Clinical trial NCT02447302
Conditions: Ulcerative Colitis
Sponsor: Arena Pharmaceuticals
Start date: 2015-10-15; Completion date: 2018-02-14
Enrollment: 156 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to determine whether etrasimod is a safe and effective treatment for ulcerative colitis.

Detailed description:

Arms: arm 1: Oral, low dose, daily for 12 Weeks arm 2: Oral, high dose, daily for 12 weeks arm 3: Oral, placebo, daily for 12 weeks.
Interventions: intervention 1: Etrasimod intervention 2: Placebo
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_000.pdf: 
APD334 
Arena Pharmaceuticals, Inc. 
Clinical Trial Protocol: APD334-003 Amendment 06 
27 March 2017 
Clinical Trial Protocol: APD334-003 
Study Title: 
A Phase 2, Randomized, Double-Blind, Placebo-Controlled, 
Parallel Group, Multi-Center Study to Investigate the Safety and 
Efficacy of APD334 in Patients with Moderately to Severely 
Active Ulcerative Colitis 
Study Number: 
APD334-003 
Study Phase: 
2 
Product Name: 
APD334 
IND Number: 
125,154 
EudraCT Number: 
2015-001942‐28 
Indication: 
Ulcerative Colitis 
Investigators: 
Multicenter 
Sponsor: 
Arena Pharmaceuticals, Inc. 
6154 Nancy Ridge Drive 
San Diego, California  92121 
Date 
Original Protocol: 
08 April 2015 
Amendment 01: 
01 May 2015 
Amendment 02: 
17 June 2015 
Amendment 03: 
30 June 2015 
Amendment 04: 
21 September 2015 
Amendment 05: 
10 October 2016 
Amendment 06: 
27 March 2017 
Confidentiality Statement 
This document contains confidential information of Arena Pharmaceuticals, Inc.  Unauthorized 
distribution, copying, or disclosure is strictly prohibited unless required by applicable law.  Persons 
receiving this information must be notified that it is confidential and may not be further disclosed.  
NCT Number: NCT02447302
This NCT number has been applied to the document for 
purposes of posting on clinicaltrials.gov


APD334 
 
Arena Pharmaceuticals, Inc. 
Clinical Trial Protocol: APD334-003 Amendment 06 
 
27 March 2017 
Confidential 
Page 2 of 101 
PROTOCOL AMENDMENT SUMMARY 
The following is a list of major changes made to the APD334-003 Protocol Amendment 05 
dated 10 October 2016. Minor clarifications and corrections have been made throughout for 
consistency. These changes are incorporated in Protocol Amendment 06 dated 27 March 
2017. 
Section(s) Amended 
Description of Changes Made 
Header/Footer, Title Page, and 
TOC 
Added “Amendment 06”, updated date to reflect finalization 
of amended protocol, updated pagination and TOC.  
Protocol Amendment Summary 
Updated table to include summary of changes to the protocol. 
Synopsis 
Updated sponsor contact details 
Synopsis 
Changed Primary Objective “The primary objective will be to 
determine the effect of treatment with APD334 in inducing 
clinical remission at 12 weeks” to: 
 
Current “The primary objective of this proof-of-concept study 
is to determine the effect of treatment with APD334 in 
improving 3-component Mayo Clinic Score (score ranging 
from 0 to 9, including stool frequency, rectal bleeding and 
findings on endoscopy) at Week 12” 
Synopsis 
Added the following Secondary Objectives:  
• 
To determine the effect of treatment with APD334 on a 
combination of clinical remission and clinical response 
reflected by a composite endpoint at 12 weeks 
• 
To determine the effect of treatment with APD334 in 
inducing clinical remission at 12 weeks 
 
Synopsis 
Added the following Exploratory Objectives:  
 
• 
to determine the effect of APD334 treatment on Total 
Mayo Clinic Score at 12 weeks. 


APD334 
 
Arena Pharmaceuticals, Inc. 
Clinical Trial Protocol: APD334-003 Amendment 06 
 
27 March 2017 
 
 
 
Confidential 
Page 3 of 101 
Synopsis 
Study Design: 
Changed the study description: “phase 2, dose-ranging, 
placebo-controlled clinical study” to: 
 
Current “phase 2, proof-of-concept and dose-ranging, 
placebo-controlled clinical study” 
 
Changed patients with the option to enroll in an extension 
study APD334-005: “responder patients” to: 
Current “all patients” 
Synopsis 
Changed Primary Efficacy Endpoints “The proportion of 
patients achieving 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 from baseline subscore at 
Week 12” to: 
 
Current “ 
• 
The improvement of 3-component Mayo Clinic Score 
(score ranging from 0 to 9, including stool frequency, rectal 
bleeding and findings on endoscopy) at Week 12.” 
Synopsis 
Added the following Secondary Efficacy Endpoints:  
 
• 
The trichotomous composite endpoint of clinical remission 
and clinical response (score ranging 0 to 2: score 2 for 
achieving both clinical remission and clinical response; 1 for 
achieving only clinical response, and 0 for achieving neither) 
at Week 12 
• 
The proportion of patients achieving 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 from baseline subscore at Week 12 
Synopsis 
Added the following Exploratory Objectives:  
 
• 
Improvement in Total Mayo Clinic Score (score ranging 
from 0 to 12, including stool frequency, rectal bleeding and 
findings on endoscopy, and physician’s global assessment) at 
Week 12 


APD334 
 
Arena Pharmaceuticals, Inc. 
Clinical Trial Protocol: APD334-003 Amendment 06 
 
27 March 2017 
Confidential 
Page 4 of 101 
Synopsis 
Data Analysis section updated to reflect new primary, 
secondary and exploratory Endpoints. 
Study Definition 
Added “Trichotomous composite endpoint” definition 
2. Study Objectives 
Updated Primary and Secondary Objectives according to 
changes highlighted in the Synopsis.  
3.1 Overall Study Design and 
Plan 
Study Design: 
Changed the study description: “phase 2, dose-ranging, 
placebo-controlled clinical study” to: 
Current “phase 2, proof-of-concept and dose-ranging, 
placebo-controlled clinical study” 
 
Changed patients with the option to enroll in an extension 
study APD334-005: “responder patients” to: 
Current “all patients (responders and non-responders)” 


APD334 
 
Arena Pharmaceuticals, Inc. 
Clinical Trial Protocol: APD334-003 Amendment 06 
 
27 March 2017 
Confidential 
Page 5 of 101 
4.2 Inclusion Criteria 
4.3 Exclusion Criteria 
6.12.1 Permitted Medications for 
the Treatment of UC 
Changed “for the 4 weeks immediately prior to screening” to: 
 
Current “for the 4 weeks immediately prior to screening 
endoscopy assessment” 
6.15 Study and Site 
Discontinuation 
Added section 6.15 to provide reasons to terminate the study 
or replace a site. 
9 Planned Statistical Methods 
Added specifications related to the intention of Section 9. 
9.1.1 Hypotheses and Objectives 
Primary, Secondary and Exploratory Objectives and 
Hypothesis were updated to reflect the updated Primary, 
Secondary and Exploratory Endpoints. 


APD334 
 
Arena Pharmaceuticals, Inc. 
Clinical Trial Protocol: APD334-003 Amendment 06 
 
27 March 2017 
 
 
 
Confidential 
Page 6 of 101 
9.5 Efficacy Endpoints 
Primary, Secondary and Exploratory Efficacy Endpoints were 
updated reflecting the changes highlighted in the Synopsis 
amendment summary section. 
9.6.1 Primary, Secondary and 
Exploratory Efficacy Analysis 
Primary, Secondary and Exploratory Efficacy Analysis were 
updated reflecting the changes highlighted in the Primary, 
Secondary and Exploratory Endpoints section. 
9.6.3 Multiplicity 
Updated to reflect the new Primary, Secondary and 
Exploratory Endpoints. 
 
Removal of Figure 1 – Statistical testing procedure in the UC 
Trial 
9.6.4 Interim Analysis 
Changed “No interim analyses are planned for this study”, to: 
 
Current “Sponsor may plan an unblinded interim analysis at 
time when sufficient number of patients have finished 12 
weeks of treatment. If Sponsor decides to perform an interim 
analysis, it will be operated by an independent Data Review 
Committee (DMC).  The revision of statistical analysis plan 
(SAP) with detailed interim analysis specifications and a DMC 
charter will be provided to regulatory agency in timely manner 
and will be finalized prior to the interim analysis.” 


APD334 
 
Arena Pharmaceuticals, Inc. 
Clinical Trial Protocol: APD334-003 Amendment 06 
 
27 March 2017 
Confidential 
Page 7 of 101 
TABLE OF CONTENTS 
PROTOCOL AMENDMENT SUMMARY ..............................................................................2 
TABLE OF CONTENTS ...........................................................................................................7 
SYNOPSIS ...............................................................................................................................12 
LIST OF ABBREVIATIONS ..................................................................................................20 
STUDY DEFINITIONS ..........................................................................................................23 
1 
INTRODUCTION ...........................................................................................................25 
1.1 
Background Information ........................................................................................26 
1.1.1 
Rationale for Proposed Clinical Study .........................................................26 
1.1.2 
Summary of Preclinical Data .......................................................................26 
1.1.3 
Summary of Clinical Data ...........................................................................27 
1.2 
Ethics and Regulatory Considerations ...................................................................29 
2 
STUDY OBJECTIVES ....................................................................................................31 
2.1 
Primary Objective ..................................................................................................31 
2.2 
Secondary Objectives.............................................................................................31 
3 
INVESTIGATIONAL PLAN ..........................................................................................32 
3.1 
Overall Study Design and Plan ..............................................................................32 
3.2 
Study Duration and Dates ......................................................................................32 
4 
STUDY POPULATION SELECTION ...........................................................................36 
4.1 
Study Population ....................................................................................................36 
4.2 
Inclusion Criteria ...................................................................................................36 
4.3 
Exclusion Criteria ..................................................................................................39 
5 
STUDY TREATMENT(S) ..............................................................................................42 
5.4 
Test Article Accountability ....................................................................................42 
5.5 
Investigational Product Retention at Study Site ....................................................42 
5.6 
Dosage and Administration....................................................................................42 
5.7 
Method of Assigning Patients to Treatment Groups..............................................43 
5.8 
Randomization and Blinding .................................................................................43 
5.8.1 
Randomization .............................................................................................43 
5.8.2 
Blinding........................................................................................................43 
5.8.3 
Maintenance of Randomization Codes and Code-break Procedures ...........44 
5.9 
Study Restrictions ..................................................................................................44 
5.9.1 
Fluid and Food Intake ..................................................................................44 


APD334 
 
Arena Pharmaceuticals, Inc. 
Clinical Trial Protocol: APD334-003 Amendment 06 
 
27 March 2017 
Confidential 
Page 8 of 101 
5.10 
Data Safety Monitoring Board ...............................................................................45 
6 
STUDY PROCEDURES .................................................................................................46 
6.1 
Informed Consent...................................................................................................46 
6.2 
Medical and Social History ....................................................................................46 
6.2.1 
Prior Therapies .............................................................................................46 
6.2.2 
History of UC ...............................................................................................46 
6.3 
Physical and Neurological Examinations ..............................................................46 
6.3.1 
Physical Examination...................................................................................46 
6.3.2 
Neurological Examination ...........................................................................47 
6.4 
Vital Signs ..............................................................................................................47 
6.6 
Tuberculosis Screening and Chest X- ray ..............................................................49 
 
 
6.8 
Clinical Laboratory Tests .......................................................................................50 
6.8.1 
Laboratory Parameters .................................................................................50 
6.8.2 
Virology .......................................................................................................50 
6.8.3 
Drugs of Abuse Screen ................................................................................51 
6.8.4 
Urinalysis .....................................................................................................51 
 
 
6.8.6 
Sample Collection, Storage, and Shipping ..................................................51 
6.8.7 
Blood Volume ..............................................................................................51 
6.9 
Efficacy Assessments.............................................................................................51 
6.9.1 
Flexible Proctosigmoidoscopy .....................................................................51 
 
 
6.9.3 
Stool Sample ................................................................................................52 
 
 
 
 
6.9.6 
Electronic Clinical Outcomes Assessments (eCOA) ...................................52 
6.9.7 
Complete Mayo Clinic Score, 3-component Mayo Clinic Score, and 
 .........................................................................................53 
6.10 
and Hematologic Assessments ...................................................54 
 
 
6.10.2 
Hematologic Sampling.................................................................................54 


APD334 
 
Arena Pharmaceuticals, Inc. 
Clinical Trial Protocol: APD334-003 Amendment 06 
 
27 March 2017 
Confidential 
Page 9 of 101 
6.10.3 
Total Blood Volume ....................................................................................55 
6.11 
Adverse Events Assessments .................................................................................55 
6.11.1 
Adverse Event Reporting .............................................................................55 
6.11.1.1 
Progressive Multifocal Leukoencephalopathy (PML) Checklist .......56 
6.11.2 
Serious Adverse Events and Expedited Reporting of Adverse Events ........57 
6.11.2.1 
Patient and Patient-partner Pregnancy ...............................................58 
6.11.3 
Assessment of Adverse Event Severity .......................................................58 
6.11.4 
Assessment of Adverse Event Relationship to Study Medication ...............59 
6.11.5 
Assessment of Adverse Event Outcome ......................................................59 
6.11.6 
Action Taken for Adverse Event .................................................................59 
6.11.7 
Action Taken for Study Drug ......................................................................60 
6.11.8 
Collection of Extra Laboratory Samples/Investigations ..............................60 
6.11.9 
Follow-up of Adverse Events Present at Last Scheduled Study Visit .........60 
6.12 
Concomitant Medications and Procedures.............................................................60 
6.12.1 
Permitted Medications for the Treatment of UC .........................................61 
6.12.2 
Excluded Medications ..................................................................................61 
6.13 
Removal of Patients from the Trial or Study Drug ................................................61 
6.13.1 
Handling of Withdrawals .............................................................................62 
6.13.2 
Replacements ...............................................................................................62 
6.14 
Allowable Visit and Procedure Windows ..............................................................62 
6.15 
Study and Site Discontinuation ..............................................................................63 
7 
STUDY ACTIVITIES .....................................................................................................64 
 
 ............................................................................64 
7.2 
Screening Failures ..................................................................................................65 
7.2.1 
Re-screening ................................................................................................65 
7.3 
 Holter Fitting and Monitoring ....................................................................66 
7.4 
Treatment Period ....................................................................................................66 
 
 ............................................................................66 
7.4.2 
At-home Holter Removal .............................................................................67 
 
 ..................................................................67 
 
 ..........................................67 
 
68 
8 
DATA MANAGEMENT.................................................................................................69 
8.1 
Data Collection ......................................................................................................69 
8.2 
Data Coding ...........................................................................................................69 
8.2.1 
Adverse Events ............................................................................................69 
8.2.2 
Concomitant Medications and Non-drug Treatments ..................................69 


APD334 
 
Arena Pharmaceuticals, Inc. 
Clinical Trial Protocol: APD334-003 Amendment 06 
 
27 March 2017 
Confidential 
Page 10 of 101 
8.2.3 
Medical History ...........................................................................................69 
9 
PLANNED STATISTICAL METHODS ........................................................................70 
9.1 
Hypotheses and Objectives ....................................................................................70 
9.1.1 
Objectives ....................................................................................................70 
9.1.1.1 
Primary Objective ..............................................................................70 
9.1.1.2 
Secondary Objective(s) ......................................................................70 
9.1.1.3 
Safety Objective .................................................................................70 
9.1.1.4 
Exploratory Objective(s) ....................................................................70 
9.1.2 
Hypotheses ...................................................................................................71 
9.1.2.1 
Primary Hypothesis ............................................................................71 
9.1.2.2 
Secondary Hypotheses .......................................................................72 
9.2 
Sample Size and Power Calculations .....................................................................72 
9.3 
Analysis Populations ..............................................................................................72 
9.4 
Demographics and Baseline Characteristics ..........................................................73 
9.5 
Efficacy Endpoints .................................................................................................73 
9.6 
Statistical Methods .................................................................................................74 
9.6.1 
Primary Efficacy Analysis ...........................................................................74 
9.6.1.1 
Secondary and Exploratory Efficacy Analyses..................................75 
9.6.2 
Subgroup Analyses ......................................................................................76 
9.6.3 
Multiplicity ..................................................................................................77 
9.6.4 
Interim Analysis ...........................................................................................78 
9.6.5 
Data Safety Monitoring Board .....................................................................78 
 
 
9.8 
Safety Analysis ......................................................................................................78 
9.8.1 
Adverse Events ............................................................................................79 
9.8.2 
Physical Examinations .................................................................................79 
9.8.3 
Concomitant Medication ..............................................................................79 
9.8.4 
Vital Signs ....................................................................................................79 
9.8.5 
Clinical Laboratory Values ..........................................................................80 
 
 
10 REGULATORY REQUIREMENTS...............................................................................81 
10.1 
Pre-Study Documentation ......................................................................................81 
10.2 
Investigator Obligations .........................................................................................81 
10.3 
Patient Confidentiality ...........................................................................................81 
10.4 
Informed Consent...................................................................................................81 
10.5 
Institutional Review Board ....................................................................................82 
11 PROTOCOL MANAGEMENT AND ADMINISTRATIVE CONSIDERATIONS ......83 


APD334 
 
Arena Pharmaceuticals, Inc. 
Clinical Trial Protocol: APD334-003 Amendment 06 
 
27 March 2017 
 
 
 
Confidential 
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11.1 
Study Documentation.............................................................................................83 
11.2 
Protocol Interpretation and Compliance ................................................................83 
11.3 
Study Monitoring ...................................................................................................83 
12 PRINCIPAL INVESTIGATOR SIGNATURE PAGE ...................................................84 
13 REFERENCES ................................................................................................................86 
PROTOCOL SIGNATURE PAGE .........................................................................................89 
LIST OF IN-TEXT TABLES 
 
 
Table 2. 
Examples of eDiary Subscore Entries for Study Eligibility and 
Corresponding Subscore Derivation ...............................................................53 
 
LIST OF APPENDICES 
Appendix 1 Progressive Multifocal Leukoencephalopathy (PML) Checklist ...................90 
 
Appendix 3 Mayo Clinic Score – SAMPLE ....................................................................101 
 


APD334 
 
Arena Pharmaceuticals, Inc. 
Clinical Trial Protocol: APD334-003 Amendment 06 
 
27 March 2017 
 
 
 
Confidential 
Page 12 of 101 
SYNOPSIS 
Name of Drug: 
APD334 
Indication: 
Ulcerative Colitis 
Sponsor: 
Arena Pharmaceuticals, Inc. 
6154 Nancy Ridge Drive 
San Diego, California 92121 
Name of Sponsor 
Contact: 
 
 
Arena Pharmaceuticals, Inc 
6154 Nancy Ridge Drive 
San Diego, California 92121 
Phone 
 
 
 
Name of Principal 
Investigator(s): 
Multi-center 
Medical Monitor: 
 
 
Arena Pharmaceuticals, Inc. 
Phone: 
 
Mobile: 
 
 
Test Product, Dose 
and Mode of 
Administration: 
• 1 mg APD334 once daily (q.d.) for 12 weeks  
• 2 mg APD334 once daily (q.d.) for 12 weeks  
• Placebo once daily (q.d.) x 12 weeks 
 
The route and mode of administration of APD334 and placebo 
capsules will be oral with an adequate amount of water (240 
mL). 
Concurrent 
Control: 
Placebo; microcrystalline cellulose in hard gelatin capsules 
Objectives: 
Primary Objective: 
The primary objective of this proof-of-concept study is to 
determine the effect of treatment with APD334 in improving 3-
component Mayo Clinic Score (score ranging from 0 to 9, 
including stool frequency, rectal bleeding and findings on 
endoscopy) at Week 12 
 


APD334 
 
Arena Pharmaceuticals, Inc. 
Clinical Trial Protocol: APD334-003 Amendment 06 
 
27 March 2017 
 
 
 
Confidential 
Page 13 of 101 
Secondary Objectives: 
The secondary objectives of this study are: 
• To determine the effect of treatment with APD334 on a 
combination of clinical remission and clinical response 
reflected by a composite endpoint at 12 weeks 
• To determine the effect of treatment with APD334 in 
inducing clinical remission at 12 weeks 
• To determine the effect of treatment with APD334 in 
inducing clinical response at 12 weeks 
• To determine the effect of treatment with APD334 on 
endoscopic improvement at 12 weeks 
 
Safety Objective: 
The safety objective of this study is to determine the safety 
profile and tolerability of APD334 induction treatment. 
 
 
Exploratory Objectives: 
The exploratory objectives of the study are: 
• to determine the effect of APD334 treatment on Total 
Mayo Clinic Score at 12 weeks. 


APD334 
 
Arena Pharmaceuticals, Inc. 
Clinical Trial Protocol: APD334-003 Amendment 06 
 
27 March 2017 
 
 
 
Confidential 
Page 14 of 101 
Study Design: 
This phase 2, proof-of-concept and dose-ranging, placebo-
controlled clinical study will test 2 doses of APD334 or placebo 
in up to 240 patients with moderately to severely active 
ulcerative colitis. 
 
 will be 
randomized into a double-blind, placebo-controlled study, 
receiving one of 2 doses of APD334 or matching placebo for 12 
weeks.  
Treatment arms will consist of once daily (q.d.) doses of 1 mg 
APD334, 2 mg APD334, or matching placebo. Patients will be 
randomized in a 1:1:1 ratio and will be stratified by presence or 
absence of current oral corticosteroid usage and previous 
exposure to TNFα antagonists.  
Entry criteria will be based on confirmation of moderately to 
severely active UC, as defined by a 3-component Mayo Clinic 
 
 
 


APD334 
 
Arena Pharmaceuticals, Inc. 
Clinical Trial Protocol: APD334-003 Amendment 06 
 
27 March 2017 
 
 
 
Confidential 
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At the end of the study all patients will have the option to enroll 
in an extension of the study (APD334-005) following 
completion of all study procedures and providing they meet all 
inclusion criteria for the extension study.  
Patients who do not participate in the extension study (APD334-
005) will have a 2-week follow-up visit after the last clinical 
visit.  
Study Site(s): 
This study will be conducted in approximately 100 clinical 
centers worldwide. 
Patient Population:  
 
 
 
 
 
  
Duration per 
Patient: 
~18 weeks: ~28 days of screening, followed by a 12-week 
induction period. Patients who do not participate in the 
APD334-005 extension study will have a 2-week follow-up visit 
after the last clinical visit. 
Clinic visits will occur during the screening period (to be 
completed up to ~28 days before first dose of study medication) 
and approximately every 2-4 weeks during the study. Additional 
visits may occur at the discretion of the investigator. 
Patient 
Assignment: 
Eligible patients will be randomized in a 1:1:1 ratio to receive 
once daily (q.d.) doses of 1 mg APD334, 2 mg APD334, or 
matching placebo. 
Sample Size:  
Up to 240 patients total. 
Efficacy Endpoints 
Primary: 
• The improvement of 3-component Mayo Clinic Score 
(score ranging from 0 to 9, including stool frequency, 
rectal bleeding and findings on endoscopy) at Week 12.  
 
Secondary: 
• The trichotomous composite endpoint of clinical 
remission and clinical response (score ranging 0 to 2: 
score 2 for achieving both clinical remission and clinical 
response; 1 for achieving only clinical response, and 0 
for achieving neither) at Week 12 


APD334 
 
Arena Pharmaceuticals, Inc. 
Clinical Trial Protocol: APD334-003 Amendment 06 
 
27 March 2017 
 
 
 
Confidential 
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• The proportion of patients achieving 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 from baseline subscore at 
Week 12 
• The proportion of patients who achieve clinical response 
[defined as a decrease in the 3-component Mayo Clinic 
score of ≥ 2 points and a decrease of ≥ 30% with either a 
decrease of rectal bleeding of ≥ 1 or rectal bleeding score 
of 0 or 1] at Week 12 
• The proportion of patients who achieve endoscopic 
improvement [defined as Mayo endoscopic subscore 
(using findings of flexible proctosigmoidoscopy) of ≤ 1 
point] at Week 12 
 
Exploratory: 
• Improvement in Total Mayo Clinic Score (score ranging 
from 0 to 12, including stool frequency, rectal bleeding 
and findings on endoscopy, and physician’s global 
assessment) at Week 12 


APD334 
 
Arena Pharmaceuticals, Inc. 
Clinical Trial Protocol: APD334-003 Amendment 06 
 
27 March 2017 
 
 
 
Confidential 
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Safety 
Assessments: 
• Physical examinations including ophthalmoscopy (and 
optical coherence tomography [OCT], where available) 
• Clinical laboratory tests to include hematology, serum 
chemistry, coagulation, and urinalysis 
• Vital sign measurements 
• Pulmonary Function Tests (PFTs)  
• 12-lead electrocardiograms (ECGs) 
• Adverse event reporting 
 
 
 
 
  


APD334 
 
Arena Pharmaceuticals, Inc. 
Clinical Trial Protocol: APD334-003 Amendment 06 
 
27 March 2017 
 
 
 
Confidential 
Page 18 of 101 
 
 
Data Analyses: 
The primary analysis will be based on the change of 3-
component Mayo Clinic Score at Week 12 from baseline using 
an analysis of covariate (ANCOVA) model with terms for 
treatment, current oral corticosteroid use, prior exposure to 
TNFα antagonists and baseline value as covariate.  Least-
squares mean (LSM) by treatment group and its 95% confidence 
interval (CI), and least-squares mean difference between 
treatment group and its 95% CI will be reported. 
The secondary analyses include following: 
• Trichotomous composite endpoint of clinical remission 
and clinical response at Week 12 is an ordinal 
categorical endpoint with 3 categories (2, 1, 0).  It will 
be analyzed using Cochran-Mantel-Haenszel method 
adjusted for the stratification factors of presence or 
absence of current oral corticosteroid therapy at baseline 
and previous exposure to TNFα antagonists.  The testing 
statistic will be computed using modified ridit score for 
between-treatment comparison.  
• The proportion of patients who achieve clinical 
remission, clinical response, or endoscopic improvement 
will be analyzed individually using Cochran-Mantel-
Haenszel (CMH) test adjusted for the stratification 
factors of presence or absence of current oral 
corticosteroid therapy at baseline and previous exposure 
to TNFα antagonists, to compare the difference of 
proportions between treatment group. The CMH 
stratified risk difference and its 95% confidence interval 
will be provided 
Mayo Clinic Score data handling: for each visit during the study 
(excluding the screening/baseline visit which uses 10 prior 
days), stool frequency and rectal bleeding subscores will be 
derived from electronic patient diaries completed over the 7 
days prior to a study visit. Note that the day prior, day of and 
day after proctosigmoidoscopy will not be used for patient diary 
entry because of the required bowel prep for the procedure. 
These subscores will be calculated using the following rules: 
 


APD334 
 
Arena Pharmaceuticals, Inc. 
Clinical Trial Protocol: APD334-003 Amendment 06 
 
27 March 2017 
 
 
 
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1. The scores from the 3 most recent days prior to the 
actual day of the study visit will be averaged and 
rounded to the nearest integer. 
2. If patient diary entries from 3 days are not available, the 
scores from the 2 most recent entries will be averaged 
and rounded to the nearest integer. 
3. If less than 2 days of diary data are available, the 
subscore will be considered missing. 
All patients who prematurely discontinue for any reason will be 
considered failures (non-responders) for all the proportion based 
endpoints. 
Exploratory efficacy analyses: 
Dose response analyses will be performed using ANCOVA 
model for continuous variables, or logistic regression model for 
categorical variables, as appropriate.  Treatment group and 
appropriate baseline covariates will be included in the analysis 
model.  Statistical testing of dose response trend will be based 
on appropriate contrast statement assuming monotonic dose 
response profile in placebo, APD334 low dose and APD334 
high dose.  
A statistical testing procedure will be constructed to manage 
multiplicity issues concerning primary and secondary efficacy 
analyses in order to control overall Type I error rate for efficacy 
testing not exceeding 0.05. The details of testing procedure will 
be specified in a separate Statistical Analysis Plan. 
For the comparison of the proportion of patients who achieve 
clinical remission between APD334 versus placebo, a sample of 
~80 patients per group will provide 80% power to detect a 
difference of 18% (from 10% to 28%) at α=5% (2-sided test). 
This calculation is based upon an assumed placebo rate of 10%. 
Safety information after administration of multiple doses of 
APD334 in patients with moderately to severely active 
ulcerative colitis will be evaluated by tabulating adverse 
experiences and clinical assessment of clinical laboratory data. 
Date: 
27 March 2017 


APD334 
 
Arena Pharmaceuticals, Inc. 
Clinical Trial Protocol: APD334-003 Amendment 06 
 
27 March 2017 
 
 
 
Confidential 
Page 20 of 101 
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 


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hCG 
human chorionic gonadotropin 
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 
 
 
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 


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PT 
prothrombin time  
PTT 
partial thromboplastin time 
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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STUDY DEFINITIONS 
Term 
Definition 
Mayo Clinic score (Complete 
Mayo or MCS) 
Instrument designed to measure disease activity of 
ulcerative colitis consisting of 4 subscores: stool 
frequency, rectal bleeding, findings of flexible 
proctosigmoidoscopy, and physician global assessment 
with each component ranging from 0 to 3 (0=normal, 
1=mild, 2=moderate, 3=severe). Total score therefore 
ranges from 0 to 12, with a higher score indicating more 
severe disease. 
3-component Mayo Clinic 
score 
Consists of 3 of the 4 subscores found in the complete 
Mayo Clinic score as follows: stool frequency, rectal 
bleeding, findings of flexible proctosigmoidoscopy. Total 
score range: 0 to 9, each component ranging from 0 to 3 
(0=normal, 1=mild, 2=moderate, 3=severe). 
Physician’s global 
assessment 
The physician’s global assessment acknowledges the three 
other criteria findings of the Mayo Clinic score; the 
patient’s daily record of abdominal discomfort and general 
sense of well-being, and other observations, such as 
physical findings and the patient’s performance. Total 
score range: 0 to 3 (0=normal, 1=mild, 2=moderate, 
3=severe). 
Clinical Response 
Decrease in the 3-component Mayo Clinic score of ≥ 2 
points and a decrease of ≥ 30% with either a decrease of 
rectal bleeding of ≥ 1 or rectal bleeding score of 0 or 1 at 
Week 12.  
Clinical Remission 
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 from baseline at Week 12. 
Trichotomous composite 
endpoint 
An ordinal categorical endpoint with 3 scores: score 2 for 
achieving both clinical remission and clinical response, 1 
for achieving only clinical response, 0 for achieving 
neither. 


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Term 
Definition 
Endoscopic Improvement 
Mayo endoscopic subscore (using findings of flexible 
proctosigmoidoscopy) of ≤ 1 point at Week 12. 
Intolerable AE 
Adverse event leading to study drug discontinuation. 


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1 
INTRODUCTION 
APD334 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.  S1P1 receptor surface expression is required for S1P gradient-mediated 
lymphocyte migration out of lymphoid tissue into the circulation.1  
APD334 is being developed to treat autoimmune diseases. Initial investigations will focus on 
Inflammatory Bowel Disease (IBD), which is a broad term that describes conditions with 
chronic or recurring immune response and inflammation of the gastrointestinal tract.2 There 
are two major types of IBD: Crohn’s disease (CD) and ulcerative colitis (UC). These are 
chronic remittent or progressive inflammatory conditions that may affect the entire 
gastrointestinal tract (CD) and the colonic mucosa (UC), and are associated with an increased 
risk for colon cancer.11  Collectively, patients with IBD suffer from a multitude of GI 
symptoms, including diarrhea, rectal bleeding and abdominal pain.  
The causes of these IBDs are not completely understood, but 3 characteristics define their 
etiology: (1) genetic predisposition; (2) an altered, dysregulated immune response; and (3) an 
altered response to gut microorganisms.2 The triggering event for the activation of the 
immune response in IBD has yet to be identified, but possible factors related to this event 
include a pathogenic organism (as yet unidentified) or an inappropriate response to a 
normally innocuous microbial or other antigen (perhaps due to failure to downgrade the 
inflammatory response, and/or to repeated exposure to such antigen from an alteration in 
barrier function).2  Once the inflammation has been triggered, it may be difficult for the IBD 
patient’s immune system to turn off the response.3 
The number of patients diagnosed with IBD has dramatically increased worldwide over the 
past 50 years.5 In 2014, The Crohn’s and Colitis Foundation of American estimated that 
approximately 1.6 million people are affected by IBD in the United States (US) alone6, with 
as many as 70,000 new cases diagnosed in the US each year7. In Europe, an estimated 2.5 – 3 
million people are affected by IBD8 and as many as 5 million may be affected worldwide9.  
Universally, incidence rates for both Crohn's disease and ulcerative colitis were highest 
among individuals between 20 and 40 years old. Thus, IBD affects individuals in the most 
healthy and productive years of life, resulting in long-term cost to the patient, health-care 
system and society.10 
Treatment for patients with IBD is generally for symptomatic care (relief of symptoms) and 
mucosal healing and includes 5 major classes of medications: aminosalicylates (5-ASA), 
antibiotics, corticosteroids, immunomodulators, and biologic therapies. These drugs are 
generally prescribed in a “step-up” approach, with escalation of the medical regimen until a 
response is achieved14.   


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 Lymphocyte trafficking agents such as 
natalizumab and vedolizumab, both injectable or infused therapies, have demonstrated proof-
of-concept in IBD indications.  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 in a symmetrical, circumferential, 
and uninterrupted pattern to involve parts or all of the large intestine.12 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.12 
The S1P1 receptor signaling on lymphocytes allows their exit from lymph nodes along a S1P 
gradient. Functional antagonism of these S1P1 receptors results in retention of lymphocytes 
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 different inflammatory and autoimmune diseases. 
This study is designed to test the safety and efficacy of APD334 as a means to reduce the 
inflammation in the GI tract and induce a clinical response or remission in patients with 
severely to moderately active ulcerative colitis. 
1.1.2 
Summary of Preclinical Data 


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1.1.3 
Summary of Clinical Data 


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1.2 
Ethics and Regulatory Considerations   
The study will be conducted in compliance with the International Conference on 
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 proof-of-concept study will be to determine the effect of 
treatment with APD334 in improving 3-component Mayo Clinic score (score ranging from 0 
to 9, including stool frequency, rectal bleeding and findings on endoscopy) at 12 weeks. 
2.2 
Secondary Objectives  
The secondary objectives of the study are: 
• To determine the effect of treatment with APD334 on a combination of clinical 
remission and clinical response reflected by a composite endpoint at 12 weeks 
• To determine the effect of treatment with APD334 in inducing clinical remission at 
12 weeks 
• To determine the effect of treatment with APD334 in inducing clinical response at 12 
weeks 
• To determine the effect of treatment with APD334 on endoscopic improvement at 12 
weeks 
 
This amendment clarifies that the primary endpoint is being changed to a 3-component Mayo 
Clinic Score (stool frequency, rectal bleeding, and findings on endoscopy) derived from the 
Total Mayo Clinic Score. Thus, the primary endpoint is a continuous variable ranging from 0 
to 9. The rationale for this change is that the endpoint should be more sensitive to detecting 
clinically important differences between two doses of APD334 and placebo compared to a 
dichotomous complete remission endpoint. Because the trial is considered a proof-of-concept 
trial and dose ranging study, the primary endpoint will reflect a broad examination of 
potential clinical improvement across three domains (stool frequency, rectal bleeding, and 
and findings on endoscopy). The secondary endpoints reflect clinical endpoints that are well 
recognized in the clinical community (complete remission, clinical response, and endoscopic 
score) and a combination of both clinical remission and clinical response reflected by a 
trichotmous endpoint. 


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3 
INVESTIGATIONAL PLAN 
3.1 
Overall Study Design and Plan 
APD334-003 is a phase 2, proof-of-concept and dose ranging clinical study designed to test 
the ability of APD334 to induce clinical response and/or remission in patients with 
moderately to severely active ulcerative colitis. Up to 240 eligible patients will be 
randomized into a double-blind, placebo-controlled study to receive once daily (q.d.) doses 
of APD334 (1 mg or 2 mg) or matching placebo in a 1:1:1 ratio for 12 weeks. The screening 
period for the study is up to ~28 days which includes several assessments that must be 
completed within 10 days prior to randomization to ensure eligibility for the study. Patient’s 
vital signs will be monitored using a Holter monitor for up to 24 hours pre-dose through 24 
hours post dose. Patients will report daily stool frequency and rectal bleeding using an 
electronic device throughout the study and will be scheduled at regular intervals for safety, 
, and efficacy assessments. A 34-week extension study (APD334-005) is offered to all 
patients (responders and non-responders) who complete the study and will meet the relevant 
eligibility criteria. Patients who do not participate in the extension study or who have 
discontinued prematurely from the study will have a 2-week follow-up visit after the last 
clinical visit. 
3.2 
Study Duration and Dates 
The total study participation/duration is approximately 18 weeks; ~4 weeks for screening 
procedures, followed by 12 weeks of dosing, and a possible follow-up visit at Week 14.   
The schedule of procedures and visits for the study is provided in 
 


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4 
STUDY POPULATION SELECTION 
4.1 
Study Population 
Adult men and women, ages 18-80 years, who have moderately to severely active ulcerative 
colitis 
 
 
Eligible patients must meet all entry criteria prior to being randomized to receive study 
medication as outlined below. Any patient-specific concerns or questions regarding these 
criteria must be discussed with the medical monitor or Arena Pharmaceuticals, Inc. prior to 
the patient being randomized. 
4.2 
Inclusion Criteria 
Each patient must meet the following inclusion criteria to be enrolled in the study: 
 
6. Moderately to severely active ulcerative colitis defined as a 3-component Mayo Clinic 
 


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7. Evidence of colonic ulcerative colitis activity on endoscopy 
 
 


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4.3 
Exclusion Criteria 
Patients meeting any of the following exclusion criteria are not to be enrolled in the study: 
 
4. Within 30 days prior to randomization, receipt of any of the following for the treatment 
of underlying disease: 
a. Non-biologic therapies (e.g., cyclosporine, tacrolimus, tofacitinib, thalidomide) other 
than those specifically listed in Section 6.12.1. 
b. A non-biologic investigational therapy 
c. An approved non-biologic therapy in an investigational protocol 
 
5. Within 60 days prior to randomization, receipt of any of the following: 
a. Infliximab, adalimumab, golimumab, certolizumab, vedolizumab 
b. Any other investigational or approved biologic agent 
6. Any prior exposure to natalizumab, efalizumab, or rituximab 


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5 
STUDY TREATMENT(S) 
5.4 
Test Article Accountability 
The investigator will maintain accurate records of the receipt of all study medication. In 
addition, accurate records will be kept regarding when and how much study medication is 
dispensed and used by each patient in the study. Reasons for deviation from the expected 
dispensing regimen must also be recorded. Study medication will be reconciled by the Arena 
monitor or contracted designee. The investigator agrees to provide sufficient access to study 
medication as required for the reconciliation process to be completed in a timely fashion. 
5.5 
Investigational Product Retention at Study Site 
At completion of the study, all study medication will be reconciled by the Arena monitor or 
contracted designee and then returned at the direction of the Arena to be retained or 
destroyed according to applicable country regulations. Prior to any action being taken with 
study medication after the study is completed, the investigator will contact Arena (or 
contracted CRO) for approval of such action. 
5.6 
Dosage and Administration 
Investigational product will be dispensed in a double-blind fashion to the patients under the 
supervision of the investigator or his/her designee as determined by the randomization 
schedule. All enrolled patients will receive 1 oral dose per day of 1 mg APD334, 2 mg 


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APD334, or matching placebo for 12 weeks. 
 
 
 
 
On days with scheduled study visits, patients should not take their dose of study medication 
at home in order to complete pre-dose study procedures.  
 
 
5.7 
Method of Assigning Patients to Treatment Groups 
After signing the voluntary informed consent form (VICF) and completing all screening 
procedures, eligible patients will be randomly assigned in a 1:1:1 ratio to receive 1 of 3 study 
treatments:  
• 1 mg APD334 x 12 weeks 
• 2 mg APD334 x 12 weeks 
• Placebo x 12 weeks 
 
5.8 
Randomization and Blinding 
5.8.1 
Randomization 
Sites will randomize approximately 240 patients for entry into the study in a 1:1:1 ratio to 
receive once daily doses of 1 mg APD334, 2 mg APD334, or matching placebo and will be 
stratified by presence or absence of current oral corticosteroid usage and previous exposure 
to TNFα antagonists. The number of patients with previous exposure to TNFα antagonists 
will be capped at 50% (or at most 120 with previous exposure to TNFα antagonists will be 
randomized). 
5.8.2 
Blinding 
The sponsor, patients, and personnel involved with the conduct of the study, with the 
exception of the clinical supply staff, safety staff, and the unblinded statistician supporting 
the Data Safety Monitoring Board (DSMB), will be blinded to the identity of study 
medication.  
In addition, the sponsor, patients, and personnel involved with the conduct of the study will 
also be blinded to the total WBC and 
, as access to this information may 


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lead to unintentional unblinding of a patient (due to Investigational Product’s mechanism of 
action). A central CRO physician(s) unblinded to the 
 and leucocyte counts, but 
blinded to the study medication, will review and monitor the total WBC and 
 
counts for safety purposes in the trial. The study site personnel will not receive laboratory 
results for the total WBC or 
. 
5.8.3 
Maintenance of Randomization Codes and Code-break Procedures 
The randomization code will be generated by a CRO statistician not directly involved with 
the study. All other personnel directly related to this study (i.e., investigators, site personnel, 
monitors, CRO personnel, Arena personnel) with the exception the individuals stipulated in 
Section 5.8.2, will remain blinded for the duration of the study. After APD334-003 has been 
completed, the study will be unblinded to selected individuals (which may or may not 
include: CRO statistician, Sponsor designate[s], DMPK representative[s]) in order to conduct 
the analyses and reporting for the study.  As these activities will occur while APD334-005 is 
ongoing, patients, investigators and site will remain blinded to patient-level data of the 
APD334-003 study until the completion of APD334-005.  The CRO will obtain written 
consent from Arena prior to breaking the code. 
Breaking of the randomization code without Arena’s permission is expressly forbidden 
except in the event of a medical emergency where the identity of the study medication must 
be known in order to properly treat the patient. In the event of a medical emergency, it is 
requested that the investigator make every effort to contact the study monitor or designee 
prior to breaking the code. If the blind is broken, the individual responsible should document 
the date, time, and reason for breaking the blind. A written communication should be sent to 
Arena within 1 working day. 
5.9 
Study Restrictions 
5.9.1 
Fluid and Food Intake 
Consumption of foods and beverages containing the substances listed below will be 
prohibited as indicated. Exceptions may be permitted upon the joint agreement of the Arena 
and the investigator provided the safety of the patient and integrity of the study are not 
compromised. 
• Poppy seeds: Consumption of poppy seeds within 48 hours prior to drug screen 
may cause a positive drug screen. Patients who report that they have consumed 
poppy seeds within 48 hours of the screening visit should not be screened.  They 
may return 48 hours after the last poppy seed consumption for screening.  Poppy 
seeds should not be eaten between screening and Week 0/Day 1 and throughout 
the inpatient period. 


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5.10 Data Safety Monitoring Board 
The Data Safety Monitoring Board (DSMB), independent from Arena, will be established to 
review safety data from this study including, but not limited to, AEs of special interest (e.g., 
bradycardia, infections, PML) at regular intervals and make recommendations. The roles and 
responsibilities of the DSMB will be outlined in a separate charter. 


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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 screening, a complete medical history and a social history, including tobacco, alcohol and 
caffeine use, as well as a full history of UC, will be collected by patient interview. 
Concomitant medications, recent blood donations, illnesses, and participation in other 
investigational drug studies will also be recorded. A partial examination will be performed at 
check-in to update findings from screening and document any pre-treatment AEs. 
6.2.1 
Prior Therapies 
Prior therapies related to UC will be collected during screening. 
6.2.2 
History of UC 
A detailed history of UC, including date of diagnosis, disease severity, hospitalizations, and 
extraintestinal manifestations will be collected during screening. 
6.3 
Physical and Neurological Examinations 
6.3.1 
Physical Examination 
The physical examination include assessments of general appearance, skin, head (eyes, ears, 
nose, and throat), neck, thyroid, lungs, heart, abdomen, back, lymph nodes, and extremities, 
and body weight will be performed during
by the principal 
investigator or subinvestigator. A limited examination to assess clinically significant changes 
from the examination performed at screening will be completed during the
visit. Height will only be obtained at screening. 
The physical examination will also include visual acuity and dilated ophthalmoscopy (by an 
ophthalmologist) and with OCT (where available) at screening and 
visit to rule 
out and monitor for any significant retinal disease, including macular edema. Retinal photos 
will be taken during the screening visit
visit and any subsequent unscheduled 
ophthalmoscopy.  


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Safety ECGs will also be performed as outlined in the schedule of procedures and visits 
(
).  
Clinically significant findings from the physical/neurological examination performed at 
screening will be recorded as medical history. Any new clinically significant findings from 
the time of screening through the first dose of study drug will be recorded as pre-treatment 
AEs. After the administration of the first dose of study drug, clinically significant findings 
will be recorded as AEs. 
6.3.2 
Neurological Examination 
The neurological examination includes assessments of the neurological system (cranial 
nerves, motor and sensory function, coordination, and mental status), and will be performed 
during screening, 
 (limited examination to assess clinically significant changes 
from the screening), and at 
 by the principal investigator or subinvestigator. In 
addition, monitoring for progressive multifocal leukoencephalopathy (PML), a potential 
adverse effect of S1P1 agonists, will be performed at each site visit (except for the 
 
) using a subjective PML checklist.  
The investigator or subinvestigator will administer the subjective PML checklist during 
screening to exclude patients with positive responses from enrolling into the study. The 
subjective PML checklist will also be administered at each site visit (except Day
 to probe 
for symptoms suggestive of PML. Any patients reporting signs and/or symptoms of PML 
will undergo objective testing and may be referred to a neurologist for a full evaluation.  
Additional information on PML is provided in Section 6.11.1.1 and a copy of the PML 
checklist is provided in Appendix 1. 
6.4 
Vital Signs 
Supine (laying face upward) blood pressure, heart rate, temperature, and respiratory rate will 
be measured after the patient has been resting for 5 minutes. Vitals signs will be measured 
prior to any blood draw that occurs at the same time point. Vital signs will be measured 
according to the time points in the schedule of procedures and visits (
).  


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6.6 
Tuberculosis Screening and Chest X- ray 
All patients will complete tuberculosis (TB) screening to determine eligibility. All patients 
who do not report a history of TB must complete a diagnostic TB test within 
 prior to 
randomization and a chest X-ray within 
 prior to randomization. (In most countries 
where the BCG vaccine is standard, the TB skin test will likely be positive and a Quantiferon 
test will be needed.) Patients will be excluded from the study if they have active or latent TB, 
regardless of treatment history, as evidenced by any of the following: 
• History of TB (that has not been acceptably treated)  
• A positive diagnostic TB test within 1 month of randomization defined as: 
- 
A positive QuantiFERON® test or 2 successive indeterminate QuantiFERON® 
tests OR 
- 
A tuberculin skin test reaction ≥ 10 mm ( ≥ 5 mm in patients receiving the 
equivalent of > 15 mg/day prednisone) 
• Chest X-ray within 12 months of randomization in which active or latent pulmonary 
TB cannot be excluded 


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6.8 
Clinical Laboratory Tests 
All details regarding clinical laboratory sample collection, preparation, and shipment are 
included in the laboratory manual provided by the local or central laboratory and the 
 
manual provided by Arena. 
In the event of abnormal clinical laboratory values, the physician will make a judgment 
whether or not the abnormality is clinically significant and is deemed an adverse event.   
6.8.1 
Laboratory Parameters 
Clinical safety laboratory tests will be conducted as outlined in 
 and should be 
completed pre-dose. Laboratory tests will include the following. Complete blood count 
(CBC) will be obtained prior to dosing. Results of the total white blood cell and 
 
 will be reviewed and monitored per Section 5.8.2.  
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) 
Total bilirubin  
Total cholesterol  
Total protein  
Triglycerides 
Hematology  
Hematocrit (Hct) 
Hemoglobin (Hb) 
Mean corpuscular hemoglobin (MCH) 
Mean corpuscular volume (MCV) 
Platelet count 
Red blood cell count (RBC) 
White blood cell count (WBC) with differential 
(% and absolute counts) 
 
Coagulation 
Prothrombin time (PT) 
Activated partial thromboplastin time (PTT) 
International Normalized Ratio (INR) 
 
Additional tests  
Serum human chorionic gonadotropin (hCG) 
HIV test 
HBsAg 
Anti- HCV 
VZV IgG 
6.8.2 
Virology 
Human immunodeficiency virus (HIV antibody), hepatitis B (HBsAg), hepatitis C virus 
(RIBA 2 or 3), and varicella zoster virus (VZV) IgG antibody will be performed at 
 
 


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6.8.3 
Drugs of Abuse Screen 
Urine samples for the drugs of abuse screen will be collected according to the laboratory 
manual provided by the local or central laboratory and according to the schedule of 
procedures and events (
). 
The drugs of abuse screen will include amphetamines, barbiturates, cocaine metabolites, 
opiates, benzodiazepines and cannabinoids. 
6.8.4 
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. 
6.8.6 
Sample Collection, Storage, and Shipping 
Blood samples for hematology, coagulation parameters, serum chemistry, HIV and hepatitis 
screens, serum hCG, will be collected according to the laboratory manual provided by the 
local or central laboratory and according to the schedule of procedures and visits (
). 
6.8.7 
Blood Volume 
Total blood volume for clinical laboratory tests during study conduct is less than 150 mL. 
6.9 
Efficacy Assessments 
6.9.1 
Flexible Proctosigmoidoscopy 
A flexible proctosigmoidoscopy, performed with a videoendoscope following a cleansing 
prep (oral or rectal cathartic), will be performed during screening 
 
 and at Week 12/Exit visit.  


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A repeat flexible proctosigmoidoscopy may be permitted by the sponsor when the central 
reader indicates that the videoendoscope data was acquired incorrectly, or did not meet the 
minimal required quality standards. 
6.9.3 
Stool Sample 
A stool sample will be obtained for culture, ova and parasite evaluation for C. difficile assay. 
A sample will be collected and cultured during screening and at any point in the study when 
a patient becomes symptomatic, including worsening or return of disease activity.   
 
6.9.6 
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 called a TrialMax Touch Android (HTC Desire 
310). 
During screening, patients will be instructed on how to appropriately complete the electronic 
diary. The symptoms of UC must be recorded throughout the study, including the screening 
period. Diary entries will be reviewed by site personnel during screening and (prior to 
dosing, if applicable) at 
 
  
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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6.9.7 
Complete Mayo Clinic Score, 3-component Mayo Clinic Score, 
 
 
COMPLETE MAYO CLINIC SCORE (MCS): SCREENING AND WEEK 12/EXIT ASSESSMENT 
The complete Mayo Clinic Score (MCS) is an instrument designed to measure disease 
activity of ulcerative colitis and consists of 4 subscores: stool frequency, rectal bleeding, 
findings of flexible proctosigmoidoscopy, and physician global assessment with each 
component ranging from 0 to 3 (0=normal, 1=mild, 2=moderate, 3=severe). Total score 
therefore ranges from 0 to 12, with a higher score indicating more severe disease. 
The MCS will be evaluated during screening using patient diary entries within the 10 days 
prior to randomization and flexible proctosigmoidoscopy results within 10 days prior to 
randomization. The subscores for stool frequency and rectal bleeding are derived from the 
patient diaries. The scores from the 3 most recent days prior to the actual day of the study 
visit will be averaged and rounded to the nearest integer. Note that the day prior, day of and 
day after proctosigmoidoscopy cannot be used for patient diary entry because of the required 
bowel prep for the procedure. Patients who have less than 3 days of diary data during 
screening are not eligible for randomization. Examples of the subscore entries for eligibility 
and subscore derivation are provided in Table 2. The rounding will be applied to each 
subscore prior to the creation of the total score. The MCS will also be evaluated at 
Week 12/Exit using the Week 12/Exit proctocsigmoidoscopy and stool frequency and rectal 
bleeding scores completed by the patients up to seven days prior to the visit. 
 
Table 2. 
Examples of eDiary Subscore Entries for Study Eligibility and 
Corresponding Subscore Derivation 
Example 
Diary Day 
Valid Days 
for 
Calculation 
of 
Subscore 
Average 
Subscore 
Final 
Subscore 
-10 
-9 
-8 
-7 
-6 
-5 
-4 
-3 
-2 
-1 
1 
Diary #1 
1 
2 
3 
X 
P 
X 
2 
1 
3 
1 
E 
-1, -2, -3 
1.66 
2 
Diary #2 
2 
2 
2 
3 
X 
P 
X 
M 
1 
3 
E 
-1, -2, -7 
2.33 
2 
Diary #3 
3 
2 
3 
3 
3 
X 
P 
X 
3 
M 
E 
-2, -6, -7 
3.00 
3 
Diary #4 
3 
0 
1 
X 
P 
X 
M 
M 
M 
M 
E 
-8, -9, -10 
1.33 
1 
Diary #5 
1 
2 
X 
P 
X 
M 
M 
M 
M 
M 
E 
Missing 
N/A 
Missing 
Abbreviations: E = eligibility; M = missing; P = proctosigmoidoscopy; X = non-scoring day before and after 
proctosigmoidoscopy  
 
 
3-COMPONENT MAYO CLINIC SCORE: STUDY ENTRY CRITERIA AND PRIMARY ENDPOINT 
The 3-component Mayo Clinic score consists of 3 of the 4 subscores found in the MCS as 
follows: stool frequency, rectal bleeding, and findings of flexible proctosigmoidoscopy. Total 
score range: 0 to 9, each component ranging from 0 to 3 (0=normal, 1=mild, 2=moderate, 
3=severe). 
Entry criteria will be based on a 3-component Mayo Clinic score (as defined in the inclusion 
criteria).  


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Physician’s Global Assessment (PGA) 
The physician’s global assessment acknowledges the three other criteria findings of the 
MCS, the patient’s daily record of abdominal discomfort and general sense of well-being, 
and other observations, such as physical findings and the patient’s performance. The PGA 
will be used in calculation of the MCS at screening and Week 12/Exit.  
A sample of the complete Mayo Clinic score is provided in 
 
6.10 
 and Hematologic Assessments 
6.10.2 
Hematologic Sampling 
Blood samples for CBC with differential and platelet count will be assessed during screening, 
and at
for those not continuing 
on to the extension study and with abnormal CBC results at exit.   
If the absolute peripheral 
 has not recovered to at least 80% of the baseline 
value at th
 patients should return for weekly CBCs until the absolute 
peripheral 
 has returned to at least this value.  


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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 
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. AEs that occur from ICF 
signature until the time of administration of the first dose of APD334 will be regarded as 
‘pre-treatment’ and recorded as an AE. All events reported following study medication 
administration up to 30 days after the last medication intake will be presented as treatment 
emergent AEs (TEAEs)  
Monitoring of 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 study medication (APD334 or placebo) 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 


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• Concomitant disease or accidents 
• Clinically relevant adverse changes in laboratory parameters observed in a patient 
in the course of a clinical study 
• Pre-existing conditions which worsen in severity or frequency or which have new 
signs/symptoms associated with them 
Lymphopenia will not be captured as an adverse event both to maintain the study blind, and 
also because it is an expected pharmacologic effect of the drug. In order to ensure safe 
conduct of the study and minimize the risk of study personnel or sponsor becoming 
unblinded to treatment assignment, total WBC and 
 will be monitored by a 
central  CRO physician(s) unblinded to the 
 and leucocyte counts. This person 
will remain blinded to the study medication 
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 agonist25, and enablement of the 
John Cunningham (JC) virus is therefore a potential adverse effect of this therapeutic class. 
Patients in this trial should therefore be monitored for any new onset or worsening of 
neurological signs and symptoms. Signs and symptoms associated with PML are diverse, 
progress over days to weeks, and include progressive weakness on one side of the body or 
clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation 
leading to confusion and personality changes. The progression of deficits usually leads to 
death or severe disability over weeks or months. If PML is suspected, withhold dosing and 
refer to a neurologist; if confirmed, discontinue dosing permanently. 
The investigator or subinvestigator will administer the subjective PML checklist during 
screening to exclude patients with positive responses from enrolling into the study. The 
subjective PML checklist will be administered at
to probe for 
symptoms suggestive of PML. Any patients reporting signs and/or symptoms of PML will 
undergo objective testing and may be referred to a neurologist for a full evaluation. 
A copy of the PML checklist is provided in Appendix 1. 


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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: 
PPD Medical Affairs/Pharmacovigilance 
PPD PVG Hotline EMEA and APAC: 
 
PPD PVG Hotline NA: 
PPD PVG Fax line: 
In the event that RDC entry is not possible (e.g., system failure or access problems), the 
study site should complete the paper SAE report form and fax the form to PPD PVG within 
24 hours of awareness of the event. The RDC system should be updated as soon as it is 
available.  
A full description of every serious adverse event will need to be provided to PPD PVG (this 
may be supported by source documentation such as laboratory reports or a discharge 
summary should the patient be hospitalized).  


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Other safety issues as defined in ICH Topic E2A, 21 code of federal regulations (CFR) 
§312.32, and EU Volume 10 also qualify for expedited reporting. In these situations the 
process will be as detailed for SAEs above: 
• SAEs which could be associated with the trial procedures; 
• SAEs and AEs of special interest that could materially influence the benefit-risk 
assessment of a medicinal product, such as: a clinically important increase in the 
rate of a serious suspected adverse reaction over that listed in the investigator 
brochure. 
6.11.2.1 
Patient and Patient-partner Pregnancy 
Patients who become pregnant during the study will be discontinued immediately. Although 
not considered an SAE or AE, pregnancies occurring during the period of study drug 
administration 
of study drug should 
be reported to the sponsor contact and IRB/IEC in the same manner as an SAE. 
Pregnancies will be followed every trimester through the first well baby visit. For female 
partners whom become pregnant by male study patients during the course of the study, 
reasonable efforts will be made to collect information on the partner’s pregnancy through the 
first well baby visit as provided by the male study patient. 
6.11.3 
Assessment of Adverse Event Severity 
The severity of each AE will be assessed at onset by a nurse and/or physician. When 
recording the outcome of the AE the maximum severity of the AE experienced will also be 
recorded. The severity of the AE will be graded according to the CTCAE v4.0322 definitions,   
listed below: 
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
Grade 2:  Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental Activities of Daily Living (ADL)*. 
Grade 3:  Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care 
ADL**. 
Grade 4:  Life-threatening consequences; urgent intervention indicated. 
Grade 5:  Death related to AE. 
Activities of Daily Living (ADL): 
*Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc. 


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**Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, 
taking medications, and not bedridden. 
 
6.11.4 
Assessment of Adverse Event Relationship to Study Medication  
The relationship of an AE to investigational product(s) will be classified using modified 
WHO criteria (Edwards and Biriell, World Health Organization Collaborating Centre for 
International Drug Monitoring 1994) as follows. 
Related:  a clinical event, including laboratory test abnormality, with a reasonable time 
sequence to administration of the drug, unlikely to be attributed to concurrent disease or 
other drugs or chemicals, and which follows a clinically reasonable response on withdrawal 
(dechallenge). Rechallenge information is not required to fulfill this definition; or an event 
that could also be explained by concurrent disease or other drugs or chemicals where 
information on drug withdrawal may be lacking or unclear. 
Not related:  a clinical event, including laboratory test abnormality, with sufficient evidence 
to accept that there is no causal relationship to drug administration (e.g., no temporal 
relationship to drug administration, because the drug was administered after onset of event; 
investigation shows that the drug was not administered; proof of other cause; etc.); or an 
event with a temporal relationship to drug administration which makes a causal relationship 
improbable, and in which other drugs, chemicals or underlying disease provide plausible 
explanations. 
6.11.5 
Assessment of Adverse Event Outcome 
Outcome of AEs will be defined according to ICH Topic E2B, ICH Guideline. 
• Recovered/Resolved 
• Recovered/Resolved with Sequelae 
• 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 


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6.11.7 
Action Taken for Study Drug 
Any action taken with study drug will be defined according to ICH Topic E2B, ICH 
Guideline and documented in the CRF according to the following: 
• Drug Withdrawn 
• None (not changed) 
• Dose Interrupted 
• Unknown 
• Not Applicable 
6.11.8 
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 (Week 12/Exit) 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. 
6.12 Concomitant Medications and Procedures 
All medications (OTC and prescribed) that are taken by patients and all procedures that are 
performed during the screening period and during the study must be recorded in the 
electronic case report form (eCRF) with start date/time and stop date/time, if known.  
Concomitant medication for medical conditions other than UC are permitted as clinically 
indicated patient to specific protocol requirements outlined in Section 4.2 and Section 4.3. 
The following should be taken into account with regard to concomitant procedures: 
• Patients may not undergo major elective surgery while enrolled in this study. 
• Patients may not donate sperm, or oocytes during the study and for 30 days after 
the last dose of study drug. 


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6.12.1 
Permitted Medications for the Treatment of UC 
Oral 5-ASA treatment is permitted for the treatment of UC, provided that the patient was 
receiving the medication(s) at baseline, and that the dose(s) has been stable as specified in 
Section 4.2. These medications should remain stable throughout the study. 
Oral corticosteroids that the patient is receiving at baseline may be continued, provided that 
the dose has been stable for the 4 weeks immediately prior to screening endoscopy 
assessment if corticosteroids have just been initiated as specified in Section 4.2. These 
medications should remain stable throughout the study (tapering may be initiated after 
participation in this study or during extension study APD334-005).  
Azathioprine or 6-mercaptopurine, provided that the dose has been stable for the 8 weeks 
immediately prior to screening. (These immunosuppressive agents must be discontinued 
at the time of randomization.) 
Probiotics (e.g., Culturelle, Saccharomyces boulardii) provided that the dose has been stable 
for the 2 weeks immediately prior to randomization. 
Antidiarrheals are allowed throughout the study as necessary for control of chronic diarrhea; 
stable doses are encouraged. 
6.12.2 
Excluded Medications 
The following medications are excluded from the study: 
• Treatments for UC other than those listed in Section 6.12.1 (either approved or 
investigational) 
• All live vaccines, during study treatment and for at least 6 months after the last dose 
of study drug 
• Moderate to strong inhibitors of CYP2C9  
6.13 Removal of Patients from the Trial or Study Drug 
The study may be terminated early if, in the opinion of the sponsor, investigator, or IRB/IEC, 
an unacceptable risk to the safety and welfare of patients is posed by the continuation of the 
study in light of review of the key safety data. 
Patients will be free to withdraw from the study at any time should they so wish. A patient 
may be withdrawn from the study for any of the following reasons (including but not limited 
to): 
• Clinical investigator may remove a patient if, in his/her opinion, it is in the best 
interest of the patient 


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• Withdrawal of consent - Any patient may withdraw his/her consent from the study at 
any time. The investigator should make a reasonable attempt to document the specific 
reason why consent was withdrawn. 
• Deviation/noncompliance with the protocol or study drug 
• An adverse event 
• Lost to follow up 
6.13.1 
Handling of Withdrawals 
Although a patient is not obliged to give his/her reason for withdrawing prematurely, the 
investigator will make a reasonable effort to obtain the reason while fully respecting the 
patient’s rights. If there is a medical reason for withdrawal, the patient will remain under the 
supervision of the study physician until in satisfactory health. Reasonable efforts will be 
made to contact a patient who fails to attend any follow-up appointments, in order to ensure 
that he/she is in satisfactory health.  
If a patient is prematurely discontinued from this study, every attempt will be made to follow 
the Week 12/Exit visit procedures described in Section 7.4.4. 
6.13.2 
Replacements 
Patients who terminate early from the study will not be replaced. 
6.14 Allowable Visit and Procedure Windows 
• 
If screening process is interrupted due to technical issues (timing, medical devices 
functioning etc.), patient can continue the screening after the
have passed, but 
time extension must not exceed
 In 
this case, all medical evaluations performed previously are considered still valid, 
except for the following procedures, which have to be performed within
to randomization: 
- 
Flexible proctosigmoidoscopy with 
 
- 
Diary review 
- 
Complete Mayo score (MCS) 
- 
Record adverse events 
- 
Record concomitant medications/procedures 
- 
 


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• There are no visit windows after randomization. 
 
6.15 Study and Site Discontinuation 
The Sponsor has the right to terminate this study at any time.  Reasons for terminating the 
study may include, but are not limited to, the following: 
• The incidence or severity of AEs in this or other studies indicates a potential health 
hazard to patients. 
• Patient enrollment is unsatisfactory. 
• The Sponsor will notify the investigator if the study is placed on hold, or if the 
Sponsor decides to discontinue the study or development program.   
 
The Sponsor has the right to replace a site at any time.  Reasons for replacing a site may 
include, but are not limited to, the following: 
• Excessively slow recruitment 
• Poor protocol adherence 
• Inaccurate or incomplete data recording 
Non-compliance with the ICH guidelines for GCP 


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7 
STUDY ACTIVITIES 
 
At the initial screening visit, potential patients will have a detailed oral presentation of the 
nature, purpose, risks, and requirements of the study in addition to receiving detailed written 
information. They will have adequate opportunity to ask the appropriate person of the clinical 
staff (i.e., principal investigator or designee) presenting the study about any aspect of the 
study. Once the patient is satisfied that he/she is willing to participate in the study, he/she 
will be asked to sign the study VICF. The clinical personnel obtaining written consent from 
the patient will also sign the form to confirm consent has been obtained. Once signed, the 
investigator will retain the original for the patient’s study records and provide the patient 
with a signed copy. The investigator will verify that informed consent has been obtained 
from each patient prior to admission into the study and prior to the patient undergoing any 
study-related procedures. If it is standard practice at the site to conduct a few general non-
invasive study procedures (i.e., medical/social history, collection of concomitant 
medications, etc.) before a patient can be considered for a specific study, the study center 
must have a written SOP detailing the procedure, and also ensure that each patient signs a 
general consent prior to undergoing the general procedures. 
A unique patient screening number will be assigned upon completion of the VICF. 
Within 28 days before administration of the study medication, or sooner, all screening 
activities subsequent to obtaining informed consent will be conducted and consist of the 
following: 
• Review of all inclusion and exclusion criteria 
• Collection of demographic data (sex, age, race/ethnicity)  
• Completion of medical and social history (to include tobacco, alcohol, and caffeine 
use) 
• UC medical history 
• Physical/neurological examination, including height, weight, vital signs (i.e., supine 
blood pressure, heart rate, respirations, and temperature after a 5 minute rest) and 
ophthalmoscopy with OCT (where available) and retinal photos 
• 
 
• PML checklist 
• Safety ECG (12-lead) 
• Pulmonary function test (spirometry) 
• Stool sample 


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• 
 
• TB screening  
• Chest X-ray, Posteroanterior (PA) and Lateral (per 
) 
• Clinical laboratory tests (hematology, serum chemistry, coagulation parameters, 
urinalysis, 
, and drugs of abuse screen), and virology screen (HBsAg, HIV 
antibodies, and HCV antibodies).  
• CBC with differential and platelet count 
• Serum hCG pregnancy test (non-postmenopausal females only)  
• Diary instruction  
• Record adverse events 
• Record concomitant medications/procedures 
The following activities must occur within 10 days prior to randomization:  
• Flexible proctosigmoidoscopy with 
  
• Diary review 
• Complete Mayo Clinic score (MCS) 
• Record adverse events 
• Record concomitant medications/procedures  
Extension of screening time-window (up to 35 days) might be allowed, and performed as per 
Section 6.14. 
7.2 
Screening Failures 
A screening failure is defined as a patient who has signed the VICF, does not meet all the 
entry criteria as outlined in this protocol and has not been randomized or received study 
medication.  
7.2.1 
Re-screening 
In case of screening failure (e.g. due to low ulcerative colitis severity, temporary intestinal 
infection, concomitant medication etc.), a patient can be re-screened. During re-screening, if 
not feasible for the patient, ophthalmology and pulmonary function tests do not have to be 
repeated if the last assessment was not done longer than three months before. All other 
assessments have to be repeated. 


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7.3 
 Holter Fitting and Monitoring 
Patients who meet all the entry criteria and are eligible for the study will report to the site on 
the morning of 
 to receive their Holter monitor for the
 monitoring period. Patients will be monitored on site to confirm the monitor is 
working correctly before being released to return on 
 
7.4 
Treatment Period 
 
 
• Medical history (partial history, to update findings from screening and document any 
pre-treatment AEs) 
• Physical and neurological exam (limited examination to assess clinically significant 
changes from screening)  
• 
 
• Holter monitoring (per 
) 
• PML checklist 
• Clinical laboratory tests (serum chemistry, hematology, coagulation parameters, 
urinalysis and 
) (per 
) 
• CBC with differential and platelets (per 
) 
• 
 
• Drugs of abuse screen (to include amphetamines, barbiturates, cocaine metabolites, 
opiates, benzodiazepines and cannabinoids). 
• Urine pregnancy test (women only) 
• 
 
. 
• Diary review 
• 
  
• Vital signs (per 
) 
• Drug dispensation 
• Record adverse events 
• Record concomitant medications/ procedures 
• Randomization 


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• Study drug administration (per 
) 
 
7.4.2 
At-home Holter Removal 
Patients will remove their Holter monitors after the
monitoring periods 
have completed (on
. Removal time and instructions will be provided to the patient by 
the site.  For convenience, the patients may return the Holter monitor at the next visit. 
• Safety ECG (12-lead) (per 
) 
• PML checklist 
• Clinical laboratory tests (serum chemistry, hematology, coagulation parameters, 
urinalysis and 
) (per 
) 
• CBC with differential and platelets (per 
) 
• Urine pregnancy test (women only) (per 
) 
• 
 
• Diary review 
• 
 
• Stool sample
 per 
) 
• 
 
• Vital signs (per 
) 
• Study drug dispensation/administration (per 
) 
• Drug accountability 
• Record adverse events 
• Record concomitant medications/ procedures 
• Physical/ neurological exam and ophthalmoscopy with OCT and retinal photos (per 
) 
• Safety ECG (per 
) 
• PML checklist 


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• 
 
• Pulmonary function test (spirometry) (per
)  
• Clinical laboratory tests (serum chemistry, hematology, coagulation parameters, 
urinalysis and 
) 
• CBC with differential and platelets (per
) 
• Serum pregnancy test (women only) 
• 
 
• Diary review 
• Flexible proctosigmoidoscopy with 
  
• Complete Mayo Clinic score (MCS) 
• Determine clinical responder/non-responder status of patient based on the following 
criteria:  a decrease (from baseline) in 3-component Mayo Clinic score of ≥ 2 points 
and a decrease of ≥ 30% with either a decrease of rectal bleeding of ≥ 1 or rectal 
bleeding score of 0 or 1 at Week 12. 
• Stool sample 
• 
 
• Vital signs 
• Study drug administration (per 
) 
• Drug accountability 
• Record adverse events 
• Record concomitant medications/ procedures 
Patients who do not wish to continue into the extension study will have a
visit after their final visit to have additional safety assessments performed as outlined in the 
schedule of procedures and visits (
). 


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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 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’. 
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), Format C. 
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. The intention of Section 9 is to provide overview of statistical analyses.  Details of the 
statistical analyses and statistical testing procedure will be included in a separate statistical 
analysis plan (SAP) which will be finalized before database lock.  If, after the study has been 
unblinded, 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 proof-of-concept study will be to determine the effect of 
treatment with APD334 in improving 3-component Mayo Clinic Score (score ranging from 0 
to 9, including stool frequency, rectal bleeding and findings on endoscopy) at Week 12. 
9.1.1.2 
Secondary Objective(s) 
The secondary objectives of the study are:  
• To determine the effect of treatment with APD334 on a combination of clinical 
remission and clinical response reflected by a composite endpoint at 12 weeks 
• To determine the effect of treatment with APD334 in inducing clinical remission at 
12 weeks 
• To determine the effect of treatment with APD334 in inducing clinical response at 12 
weeks 
• To determine the effect of treatment with APD334 on endoscopic improvement at 12 
weeks  
9.1.1.3 
Safety Objective 
The safety objective of this study is to determine the safety profile and tolerability of 
APD334 induction treatment. 
9.1.1.4 
Exploratory Objective(s) 
The exploratory objectives of the study are: 
• To determine the effect of APD334 treatment on Total Mayo Score at 12 weeks. 


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9.1.2 
Hypotheses 
9.1.2.1 
Primary Hypothesis 
In patients with moderately to severely active ulcerative colitis, treatment with APD334 
compared with placebo will provide greater improvement in 3-component Mayo Clinic Score 
at 12 weeks.  


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9.1.2.2 
Secondary Hypotheses 
• In patients with moderately to severely active ulcerative colitis, treatment with 
APD334 compared with placebo will provide better combination of clinical remission 
and clinical response reflected by a composite endpoint at 12 weeks. 
• In patients with moderately to severely active ulcerative colitis, treatment with 
APD334 compared with placebo will provide more patients that achieve clinical 
remission at 12 weeks. 
• In patients with moderately to severely active ulcerative colitis, treatment with 
APD334 compared with placebo will provide more patients that achieve clinical 
response at 12 weeks. 
• In patients with moderately to severely active ulcerative colitis, treatment with 
APD334 compared with placebo will provide more patients that achieve endoscopic 
improvement at 12 weeks. 
 
9.2 
Sample Size and Power Calculations 
For the comparison of the proportion of patients who achieve clinical remission between 
APD334 versus placebo, a sample of ~80 patients per group will provide 80% power to 
detect a difference of 18% (from 10% to 28%) at α=5% (2-sided test). This calculation is 
based upon an assumed placebo rate of 10%.  
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 primary endpoint, secondary endpoints and other 
efficacy endpoints.   
INTENT-TO-TREAT POPULATION (ITT): 
This population consists of all randomized patients, who received at least 1 dose of study 
medication. Under this approach, patients are counted in the treatment group to which they 
were randomized, regardless of the treatment received during the course of the trial. 
MODIFIED INTENT-TO-TREAT POPULATION (MITT): 
This population consists of all randomized patients, who received at least 1 dose of study 
medication, have a baseline measurement, and have at least one post-randomization 
measurement.  Under this approach, patients are counted in the treatment group to which they 
were randomized, regardless of the treatment received during the course of the trial. Note that 


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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 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 randomized patients who received study medication. 
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. 
Demographic data will be summarized and tabulated. Continuous variables will be 
summarized using number of observations (n), mean, standard deviation (SD), median, 
minimum, and maximum. Frequencies and percentages will be reported for all categorical 
data. 
9.5 
Efficacy Endpoints 
Primary: 
• The improvement of 3-component Mayo Clinic Score (score ranging from 0 to 9, 
including stool frequency, rectal bleeding and findings on endoscopy) at Week 12. 
 
Secondary: 
• The trichotomous composite score of clinical remission and clinical response (score 
ranging 0 to 2: score 2 for achieving both clinical remission and clinical response; 1 
for only achieving clinical response, and 0 for achieving neither) at Week 12. 
• The proportion of patients achieving 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 from baseline subscore at 
Week 12 
• The proportion of patients who achieve clinical response [defined as a decrease in 3-
component Mayo Clinic score of ≥ 2 points and a decrease of ≥ 30% with either a 
decrease of rectal bleeding of ≥ 1 or rectal bleeding score of 0 or 1] at Week 12 


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• The proportion of patients who achieve endoscopic improvement [defined as Mayo 
endoscopic subscore (using findings of flexible proctosigmoidoscopy) of ≤ 1 point] at 
Week 12 
Exploratory: 
• Improvement in Total Mayo Clinic Score (score ranging from 0 to 12, including stool 
frequency, rectal bleeding and findings on endoscopy, and physician’s global 
assessment) at Week 12 
9.6 
Statistical Methods 
9.6.1 
Primary Efficacy Analysis 
The primary analysis will be based on the change from baseline in 3-component Mayo Clinic 
Score at Week 12 using an analysis of covariate (ANCOVA) model with terms for treatment, 


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current oral corticosteroid use, prior exposure to TNFα antagonists and baseline value as 
covariate.  Least-squares mean (LSM) by treatment group and its 95% confidence interval 
(CI), and least-squares mean difference between treatment group and its 95% CI will be 
reported. 
 
Mayo Clinic Score data handling: for each study visit during the study (excluding the 
screening/baseline visit which uses 10 prior days), stool frequency and rectal bleeding 
subscores will be derived from electronic patient diaries completed over the 7 days prior to a 
study visit. Note that the day prior, day of and day after proctosigmoidoscopy will not be 
used for patient diary entry because of the required bowel prep for the procedure. These 
subscores will be calculated using the following rules: 
 
1. The scores from the 3 most recent days prior to the actual day of the study visit will 
be averaged and rounded to the nearest integer. 
2. If patient diary entries from 3 days are not available, the scores from the 2 most 
recent entries will be averaged and rounded to the nearest integer. 
3. If less than 2 days of diary data are available, the subscore will be considered 
missing. 
 
The rounding will be applied to each subscore prior to the creation of the total score. 
 
9.6.1.1 
Secondary and Exploratory Efficacy Analyses 
The secondary analyses include following: 
 
• Trichotomous composite score of clinical remission and clinical response at Week 12 
is an ordinal categorical endpoint with 3 scores (2, 1, 0).  It will be analyzed using 
Cochran-Mantel-Haenszel method adjusted for the stratification factors of presence or 
absence of current oral corticosteroid therapy at baseline and previous exposure to 
TNFα antagonists, and using modified ridit score to compute testing statistic and p-
value for between-treatment comparison.  
• The proportion of patients who achieve clinical remission, clinical response, and 
endoscopic improvement will be analyzed individually using Cochran-Mantel-
Haenszel (CMH) test adjusted for the stratification factors of presence or absence of 
current oral corticosteroid therapy at baseline and previous exposure to TNFα 
antagonists, to compare the difference of proportions between treatment group. The 
CMH stratified risk difference and its 95% confidence interval will be provided. 
 
All patients who prematurely discontinue for any reason will be considered failures (non-
responders) for all the proportion based endpoints. To assess the robustness of the results, 


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several imputation/sensitivity analyses will be performed (i.e. completers population; more 
details will be specified in the SAP). 
Exploratory efficacy analyses 
 
 
 
 
Dose response analyses will be performed using ANCOVA model for continuous variables, 
or logistic regression model for categorical variables, as appropriate.  Treatment group and 
appropriate baseline covariates will be included in the analysis model.  Statistical testing of 
dose response trend will be based on appropriate contrast statement assuming monotonic 
dose response profile in placebo, APD334 low dose and APD334 high dose. 
For the repeated measures analysis, no explicit imputations will be made for this approach.  
Missing data are assumed to be missing at random (that is, ignorable missingness), which 
means that the missingness of the data does not depend on the value that is missing after 
adjusting for the effect of the data that are observed. 
An analysis of covariance (ANCOVA) with LOCF imputation for missing data will be 
performed for Week 12 change from baseline in the complete Mayo Clinic Score,
 
 
 The 
ANCOVA model will include terms for treatment, current oral corticosteroid use, previous 
exposure to TNFα antagonists and baseline value as a covariate.  
9.6.2 
Subgroup Analyses 
Subgroup analyses for the primary efficacy endpoint will be performed in order to explore 
whether the treatment effects are consistent across different subgroups. The baseline patient 
characteristics below are the subgroup factors to be explored. 
• Sex (Male, Female) 
• Age: > or ≤ median age, ≥ or < 65 years 
• Race 
• Presence or absence of current oral corticosteroid use  


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• Previous exposure to TNFα antagonists  
• 
 
• 
 
In addition to the subgroup analyses for the primary endpoint, the following analyses will be 
performed: 
• 
 
 
• 
 
 
9.6.3 
Multiplicity 
A statistical testing procedure will be constructed to manage multiplicity issues concerning 
primary and secondary efficacy analyses in order to control overall Type I error rate for 
efficacy testing not exceeding 0.05. The details of testing procedure will be specified in a 
separate SAP. 
 


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9.6.4 
Interim Analysis 
Sponsor may plan an unblinded interim analysis at time when sufficient number of patients 
have finished 12 weeks of treatment. If Sponsor decides to perform an interim analysis, it 
will be operated by an independent Data Review Committee (DMC).  The revision of 
statistical analysis plan (SAP) with detailed interim analysis specifications and a DMC 
charter will be provided to regulatory agency in timely manner and will be finalized prior to 
the interim analysis. 
9.6.5 
Data Safety Monitoring Board 
The DSMB will monitor emerging study safety data and has the responsibility to review 
specific safety data reports, and to request additional reports as needed. Unblinded data 
reports generated by the unblinded statistician will be reviewed for adverse treatment effects 
and patient safety. The DSMB must keep results from blinded and unblinded data reports 
confidential.  The roles and responsibilities of the DSMB will be outlined in a separate 
charter. 
9.8 
Safety Analysis 
Safety and tolerability will be assessed by a review of all safety parameters including adverse 
experiences (AEs), laboratory safety parameters, vital signs, and ECG. Only summary 
tabulations (N, mean [or median], SD, mean [or median] change/percent change) and 95% 
CIs for between-group differences will be obtained. Adverse experiences will only be 
presented as summary tabulations. The analyses for all safety outcomes (categorical or 
continuous measures) will use the safety population which consists of all randomized patients 
who received at least 1 dose of study drug; in addition, if a patient is found to have taken a 
study therapy for the entire duration of the study different from that to which he/she was 
randomized, then the patient is counted in the treatment group of the drug he/she actually 
received. 
For analysis based on laboratory measurements, at least 1 laboratory test post-randomization 
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-randomization measurement. No missing data will be imputed for the safety analysis. 


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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 and by treatment. They will be 
summarized per treatment 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 by treatment group. 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 in each treatment group 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 and by treatment. 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 by treatment summarized using descriptive 
statistics. Summary statistics will also be provided for change from baseline in vital sign 
measurements by treatment.  Baseline is defined as the last pre-randomization measurement. 


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9.8.5 
Clinical Laboratory Values 
Individual lab values will be listed by treatment and visit, and summarized using descriptive 
statistics. Summary statistics will also be provided for change from baseline in lab values. 
Baseline is defined as the last pre-randomization measurement. Shift tables from baseline to 
last double-blind visit will also be produced for the laboratory assessments based on the 
categories of Low, Normal, and High. A clinically significant change from baseline may be 
recorded as an AE if deemed appropriate by the PI or sponsor. 


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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 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 


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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). 
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, “A Phase 2, Randomized, 
Double-Blind, Placebo-Controlled, Parallel Group, Multi-Center Study to Investigate the 
Safety and Efficacy of APD334 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. 


APD334 
 
Arena Pharmaceuticals, Inc. 
Clinical Trial Protocol: APD334-003 Amendment 06 
 
27 March 2017 
 
 
Confidential 
Page 85 of 101 
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 
 


APD334 
 
Arena Pharmaceuticals, Inc. 
Clinical Trial Protocol: APD334-003 Amendment 06 
 
27 March 2017 
 
 
Confidential 
Page 86 of 101 
13 REFERENCES 
1. Brinkmann V, Billich A, Baumruker T, et al. Fingolimod (FTY720): discovery and 
development of an oral drug to treat multiple sclerosis. Nat Rev Drug Discov 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. Danese S and Fiocchi C. Ulcerative Colitis. N Engl J Med.  2011 Nov;365;18:1713-1725. 
4. IBD Insights. IBD etiology and pathophysiology: Understanding the process. 
https://www.ibdinsights.com/about/etiology-pathophysiology/. Accessed January 8, 
2015. 
5. 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. 
6. 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. 
7. Loftus EV, Jr. Clinical epidemiology of inflammatory bowel disease: Incidence, 
prevalence, and environmental influences. Gastroenterology. 2004; 126:1504-17. 
8. 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. 
9. World IBD Day. http://www.worldibdday.org/index.html. Accessed January 7, 2015. 
10. American Gastroenterological Association. Inflammatory bowel disease emerges as a 
global disease. (2012, January 5). ScienceDaily. 
www.sciencedaily.com/releases/2012/01/120104135402.htm. Accessed January 7, 2015. 
11. Kaser A, Zeissig S, Blumberg RS. Inflammatory Bowel Disease. Annu Rev Immunol. 
2010;28:573-621.  
12. 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. 
13. Lichtenstein GR, Hanauer SB, Sandborn WJ, and The Practice Parameters Committee of 
the American College of Gastroenterology. Management of Crohn’s Disease in Adults. 


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Arena Pharmaceuticals, Inc. 
Clinical Trial Protocol: APD334-003 Amendment 06 
 
27 March 2017 
Confidential 
Page 87 of 101 
Am J Gastroenterol advance online publication, 6 January 2009; doi: 
10.1038/ajg.2008.168. 
14. Medscape. Inflammatory Bowel Disease: Practice Essentials.  
http://emedicine.medscape.com/article/179037-overview#aw2aab6b2b4. Accessed 
January 8, 2015.  
15. World Health Organization Atlas, “Multiple Sclerosis Resources in the World,” 2008. 
16. Lutton JD, Winston R, Rodman TC. Multiple sclerosis: etiological mechanisms and 
future directions. Exp Biol Med (Maywood) 2004 January;229(1):12-20. 
17. Wipfler P, Harrer A, Pilz G, et al. Recent developments in approved and oral multiple 
sclerosis treatment and an update on future treatment options. Drug Discov. Today 2011 
January; 16: 8-21. 
22. 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. 
23. 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. 
24. 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. 
25. http://www.fda.gov/drugs/drugsafety/ucm366529.htm. Accessed 27-April-2015. 
26. 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 


APD334 
 
Arena Pharmaceuticals, Inc. 
Clinical Trial Protocol: APD334-003 Amendment 06 
 
27 March 2017 
 
 
Confidential 
Page 88 of 101 
27. Rutgeerts P, Sandborn WJ, Feagan BG et al. Infliximab for induction and maintenance 
therapy for ulcerative colitis. N Engl J Med. 2005 Dec 8;353(23):2462-2476. 
28. 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. 


APD334 
 
Arena Pharmaceuticals, Inc. 
Clinical Trial Protocol: APD334-003 Amendment 06 
 
27 March 2017 
 
 
Confidential 
Page 89 of 101 
PROTOCOL SIGNATURE PAGE 
Protocol Title: A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Parallel Group, 
Multi-Center Study to Investigate the Safety and Efficacy of APD334 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: 
APD334-003 
Arena Pharmaceuticals, Inc. Signatures: 
 
 
 


APD334 
 
Arena Pharmaceuticals, Inc. 
Clinical Trial Protocol: APD334-003 Amendment 06 
 
27 March 2017 
 
 
Confidential 
Page 90 of 101 
Appendix 1 
Progressive Multifocal Leukoencephalopathy (PML) 
Checklist 
Symptoms 
“Compared to how you 
usually feel, have you had a 
significant change in any of 
the following?” 
If the answer is 
“yes”, obtain a 
description of the 
symptom(s) with 
examples. 
Applicable Objective 
Test(s): Document 
results on PML 
Object Checklist 
 
Yes 
No 
 
 
1) Have you been experiencing 
any persistent difficulty with 
your vision such as loss of 
vision or double vision? Have 
you been having trouble 
reading? 
 
 
 
Test visual fields and 
ocular motility 
2) Have you been experiencing 
any persistent difficulty 
speaking or having your speech 
understood by others? 
 
 
 
Casual observation of 
speech output for 
dysarthria or aphasia. 
Ask patient to name a 
few objects and repeat 
a multipart phrase. 
3) Have you been experiencing 
any persistent weakness in an 
arm or leg? 
 
 
 
Test for pronator draft 
(Barre maneuver) 
and/or fixation on arm 
roll, Assess the ability 
to hop on either foot; 
foot and finger 
tapping. Test muscle 
strength. 
4) Have you noticed yourself 
regularly bumping into things 
or having difficulty writing? 
 
 
 
Ask for spontaneous 
writing sample and 
observe finger to nose, 
heel to shin, and 
tandem gait. 
5) Have you regularly been 
experiencing difficulty 
understanding others? 
 
 
 
Ability to follow serial 
commands 
6) Have you had persistent 
problems with your memory or 
thinking? 
 
 
 
Recall of 3 objects 
over 1 minute to 
distraction; ability to 
follow commands. 
7) Have you been experiencing 
any persistent numbness or 
other loss of sensation? 
 
 
 
Test sensation side to 
side with pinprock. 
 
 
 


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Clinical Trial Protocol: APD334-003 Amendment 06 
 
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Clinical Trial Protocol: APD334-003 Amendment 06 
 
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Clinical Trial Protocol: APD334-003 Amendment 06 
 
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Clinical Trial Protocol: APD334-003 Amendment 06 
 
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Clinical Trial Protocol: APD334-003 Amendment 06 
 
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Arena Pharmaceuticals, Inc. 
Clinical Trial Protocol: APD334-003 Amendment 06 
 
27 March 2017 
 
 
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Appendix 3 
Mayo Clinic Score – SAMPLE 
Mayo Scoring System for Assessment of Ulcerative Colitis Activity27,* 
Stool Frequency† 
0 = Normal number of stools for this patient 
1 = 1–2 stools more than normal 
2 = 3–4 stools more than normal 
3 = 5 or more stools more than normal 
Subscore, 0 to 3 
Rectal bleeding‡ 
0 = No blood seen 
1 = Streaks of blood with stool less than half the time 
2 = Obvious blood with stool most of the time 
3 = Blood alone passes 
Subscore, 0 to 3 
Findings on endoscopy† 
0 = Normal or inactive disease 
1 = Mild disease (erythema, decreased vascular pattern) 
2 = Moderate disease (marked erythema, lack of vascular pattern, friability, erosions) 
3 = Severe disease (spontaneous bleeding, ulceration) 
Subscore, 0 to 3 
Physician’s Global Assessment§ 
0 = Normal 
1 = Mild disease 
2 = Moderate disease 
3 = Severe disease 
Subscore, 0 to 3 
 
* The Mayo score ranges from 0 to 12, with higher scores indicating more severe disease.28 
† Each patient serves as his or her own control to establish the degree of abnormality of the stool 
frequency. 
† The daily bleeding score represents the most severe bleeding of the day. 
§ The physician’s global assessment acknowledges the three other criteria, the patient’s daily 
recollection of abdominal discomfort and general sense of well-being, and other observations, such 
as physical findings and the patient’s performance status. 
 
 


 
This is a representation of an electronic record that was signed electronically, and this 
page is the manifestation of the electronic signature. 
 
UserName: 
 
Title:  
 
Date: Monday, 03 April 2017, 10:36 AM   Pacific Daylight Time 
Meaning: Author Approval 
================================================
UserName: 
 
Title:  
  
Date: Monday, 03 April 2017, 12:39 PM   Pacific Daylight Time 
Meaning: Approval 
================================================
UserName: 
 
Title:  
 
Date: Monday, 03 April 2017, 01:05 PM   Pacific Daylight Time 
Meaning: Approval 
================================================
UserName: 
 
Title:  
 
Date: Monday, 03 April 2017, 01:07 PM   Pacific Daylight Time 
Meaning: Approval 
================================================
UserName: 
 
Title:  
 
Date: Monday, 03 April 2017, 01:10 PM   Pacific Daylight Time 
Meaning: Approval 
================================================


APD334
Arena Pharmaceuticals, Inc.
Clinical Trial Protocol: APD334-003 Amendment 05
10 October 2016
Confidential
Page 2 of 97
PROTOCOL AMENDMENT SUMMARY
The following is a list of major changes made to the APD334-003 Protocol Amendment 04
dated 21 September 2015. Minor clarifications and corrections have been made throughout 
for consistency. These changes are incorporated in Protocol Amendment 05 dated 10 October 
2016.
Section(s) Amended
Page No(s).
Description of Changes Made
Header/Footer, Title Page, and 
TOC
All
Added “Amendment 05”, updated date to 
reflect finalization of amended protocol, 
updated pagination and TOC.
Title Page
1
Removed “Sponsor Contact”
Protocol Amendment Summary
2-5
Updated table to include summary of 
changes to the protocol.
Synopsis
11
Updated sponsor contact and medical 
monitor.
Synopsis
13, 15

Study Design:
Changed patients with the option 
to enroll in the APD334-005 
extension study: “all patients 
(responders and non-responders)”, 
to: 
Current “responder patients”

3.1 Overall Study Design and 
Plan
29
Reviewed extension study: “A 40-week 
extension study (APD334-005) is offered 
to all patients (responders and non-
responders)”, to:
Current “A 34-week extension study 
(APD334-005) is offered to responder
patients”.
30-32
•


APD334
Arena Pharmaceuticals, Inc.
Clinical Trial Protocol: APD334-003 Amendment 05
10 October 2016
Confidential
Page 3 of 97
Section(s) Amended
Page No(s).
Description of Changes Made
•
•
•
•

 
4.2 Inclusion Criteria #6
33
 
 
 
4.3 Exclusion Criteria, #7
36
Revised exclusion of patients that, within 
60 days prior to randomization, received 
treatment with more than 2 biologic agents 


APD334
Arena Pharmaceuticals, Inc.
Clinical Trial Protocol: APD334-003 Amendment 05
10 October 2016
Confidential
Page 4 of 97
Section(s) Amended
Page No(s).
Description of Changes Made
Current exclusion of patients that, within 
60 days prior to randomization, received
treatment with more than 3 biologics
5.6 Dosage and Administration
40
Changed “Patients will be observed at the 
clinic site for 8 hours post-dose on Day 
1”, to:
Current Patients will be observed at the 
clinic site for 6 hours post-dose on Day 1
5.8.3
Maintenance of 
Randomization Codes and Code-
break Procedures
41
Added specification that APD334-003 
study will remain blinded until completion 
of the APD334-005 study.
6.4 Vital Signs
44
Updated to highlight need for extended 
monitoring if heart rate at 6 hours is the 
lowest since the first dose was 
administered.
6.8.1
Laboratory Parameters
47
Added the following procedure 
information:

clinical safety laboratory tests should 
be completed pre-dose 

Complete blood count (CBC) will be 
obtained prior to dosing.
6.9.1 Flexible 
Proctosigmoidoscopy
48
Revised assessment window from “will be 
performed during screening (within 7 days 
prior to the administration of the first dose 
of study drug)” to
Current: “will be performed during 
screening (within 10 days prior to the 
administration of the first dose of study 
drug)”.
6.9.7 Complete Mayo Clinic 
Score, 3-component Mayo Clinic 
Score, and 
50
Revised MCS from “using … flexible 
proctosigmoidoscopy results within 7 days 
prior to randomization” to
Current: “within 10 days prior to 
randomization”.


APD334
Arena Pharmaceuticals, Inc.
Clinical Trial Protocol: APD334-003 Amendment 05
10 October 2016
Confidential
Page 5 of 97
Section(s) Amended
Page No(s).
Description of Changes Made
 
51
 
6.11.2 Serious Adverse Events 
and Expedited Reporting of 
Adverse Events
54, 55
Changed recipient of notification of 
serious adverse event from sponsor to 
PPD
6.14
Allowable Visit and 
Procedure Windows
59, 60
Added possibility to prolong time window 
for screening to 35 days. Extended 
window for specified procedures 
(proctosigmoidoscopy) to 10 days. 
Removed all other visit and procedure 
windows.
7.1
 
62
Extended window for specified procedures 
to 
 days. Added possibility to prolong 
time window for screening to 
 days.
7.2.1 Re-screening
62
Added clarification of re-screening 
procedures.
7.4.1 
63
Changed “Safety ECG (12-lead) pre-dose 
and hourly through hours post-dose”, to:
Current “Safety ECG (12-lead) pre-dose 
and hourly through hours post-dose”
7.4.3
 
64
 
7.4.4
Week 12/Exit or Early 
Termination Procedures
65
Changed “Determine responder/non-
responder status of patient for treatment 
assignment in extension study (APD334-
005)”, to:
Current “Determine clinical 
responder/non-responder status of patient 
based on the following criteria…”.


APD334
Arena Pharmaceuticals, Inc.
Clinical Trial Protocol: APD334-003 Amendment 04
21 September 2015
Confidential
PROTOCOL AMENDMENT SUMMARY
The following is a list of major changes made to the APD334-003 Protocol Amendment 03 
dated 30 June 2015. Minor clarifications and corrections have been made throughout for 
consistency. These changes are incorporated in Protocol Amendment 04 dated 21 September
2015.
Section(s) Amended
Page No(s).
Description of Changes Made
Header/Footer, Title Page, and 
TOC
All
Added “Amendment 04”, updated date to 
reflect finalization of amended protocol, 
updated pagination and TOC.
Protocol Amendment Summary
2-3
Updated table to include summary of 
changes to the protocol.
Synopsis
9
Updated medical monitor for the study.
 
28-30
•
•
4.2 Inclusion Criteria, #10b
6.12.1 Permitted Medications for 
the Treatment of UC
33, 55
 
 
 
 
  
4.3 Exclusion Criteria
35
 
 
 
Page 2 of 97


APD334
Arena Pharmaceuticals, Inc.
Clinical Trial Protocol: APD334-003 Amendment 04
21 September 2015
Confidential
Section(s) Amended
Page No(s).
Description of Changes Made
 
6.3.1 Physical Examination
41
Revised section to denote that an 
ophthalmoscopy would be performed as 
part of the physical examination at 
visits and that 
retinal photos will be taken during each 
ophthalmoscopy.
Table 2. Examples of eDiary 
Subscore Entries for Study 
Eligibility and Corresponding 
Subscore Derivation
47
Minor corrections to example table.
7.1
 
and
7.4.4
 
58, 61
Added retinal photos to 
physical/neurological examination section.
Page 3 of 97


APD334
Arena Pharmaceuticals, Inc.
Clinical Trial Protocol: APD334-003 Amendment 03
30 June 2015
Confidential
PROTOCOL AMENDMENT SUMMARY
The following is a list of major changes made to the APD334-003 Protocol Amendment 02
dated 17 June 2015. Minor clarifications and corrections have been made throughout for 
consistency. These changes are incorporated in Protocol Amendment 03 dated 30 June 2015.
Section(s) Amended
Page No(s).
Description of Changes Made
Header/Footer, Title Page, and 
TOC
All
Added “Amendment 03”, updated date to 
reflect finalization of amended protocol, 
updated pagination and TOC.
Protocol Amendment Summary
2
Updated table to include summary of 
changes to the protocol.
Section 4.3 Exclusion Criteria
33
Section 6.9.1 Flexible 
Proctosigmoidoscopy
45
The following provision is added to this 
section:
“A repeat flexible 
proctosigmoidoscopy may be 
permitted by the sponsor when the 
central reader indicates that the 
videoendoscope data was acquired 
incorrectly, or did not meet the 
minimal required quality standards."
Page 2 of 96


APD334
Arena Pharmaceuticals, Inc.
Clinical Trial Protocol: APD334-003 Amendment 02
17 June 2015
Confidential
PROTOCOL AMENDMENT SUMMARY
The following is a list of major changes made to the APD334-003 Protocol Amendment 01 
dated 01 May 2015. Minor clarifications and corrections have been made throughout for 
consistency. These changes are incorporated in Protocol Amendment 02 dated 17 June 2015.
Section(s) Amended
Page No(s).
Description of Changes Made
Header/Footer, Title Page, and 
TOC
All
Added “Amendment 02”, updated date to 
reflect finalization of amended protocol, 
updated pagination and TOC.
Title page
1
Updated medical monitor for study.
Protocol Amendment Summary
2-4
Updated table to include summary of 
changes to the original protocol.
Synopsis
Section 9.1.1.4 Exploratory 
Objective(s)
Section 9.5 Efficacy Endpoints 
11, 13-14, 
63-64
Synopsis
Section 9.6.1 Primary Efficacy 
analysis
14, 67
Added the following secondary analysis:
•
a logistic regression analysis with 
terms for treatment, presence or 
absence of current oral corticosteroid 
therapy at baseline and previous 
exposure to TNFα antagonists and the 
interaction between the 2 stratification 
factors (if appropriate) 
Page 2 of 96


APD334
Arena Pharmaceuticals, Inc.
Clinical Trial Protocol: APD334-003 Amendment 02
17 June 2015
Confidential
Section(s) Amended
Page No(s).
Description of Changes Made
 
Section 7.1
 
Section 7.4.4
 
29, 59 and 
61
 
 
 
30
Section 4.2 Inclusion Criteria #8
32
Section 4.3 Exclusion Criteria 
#27
Section 6.8.1 Laboratory 
Parameters
Section 6.8.2 Virology
35, 44-45
 
Section 4.3 Exclusion Criteria
36
 
 
Section 5.6 Dosage and 
Administration
38
Added the following clarification: 
On days with scheduled study visits, 
patients should not take their dose of 
study medication at home in order to 
complete pre-dose study procedures.  
Patients must be fasting on the days of 
their scheduled study visits.
Section 6.9.7 Complete Mayo 
Clinic Score, 3-component Mayo 
Clinic Score, and 
 
47, 67
Clarified the rounding procedure for the 
primary endpoint.
Page 3 of 96


APD334
Arena Pharmaceuticals, Inc.
Clinical Trial Protocol: APD334-003 Amendment 02
17 June 2015
Confidential
Section(s) Amended
Page No(s).
Description of Changes Made
Section 9.6.1 Primary Efficacy 
Analysis 
Section 6.12.2 Excluded 
Medications
55
Added moderate to strong inhibitors of 
CYP2C9 to the excluded medications 
section.
Section 9.6.1.1 Secondary and 
Exploratory Efficacy Analyses
68
Updated the various analyses to be 
performed by ANCOVA.
Section 9.6.2 Subgroup Analyses
68
Page 4 of 96


APD334
Arena Pharmaceuticals, Inc.
Clinical Trial Protocol: APD334-003 Amendment 01 
01 May 2015
Confidential
PROTOCOL AMENDMENT SUMMARY
The following is a list of major changes made to the APD334-003 Protocol dated 08 April 
2015. Minor clarifications and corrections have been made throughout for consistency. These 
changes are incorporated in Protocol Amendment 01 dated 30 April 2015.
Section(s) Amended
Page No(s).
Description of Changes Made
Header/Footer, Title Page, and 
TOC
All
Added “Amendment 01”, updated date to 
reflect finalization of amended protocol, 
updated pagination and TOC.
Title page
1
Updated medical monitor for study.
Protocol Amendment Summary
2-3
Updated table to include summary of 
changes to the original protocol.
Throughout
--
Changed the term Partial Mayo Clinic 
score to 3-component Mayo Clinic score.
Synopsis, 
List of Abbreviations, 
Study Definition, 
 
 
7 Study Activities, 
9.1.1.4 Exploratory Objectives, 
9.5 Efficacy Endpoints, 
9.6.1.1 Secondary and 
Exploratory Endpoints, 
11, 13, 17, 
29, 44, 55, 
58, 61, 64, 
65, 82-92
 
Study Definitions
19
Added definition of intolerable AE
1 Introduction
20
Minor changes to text for clarification
1.2 Ethics and Regulatory 
Considerations, 
Protocol Signature Page
24, 80
Removed reference to Declaration of 
Helsinki
 
27-29
•
•
Page 2 of 95


APD334
Arena Pharmaceuticals, Inc.
Clinical Trial Protocol: APD334-003 Amendment 01 
01 May 2015
Confidential
Section(s) Amended
Page No(s).
Description of Changes Made
•
 
 
7.4.4 Week 12/Exit or Early 
Termination Procedures
27, 58
•
 
 
 
 
5.6 Dosage and Administration
27, 36-37
 
 
4.2 Inclusion Criteria,
6.12.1 Permitted Medications for 
the Treatment of UC
32, 53
 
 
4.2 Inclusion Criteria
31-32
 
4.3 Exclusion Criteria
33-35
Removed separate exclusion criteria 
categories.
5.8.1 Randomization
37
Added statement capping the number of 
patients with previous exposure to TNFα 
antagonists 
5.8.2 Blinding, 
6.8.1 Laboratory Parameters, 
6.11.1 Adverse Event Reporting
37, 42, 48
Added blinding of 
 and 
White Blood Cell (WBC) counts from 
sponsor, patients and personnel involved 
in the conduct of the study. These values 
will not be sent to the sites, but reviewed 
by an unblinded CRO physician(s) for 
safety purposes.
Page 3 of 95


APD334
Arena Pharmaceuticals, Inc.
Clinical Trial Protocol: APD334-003 Amendment 01 
01 May 2015
Confidential
Section(s) Amended
Page No(s).
Description of Changes Made
6.8.1 Laboratory Parameters
42
Added (% and total MB) to creatinine 
kinase and MB subtype.
6.8.1 Laboratory Parameters,
7.1 Screening Visit
42, 56
Removed thyroid function tests.
6.8.3 Drugs of Abuse Screen,
7.4.1 Week 0/Day 1 Procedures
43, 57
Removed alcohol (breathalyzer).
6.8.4 Urinalysis
43
Added the following detail to section: 
“Microscopic urinalysis will be performed 
when there is a positive or abnormal 
macroscopic urinalysis result”.
6.10 
 and 
Hematologic Assessments
46-47
Replaced pharmacodynamic with 
“hematologic”
6.14 Allowable Visit and 
Procedure Windows
54
Revised window for 2-week follow-up 
visit to ± 3 days from last dose
7.4.1 Week 0/Day 1 Procedures, 
7.4.4 Week 12/Exit or Early 
Termination Procedures
57, 58
Corrected list of laboratory tests to be 
administered to include hematology.
9.6.2 Subgroup Analyses
66
 
Page 4 of 95

SAP_001.pdf: 
Statistical Analysis Plan 
Title: 
A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Parallel 
Group, Multi-Center Study to Investigate the Safety and Efficacy of 
APD334 in Patients with Moderately to Severely Active Ulcerative 
Colitis 
Document Number: APD334-003 
Product Name: 
APD334 
Formulation: 
Capsules 
Indication: 
Ulcerative Colitis 
Sponsor: 
Arena Pharmaceuticals, Inc.  
6154 Nancy Ridge Drive 
San Diego, CA 92121 
Authors: 
PPD Global Ltd. 
 PPD 
Approval: 
Arena Pharmaceuticals, Inc 
Date: 
27 Feb 2018 
Confidentiality Statement 
This document contains confidential information of Arena Pharmaceuticals, Inc.  Unauthorized 
distribution, copying, or disclosure is strictly prohibited unless required by applicable law.  Persons 
receiving this information must be notified that it is confidential and may not be further disclosed. 
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NCT Number: NCT02447302
This NCT number has been applied to the document for
purposes of posting on clinicaltrials.gov


Statistical Analysis Plan: APD334-003 
 
Arena Pharmaceuticals, Inc. 
APD334 
 
27 Feb 2018 
 
 
TABLE OF CONTENTS 
List of In-Text Tables ..........................................................................................................4 
List of Appendices ...............................................................................................................4 
LIST OF ABBREVIATIONS ....................................................................................................5 
1 
INTRODUCTION .............................................................................................................7 
1.1 
Objective of the Statistical Analysis Plan ................................................................7 
1.2 
Description of the Study and Objectives/Hypotheses ..............................................7 
1.2.1 
Summary of Study Design .............................................................................7 
1.2.2 
Efficacy Questionnaire:  Mayo Clinic Score (MCS) .....................................8 
1.2.2.1 
Complete Mayo Clinic Score (Total Mayo Score, TMS) ....................8 
1.2.2.2 
3-Component Mayo Clinic Score (Partial Mayo Score, PMS) ............9 
1.2.2.3 
2-Component Mayo Clinic Score ......................................................10 
1.2.3 
Efficacy Questionnaire:  
 
 .........................................................................................................10 
1.2.4 
Objectives ....................................................................................................10 
1.2.5 
Hypotheses ...................................................................................................13 
1.2.5.1 
Primary Hypothesis ............................................................................13 
1.2.5.2 
Secondary Hypotheses .......................................................................13 
2 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ..........................14 
3 
PATIENT DISPOSITION ...............................................................................................15 
4 
EFFICACY ANALYSES ................................................................................................16 
4.1 
Efficacy Endpoints .................................................................................................16 
4.2 
Analysis Population ...............................................................................................19 
4.3 
Approaches to Efficacy Analysis ...........................................................................19 
4.3.1 
Primary Efficacy Analysis ...........................................................................20 
4.3.2 
Secondary Efficacy Analyses ......................................................................20 
4.3.3 
Exploratory Efficacy Analyses ....................................................................20 
4.5 
Definition of Compliance Measure ........................................................................23 
5 
SAFETY ANALYSES.....................................................................................................24 
5.1 
Safety Population ...................................................................................................24 
5.2 
Dose and Duration .................................................................................................24 
5.3 
Adverse Events ......................................................................................................24 
5.4 
Physical Examinations ...........................................................................................25 
5.5 
Concomitant Medication ........................................................................................25 
5.6 
Vital Signs ..............................................................................................................25 
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Statistical Analysis Plan: APD334-003 
 
Arena Pharmaceuticals, Inc. 
APD334 
 
27 Feb 2018 
 
 
5.7 
Clinical Laboratory Values ....................................................................................25 
5.8 
Safety ECG (12-lead ECG) and Holter Monitoring ..............................................25 
6 
OTHER ANALYSES ......................................................................................................27 
6.1 
Interim Analyses ....................................................................................................27 
6.2 
Subgroup Analyses ................................................................................................27 
6.3 
Multiplicity ............................................................................................................28 
6.4 
Statistical Assumptions Checking..........................................................................29 
6.5 
Data/Study Reviewing Committees .......................................................................30 
7 
STATISTICAL TECHNICAL ISSUES ..........................................................................31 
7.1 
Planned Statistical Power and Sample Size ...........................................................31 
7.2 
Method of Assigning Participants to Treatment Groups Study .............................31 
7.3 
Blinding/Unblinding ..............................................................................................31 
7.4 
Handling of Missing Data and Sensitivity Analysis ..............................................31 
7.4.1 
Multiple Imputation for Primary Efficacy Analysis ....................................31 
7.4.2 
Additional Sensitivity Analyses ...................................................................33 
8 
DATA HANDLING CONVENTIONS ...........................................................................35 
8.1 
Baseline Definitions or Conventions .....................................................................35 
8.2 
Time Points, and Day Ranges ................................................................................35 
8.3 
Description of Data Handling Procedures Prior to Unblinding .............................37 
9 
CHANGES IN THE PLANNED ANALYSIS FROM THE PROTOCOL .....................38 
10 REFERENCES ................................................................................................................40 
 
 
 
 
 
 
 
 
 
 
 
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Statistical Analysis Plan: APD334-003 
 
Arena Pharmaceuticals, Inc. 
APD334 
 
27 Feb 2018 
 
 
 
List of In-Text Tables 
Table 1. 
Examples of eDiary Subscore Entries for Study Eligibility and Corresponding 
Subscore Derivation ...........................................................................................8 
Table 2. 
Examples of eDiary Subscore Entries and Corresponding Subscore Derivation9 
 
List of Appendices 
Appendix 2 
Listing of Efficacy Parameters and Study Populations Analysed ...................45 
Appendix 3 
Mayo Clinic Score ...........................................................................................46 
Appendix 5 
Multiple Imputation Model ..............................................................................57 
 
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Statistical Analysis Plan: APD334-003 
 
Arena Pharmaceuticals, Inc. 
APD334 
 
27 Feb 2018 
 
 
LIST OF ABBREVIATIONS 
μg 
microgram 
ANCOVA 
analysis of covariance 
BLQ 
below limit of quantification 
CBC 
complete blood count (test) 
CI 
confidence interval 
CRF 
case report form 
CMH 
Cochran-Mantel-Haenszel 
CRO 
contract research organization 
DMC 
Data Monitoring  Committee 
DSMB  
Data Safety Monitoring Board 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
FCS 
fully conditional specification 
ITT 
intent-to-treat 
LOCF 
Last Observation Carried Forward 
LSM 
least square mean 
MAR 
missing at random 
MCS 
Mayo Clinic Score 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Multiple imputation 
MITT 
modified intent-to-treat 
MNAR 
missing not at random 
PGA 
Physician’s Global Assessment 
PMS 
Partial Mayo Score 
POC 
Proof of concept 
PRO 
patient reported outcome 
q.d. 
once daily 
QTc 
QT interval corrected for HR 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SOC 
System Organ Class 
TEAE 
treatment-emergent adverse event 
TMS 
Total Mayo Score 
WHODRUG 
World Health Organization Drug Dictionary 
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Statistical Analysis Plan: APD334-003 
 
Arena Pharmaceuticals, Inc. 
APD334 
 
27 Feb 2018 
 
 
1 
INTRODUCTION 
1.1 
Objective of the Statistical Analysis Plan 
This statistical analysis plan (SAP) provides the statistical rationale and methods that will be 
applied to data gathered in clinical trial Protocol No.APD334-0031  in order to assess the safety 
and efficacy of APD334 in patients with moderately to severely active ulcerative colitis. Section 
9 of this SAP discusses the changes in the planned analysis from the protocol. This SAP is 
finalized prior to database lock and data analysis start.  Major changes in the analysis that are 
made after database lock will be documented in the Clinical Study Report with the rationales and 
details. 
Unless otherwise noted, all statistical testing is one-sided and it is appropriate for this proof-of-
concept phase 2 study to assess treatment effects of APD334 in patients with moderately to 
severely active ulcerative colitis. 
1.2 
Description of the Study and Objectives/Hypotheses 
1.2.1 
Summary of Study Design 
APD334-003 is a phase 2, proof-of-concept and dose ranging clinical study designed to test the 
safety and efficacy of APD334 in patients with moderately to severely active ulcerative colitis 
and who have demonstrated, over the previous 5 year period, an inadequate response to, loss of 
response to, or intolerance of at least one of the following agents: oral 5-aminosalicylates, 
corticosteroids, immunosuppressives, TNFα antagonists, or integrin antagoinists. Eligible 
patients will be randomized into a double-blind, placebo-controlled study to receive once daily 
(q.d.) doses of APD334 (1 mg or 2 mg) or matching placebo in a 1:1:1 ratio for 12 weeks and 
will be stratified by presence or absence of current oral corticosteroid usage and previous 
exposure to TNFα antagonists.  Patients who are receiving corticosteroids at baseline must 
remain on the same dose for the duration of the study.  No more than 50% of patients will have 
been previously exposed to TNFα antagonists.  The trial will include adult men and women, ages 
18-80 years, who have moderately to severely active ulcerative colitis (defined as a 3 component 
Mayo score (including the endoscopic, stool frequency, and rectal bleeding) of 4 to 9 with an 
endoscopic subscore of ≥ 2 and a rectal bleeding score of ≥ 1)
 
   
The total study duration is approximately 18 weeks; 4 weeks for screening procedures, followed 
by 12 weeks of dosing, and a possible follow-up visit at week 14.  Patients will capture daily 
stool frequency and rectal bleeding using an electronic device throughout the study and will 
return to the study at regular intervals for safety, 
, and efficacy assessments. A 34-week 
extension study is offered to patients who wish to continue treatment (APD334-005). Patients 
who choose not to participate in the extension study or who have discontinued prematurely from 
the study will have a 2-week follow-up visit after the last clinical visit.  The schedule of 
procedures and visits for the study is provided in 
. 
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Statistical Analysis Plan: APD334-003 
 
Arena Pharmaceuticals, Inc. 
APD334 
 
27 Feb 2018 
 
 
1.2.2 
Efficacy Questionnaire:  Mayo Clinic Score (MCS)   
1.2.2.1 
Complete Mayo Clinic Score (Total Mayo Score, TMS) 
The complete Mayo Clinic Score is an instrument designed to measure disease activity of 
ulcerative colitis and consists of 4 subscores: stool frequency, rectal bleeding, findings of 
flexible proctosigmoidoscopy, and physician global assessment and total score ranging from 0 to 
12 (see Appendix 3). Each component is scored individually on an integer scale of 0 to 3 
(0=normal, 1=mild, 2=moderate, 3=severe), with higher scores indicating greater disease 
activity. 
At Screening Visit: 
The MCS will be evaluated during screening using patient diary entries within the 10 days prior 
to randomization and flexible proctosigmoidoscopy results within 10 days prior to 
randomization. The subscores for stool frequency and rectal bleeding are derived from the 
patient diaries. The scores from the 3 most recent days prior to the actual day of the study visit 
will be averaged and rounded to the nearest integer.  The rounding will be applied to each 
subscore prior to the creation of the total score. Note that the day prior, day of and day after 
proctosigmoidoscopy cannot be used for patient diary entry because of the required bowel prep 
for the procedure. Patients who have less than 3 days of diary data during screening are not 
eligible for randomization. Examples of the subscore entries for eligibility and subscore 
derivation are provided in Table 1.  
Table 1. 
Examples of eDiary Subscore Entries for Study Eligibility and 
Corresponding Subscore Derivation 
Example 
Diary Day 
Valid Days 
for 
Calculation 
of Subscore 
Average 
Subscore 
Final 
Subscore 
-10 
-9 
-8 
-7 
-6 
-5 
-4 
-3 
-2 
-1 
1 
Diary #1 
1 
2 
3 
X 
P 
X 
2 
1 
3 
1 
E 
-1, -2, -3 
1.66 
2 
Diary #2 
2 
2 
2 
3 
X 
P 
X 
M 
1 
3 
E 
-1, -2, -7 
2.33 
2 
Diary #3 
3 
2 
3 
3 
3 
X 
P 
X 
3 
E 
 
-2, -6, -7 
3.00 
3 
Diary #4 
3 
0 
1 
X 
P&
E 
X 
 
 
 
 
 
-8, -9, -10 
1.33 
1 
Diary #5 
1 
2 
X 
P&E 
X 
 
 
 
 
 
 
Missing 
N/A 
Missing 
Diary #6 
1 
2 
3 
1 
3 
3 
3 
2 
3 
X 
P&E 
-2, -3, -4 
2.67 
3 
Abbreviations: E = eligibility; M = missing; P = proctosigmoidoscopy; X = non-scoring day before and after 
proctosigmoidoscopy  
 
The physician’s global assessment (PGA) acknowledges the three other criteria findings of the 
MCS, the patient’s daily record of abdominal discomfort and general sense of well-being, and 
other observations, such as physical findings and the patient’s performance.  
At Other Study Visits: 
For each study visit during the study (excluding the screening/baseline visit which uses 10 prior 
days), stool frequency and rectal bleeding subscores will be derived from electronic patient 
diaries completed over the 7 days prior to a study visit. Note that the day prior, day of and day 
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Statistical Analysis Plan: APD334-003 
 
Arena Pharmaceuticals, Inc. 
APD334 
 
27 Feb 2018 
 
 
after proctosigmoidoscopy will not be used for patient diary entry because of the required bowel 
prep for the procedure. These subscores will be calculated using the following rules: 
1. The scores from the 3 most recent days prior to the actual day of the study visit will be 
averaged and rounded to the nearest integer. 
2. If patient diary entries from 3 days are not available, the scores from the 2 most recent 
entries will be averaged and rounded to the nearest integer. 
3. If less than 2 days of diary data are available, the subscore will be considered missing. 
 
The rounding will be applied to each subscore prior to the creation of the total score.  Table 2 
provide examples of the subscore entries and subscore derivation. 
Table 2. 
Examples of eDiary Subscore Entries and Corresponding Subscore 
Derivation 
Example 
Diary Day1 
Valid Days for 
Calculation of 
Subscore 
Average 
Subscore 
Final 
Subscore 
-7 
-6 
-5 
-4 
-3 
-2 
-1 
Diary #1 
1 
2 
3 
1 
0 
0 
3 
-1, -2, -3 
1.00 
1 
Diary #2 
X 
P 
X 
2 
1 
3 
1 
-1, -2, -3 
1.66 
2 
Diary #3 
1 
2 
3 
X 
P 
X 
2 
-1, -5, -6,   
2.33 
2 
Diary #4 
2 
M 
M 
1 
M 
M 
M 
-4, -7 
1.5 
2 
Diary #5 
M 
M 
3 
M 
M 
M 
M 
Missing 
N/A 
Missing 
1 Days are named relative to the Day of Study Visit; Abbreviations: M = missing; P = proctosigmoidoscopy; X = 
non-scoring day before and after proctosigmoidoscopy  
 
The MCS will also be evaluated at Week 12 using the Week 12 proctosigmoidoscopy and stool 
frequency and rectal bleeding scores completed by the patients seven days prior to the visit.   
The proctosigmoidoscopy subscore is evaluated by the investigator and a blinded central reader. 
For analysis purposes, only the central reader results be will used and the derived Mayo Clinic 
Scores calculated by case report form (CRF) Health eDiary vendor will be analysed. 
1.2.2.2 
3-Component Mayo Clinic Score (Partial Mayo Score, PMS) 
There are two 3-component Mayo Clinic Scores consisting of 3 of the 4 subscores found in the 
MCS. 
1. PMS#1: the primary endpoint, consists of subscores for stool frequency, rectal bleeding 
and findings of flexible proctosigmoidoscopy. 
2. 
Total score for the 3-component MCS range: 0 to 9, each component ranging from 0 to 3 
(0=normal, 1=mild, 2=moderate, 3=severe).  Both 3-component Mayo scores will be evaluated at 
baseline and Week 12.   
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Statistical Analysis Plan: APD334-003 
 
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APD334 
 
27 Feb 2018 
 
 
1.2.2.3 
2-Component Mayo Clinic Score  
 The 2-component Mayo Clinic Score consists of 2 of the 4 subscores found in the MCS (i.e. 
rectal bleeding and findings on endoscopy). Total score for the 2-component MCS range: 0 to 6, 
each component ranging from 0 to 3 (0=normal, 1=mild, 2=moderate, 3=severe).  The 2-
component Mayo score will be evaluated at baseline and Week 12.   
1.2.3 
Efficacy Questionnaire: 
1.2.4 
Objectives 
Primary Objective: The primary objective of this proof-of-concept study is to determine the 
effect of treatment with APD334 in improving PMS#1, 3-component Mayo Clinic Score (score 
ranging from 0 to 9, including stool frequency, rectal bleeding and findings on endoscopy) at 
Week 12 
 
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Statistical Analysis Plan: APD334-003 
 
Arena Pharmaceuticals, Inc. 
APD334 
 
27 Feb 2018 
 
 
Secondary Objectives: 
 To determine the effect of treatment with APD334 on endoscopic improvement at 12 
weeks 
 To determine the effect of APD334 treatment on 2-component Mayo Clinic Score (rectal 
bleeding and findings on endoscopy) at 12 weeks 
 
 To determine the effect of APD334 treatment Total Mayo Clinic Score at 12 weeks 
 
     Medical Rationale for Choice of Secondary Endpoints 
 
 Endoscopic improvement of mucosal inflammation, as assessed by proctosigmoidoscopy, is a 
secondary endpoint for this study, and is considered a lead indicator of endoscopic mucosal 
healing in a proof-of-concept clinical trial. This endpoint measure is selected because 
colorectal mucosal inflammation is a defining, diagnostic feature of ulcerative colitis that 
provides direct, visual evidence of the inflammation characteristic of the disease2, and a key 
goal in treating patients with ulcerative colitis is to control inflammation3,4. Mucosal healing 
is considered an important treatment goal in both clinical trials and clinical practice because 
it is associated with improved outcomes, including sustained clinical remission, steroid-free 
remission, decreased rates of surgery, and fewer hospitalizations4. Endoscopic assessments of 
mucosal inflammation are encouraged by the Food and Drug Administration (FDA) 
according to the interim approaches to efficacy assessments described in the current Draft 
Guidance for Industry5. The European Medicines Agency (EMA) requires demonstration of 
treatment effects on the inflammatory process in ulcerative colitis by endoscopic 
assessments, as described in the Agency’s Draft Guideline6. 
 
 A two-component Mayo Clinic Score (selecting the “Rectal bleeding” and “Findings on 
flexible sigmoidoscopy” components, and omitting the “Stool frequency” and “Physician’s 
global assessment” components as originally described7) is a secondary endpoint for this 
study. The rectal bleeding component is selected because of the clarity and ease of patients’ 
reports of this finding on a contemporaneous basis. The findings on flexible sigmoidoscopy 
component is selected based on the rationale provided in the preceding paragraph. The stool 
frequency component is omitted because the scoring method requires patients to assess 
contemporaneous stool frequency in comparison to that during a previous “normal” health 
state, either before symptoms of ulcerative colitis began or during periods of remitted and 
quiescent disease. As such, the “normal” stool frequency is subject to patient recall bias. 
Further, the difficulties in patients’ capabilities in accurately reporting numbers of stools 
necessitates specific instruction, as described in the FDA Guidance5, and which unfortunately 
may not be heeded or consistently followed by investigators or understood by patients. The 
physician’s global assessment component is omitted because, per the FDA Guidance5, 
clinician-reported outcome measures cannot directly assess symptoms that are known only to 
the patient, and FDA encourages sponsors to develop patient-reported outcome (PRO) 
instruments as an ideal primary efficacy assessment tool for the treatment of ulcerative 
colitis5. 
 
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Statistical Analysis Plan: APD334-003 
 
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APD334 
 
27 Feb 2018 
 
 
 Total Mayo Score (4-component and ranging 0 to 12), will reflect a broad examination of 
potential clinical improvement across four domains (stool frequency, rectal bleeding, 
findings on flexible proctosigmoidoscopy and physician’s global assessment). 
 
Safety Objective:  
To determine the safety profile and tolerability of APD334 induction treatment 
Exploratory Objectives: 
 To determine the effect of treatment with APD334 in inducing clinical remission at 12 
weeks 
 To determine the effect of treatment with APD334 in inducing clinical response at 12 
weeks  
 To determine the effect of treatment with APD334 on a combination of clinical remission 
and clinical response reflected by a composite endpoint at 12 weeks 
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Statistical Analysis Plan: APD334-003 
 
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APD334 
 
27 Feb 2018 
 
 
 
1.2.5 
Hypotheses  
1.2.5.1 
Primary Hypothesis  
In patients with moderately to severely active ulcerative colitis, treatment with APD334 
compared with placebo will provide greater improvement in 3-component Mayo Clinic Score 
(consisting of subscores for stool frequency, rectal bleeding and findings of endoscopy) at 12 
weeks. 
1.2.5.2 
Secondary Hypotheses 
 In patients with moderately to severely active ulcerative colitis, treatment with APD334 
compared with placebo will provide more patients that achieve endoscopic improvement 
at 12 weeks. 
 
 In patients with moderately to severely active ulcerative colitis, treatment with APD334 
compared with placebo will provide greater improvement in 2-component Mayo Clinic 
Score (consisting of rectal bleeding and findings on endoscopy) at 12 weeks. 
 
 In patients with moderately to severely active ulcerative colitis, treatment with APD334 
compared with placebo will provide greater improvement in Total Mayo Clinic Score 
(consisting of stool frequency, rectal bleeding, findings of flexible proctosigmoidoscopy, 
and physician global assessment) at 12 weeks. 
 
 
 
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Statistical Analysis Plan: APD334-003 
 
Arena Pharmaceuticals, Inc. 
APD334 
 
27 Feb 2018 
 
 
2 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
All baseline patient characteristics of demographic data (age, height, and weight), ulcerative 
colitis history, social history, medical history (abnormalities only), physical examination 
(abnormalities only), and concomitant medications at study entry will be listed for all patients.  
Demographic and baseline characteristics of the safety population will be summarized by 
treatment group and for the overall population.  Baseline for the demographic variables will be 
the last pre-randomization value collected at the screening visit. Continuous variables will be 
summarized using number of values (n), mean, standard deviation (SD), median, minimum, and 
maximum.  Frequencies and percentages will be reported for all categorical data.  No formal 
statistical testing comparing treatment groups will be performed. 
The following variables will be summarized by treatment group: 
1. Continuous baseline demographic variables: age (years). 
2. Categorical baseline demographic variables: sex (female or male), race (American Indian 
or Alaska Native, Asian, Black or African-American, Native Hawaiian or Other Pacific 
Islander, White or Caucasian, or Other) and ethnicity (Hispanic or Latino, Not Hispanic 
or Latino). 
3. Ulcerative colitis history which include:  
 Duration of Ulcerative Colitis (in years) 
 Disease localization (Proctosigmoiditis/Left sided colitis, Pancolitis/ Extensive 
colitis) 
 Presence or absence of current oral corticosteroid usage at baseline 
 Inadequate responders/Lost response and/or Intolerant to corticosteroid (including 
duration of treatment) 
 Previous exposure to TNFα antagonists (including duration of treatment) 
 Inadequate responders/Lost response and/or Intolerant to TNFα antagonists 
 Previous exposure to immunosuppressives (including duration of treatment) 
 Inadequate responders/Lost response and/or Intolerant to immunosuppressives 
 Previous use of integrin antagonist (including duration of treatment) and response 
 Previous use of oral 5-aminosalicylates (including duration of treatment) and 
response 
 Baseline Disease Activity (Mayo Clinic Scores) 
 
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Statistical Analysis Plan: APD334-003 
 
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27 Feb 2018 
 
 
3 
PATIENT DISPOSITION 
The number of patients enrolled in the study by country and treatment group will be tabulated.  
Tables showing study participant accounting will be provided.  Tables will indicate number of 
patients who were randomized into the study, the number of patients who completed treatment 
and/or completed the study, and the number of patients who discontinued treatment and/or 
discontinued study prematurely (early termination) for any of the following reasons:  
 Adverse event(s) 
 Patient lost to follow up 
 Patient withdrawal of consent 
 Investigator decision 
 Sponsor decision 
 Death 
 Other 
Protocol deviations will be listed and tabulated by subtype. 
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Statistical Analysis Plan: APD334-003 
 
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APD334 
 
27 Feb 2018 
 
 
4 
EFFICACY ANALYSES  
4.1 
Efficacy Endpoints 
A table is provided in Appendix 2 summarizing the efficacy variables and their analysis 
populations.   
Primary Endpoint 
Improvement of PMS#1, 3-component Mayo Clinic Score (score ranging from 0 to 9, including 
stool frequency, rectal bleeding and findings on endoscopy) at Week 12. 
 
Secondary Endpoints 
Secondary efficacy variables include: 
 Proportion of patients who achieve endoscopic improvement at Week 12 
Endoscopic improvement is defined as Mayo endoscopic subscore (using findings of 
flexible proctosigmoidoscopy) of ≤ 1 point. 
 
 Improvement in 2-component Mayo score (score ranging from 0 to 6, including rectal 
bleeding and findings on endoscopy) at Week 12  
 
 Improvement in Total Mayo Clinic Score (score ranging from 0 to 12, including stool 
frequency, rectal bleeding, findings on endoscopy and physician’s global assessment) at 
Week 12. 
       
Exploratory Endpoints 
The exploratory efficacy endpoints are listed below: 
 The trichotomous composite endpoint of clinical remission and clinical response (score 
ranging 0 to 2: score 2 for achieving both clinical remission and clinical response; 1 for 
achieving only clinical response, and 0 for achieving neither) at Week 12. 
 The proportion of patients achieving clinical remission at Week 12  
A patient has achieved clinical remission if he/she has:  
 an endoscopy score using flexible proctosigmoidoscopy of 0 or 1 (excluding 
friability) and 
 a rectal bleeding score of 0 or 1 and 
 a stool frequency score of 0 or 1 with a decrease of  ≥ 1 point from baseline 
 
 Proportion of patients who achieve clinical response at Week 12 
A patient has achieved clinical response if he/she meets criteria of clinical remission 
defined above, or meet criteria of clinical response defined in the protocol. Clinical 
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Statistical Analysis Plan: APD334-003 
 
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APD334 
 
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response is defined as a decrease in 3-component Mayo Clinic score of ≥ 2 points and a 
decrease of ≥ 30% with either a decrease of rectal bleeding of ≥ 1 or rectal bleeding score 
of 0 or 1 
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Statistical Analysis Plan: APD334-003 
 
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27 Feb 2018 
 
 
4.2 
Analysis Population 
All analyses on efficacy variables will use the Modified Intent-to-Treat (MITT) population as 
primary.  A completer’s population will be used as a secondary analysis population for the 
primary and secondary endpoints. The Intent-to-Treat (ITT) population will be used as 
sensitivity analysis population for proportion-based efficacy endpoints. 
Intent-to-Treat Population (ITT):  
This population consists of all randomized patients, who received at least 1 dose of study 
medication. Under this approach, patients are counted in the treatment group to which they were 
randomized, regardless of the treatment received during the course of the trial. In this population, 
missing data handling for efficacy analyses will be specified in Section 7.4.   
Modified Intent-to-Treat Population (MITT):  
This population consists of all randomized patients, who received at least 1 dose of study 
medication, have a baseline measurement, and have a post-randomization measurement. Under 
this approach, patients are counted in the treatment group to which they were randomized, 
regardless of the treatment received during the course of the trial.  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 in the MITT population who completed the 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 randomized patients who received study medication. 
4.3 
Approaches to Efficacy Analysis 
The efficacy endpoints at Week 12 will be analysed in the ITT population using the multiple 
imputation (MI) method to handle missing data.  See Section 7.4.1, Section 9 and Appendix 5 for 
details.  
For all analyses, two models will be fitted. One model will be fitted for the individual treatment 
comparisons (APD334 2mg vs Placebo, APD334 1mg vs Placebo, APD334 2mg vs APD334 
1mg) with the treatment term containing the three treatment groups, namely APD334 2mg, 
APD334 1mg and Placebo, and a second model will be fitted for the pooled treatment 
comparison (APD334 2mg & 1mg vs Placebo) with the treatment term containing two treatment 
groups, pooled APD334 2mg & 1mg and Placebo. 
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Statistical Analysis Plan: APD334-003 
 
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27 Feb 2018 
 
 
4.3.1 
Primary Efficacy Analysis 
The primary analysis will be based on the change from baseline in 3-component Mayo Clinic 
Score (consisting of subscores for stool frequency, rectal bleeding and findings of endoscopy) at 
Week 12 using an analysis of covariance (ANCOVA) model with terms for treatment, current 
oral corticosteroid use, prior exposure to TNFα antagonists and baseline value as covariate. 
Least-squares mean (LSM) by treatment group and its 90% confidence interval (CI), and least-
squares mean difference between treatment group and its 90% CI will be reported. 
 
4.3.2 
Secondary Efficacy Analyses 
The secondary analyses include the following: 
 The proportion of patients who achieve endoscopic improvement will be analysed 
individually using Cochran-Mantel-Haenszel (CMH) test adjusted for the stratification 
factors of presence or absence of current oral corticosteroid therapy at baseline and previous 
exposure to TNFα antagonists, to compare the difference of proportions between treatment 
groups. The CMH stratified risk difference and its 90% confidence interval will be provided. 
 
 The analyses based on the change from baseline in 2-component Mayo Clinic Score and 
Total Mayo Clinic Score at Week 12 will be performed using an ANCOVA model with 
terms for treatment, current oral corticosteroid use, prior exposure to TNFα antagonists and 
baseline value as covariate. Least-squares mean (LSM) by treatment group and its 90% 
confidence interval (CI), and least-squares mean difference between treatment group and its 
90% CI will be reported. 
 
 
4.3.3 
Exploratory Efficacy Analyses 
Trichotomous composite endpoint of clinical remission and clinical response at Week 12 is an 
ordinal categorical endpoint with 3 categories (2, 1, 0). It will be analysed using Cochran-
Mantel-Haenszel method adjusted for the stratification factors of presence or absence of current 
oral corticosteroid therapy at baseline and previous exposure to TNFα antagonists. The testing 
statistic and p-value will be computed using modified ridit scores for between-treatment 
comparison. 
For proportion based efficacy endpoints such as
 
patients who achieve clinical remission and proportion of patients who achieve clinical response 
similar analyses specified for secondary analyses, such as CMH test will be performed.  
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Dose response analyses will be performed using an ANCOVA model for continuous variables, or 
logistic regression model for categorical variables, as appropriate. Treatment group and 
appropriate baseline covariate will be included in the analysis model. Statistical testing of dose 
response trend will be based on appropriate contrast statement assuming monotonic dose 
response profile in placebo (lowest response), APD334 low dose (middle-range response) and 
APD334 high dose (highest response). 
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4.5 
Definition of Compliance Measure  
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 compliance rate for each patient will be computed as 100% x (actual number of 
tablets taken over the study period)/ (designated total number of tablets that should have been 
taken over the study period).  Study period is defined as the number of days that the patient has 
been in the active treatment phase of the trial.  Compliance rates will be summarized for each 
treatment group. 
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5 
SAFETY ANALYSES 
Safety and tolerability will be assessed by a review of all safety parameters including adverse 
experiences (AEs), laboratory safety parameters, vital signs, and electrocardiogram (ECG).  Only 
summary tabulations (N, mean [or median], SD, mean [or median] change/percent change) and 
90% CIs for between-group differences will be obtained.  Adverse experiences will only be 
presented as summary tabulations.   
5.1 
Safety Population 
The analyses for all safety outcomes (categorical or continuous measures) will use the safety 
population which consists of all randomized patients who received at least 1 dose of study drug; 
in addition, if a patient is found to have taken a study therapy for the entire duration of the study 
different from that to which he/she was randomized, then the patient is counted in the treatment 
group of the drug he/she actually received.   
For analysis based on laboratory measurements, at least 1 laboratory test post-randomization is 
required for inclusion in the safety population.  When assessing change from baseline, a baseline 
measurement is also required.  No missing data will be imputed for the safety analysis. 
5.2 
Dose and Duration 
The duration of treatment for each patient will be assessed by calculating the number of weeks 
on drug.  For each dosage, the range (minimum and maximum) of values for days on drug and 
the mean number of days on drug and exposure in patient-weeks will be calculated. 
5.3 
Adverse Events 
Adverse events will be coded using the most current Medical Dictionary for Drug Regulatory 
Affairs (MedDRA, version 18.0 or later) 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 or placebo and will be recorded as medical history. 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 patient and by treatment.  They will be 
summarized per treatment and expressed in terms of maximum severity and relationship to study 
medication.  The incidence of TEAEs classified according to system organ class (SOC) will be 
summarized by treatment group.  TEAEs will also be summarized by maximum intensity 
(assessed according to the Common Terminology Criteria for Adverse Events v4.038definitions) 
and relatedness to study medication. 
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Summaries of the number (%) of patients in each treatment group 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 and by treatment.  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. 
5.4 
Physical Examinations 
Physical examination dates will be listed. 
5.5 
Concomitant Medication 
Pre-treatment and concomitant medication administered during the study will be listed.  
Concomitant medications will be coded using the World Health Organization Drug Dictionary 
(WHODRUG Dictionary) and will be tabulated by drug class and preferred term. 
5.6 
Vital Signs 
Individual vital sign measurements will be listed by treatment and summarized using descriptive 
statistics.  Summary statistics will also be provided for change from baseline in vital sign 
measurements by treatment.  If Day 1 pre-dose assessment is completed then this will be used for 
baseline. If the Day 1 pre-dose assessment is missing, then the last non-missing assessment prior 
to randomization will be used.      
5.7 
Clinical Laboratory Values 
Individual lab values will be listed by treatment and visit, and summarized using descriptive 
statistics.  Summary statistics will also be provided for change from baseline in lab values. Shift 
tables from baseline to last double-blind visit will also be produced for the laboratory 
assessments based on the categories of Low, Normal, and High.  Baseline is defined as the last 
value of a specific endpoint measured before first dose of study medication. 
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. 
 
5.8 
Safety ECG (12-lead ECG) and Holter Monitoring 
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6 
OTHER ANALYSES 
6.1 
Interim Analyses  
Sponsor may plan an unblinded interim analysis at time when sufficient number of patients have 
finished 12 weeks of treatment. If sponsor decides to perform an interim analysis, it will be 
operated by an independent Data Monitoring Committee (DMC). 
 
6.2 
Subgroup Analyses  
Subgroup analyses for the primary efficacy endpoint (i.e., improvement of 3-component Mayo 
Clinic Score consisting of subscores for stool frequency, rectal bleeding and findings of 
endoscopy at Week 12) and other important efficacy endpoints will be performed in order to 
explore whether the treatment effects are consistent across different subgroups.  The baseline 
patient characteristics below are the subgroup factors to be explored. 
 Sex (Male, Female) 
 Age: > or ≤ median age, ≥ or < 65 years 
 Race 
 Presence or absence of current oral corticosteroid usage 
 Previous exposure to TNFα antagonists 
 Responders vs. subjects who had inadequate / loss of response in previous exposure 
to TNFα antagonists 
 Baseline Total Mayo score ≤ 8 vs > 8. 
 
The change from baseline in 3-component Mayo Clinic Score at Week 12 using an ANCOVA 
model with terms for treatment, subgroup, treatment-by-subgroup interaction, and baseline value 
as covariate will be provided. Least-squares mean (LSM) by treatment group for each of the 
subgroups and its 90% confidence interval (CI), and least-squares mean difference between 
treatment group for each of the subgroups and its 90% CI will be reported. A forest plot for all 
subgroups will be presented for the least-squares mean differences. 
In addition to the subgroup analyses for the primary endpoint, the following analyses will be 
performed: 
 
 
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6.3 
Multiplicity 
Primary comparison is between APD334 2 mg vs placebo
 
The primary analysis will compare PMS#1 change from baseline between treatment groups using 
a one-sided test at the 0.05 level of significance and 90% CI will be reported. If the result is 
significant, the primary hypothesis will be considered satisfied and this study will be declared 
positive. If this primary test is significant the secondary testing will proceed as following. 
Secondary endpoints: 
1. Proportion of patients who achieve endoscopic improvement at Week 12 
2. Improvement in 2 component Mayo score (score ranging from 0 to 6, including rectal 
bleeding and findings on endoscopy) at Week 12  
3. Improvement in Total Mayo Clinic Score (score ranging from 0 to 12, including stool 
frequency, rectal bleeding and findings on endoscopy, and physician’s global assessment) at 
Week 12. 
If the primary testing is significant, testing for secondary endpoints will proceed in pre-specified 
order.  Provided that all previously specified tests are statistically significant (p < 0.05), each of 
these comparisons will be assessed using the one-sided test at the 0.05 level of significance. 
However, if a comparison is not statistically significant, then subsequent comparison(s) will be 
considered exploratory. 
Exploratory endpoints: 
 The trichotomous composite endpoint of clinical remission and clinical response (score 
ranging 0 to 2: score 2 for achieving both clinical remission and clinical response; 1 for 
achieving only clinical response, and 0 for achieving neither) at Week 12. 
 The proportion of patients achieving clinical remission at Week 12  
 Proportion of patients who achieve clinical response at Week 12 
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Non-formal statistical testing on treatment effect will be performed and reported along with 
nominal p-values.  
6.4 
Statistical Assumptions Checking 
For score or continuous measures, the assumptions for ANCOVA may be checked by the 
following tests:  
 parallel regressions tested in a supplemental ANCOVA that includes baseline by 
treatment interaction term  
 assumption of homogeneous variability between groups may be tested, using Levene's 
test or the Brown-Forsythe test, whichever appropriate 
 visual inspection of linearity of regression 
If there is evidence of gross violation of the assumptions for ANCOVA, then the offending 
endpoint may be analysed by ordinal logistic regression.  
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For categorical measures, if a logistic model gives non-estimable odds across a treatment group 
due to complete or quasi-separation then the variable causing the separation may be removed 
from the model. This may be noted in the results table. 
If the proportional odds assumption in an ordinal logistic regression model is violated, which is 
indicated by p-value<0.05 by score test for the proportional odds assumption, then treatment 
effects may be estimated using analysis of covariance (ANCOVA).  
 
6.5 
Data/Study Reviewing Committees 
The Data Safety Monitoring Board (DSMB) will monitor emerging study safety data and has the 
responsibility to review specific safety data reports, and to request additional reports as needed. 
Unblinded data reports generated by the unblinded statistician will be reviewed for adverse 
treatment effects and patient safety. The DSMB must keep results from blinded and unblinded 
data reports confidential. The roles and responsibilities of the DSMB will be outlined in a 
separate charter. 
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7 
STATISTICAL TECHNICAL ISSUES 
7.1 
Planned Statistical Power and Sample Size 
For the comparison of the primary efficacy measure in PMS#1 (including subscores for stool 
frequency, rectal bleeding and findings of flexible proctosigmoidoscopy) change from baseline, a 
sample of ~39 evaluable patients (having non-missing PMS at baseline and at Week 12) per 
group will provide approximately 80% power to detect a difference of 1.15 at α=5% (1-sided 
test) based on an estimated pooled standard deviation 2.03. Sponsor will enroll sufficient patients 
to reach at least 117 evaluable patients. 
 
7.2 
 Method of Assigning Participants to Treatment Groups Study  
Patients who meet all the entry criteria and are eligible for the study will report to the 
investigator to be randomized on Day 1. Sites will randomize eligible patients for entry into the 
study in a 1:1:1 ratio to receive once daily doses of 1 mg APD334, 2 mg APD334, or matching 
placebo across the entire study, and is not constrained within a center. Randomization will be 
stratified by presence or absence of current oral corticosteroid usage and previous exposure to 
TNFα antagonists.  All pre-specified efficacy analysis model will include for these two factors 
using CRF recorded data.  Potential discrepancy between CRF recorded data and IVRS data 
entered by site staff will be investigated. A post-hoc analysis may be performed to evaluate the 
impact on main study endpoints caused by such discrepancy. 
7.3 
Blinding/Unblinding 
The sponsor, patients, and personnel involved with the conduct of the study, with the exception 
of the clinical supply staff, safety staff, and the unblinded statistician supporting the Data Safety 
Monitoring Board (DSMB), will be blinded to the identity of study medication until the database 
lock. Blinding is accomplished by the random, masked, assignment of allocation numbers to the 
treatment groups, and by ensuring the drug supplies administered in the treatment groups appear 
identical.  The contract research organization (CRO) will obtain written consent from Arena 
prior to breaking the code. 
Breaking of the randomization code without Arena permission is expressly forbidden except in 
the event of a medical emergency where the identity of the study medication must be known in 
order to properly treat the patient.  In the event of a medical emergency, it is requested that the 
investigator make every effort to contact the study monitor or designee prior to breaking the 
code.  If the blind is broken, the individual responsible should document the date, time, and 
reason for breaking the blind. A written communication should be sent to Arena within 1 
working day. 
7.4 
Handling of Missing Data and Sensitivity Analysis 
7.4.1 
Multiple Imputation for Primary Efficacy Analysis 
Multiple imputation has 3 distinct phases: Imputation, Analysis and Combining.  During the 
Imputation Phase, the missing data values are filled-in to form a complete dataset.  This is done 
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‘m’ times.  For the Analysis Phase, each of the ‘m’ complete datasets are analysed by a statistical 
model (as specified in Section 4.3 for each endpoint). The Combining Phase pools the parameter 
estimates with their standard errors across the ‘m’ complete datasets and produces an average 
estimate with a standard error calculated using Rubin’s formula9,10 this allows for the uncertainty 
between imputations as well as the variability within each analysis. 
 
Multiple imputation assumes that the data are missing at random (MAR).  MAR assumes that the 
missingness does not depend on the actual missing values, but that the missing data can be 
completely explained by the observed data.  To test the robustness of the multiple imputation 
strategy a tipping point analysis may be implemented.   
 
A tipping point analysis may be implemented for the primary endpoint to explore the influence 
of missing data on the overall conclusion of the primary efficacy analysis results. In this analysis, 
a wide spectrum of assumptions can be imposed regarding the missing data (from less 
conservative to more conservative) to find the “tipping” point assumption, at which conclusions 
change from being favorable toward APD334 to being unfavorable. After such a tipping point is 
determined, clinical judgment can be applied as to the plausibility of the assumptions underlying 
this tipping point. A delta (δ) method is often used to clearly formulate clinical assumption about 
Missing Not At Random (MNAR) mechanism. More specifically, the assumption is that, after 
dropout, subjects from APD334 have, on average, their PMS score worsen by some amount δ (δ 
=0 to 9, with a max PMS score of 9) from the time of dropout to Week 12.  
 
Whether the missing data pattern is monotone or arbitrary (non-monotone), a fully conditional 
specification (FCS) method11,12 with predictive mean matching for continuous variables13,14 can 
be used. The FCS method allows for separate conditional distributions for each imputed variable. 
The predictive mean matching approach creates a regression model using parameters sampled 
from the posterior distribution and then a predicted value for each missing value is computed. The 
missing value is replaced by randomly selecting an observation from a set of ‘k’ values that are 
the closest predicted values to the missing predicted value.  
In the case of Mayo scores, a multiple imputation approach is implemented for the missing 
individual components of the Total Mayo Score (TMS), which include stool frequency, rectal 
bleeding, findings of flexible proctosigmoidoscopy (endoscopy), and physician global assessment. 
Each individual subscore is imputed and then the composite endpoint measures are created (see 
list of endpoints below) following the specified algorithms or formulas in the SAP. The rectal 
bleeding, stool frequency, endoscopy, physician’s global assessment, treatment, stratification 
factors (oral corticosteroid use and prior exposure to TNFα antagonists), biomarker variables (e.g. 
 inform the imputation model. 
The imputation model may include all these variables at all planned time points (e.g. Screening, 
Baseline, Week 1, 2, 4, 8, 12 and may be specific for each variable).  These variables are included 
because they are correlated with the endpoint and/or missingness.  The multiple imputation process 
creates
 complete datasets using PROC MI in SAS 9.4. During post-processing, the endpoints 
are derived in each of the 
 complete datasets.  The endpoints and analysis model in parentheses 
are listed below: 
 
 PMS#1 (bleeding, stool, endoscopy) change at Week12 (ANCOVA) 
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 %-endoscopic improvement at W12 (Logistic regression) 
 2-component Mayo scores (bleeding, endoscopy) change at Week12 (ANCOVA) 
 Total Mayo score (4-component) change at Week12 (ANCOVA) 
 %-clinical remission at Week12 (Logistic regression) 
 %-clinical response at Week12 (Logistic regression) 
 Endoscopic score change at Week12 (ANCOVA) 
 Combination of clinical remission and response (trichotomy) at Week12 (Ordinal 
Logistic)  

An analysis model (e.g. ANCOVA or Logistic as specified in the Section 4.3) for each endpoint 
is run on each of the 
 multiply imputed datasets.  Thus, for any estimator of interest, there will 
be 
 estimates with standard errors obtained; these are pooled using PROC MIANALYZE to 
produce an overall estimate
and a standard error (based on 
Rubin’s formula) with associated confidence interval and p-value.  
 
  
The multiple imputation model will be pre-defined before database lock.  However, there could 
be certain adjustments due to unexpected data issues after unblinding treatment and 
 
. All post-unblinding modifications to the multiple imputation model or approaches to 
address missing data will be described in the Clinical Study Report. 
7.4.2 
Additional Sensitivity Analyses 
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8 
DATA HANDLING CONVENTIONS 
8.1 
Baseline Definitions or Conventions 
For the stool frequency and rectal bleeding components of the Mayo Clinic Score, baseline will 
be based on patient diary entries within the 10 days prior to randomization.  The scores from the 
3 most recent days prior to the actual randomization day will be averaged and rounded to the 
nearest integer.  The rounding will be applied to each subscore prior to the creation of the total 
score. Note that the day prior, day of and day after proctosigmoidoscopy cannot be used for 
patient diary entry because of the required bowel prep for the procedure. Patients who have less 
than 3 days of diary data during screening are not eligible for randomization.  Baseline 
endoscopy subscore will be based on flexible proctosigmoidoscopy results within 10 days prior 
to randomization. 
For other efficacy and safety endpoints, baseline value is defined as the last pre-randomization 
measurement, unless otherwise specified. 
8.2 
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 patient’s visit will be defined by 
the following relative day ranges.  Tables 3 to 7 below give the mapping of relative day ranges to 
Week.  
 
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If a patient has more than one assessment in a window, the assessment date closest to the target 
date will be selected.  If a patient has 2 assessments that are equidistant from the target date, the 
later assessment will be selected.   
8.3 
Description of Data Handling Procedures Prior to Unblinding 
All data will be screened, reviewed, and declared clean before data are unblinded according to 
PPD (Data Management CRO) guidelines and standard operating procedures.  The PPD 
unblinded database will be locked in order to insure that analyses in response to regulatory 
queries are performed on the same data used for submission.  The freeze and unblinding will 
occur at the end of the study. 
 
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9 
CHANGES IN THE PLANNED ANALYSIS FROM THE PROTOCOL 
The following secondary objective and endpoint have been added to the SAP in comparison with 
Protocol Amendment #6: 
1. 2-Component Mayo Clinic Score
The following changes to the secondary objectives and endpoints have been made: 
1. The order has been changed to: Endoscopic Improvement, 2-Component Mayo Score and
Total Mayo Score
2. Other objectives/endpoints previously listed as secondary (i.e. Trichotomous score,
Clinical remission and Clinical response) are considered to be exploratory
The following exploratory objectives and endpoints have been added to the SAP in comparison 
with Protocol Amendment #6: 
In addition, a change to the sample size calculation in comparison with Protocol Amendment #6 
has been made: 
Rationale for sample size calculation change: 
In Protocol Amendment 06, the primary objective was changed to reflect a broad 
examination of potential clinical improvement across three domains (stool frequency, rectal 
bleeding, and endoscopic results), which is appropriate for a proof-of-concept study. The 
current endpoint is more sensitive to detecting clinically important differences between two 
doses of APD334 and placebo compared to a dichotomous complete remission endpoint. 
The 95% CIs have been changed to 90% CIs for all analyses in comparison with Protocol 
Amendment #6. 
The clinical remission definition has been updated to include “a rectal bleeding score of 0 or 1” 
in comparison with Protocol Amendment #6. 
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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.” 
The following change to the primary efficacy analysis has been made: 
A Phase II POC study does not have as strict criteria as a pivotal Phase III study.  In recent years 
regulators have been critical of last observation carried forward (LOCF) and similar approaches 
for handling missing data and have advocated using more scientifically justifiable (e.g. multiple 
imputation methods) in primary analyses of Phase III studies alongside testing assumptions. 
Recommendation 10 of The Prevention and Treatment of Missing Data in Clinical Trials15 states, 
“Single imputation methods like last observation carried forward and baseline observation carried 
forward should not be used as the primary approach to the treatment of missing data unless the 
assumptions that underlie them are scientifically justified”.  The EMA Guideline on Missing Data 
in Confirmatory Clinical Trials16 states, “The risk of underestimating the variance of treatment 
effect when imputing can be reduced by proper implementation of techniques such as multiple 
imputation.”    
 
For APD334-003 Phase II POC study, approximately 10% missing data is anticipated for the 
endoscopic component of the 3-component Mayo Clinic Score at Week 12.  With 10% missing 
data, the balance in the original randomisation (underpinning the Intention-To-Treat (ITT) 
principle) could be lost which could result in biased estimates.  Multiple Imputation (MI) can 
reduce bias arising from missing data.   
 
Therefore, multiple imputation will be used to handle missing data in the analysis of the for 
efficacy endpoints at Week 12 for APD334-003 study. The original planned efficacy analysis in 
the protocol therefore becomes a sensitivity analysis in support of the new primary efficacy 
analysis. 
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10 REFERENCES 
1. APD Protocol 003: A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Parallel
Group, Multi-Center Study to Investigate the Safety and Efficacy of APD334 in Patients
with Moderately to Severely Active Ulcerative Colitis.
2. Kornbluth A, Sachar DB, 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
https://www.nature.com/articles/ajg2009727
3. Crohn’s and Colitis Foundation. Treatment Options (patient brochure)
http://www.crohnscolitisfoundation.org/what-are-crohns-and-colitis/newly-
diagnosed/treatments.pdf
4. Scoville EA, David A. Schwartz DA. Endoscopy in inflammatory bowel disease:
advances in disease management. Gastrointestinal Endoscopy 2017;86:952-961;
https://doi.org/10.1016/j.gie.2017.08.034
http://www.giejournal.org/article/S0016-5107(17)32243-5/fulltext
5. U.S. Department of Health and Human Services, Food and Drug Administration, Center
for Drug Evaluation and Research (CDER). Ulcerative Colitis: Clinical Trial Endpoints
Guidance for Industry (DRAFT GUIDANCE), August 2016.
https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM515143.pdf
6. European Medicines Agency. Guideline on the development of new medicinal products
for the treatment of ulcerative colitis (Draft). 21 July 2016.
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2016/07/
WC500211431.pdf
7. Schroeder KW, Tremaine WJ, Ilstrup DM. Coated oral 5-aminosalicylic acid therapy for
mildly to moderately active ulcerative colitis. New England Journal of Medicine 1987;
317:1625-1629; DOI: 10.1056/NEJM198712243172603
http://www.nejm.org/doi/full/10.1056/NEJM198712243172603
8. 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
9. Rubin, D.B. (1987), Multiple Imputation for Nonresponse in Surveys, New York: John
Wiley & Sons, Inc.
10. Little, R.J.A. and Rubin, D.B. (2002), Statistical Analysis with Missing Data, New York:
John Wiley & Sons, Inc.
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11. Brand, J. P. L. (1999), "Development, Implementation and Evaluation of Multiple
Imputation Strategies for the Statistical Analysis of Incomplete Data Sets," Ph.D.
dissertation, Erasmus University, Rotterdam.
12. van Buuren, S. (2007), "Multiple Imputation of Discrete and Continuous Data by Fully
Conditional Specification," Statistical Methods in Medical Research, 16, 219–242.
13. Heitjan, F. and Little, R. J. A. (1991), "Multiple Imputation for the Fatal Accident
Reporting System," Applied Statistics, 40, 13–29.
14. Schenker, N. and Taylor, J. M. G. (1996), "Partially Parametric Techniques for Multiple
Imputation," Computational Statistics and Data Analysis, 22, 425–446.
15. National Research Council. (2010). The Prevention and Treatment of Missing Data in
Clinical Trials. Panel on Handling Missing Data in Clinical Trials. Committee on
National Statistics, Division of Behavioral and Social Sciences and Education.
Washington, DC: The National Academies Press.
16. Committee for Medical Products for Human Use. Guideline on missing data in
confirmatory clinical trials. London: European Medicines Evaluation Agency, April 2009
(http://www.ema.europa.eu/pdfs/human/ewp/177699endraft.pdf).
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Appendix 2 
Listing of Efficacy Parameters and Study Populations 
Analysed 
Efficacy Parameters 
Response Analysed 
Study Populations 
Analysed 
Primary Endpoint 
3-Component Mayo Score1
Change from Baseline 
MITT, CP, ITT 
Secondary Endpoints  
Endoscopic Improvement 
Proportion 
MITT, CP, ITT 
2-Component Mayo Score
Change from Baseline 
MITT, CP, ITT 
Total Mayo Score 
Change from Baseline 
MITT, CP, ITT 
Exploratory Endpoints 
Trichotomous Composite Score 
Ordinal Categorical 
MITT, CP, ITT 
Clinical Remission 
Proportion 
MITT, CP, ITT 
Clinical Response 
Proportion 
MITT, CP, ITT 
1 includes subscores for stool frequency, rectal bleeding and findings on endoscopy 
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Appendix 3 
Mayo Clinic Score 
Mayo Scoring System for Assessment of Ulcerative Colitis Activity3 
Stool Frequency† 
0 = Normal number of stools for this patient 
1 = 1–2 stools more than normal 
2 = 3–4 stools more than normal 
3 = 5 or more stools more than normal 
Subscore, 0 to 3 
Rectal bleeding‡ 
0 = No blood seen 
1 = Streaks of blood with stool less than half the time 
2 = Obvious blood with stool most of the time 
3 = Blood alone passes 
Subscore, 0 to 3 
Findings on endoscopy† 
0 = Normal or inactive disease 
1 = Mild disease (erythema, decreased vascular pattern) 
2 = Moderate disease (marked erythema, lack of vascular pattern, friability, erosions) 
3 = Severe disease (spontaneous bleeding, ulceration) 
Subscore, 0 to 3 
Physician’s Global Assessment§ 
0 = Normal 
1 = Mild disease 
2 = Moderate disease 
3 = Severe disease 
Subscore, 0 to 3 
† Each patient serves as his or her own control to establish the degree of abnormality of the stool 
frequency. 
† The daily bleeding score represents the most severe bleeding of the day. 
§ The physician’s global assessment acknowledges the three other criteria, the patient’s daily
recollection of abdominal discomfort and general sense of well-being, and other observations, such
as physical findings and the patient’s performance status.
Note: The Mayo score ranges from 0 to 12, with higher scores indicating more severe 
disease.4 
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Statistical Analysis Plan: APD334-003 
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Arena Pharmaceuticals, Inc. 
27 Feb 2018 
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APD334
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APD334
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Statistical Analysis Plan: APD334-003 
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APD334
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Statistical Analysis Plan: APD334-003 
DRAFT 
APD334
Arena Pharmaceuticals, Inc. 
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Statistical Analysis Plan: APD334-003 
DRAFT 
APD334
Arena Pharmaceuticals, Inc. 
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Statistical Analysis Plan: APD334-003 
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APD334
Arena Pharmaceuticals, Inc. 
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Statistical Analysis Plan: APD334-003 
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APD334
Arena Pharmaceuticals, Inc. 
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Statistical Analysis Plan: APD334-003 
DRAFT 
APD334
Arena Pharmaceuticals, Inc. 
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Statistical Analysis Plan: APD334-003 
DRAFT 
APD334
Arena Pharmaceuticals, Inc. 
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Statistical Analysis Plan: APD334-003 
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APD334
Arena Pharmaceuticals, Inc. 
27 Feb 2018 
Appendix 5 
Multiple Imputation Model  
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Statistical Analysis Plan: APD334-003 
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Arena Pharmaceuticals, Inc. 
27 Feb 2018 
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Statistical Analysis Plan: APD334-003 
DRAFT 
APD334
Arena Pharmaceuticals, Inc. 
27 Feb 2018 
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Statistical Analysis Plan: APD334-003 
DRAFT 
APD334
Arena Pharmaceuticals, Inc. 
27 Feb 2018 
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