study facilities and pertinent records at reasonable times 
and in a reasonable manner that ensures patient confidentiality. If this study is to be 
inspected by a regulatory agency, the sponsor and CRO should be notified as soon as 
possible. 
• Submission of the proposed clinical investigation, including the protocol and the 
consent form, to a duly constituted IRB/IEC for approval, and acquisition of written 
approval for each prior to the use of the study drug. 
• Use of written informed consent that is obtained prior to administration of study drug 
or any non-routine procedures that involve risk, and that contains all the elements of 
consent as specified in the federal regulations and has been previously approved by the 
sponsor and the IRB/IEC. 
• Submission of any proposed change in the protocol to the IRB/IEC using a signed 
formal amendment document approved by the sponsor. Any proposed changes to the 
protocol require that the informed consent also reflect such changes and that the revised 
informed consent be approved as determined by the IRB/IEC.  
• Documentation and explanation of individual protocol deviations. 
• Submission of SAE reports within 24 hours after the investigator’s initial receipt of the 
information. 
• If required by local regulation, submission of reports of SAEs, as outlined in the 
protocol, to the IRB/IEC within 15 calendar days of their disclosure. 
• Submission of timely progress reports to the IRB/IEC and sponsor at appropriate 
intervals on a schedule determined by the IRB/IEC.  
• Maintenance of appropriate records: Federal regulations require an investigator to 
prepare and maintain adequate and accurate case histories designed to record all 
observations and other data (such as study drug accountability) pertinent to the 
investigation on each individual enrolled in the study. These records must be 
maintained by the investigator until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product.  
 
In addition, I agree to provide all the information requested in the CRF in a manner to assure 
legibility and accuracy. To this end, I shall carefully follow the instructions for completing 
CRFs. 
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I also agree that all information provided to me by the sponsor, including protocols, CRFs, 
and verbal and written information, will be kept strictly confidential and confined to the 
clinical personnel involved in conducting the study.  It is recognized that this information 
may be related in confidence to the IRB/IEC.  I also understand that reports of information 
about the study or its progress will not be provided to anyone not involved in the study other 
than to the PI, or in confidence to the IRB/IEC or to the FDA or other legally constituted 
authority. 
 
 
Principal Investigator 
 
 
Date 
 
Printed Name 
 
 
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13 REFERENCE LIST 
1. Brinkmann V, Billich A, Baumruker T, et al. Fingolimod (FTY720): discovery and 
development of an oral drug to treat multiple sclerosis. Nat Rev Drug Discov 2010 
November;9(11):883-97. 
2. Centers for Disease Control and Prevention. Inflammatory bowel disease (IBD). 
http://www.cdc.gov/ibd/.  Accessed January 8, 2015. 
3. Kaser A, Zeissig S, Blumberg RS. Inflammatory Bowel Disease. Annu Rev Immunol. 
2010;28:573-621.  
4. IBD Insights. IBD etiology and pathophysiology: Understanding the process. 
https://www.ibdinsights.com/about/etiology-pathophysiology/. Accessed January 8, 
2015. 
5. Danese S and Fiocchi C. Ulcerative Colitis. N Engl J Med.  2011 Nov;365;18:1713-1725. 
6. Gasparetto M and Guariso G. Highlights in IBD Epidemiology and Its Natural History in 
the Paediatric Age. Gastroenterology Research and Practice, Volume 2013 (2013), 
Article ID 829040, 12 pages. 
7. Crohn’s and Colitis Foundation of America. The Facts about Inflammatory Bowel 
Diseases. November 2014, New York, NY 10017.  
http://www.ccfa.org/assets/pdfs/ibdfactbook.pdf. Accessed January 7, 2015. 
8. Loftus EV, Jr. Clinical epidemiology of inflammatory bowel disease: Incidence, 
prevalence, and environmental influences. Gastroenterology. 2004; 126:1504-17. 
9. Burisch J, Jess T, Martinato M, Lakatos PL; ECCO -EpiCom. The burden of 
inflammatory bowel disease in Europe.  J Crohns Colitis. 2013 May;7(4):322-37. 
10. World IBD Day. http://www.worldibdday.org/index.html. Accessed January 7, 2015. 
11. American Gastroenterological Association. Inflammatory bowel disease emerges as a 
global disease. (2012, January 5). Science Daily. 
www.sciencedaily.com/releases/2012/01/120104135402.htm. Accessed January 7, 2015. 
12. Medscape. Inflammatory Bowel Disease: Practice Essentials.  
http://emedicine.medscape.com/article/179037-overview#aw2aab6b2b4. Accessed 
January 8, 2015.  
13. Kornbluth  A, Sachar D, MACG and The Practice Parameters Committee of the 
American College of Gastroenterology. Ulcerative Colitis Practice Guidelines in Adults: 
American College of Gastroenterology, Practice Parameters Committee. Am J 
Gastroenterol 2010; 105:501–523; doi: 10.1038/ajg.2009.727; published online 12 
January 2010. 
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18. Gergely P, Nuesslein-Hildesheim B, Guerini D et al. The selective sphingosine 1-
phosphate receptor modulator BAF312 redirects lymphocyte distribution and has species-
specific effects on heart rate. Br J Pharmacol 2012 Nov;167(5):1035-1047. 
19. Brossard P, Derendorf H, Xu J et al. Pharmacokinetics and pharmacodynamics of 
ponesimod, a selective S1P(1) receptor modulator, in the first-in-human study. Br J Clin 
Pharmacol 2013 Apr 18. doi:10.1111/bcp.12129. [Epub ahead of print] PubMed PMID: 
23594176. 
20. Kovarik JM, Schmouder R, Barilla D et al. Multiple-dose FTY720: tolerability, 
pharmacokinetics, and lymphocyte responses in healthy subjects. J Clin Pharmacol 2004 
May;44(5):532-537. 
21. http://www.fda.gov/drugs/drugsafety/ucm366529.htm. Accessed 27-April-2015. 
22. Common Terminology Criteria for Adverse Events v4.03 (CTCAE). Publish Date: June 
14, 2010. Accessed October 2010. 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf 
23. Schroeder KW, Tremaine WJ, Ilstrup DM. Coated oral 5-aminosalicylic acid therapy for 
mildly to moderately active ulcerative colitis: a randomized study. N Engl J Med. 
1987;317:1625-1629. 
 
 
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PROTOCOL SIGNATURE PAGE 
Protocol Title: An Extension Study of APD334-003 in Patients with Moderately to Severely 
Active Ulcerative Colitis 
This study will be conducted in accordance with the International Conference on 
Harmonization (ICH) guideline for Good Clinical Practice (GCP) (E6) and applicable Food 
and Drug Administration (FDA) guidelines. 
Protocol Number: 
APD334-005 
Arena Pharmaceuticals, Inc. Signatures: 
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SAP_001.pdf: 
Confidential 
Arena Pharmaceuticals, Inc. 
APD334-005 
An Extension Study of APD334-003 in Patients with Moderately to 
Severely Active Ulcerative Colitis 
Date Last Updated: 27 Nov 2018 
Statistical Analysis Plan 
Version 1.2 
Prepared by: 
PPD 
Granta Park, Great Abington 
Cambridge, CB21 6GQ 
UK 
NCT Number: NCT02536404
This NCT number has been applied to the document for
purposes of posting on Clinicaltrials.gov
Confidential
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Statistical Analysis Plan, Version 1.2 
APD334-005 
 
Date Last Updated: 27NOV2018 
 
  
 
II
TABLE OF CONTENTS 
1. 
INTRODUCTION ........................................................................................................1 
2. 
OBJECTIVES ...............................................................................................................2 
2.1. 
Primary Objective .........................................................................................................2 
2.2. 
Secondary Objective .....................................................................................................2 
2.3. 
Exploratory Objective ...................................................................................................2 
3. 
INVESTIGATIONAL PLAN .......................................................................................3 
3.1. 
Overall Study Design and Plan .....................................................................................3 
3.2. 
Study Endpoints ............................................................................................................3 
3.2.1. 
Primary Endpoint ..........................................................................................................3 
3.2.2. 
Secondary Endpoints ....................................................................................................4 
3.2.3. 
Exploratory Endpoints ..................................................................................................4 
3.3. 
Treatments ....................................................................................................................5 
3.3.1. 
Study Drug ....................................................................................................................5 
3.3.2. 
Placebo ..........................................................................................................................5 
4. 
GENERAL STATISTICAL CONSIDERATIONS ......................................................5 
4.1. 
Time points and Day Ranges ........................................................................................6 
4.2. 
Sample Size ..................................................................................................................9 
4.3. 
Randomization, Stratification, and Blinding ................................................................9 
4.3.1. 
Randomization and Stratification .................................................................................9 
4.3.2. 
Blinding ........................................................................................................................9 
4.4. 
Analysis Populations ..................................................................................................10 
4.4.1. 
Modified Intent-To-Treat Population (MITT) ............................................................10 
4.4.2. 
Completers Population (CP) .......................................................................................10 
4.4.3. 
Safety Population ........................................................................................................10 
5. 
PATIENT DISPOSITION ..........................................................................................10 
5.1. 
Disposition ..................................................................................................................10 
5.2. 
Protocol Deviations ....................................................................................................11 
6. 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS .................................11 
6.1. 
Demographics .............................................................................................................11 
6.2. 
Baseline Disease Characteristics ................................................................................11 
6.3. 
Alcohol, Tobacco and Caffeine Usage .......................................................................12 
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6.4. 
Medical History ..........................................................................................................12 
6.5. 
Inclusion and Exclusion Criteria ................................................................................12 
7.
TREATMENTS AND MEDICATIONS ....................................................................13 
7.1. 
Concomitant Medications ...........................................................................................13 
7.2. 
Study Treatments ........................................................................................................13 
7.2.1. 
Treatment Compliance ................................................................................................13 
7.2.2. 
Extent of Exposure .....................................................................................................14 
8.
EFFICACY ANALYSIS ............................................................................................14 
8.1. 
Efficacy Assessments .................................................................................................14 
8.1.1. 
Flexible Proctosigmoidoscopy ....................................................................................15 
8.1.2. 
Stool Sample ...............................................................................................................15 
8.1.3. 
C-reactive protein (CRP) ............................................................................................15 
8.1.4. 
Electronic Clinical Outcomes Assessments (eCOA) ..................................................15 
 
 
 
 
 
 
8.2. 
Primary Efficacy Analysis ..........................................................................................17 
8.3. 
Secondary Efficacy Analysis ......................................................................................17 
8.4. 
Exploratory Efficacy Analyses ...................................................................................18 
8.5. 
Subgroup Analyses .....................................................................................................19 
8.6. 
Multiplicity .................................................................................................................20 
9.
SAFETY ANALYSIS ................................................................................................20 
9.1. 
Adverse Events ...........................................................................................................20 
9.1.1. 
Overall Summary of Treatment Emergent Adverse Events .......................................22 
9.1.2. 
Treatment Emergent Adverse Events Summary by SOC and PT ..............................22 
9.1.3. 
Relationship of Adverse Events to Study Drug ..........................................................22 
9.1.4. 
Severity of Adverse Events ........................................................................................22 
9.1.5. 
Serious Adverse Events ..............................................................................................23 
9.1.6. 
Adverse Events Leading to Study Discontinuation ....................................................23 
9.2. 
Clinical Laboratory Evaluations .................................................................................23 
9.3. 
Vital Sign Measurements ............................................................................................24 
9.4. 
Physical and Neurological Examination .....................................................................24 
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9.5. 
Safety ECG (12-lead) 
 ............................................................24 
9.6. 
Lymphocyte Count .....................................................................................................25 
9.7. 
Other Safety Data .......................................................................................................25 
11. 
INTERIM ANALYSIS ...............................................................................................26 
12. 
CHANGES IN THE PLANNED ANALYSIS ...........................................................26 
13. 
REFERENCES ...........................................................................................................29 
14. 
APPENDICES ............................................................................................................30 
14.1. 
Schedule of Study Procedures ....................................................................................31 
14.2. 
Listing of Efficacy Parameters and Study Populations Analysed ..............................33 
 
 
 
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LIST OF ABBREVIATIONS 
 
AE 
adverse event 
BMI 
body mass index 
CI 
confidence interval 
CP 
completers population 
CRF 
case report form 
CRO 
contract research organization 
CRP 
c-reactive protein  
CSR 
clinical study report 
ECG 
electrocardiogram 
eCOA 
electronic clinical outcomes assessments 
EOS 
end of study 
EOT 
end of treatment 
HR 
heart rate 
ICF 
informed consent form 
LOCF 
last observation carried forward 
MCS 
mayo clinic score 
MedDRA 
Medical Dictionary for Regulatory Activities 
MITT 
modified intent-to-treat 
OCT 
optical coherence tomography 
PFTs 
pulmonary function tests 
 
 
PI 
principal investigator 
 
 
PML 
progressive multifocal leukoencephalopathy 
PMS 
partial mayo score 
PROs 
patient reported outcomes 
PT 
preferred term 
q.d. 
once daily 
QTc 
QT interval corrected for heart rate 
QTcB 
QTc corrected by Bazett's 
QTcF 
QTc corrected by Fridericia's 
S1P1 
sphingosine 1-phosphate 1 receptor 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SOC 
system organ class 
TEAE 
treatment-emergent adverse event 
WBC 
white blood cell 
WHODRUG 
World Health Organization Drug Dictionary 
 
 
 
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1. 
INTRODUCTION 
This statistical analysis plan (SAP) describes the analyses and data presentations that will be 
applied to data gathered in clinical trial Protocol No. APD334-005 
 in order to 
evaluate the long-term safety, tolerability and efficacy of APD344 in patients with moderately to 
severely active ulcerative colitis who have completed the APD334-003 induction study.  
This SAP is finalized prior to database lock and data analysis start. Section 9 discusses the changes 
from the planned analysis from the protocol, and the major changes in the analysis that are made 
after database lock will be documented in the Clinical Study Report (CSR) with the rationales and 
details.  
Etrasimod (APD334), hereafter referred to as etrasimod, is a new chemical entity in development 
for the treatment of autoimmune diseases 
. Etrasimod is an orally available, selective, 
sphingosine 1-phosphate 1 receptor (S1P1) agonist. The S1P1 receptor is a physiological mediator 
which has been shown to regulate lymphocyte recirculation between lymphoid tissue and blood. 
Binding and internalization of the S1P1 receptor may result in lymphocyte retention within 
lymphoid tissue, with subsequent reduction in peripheral lymphocyte count and lymphocyte 
availability for recruitment to sites of inflammation 
. It is through this mechanism 
that etrasimod may potentially reduce inflammation in inflammatory bowel disease. Lymphocyte 
lowering has been correlated with clinical efficacy for S1P functional antagonists in multiple 
sclerosis, psoriasis, and ulcerative colitis. This same mechanism may also be useful in treating a 
variety of other inflammatory and autoimmune diseases 
. 
Previous pre-clinical and clinical data showed the desired effects and the benefit/risk assessment 
based on data gathered on etrasimod justifies the further clinical development. For additional 
clinical information regarding etrasimod, refer to the latest version of Investigator Brochure 
. 
This is an extension study to APD334-003 induction study to evaluate long-term safety, 
tolerability, and efficacy (i.e., ability to achieve and maintain clinical remission and response after 
34 weeks of additional treatment) of etrasimod. 
The SAP is based on the Protocol Amendment 04 (27 Mar 2017). The key changes from the 
previous versions of the protocols include: 
• Amendment 02 (28 Sep 2015) to Amendment 03 (20 Oct 2016) 
o Changed study duration from 52 weeks to 46 weeks in total 
o Changed study design to single arm, open-label (2 mg once daily [q.d.]) for APD334-
003 responders only and removal of Placebo group 
o Updated secondary 
 outcome measures to reflect study duration of 46 
weeks total (including the APD334-003 study) 
 
 
 
o Changed Week 52 to Week 46 as End-of-Treatment 
o Removed Primary Safety and Secondary Efficacy hypotheses 
o Removed sample size and power calculations 
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o Changed ‘Randomized’ to ‘Enrolled’ and removed treatment groups 
o Removed between group differences and removal of formal statistical analysis  
 
• Amendment 03 (20 Oct 2016) to Amendment 04 (27 Mar 2017) 
o Updated to add proportion of patients who achieve clinical response to secondary 
endpoints 
o Updated to reflect APD334-003 completers to be eligible for APD334-005 study 
More details can be found in Section 12. 
2. 
OBJECTIVES 
2.1. 
Primary Objective 
The primary objective of this study is to evaluate the long-term safety and tolerability of etrasimod 
in patients with ulcerative colitis who have completed the APD334-003 study. 
2.2. 
Secondary Objective 
The secondary objective of this study is to evaluate the effect of etrasimod on achieving and 
maintaining clinical response and/or remission in patients with ulcerative colitis after 46 weeks of 
treatment. 
2.3. 
Exploratory Objective 
To examine the effect of etrasimod treatment in patients with ulcerative colitis on: 
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3. 
INVESTIGATIONAL PLAN 
3.1. 
Overall Study Design and Plan 
APD334-005 is a phase 2, open-label extension study to determine the long-term safety and 
tolerability of etrasimod as well as its ability to achieve and maintain clinical remission and 
response after 34 weeks of additional treatment in patients with ulcerative colitis who have 
completed the APD334-003 induction study.  
Eligible patients must have completed the APD334-003 induction study and must meet the 
eligibility criteria for the APD334-005 at time of entry. All eligible patients will have the option 
to enroll and receive open-label 2 mg q.d. treatment with etrasimod. For this purpose, all patients 
shall be consented for APD334-005 prior to the final procedures being performed for APD334-003 
(as some procedure results will be used for the extension study baseline). 
Selected procedures from the Week 12 visit in study APD334-003 will be carried over to the 
APD334-005 study to be included as baseline information and assist in determining eligibility for 
the APD334-005 study. 
 
 
 
. Following the 
Day 1 visit, there will be regular visits to monitor for safety and perform efficacy assessments 
throughout the treatment period. Final assessments will be conducted at Week 46 from Baseline 
of study APD334-003 (Week 34 of this study), or upon early termination from the study. A 2-week 
follow-up visit will be conducted to ensure appropriate patient safety 
 
  
The total study participation/duration is up to 36 weeks (34 weeks of treatment and a 2-week 
follow-up visit after final visit). The schedule of procedures and visits for the study is provided in 
Appendix 14.1.  
 
Patients who terminate early or discontinue from 
the study will not be replaced. 
Note: Patients that were enrolled under Protocol Amendment 02 (28 Sep 2015) followed a different 
study design (i.e. patients were randomized to Placebo or 2 mg q.d. etrasimod and remained 
blinded, and final assessments were conducted at Week 52 instead of Week 46). More details about 
changes in the study design are covered in Sections 1 and 12.  
3.2. 
Study Endpoints 
3.2.1. 
Primary Endpoint 
The primary endpoint for the study is long-term safety.  The safety of etrasimod will be monitored 
throughout the study with safety endpoints being as follows: 
• 
Treatment-emergent adverse events (TEAEs) up to 30 days following discontinuation of the 
study drug 
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• 
Treatment-emergent serious adverse events (SAEs) up to 30 days following discontinuation 
of the study drug 
3.2.2. 
Secondary Endpoints 
Secondary efficacy endpoints are achievement, durability and maintenance of clinical response 
and/or clinical improvement. They include the following: 
• 
The proportion of patients who achieve clinical response at end of treatment in APD334-
005; the proportion of patients who achieve clinical response at Week 12 in APD334-003 
and maintain clinical response at end of treatment in APD334-005. [definition of clinical 
response: a patient has achieved clinical response if he/she meets criteria of clinical remission 
defined below, or meets criteria of clinical response i.e. a decrease in 3-component Mayo 
Clinic score of ≥ 2 points and at least 30% with either a decrease of rectal bleeding of ≥ 1 or 
rectal bleeding score of 0 or 1] at Week 46 compared to APD334-003 baseline] 
 
• 
The proportion of patients who achieve clinical remission at end of treatment in APD334-
005;  the proportion of patients who achieve clinical remission at Week 12 in APD334-003 
and also maintain clinical remission at end of treatment in APD334-005 [definition of clinical 
remission: individual subscores of the 3-component Mayo Clinic score as follows: an 
endoscopy score (using flexible proctosigmoidoscopy) of 0 or 1 (excluding friability), a 
rectal bleeding score of 0 or 1, and a stool frequency score of 0 or 1 with a decrease of ≥ 
1 point] at Week 46 compared to APD334-003 baseline] 
3.2.3. 
Exploratory Endpoints 
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3.3. 
Treatments   
3.3.1. 
Study Drug 
Arena Pharmaceuticals will provide adequate supplies of etrasimod tablets. Etrasimod 
tablets will be provided as a 2 mg strength. 
3.3.2. 
Placebo 
Not applicable. 
Note: Under Protocol Amendment 02 (28 Sep 2015), patients that were randomized to Placebo 
received 
 tablets 
 that matched the active tablets in size, shape and 
appearance.  
4. 
GENERAL STATISTICAL CONSIDERATIONS 
Continuous data will be summarized using descriptive statistics (i.e., n, mean, median, standard 
deviation (SD), 90% confidence interval (CI) for change or percent change from baseline, 
minimum and maximum). For the summary statistics of all numerical variables unless otherwise 
specified, minimum and maximum will be displayed to the same level of precision as reported.  
Mean, median and 90% CIs will be displayed to one level of precision greater than the data 
collected. Standard deviation will be displayed to two levels of precision greater than the data 
collected. 
For proportion-based measures, n, frequencies, proportion and its 90% CI will be produced. The 
denominator for all percentages will be the number of patients within the treatment group for the 
analysis set of interest, unless otherwise stated. Percentages will be presented to 1 decimal place. 
When count data are presented, the percentage will be suppressed when the count is zero in order 
to draw attention to the non-zero counts. A row denoted “Missing” will be included in count 
tabulations where specified on the shells to account for dropouts and missing values. 
There is no formal between group inferential comparisons for study endpoints due to lack of 
control group. Summary statistics will be provided for the primary safety endpoint, secondary 
efficacy endpoints, exploratory efficacy endpoints, and additional safety measures. All analysis 
summaries will be presented as follows: 
 
Previously Treated in APD334-003 
(APD334-005 treatment: 2 mg etrasimod) 
APD334-005 
treatment: 
APD334-005 
treatment: 
 
Placebo 
1 mg etrasimod 
2 mg etrasimod 
1 mg & 2 mg 
etrasimod 
2 mg etrasimod 
Placebo 
 
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Listings will include a subtitle to indicate both treatments, i.e. treatment received in APD334-003 
study and treatment received in APD334-005 study. 
If endoscopy was performed prior to Week 46, then last observation carried forward (LOCF) 
imputation method will be used for the endoscopy subscore. Any endoscopy performed during the 
APD334-005 extension study (after Week 12 visit) will be used for LOCF imputation.  
All data summaries and statistical analyses will be performed using the SAS software version 9.3 
or higher (SAS Institute, Cary, NC). 
4.1. 
Time points and Day Ranges 
Since it is not always possible for all study participants to come in for their clinic visits on the 
exact day specified in the protocol schedule, the ‘Week’ of a patients visit will be defined by the 
following relative day ranges.  
 
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4.2. 
Sample Size 
Patient enrollment is limited by the number of patients who complete the APD334-003 study. 
Therefore, sample size calculation is not needed. 
4.3. 
Randomization, Stratification, and Blinding 
4.3.1. 
Randomization and Stratification 
Not applicable for this open-label extension study.  
Note: Patients that were enrolled under Protocol Amendment 02 (28 Sep 2015) were randomized 
to Placebo or 2 mg q.d. etrasimod and remained blinded. More details about changes in the study 
design are covered in Sections 1 and 12.  
4.3.2. 
Blinding 
The extension study is an open-label study, however in order to keep the blind of the induction 
study intact, the sponsor, patients, and personnel involved with the conduct of the APD334-005 
study will continue to be blinded to the total white blood cell (WBC) and lymphocyte counts, as 
access to this information may lead to unintentional unblinding of a patient (due to Investigational 
Product’s mechanism of action). A central contract research organization (CRO) physician(s) 
unblinded to the leucocyte count will continue to review and monitor the total WBC and 
lymphocyte counts for safety purposes in the trial. The study site personnel will not receive 
laboratory results for the total WBC or lymphocyte counts. Further details are included in the 
Covance Labs Data Transfer Specifications (COVANCE 2018). 
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4.4. 
Analysis Populations 
The analyses of all proportion-based and all continuous efficacy variables will use the Modified 
Intent-to-Treat (MITT) population as primary. In addition, all endpoints that include the endoscopy 
subscore will use Completers population (CP).  
Analysis populations will be presented in a listing for all enrolled patients.  
4.4.1. 
Modified Intent-To-Treat Population (MITT) 
This MITT population consists of all patients, who received at least 1 dose of etrasimod or Placebo, 
have a baseline measurement, and have a post-enrollment measurement in the extension study for 
the specific efficacy endpoint being assessed. Note that MITT population can vary with endpoints 
since some patients may have the needed data for inclusion in the MITT population for some 
endpoints but not for others. 
4.4.2. 
Completers Population (CP) 
This CP population consists of all patients in the MITT population who completed the extension 
study based on the study completion status collected on the End of Study CRF page. No missing 
data will be imputed for this analysis. Any substantial differences between conclusions based on 
the MITT population and the CP population will be investigated. Note that CP population will be 
used only for endpoints that include the endoscopy subscore, unless otherwise stated. 
4.4.3. 
Safety Population 
The Safety population will include all patients who received study medication in the extension 
study. 
5. 
PATIENT DISPOSITION 
5.1. 
Disposition 
The number of patients enrolled in the study will be tabulated overall and by country as described 
in Section 4. Tables will indicate the number and percentage of patients who were enrolled into 
the study, who completed treatment and/or completed the study and who discontinued treatment 
and/or discontinued study prematurely (early termination) for any of the following reasons: 
• Adverse event(s) (AEs) 
• Patient lost to follow up 
• Patient withdrawal of consent 
• Investigator decision 
• Sponsor decision 
• Death 
• Other 
 
All percentages will be based on the number of enrolled patients within the relevant category. 
Patient disposition data will be presented in a listing. 
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5.2. 
Protocol Deviations 
Protocol deviations will be summarized for the Safety population and will include the number of 
patients with at least one protocol deviation, total number of protocol deviations and summaries 
by subtype category. 
Protocol deviations will be presented in a listing.  
6. 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS 
Since this is an extension study to APD334-003 study, some of the baseline characteristics data 
(i.e. ulcerative colitis history, social history and medical history) for the relevant enrolled patients 
will be taken from the APD334-003 induction study.  
6.1. 
Demographics 
All baseline patient characteristics of demographics data will be presented for the Safety 
population. Demographic characteristics will be collected at Week 12 (APD334-003 study) / Day 
-1 (APD334-005 study). 
The demographic characteristics consist of age (years), sex, race, and ethnicity. A patient’s age in 
years is calculated using the date of the informed consent and date of birth. 
The baseline characteristics consist of baseline height (cm), baseline weight (kg), and baseline 
body mass index (BMI) (kg/m2). Body mass index is calculated as (body weight in kilograms) / 
(height in meters)2. 
Continuous variables (i.e. age, height, weight and BMI) will be summarized using descriptive 
statistics (i.e. number of observations [n], mean, SD, median, minimum and maximum). 
Categorical data will be summarized by the number and percentage (n(%)) of patients within the 
relevant category i.e. age category (18-24; 25-34; 35-44; 45-54; 55-65; and >65), sex (Male, 
Female), race (American Indian or Alaska Native, Asian – Chinese, Asian – Japanese, Asian – 
Other, Black or African American, Native Hawaiian or Other Pacific Islander, White, Other and 
Not allowed per country regulation) and ethnicity (Hispanic or Latino, Not Hispanic or Latino). 
Percentages will be based on the total number of patients in the Safety population. 
Patient demographics and baseline characteristics will be presented in a listing. In addition patient 
weight data will be listed.  
6.2. 
Baseline Disease Characteristics 
Baseline ulcerative colitis disease information will be summarized for the Safety population as 
follows: 
• Duration of ulcerative colitis (years) at APD334-003 screening visit by descriptive 
statistics 
• Disease location (Proctosigmoiditis/Left sided colitis, Pancolitis/ Extensive colitis) at 
APD334-003 screening visit by n (%) 
• History of Colonic Ulcerative Activity on Endoscopy (ulcerative colitis extending ≥ 15 cm 
proximal to the rectum) at APD334-003 screening visit by n (%) 
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• Ulcerative colitis prior 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
Note: Prior ulcerative colitis treatment was collected at APD334-003 screening visit.  
• Disease Activity (Mayo Clinic Scores) at APD334-005 baseline 
• Fecal Calprotectin at APD334-005 baseline 
• CRP at APD334-005 baseline 
 
 
Baseline ulcerative colitis disease information collected at APD334-003 screening visit, including 
hospitalization history, will be listed. 
6.3. 
Alcohol, Tobacco and Caffeine Usage 
Social history collected at APD334-003 screening visit i.e. tobacco, alcohol, caffeine and other 
substances used, will be listed for the Safety population.   
6.4. 
Medical History 
Medical history will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
Version 18.0 or later. The number and percentage of patients with any medical history at APD334-
003 screening visit will be summarized overall and for each system organ class and preferred term. 
Percentages will be calculated based on number of patients in the Safety population. 
Patient medical history data including specific details will be presented in a listing.  
6.5. 
Inclusion and Exclusion Criteria 
Inclusion and exclusion data will be listed only for patients that did not meet inclusion/exclusion 
criteria.  
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7. 
TREATMENTS AND MEDICATIONS 
7.1. 
Concomitant Medications 
Concomitant medications include any medications that are taken when on study treatment in 
APD334-005 study, including medications that started prior and are ongoing during study 
treatment. 
The total number of concomitant medications and the number and percentages of patients with at 
least one concomitant medication will be summarized as described in Section 4. The number and 
percentages of all concomitant medications will be summarized by drug class and preferred term. 
All summaries will be performed using the Safety population. 
Medications will be coded using the World Health Organization Drug Dictionary (WHODRUG, 
Version December 2017). 
All medications will be listed.  
7.2. 
Study Treatments 
Investigational product will be dispensed to eligible patients under the supervision of the 
investigator or his/her designee at the Week 12 visit of the APD334-003 study. 
Patients enrolled under Protocol Amendment 02 (28 Sep 2015) were randomized to Placebo or 2 
mg q.d. etrasimod and were instructed to take their 2 mg etrasimod, or matching Placebo tablet in 
the same way as described in the paragraph above. 
Study treatment administration, drug accountability and dosing details will be listed for the Safety 
population. 
7.2.1. 
Treatment Compliance  
Compliance will be assessed using patient data recorded in the drug accountability form of the 
electronic case report forms (eCRFs). On each day, a patient should take his/her assigned 
treatment.  
The overall study drug compliance (%) will be calculated as follows:  
Compliance (%) = [(actual number of tablets taken over the study period) / (designated total 
number of tablets that should have been taken over the study period)] * 100 
The study period is defined as the number of days that the patient has been in the active treatment 
phase of the APD334-005 study. 
Summary statistics on percentage of treatment compliance as well as the number and percentage 
of patients in each compliance category (<80%, 80-100%, and >100% compliant) will be presented 
as described in Section 4 using the Safety population. 
 
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Treatment compliance data will be listed for each patient. 
7.2.2. 
Extent of Exposure 
Duration of exposure is defined as the total number of days a patient is exposed to any study drug 
in APD334-005 study and will be presented as the sum of all days from the first dose date (Day 1) 
to the last dose date (i.e. date of last dose - the date of first dose + 1) using the dose administration 
page on the CRF. If the last dose date on the dose administration page is missing, or if a patient is 
lost to follow-up, but the drug accountability log confirms that the patient has taken study drug, 
the visit date following the last completed drug accountability log will be used.  
The duration of exposure (in days and in weeks) to study drug will be summarized for all patients 
in the Safety population and will be presented in a table by summary statistics (as described in 
Section 4). The duration of exposure (cumulative) will then be classified into the following 
categories: > 0 days, ≥ 28 days, ≥ 56 days, ≥ 84 days, ≥ 112 days, ≥ 140 days, ≥ 168 days, ≥ 196 
days, ≥ 224 days, ≥ 252 days and ≥ 280 days and will be presented as the number and percentage 
of patients in each duration category. Percentages will be computed from the number of patients 
in the Safety population.  
In addition, the overall exposure will be summarized i.e. from Baseline of APD334-003 study to 
end of APD334-005 study. Duration of overall exposure is defined as the total number of days a 
patient is exposed to any study drug in APD334-003 and APD334-005 study and will be presented 
as the sum of all days from the first dose date (Day 1 of APD334-003 study) to the last dose date 
in the APD334-005 study (i.e. date of last dose - the date of first dose + 1) using the dose 
administration page on the CRF. If the last dose date on the dose administration page is missing, 
or if a patient is lost to follow-up, but the drug accountability log confirms that the patient has 
taken study drug, the visit date following the last completed drug accountability log will be used.  
The duration of overall exposure (in days and in weeks) to study drug will be summarized for all 
patients in the Safety population and will be presented in a table by summary statistics (as 
described in Section 4). The duration of overall exposure (cumulative) will then be classified into 
the following categories: > 0 days, ≥ 28 days, ≥ 56 days, ≥ 84 days, ≥ 112 days, ≥ 140 days, ≥ 168 
days, ≥ 196 days, ≥ 224 days, ≥ 252 days, ≥ 280 days, ≥ 308 days, ≥ 336 days and ≥ 364 days and 
will be presented as the number and percentage of patients in each duration category. Percentages 
will be computed from the number of patients in the Safety population.  
A summary of each patient’s exposure in APD334-005 study will be presented in a listing.  
8. 
EFFICACY ANALYSIS 
Summary statistical analyses will be performed for all efficacy measures.  
There is no between group inferential comparison for study endpoints. 
8.1. 
Efficacy Assessments 
Efficacy assessments will be listed for each patient for the MITT population where relevant. 
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8.1.1. 
Flexible Proctosigmoidoscopy 
A flexible proctosigmoidoscopy, performed with a video endoscope following a cleansing prep 
(oral or rectal cathartic) will be performed at Baseline 
 and 
EOT. A repeat flexible proctosigmoidoscopy may be permitted by the Sponsor when the 
central reader indicates that the video endoscope data was acquired incorrectly, or did not meet the 
minimal required quality standards. 
8.1.2. 
Stool Sample 
A stool sample will be collected at time points listed in the schedule of procedures and visits 
(Section 14.1) for the analysis of fecal calprotectin, 
 
8.1.3. 
C-reactive protein (CRP) 
Blood samples for analysis of CRP will be collected at time points listed in the schedule of 
procedures and visits (Section 14.1). 
8.1.4. 
Electronic Clinical Outcomes Assessments (eCOA) 
Patient reported outcomes (stool frequency and rectal bleeding) will be captured daily using a 
handheld electronic device from CRF Health 
. 
Diary entries will be reviewed by site personnel during scheduled visits and at any unscheduled 
visit(s) due to disease exacerbation. The CRF Health eDiary software runs on the device and 
includes all the security features required of an eCOA solution for 21 CFR Part 11 compliance. 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
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8.2. 
Primary Efficacy Analysis 
There is no primary efficacy endpoint in this study, therefore no primary efficacy analysis is 
performed. 
8.3. 
Secondary Efficacy Analysis 
Secondary efficacy endpoints are listed in Section 3.2.2. 
The secondary efficacy outcome of achievement or maintenance of clinical response will be based 
on the proportion of patients who achieve or maintain clinical response at end of treatment 
compared to APD334-003 baseline using the MITT and CP populations. Summary statistics i.e. 
total number of patients (N), frequencies (n), proportion (%) and its 90% CI for patients that 
achieved or maintained clinical response (responders) at end of treatment in APD334-005 will be 
produced as described in Section 4.  
 
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Similar summary statistical analyses will be produced for the second secondary efficacy outcome 
i.e. clinical remission at Week 46 compared to APD334-003 baseline. 
Each secondary efficacy endpoint will be summarized, within the same presentation, by the 
following: 
• Proportion of patients that achieved clinical response/clinical remission at Week 12 in 
APD334-003 
• Proportion of patients that achieved clinical response/clinical remission at end of treatment 
in APD334-005  
• Proportion of patients that achieved clinical response/clinical remission at both Week 12 
in APD334-003 and end of treatment in APD334-005  
8.4. 
Exploratory Efficacy Analyses 
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8.6. 
Multiplicity 
Multiplicity is not applicable for this study. 
9. 
SAFETY ANALYSIS 
The safety of etrasimod will be monitored throughout the study with safety endpoints being as 
follows: 
• Treatment-emergent adverse events (TEAEs) up to 30 days following discontinuation of 
the study drug 
• Treatment-emergent serious adverse events (SAEs) up to 30 days following 
discontinuation of the study drug 
Additional safety assessments will include: 
• Physical & neurological examinations including ophthalmoscopy (and optical coherence 
tomography [OCT], where available) 
• Progressive multifocal leukoencephalopathy (PML) checklist 
• Clinical laboratory tests to include hematology, serum chemistry, coagulation, and 
urinalysis 
• Vital sign measurements 
• Pulmonary Function Tests (PFTs) 
• ECGs 
• AE reporting 
For analyses based on laboratory measurements, vital signs and ECGs, summary tabulations (n, 
mean, SD, median, minimum and maximum for actual and change [or percent change] from 
baseline) will be presented. For analyses based on AEs, frequency and percentage will be 
presented.  The analyses for all safety outcomes (categorical or continuous measures) will use the 
Safety population. 
For analysis based on laboratory measurements, at least 1 laboratory test post-enrollment 
measurement in the extension study is required for inclusion in the Safety population. When 
assessing change from baseline, a baseline measurement is also required. Baseline for the safety 
analysis is defined as the last pre-enrollment measurement (i.e. APD334-005 Day 1 pre-dose). No 
missing data will be imputed for the safety analysis. 
9.1. 
Adverse Events 
A TEAE is defined as an AE that meets any of the following conditions: 
• begins on or after the first dose of study drug in APD334-005 study 
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• begins before the first dose of study drug in APD334-005 study and worsens in severity on or 
after the first dose of study drug in APD334-005 study 
• occurs in APD334-003 study and is ongoing in APD334-005 study 
• occurs in APD334-003 study and end date is in APD334-005 study 
• is completely missing an onset date and end date 
• is completely missing an onset date and the end date is on or after the first dose of study drug 
in APD334-005 study 
For the purpose of inclusion in TEAE tables, incomplete AE onset and end dates will be imputed 
as follows: 
Missing onset dates (where UK and UKN indicate unknown or missing day and month 
respectively):  
• UK-MMM-YYYY: If the month and year are different from the month and year of the first 
dose of study drug, assume 01-MMM-YYYY. If the month and year are the same as the 
first dose of study drug month and year, and the end date (after any imputation) is on or 
after the first dose of study drug, then assume the date of the first dose of study drug. If the 
month and year are the same as the first dose of study drug month, and year and the end 
date (after any imputation) is prior to the first dose of study drug, then assume the end date 
for the onset date 
• DD-UKN-YYYY/UK-UKN-YYYY: If the year is different from the year of first dose of 
study drug, assume 01-JAN-YYYY of the collected year. If the year is the same as the first 
dose of study drug year, and the end date (after any imputation) is on or after the first dose 
of study drug, then assume the date of the first dose of study drug. If the year is the same 
as the first dose of study drug, and the end date (after any imputation) is prior to the first 
dose of study drug, then assume the end date for the onset date  
Missing end dates (where UK and UKN indicate unknown or missing day and month respectively):  
• UK-MMM-YYYY: Assume the last day of the month 
• DD-UKN-YYYY/UK-UKN-YYYY: Assume 31-DEC-YYYY 
All AEs will be classified by System Organ Class (SOC) and Preferred Term (PT) according to 
the Medical Dictionary for Regulatory Activities (MedDRA, version 20.1). 
Patients with at least one TEAE will be summarized for the following: 
• Overall summary of TEAEs  
• Summary of TEAEs by SOC and PT 
• Summary of TEAEs by Relationship to Study Drug 
• Summary of TEAEs by Severity 
• Serious TEAEs by SOC and PT 
• TEAEs that leading to permanent discontinuation of study drug by SOC and PT 
• TEAEs with severity grade ≥ 3 by SOC and PT 
 
Patients will be monitored from Informed Consent Form (ICF) signature to 30 days after the last 
dose of study drug for adverse reactions to the study drug and/or procedures. 
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9.1.1. 
Overall Summary of Treatment Emergent Adverse Events 
An overall summary of TEAEs will be presented in a table and will include the number and 
percentage of patients with any TEAE, number of TEAEs, patients with serious TEAEs, TEAEs 
leading to death and patients that discontinued from study treatment and/or study due to TEAEs. 
In addition, the table will include number and percentage of patients in each category of severity 
(i.e. Grade 1 to Grade 5) for all TEAEs and for related TEAEs, and number and percentage of 
patients in each category of relationship to study drug (i.e. “Related” and “Not Related”). 
9.1.2. 
Treatment Emergent Adverse Events Summary by SOC and PT 
Summaries of the total number of TEAEs and the number and percentage of patients with at least 
one TEAE will be provided. TEAEs will be presented by SOC and PT. At each level of patient 
summarization, a patient is counted once if the patient reported one or more events. Percentages 
will be calculated out of the number of patients in the Safety population.  
The summary of TEAEs will be presented in descending order from the SOC with the highest total 
incidence (that is, summed across all treatment groups) to the SOC with the lowest total incidence. 
If the total incidence for any two or more SOCs is equal, the SOCs will be presented in alphabetical 
order. Within each SOC, the PTs will be presented in alphabetical order.  
All TEAEs will be presented in a listing. 
9.1.3. 
Relationship of Adverse Events to Study Drug 
A summary of total number of TEAEs and number and percentage of patients with at least one 
TEAE by relationship (i.e. “Related” and “Not Related”) to study drug will be presented in a table 
by incidence of occurrence.  
The investigator will provide an assessment of the relationship of the event to the study drug. The 
possible relationships are “Not Related” or “Related”. In the TEAE relationship table, if a patient 
reports multiple occurrences of the same TEAE, only the most closely related occurrence will be 
presented. Percentages will be calculated out of the number of patients in the Safety population. 
The TEAE data will be categorized and presented by SOC, PT, and relationship. 
9.1.4. 
Severity of Adverse Events 
A summary of total number of TEAEs and number and percentage of patients with at least one 
TEAE by severity will be presented in a table.  
The severity that will be presented represents the most extreme severity captured on the CRF page. 
The possible severities are Grade 1 to Grade 5 i.e. “Mild” “Moderate”, “Severe”, “Life-
threatening” and “Death related”, respectively. In the TEAE severity table, if a patient reported 
multiple occurrences of the same TEAE, only the most severe will be presented. Percentages will 
be calculated out of the number of patients in the Safety population. 
The TEAE data will be categorized and presented by SOC, PT, and severity. 
In addition, a similar table will be produced for TEAEs that have severity of Grade ≥ 3. 
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9.1.5. 
Serious Adverse Events 
The seriousness of an AE should be assessed by the Investigator independently from the severity 
of the AE. A SAE is defined as any untoward medical occurrence that at any dose results in death, 
is life-threatening, is a congenital anomaly/birth defect, requires in-patient hospitalization or 
prolongation, or results in significant disability/incapacity. 
Important medical events that may not result in death, be life-threatening, or require hospitalization 
may be considered SAEs when, based upon medical judgment, they may jeopardize the patient 
and may require medical or surgical intervention to prevent one of the outcomes listed above. 
Summaries of the total number of SAEs and the number and percentage of patients with at least 
one SAE will be provided. SAEs will be presented by SOC and PT. At each level of patient 
summarization, a patient is counted once if the patient reported one or more events. Percentages 
will be calculated out of the number of patient in the Safety population.  
The summary of SAEs will be presented in descending order from the SOC with the highest total 
incidence (that is, summed across all treatment groups) to the SOC with the lowest total incidence. 
If the total incidence for any two or more SOCs is equal, the SOCs will be presented in alphabetical 
order. Within each SOC, the PTs will be presented in alphabetical order.  
All SAEs will be presented in a listing by patient using the Safety population. If there are no SAEs 
at the end of the study, the tables or listings will state that there are no SAEs in the study. 
9.1.6. 
Adverse Events Leading to Study Discontinuation 
A summary of total number of TEAEs and number and percentage of patients with at least one 
TEAE that caused permanent discontinuation of study medication (i.e. study medication 
discontinued and/or withdrawal from study) will be presented. TEAEs will be presented by SOC 
and PT. At each level of patient summarization, a patient is counted once if the patient reported 
one or more events. Percentages will be calculated out of the number of patients in the Safety 
population within the subgroup category.  
The summary of TEAEs that caused permanent discontinuation of study medication will also be 
presented in descending order of frequency from the SOC with the highest total incidence (that is, 
summed across all treatment groups) to the SOC with the lowest total incidence. If the total 
incidence for any two or more SOCs is equal, the SOCs will be presented in alphabetical order.  
Within each SOC, the PTs will be presented in alphabetical order. 
9.2. 
Clinical Laboratory Evaluations 
Clinical laboratory evaluations (i.e. hematology, serum chemistry, coagulation and urinalysis) will 
be performed by a central laboratory. All summaries will be based on the units provided by the 
central laboratory, no conversion will be performed. 
Summary tabulations (i.e. n, mean, SD, median, minimum and maximum) for the observed values 
and changes from baseline will be presented for clinical laboratory evaluations with numeric 
values for patients in the Safety population. Observed results at each visit and changes from 
baselines (APD334-003 baseline and APD334-005 baseline) to each scheduled post-baseline visit 
will be presented. 
 
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All relevant clinical laboratory tests will be classified as Low, Normal, and High according to the 
normal ranges. This categorical data will be summarized in shift tables comparing the results at 
last scheduled post-baseline visit with those at the baseline visit. Baseline for APD334-003 study 
is defined as last measurement before first dose of study medication in APD334-003 study, and 
baseline for APD334-005 study is defined as last pre-enrollment measurement (APD334-005 
Day 1 pre-dose). 
If any laboratory value falls above or below the upper or lower level of quantification, the value 
of the upper or lower level of quantification will be taken (e.g. <0.2 will become 0.2) for summaries 
but left as recorded in the listing. 
All individual lab values will be listed by visit. 
9.3. 
Vital Sign Measurements 
Supine (laying face upward) blood pressure, heart rate/pulse, temperature, and respiratory rate will 
be measured after the patient has been resting for 5 minutes. Vitals signs will be measured prior to 
any blood draw that occurs at the same time point. Vital signs will be measured according to the 
time points in the schedules of procedures and visits (Section 14.1). 
Summary tabulations (i.e. n, mean, SD, median, minimum and maximum) for the observed values 
and changes from baseline will be presented for vital sign data for patients in the Safety population. 
Changes from baselines (APD334-003 baseline and APD334-005 baseline) to each scheduled 
post-baseline time point and visit will be presented. Baseline for APD334-003 study is defined as 
last measurement before first dose of study medication in APD334-003 study, and baseline for 
APD334-005 study is defined as last pre-enrollment measurement (APD334-005 Day 1 pre-dose). 
All vital sign data by patient will be presented in a listing. 
9.4. 
Physical and Neurological Examination 
Physical and neurological examinations will be listed. 
9.5. 
Safety ECG (12-lead) 
 
Safety ECGs will be recorded from an ECG machine (12-lead). All safety ECGs will be obtained 
as single tracings, with the exception of the pre-treatment ECG obtained on Day 1, which is a 
triplicate recording. 
All patients will have a standard 12-lead ECG performed during the study as clinically indicated. 
Intervals to be provided for each ECG are: RR, PR, QRS, QT, QT interval corrected for heart rate 
(QTc), QTc corrected by Bazett's (QTcB), and QTc corrected by Fridericia's (QTcF).   
 
 
 
 
 
 
 
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9.6. 
Lymphocyte Count 
Summary tabulations (i.e. n, mean, SD, median, minimum and maximum) for the absolute 
lymphocyte counts, absolute changes from baselines 
 
, and percentage changes from baselines at each visit 
 will be presented for patients 
. 
 
 
 
 
 
 
  
 
9.7. 
Other Safety Data 
Other safety data will be listed and includes: 
• PML Checklist 
• Ophthalmoscopy with OCT 
• PFT 
• Pregnancy test details (only females who are not diagnosed as postmenopausal) 
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11. 
INTERIM ANALYSIS 
No interim analyses is planned for this study. 
12. 
CHANGES IN THE PLANNED ANALYSIS 
Under Protocol Amendment 02 (28 Sep 2015) eligible responders on active treatment in the 
APD334-003 study (who choose to continue on to the APD334-005 study) underwent 1:1 
randomization to 2 mg etrasimod q.d. or matching Placebo, while eligible Placebo responders in 
the APD334-003 study (who choose to continue on to the APD334-005 study) remained on 
Placebo. Responder patients stayed blinded. Non-responders in the APD334-003 study (who 
choose to continue on to the APD334-005 study) were administered with open-label 2 mg 
etrasimod. Under Protocol Amendment 03 (20 Oct 2016) eligible patients (who choose to continue 
on to the APD334-005 study) must have completed the APD334-003 study and were administered 
open-label 2 mg etrasimod. Data gathered on patients before Protocol Amendment 03 will follow 
the Protocol Amendment 03 analyses and data presentation as described in this SAP document. 
Patients that received 2mg etrasimod under any Protocol Amendment will be pooled into a 2 mg 
etrasimod group and patients that received placebo prior to Protocol Amendment 03 will be 
included in a second group. All listings will be presented by these two treatment groups, namely 
2 mg etrasimod and Placebo, and by treatment previously received in APD334-003 study.  
The following exploratory objectives have been added to the SAP in comparison with Protocol 
Amendment 04 (27 Mar 2017) to be consistent with the objectives in the APD334-003 study: 
The following exploratory endpoints have been added to the SAP in comparison with Protocol 
Amendment 04 (27 Mar 2017) to be consistent with the endpoints in the APD334-003 study: 
The following exploratory endpoints have been removed from the SAP in comparison with 
Protocol Amendment 04 (27 Mar 2017), as these are no longer needed: 
The following subgroup analysis has been added to the SAP in comparison with Protocol 
Amendment 04 (27 Mar 2017): 
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The following subgroup analyses have been removed from the SAP in comparison with Protocol 
Amendment 04 (27 Mar 2017), as these have been already evaluated in APD334-003 study and 
are no longer needed: 
 
 
 
 
 
 
 
 
 
 
 
 
 
The 95% CIs have been changed to 90% CIs for all analyses in comparison with Protocol 
Amendment 04 (27 Mar 2017) to be consistent with the APD334-003 study. 
 
The clinical remission definition has been updated to include “a rectal bleeding score of 0 or 1” in 
comparison with Protocol Amendment 04 (27 Mar 2017) to be consistent with the definition in 
final SAP of APD334-003 study.  
 
The clinical response definition has been updated as “a patient has achieved clinical response if 
he/she meets criteria of clinical remission, or meet criteria of clinical response defined in the 
protocol.” to be consistent with the definition in final SAP of APD334-003 study.  
 
The following changes have been applied to the Analysis Populations to the SAP in comparison 
with Protocol Amendment 04 (27 Mar 2017): 
• ITT population has been removed – no longer needed as APD334-005 is an open label 
study  
• Definition of CP population has been updated to include “This CP population consists of 
all patients in the MITT population who completed the extension study” and “Note that CP 
population will be used only for endpoints that include the endoscopy subscore, unless 
otherwise stated.” – to be consistent with the definition in final SAP of APD334-003 study 
• CP population will be used only for endpoints that include the endoscopy subscore: 
 
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Sponsor was notified that laboratory tests for five patients 
 had been sent to local 
labs for the purpose of safety follow up on blood cell counts after last treatment.  Such follow up 
may still be needed at time of database lock. The local laboratory results will be translated in 
English and archived in study file. Sponsor will write a section in CSR to describe the findings 
and to assess the safety issues for these 
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13.
REFERENCES
. Investigator's brochure: Etrasimod (APD334) (Edition 06). San Diego, CA: Arena 
Pharmaceuticals, Inc.; October 25, 2018. On file at Arena. 
COVANCE. Covance laboratory data transfer specifications. Covance;2018. On file at Arena. 
 An extension study of APD334-003 in patients with moderately to severely active 
ulcerative colitis. San Diego, CA: Arena Pharmaceuticals, Inc.; March 27, 2017. Clinical 
Study Protocol APD334-005. On file at Arena. 
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14. 
APPENDICES 
 
 
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14.1. 
Schedule of Study Procedures 
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14.2. 
Listing of Efficacy Parameters and Study Populations Analysed 
Efficacy Parameters 
Response Analysed 
Study Populations 
Analysed 
Secondary Endpoints  
Clinical Response  
Proportion 
MITT, CP 
Clinical Remission 
Proportion 
MITT, CP 
Exploratory Endpoints 
 
 
 
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This is a representation of an electronic record that was signed electronically, and this 
page is the manifestation of the electronic signature. 
 
UserName: 
 
Title:  
, Biostatistics 
Date: Tuesday, 27 November 2018, 02:20 PM   Pacific Daylight Time 
Meaning: Author Approval 
================================================
UserName: 
 
Title:  
, Biostatistics & Data Management 
Date: Tuesday, 27 November 2018, 02:23 PM   Pacific Daylight Time 
Meaning: Approval 
================================================
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