Extension Study of APD334-003 in Patients With Moderately to Severely Active Ulcerative Colitis
Phase: PHASE2
Conditions: Ulcerative Colitis
Sponsor: Arena Pharmaceuticals



APD334 
 
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Clinical Trial Protocol: APD334-005 Amendment 04 
 
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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 
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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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