Clinical trial NCT03155945
Conditions: Crohn's Disease Abdominal Pain
Sponsor: Arena Pharmaceuticals
Start date: 2017-07-19; Completion date: 2018-09-10
Enrollment: 14 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this randomized, open-label, parallel, phase 2a study is to determine the tolerability, pharmacokinetics, and efficacy of olorinab in participants with Crohn's disease experiencing abdominal pain.

Detailed description:

Arms: arm 1: Participants received olorinab 25 milligrams (mg) tablet by mouth, three times daily (TID) for 8 weeks arm 2: Participants received olorinab 100 mg oral tablets TID for 8 weeks
Interventions: intervention 1: Olorinab
Intervention descriptions: intervention 1: Olorinab active treatment for 8 weeks.

Protocol documents:
Prot_000.pdf: 
Clinical Trial Protocol: APD371-004 
Study Title: 
A Randomized, Open-label, Parallel, Phase 2a Study to Determine 
the Tolerability, Pharmacokinetics, and Efficacy of APD371 in 
Subjects with Crohn’s disease experiencing Abdominal Pain  
Study Number: 
APD371-004 
Study Phase: 
2a 
Product Name: 
APD371 
Indication: 
Acute and chronic inflammatory pain 
Investigator: 
MD, PhD, MSc 
Associate Professor of Gastroenterology 
Director, Inflammatory Bowel Disease Program 
University of Michigan  
Taubman Center, Floor 3, Reception D 
1500 E Medical Center Drive 
Ann Arbor, MI 48109, USA 
Phone: 
 
Email: 
  
Sponsor: 
Arena Pharmaceuticals, Inc. 
6154 Nancy Ridge Drive 
San Diego, California 92121
Sponsor 
Contact: 
 MPH 
VP, Head of Clinical Operations 
Arena Pharmaceuticals, Inc. 
6154 Nancy Ridge Drive 
San Diego, CA 92121, USA 
Phone: 
 
Email: 
 
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.  
Date 
Original Protocol 
11 November 2016 
Amendment 01 
24 March 2017 
Amendment 02 
10 August 2017 
NCT Number: NCT03155945
This NCT number has been applied to the document for
purposes of posting on Clinicaltrials.gov


APD371 
 
Arena Pharmaceuticals, Inc 
Clinical Trial Protocol: APD371-004 
 
 
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SYNOPSIS 
Protocol Number: 
APD371-004 
Title: 
A Randomized, Open-label, Parallel, Phase 2a Study to Determine 
the Tolerability, Pharmacokinetics, and Efficacy of APD371 in 
Subjects with Crohn’s disease experiencing Abdominal Pain 
Study Phase: 
2a 
Name of Drug: 
APD371 
Indication: 
Acute and chronic inflammatory pain 
Sponsor: 
Arena Pharmaceuticals, Inc. 
6154 Nancy Ridge Drive 
San Diego, California 92121 
United States of America (USA) 
Name of Sponsor 
Medical Contact: 
 MD 
Arena Pharmaceuticals, Inc. 
6154 Nancy Ridge Drive 
San Diego, California 92121 
United States of America (USA) 
Phone: 
 
Email: 
 
Name of Principal 
Investigator: 
, MD, PhD, MSc 
Associate Professor of Gastroenterology 
Director, Inflammatory Bowel Disease Program 
University of Michigan  
Taubman Center, Floor 3, Reception D 
1500 E Medical Center Drive 
Ann Arbor, MI 48109, USA. 
Phone: 
  
Email: 
 
Medical Monitor: 
 MD, CPI 
Principal, Pacific Pharma Group, LLC 
1402 S. Brookside Terrace 
Tacoma, WA  98465-1210, USA. 
Phone: 
 
Mobile: 
 
Email: 
 
Dosage: 
APD371 dosed at 25 mg or 100 mg three times daily (TID) at 
approximately 07:00 ± 2 hr, 15:00 ± 2 hr and 23:00 ± 2 hr for 8 
weeks (Wk). 
Concurrent 
Control: 
Intra-subject screening (baseline) 


APD371 
 
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Clinical Trial Protocol: APD371-004 
 
 
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Route and 
Formulation:  
Oral, capsules which are identical for each dose 
Objectives: 
Key Objective 
• To assess the tolerability and safety of two doses of APD371 in 
subjects with Crohn’s Disease (CD) experiencing abdominal pain 
treated for up to 8 Wk.  
 
Exploratory Objectives: 
• Determination of pharmacokinetic (PK) profiles (including 
metabolites) and average PK parameters (Cmax, tmax, AUC0-8) of 
two doses of APD371 TID 
• Change in abdominal pain score (APS) from pre-dose (trough) to 
1.5 hr post-dose (peak) following the first of 3 daily doses of 
APD371; assessed daily to Day 56 and averaged weekly to Wk 8 
• Change in average abdominal pain score (AAPS) from baseline to 
Wk 8 (averaged weekly to Wk 8) 
• Proportion of subjects who are weekly responders 
• Proportion of subjects who are end-of-treatment responders 
• Number of pain-free days per week, based on responses to the 
Abdominal Pain Severity 
 
 
 
 
 
 
• Pain medication use 
• Effect of APD371 treatment on reduction in C-reactive protein 
(CRP) and other biomarkers at week 4 and week 8 
• Effect of APD371 treatment on reduction in fecal calprotectin at 
week 4 and week 8 
 
 
 
 
 
Study Design: 
A randomized, open label, parallel group, multi center, comparison of 
two doses of APD371. 
Eligible subjects will enter a screening period of up to 4 weeks and 
will then be randomized in a 1:1 ratio to receive APD371 in doses of 
25 mg or 100 mg TID for 8 weeks.  


APD371 
 
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Clinical Trial Protocol: APD371-004 
 
 
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Randomization will be stratified by sex. 
Study Population:  The study population will consist of adult male and female subjects 
aged 18 to 80 years who are diagnosed with abdominal pain due to 
quiescent to mildly active CD, as defined by a weekly average 
abdominal pain score (AAPS) ≥ 4 over one week (0 [no pain] to 10 
[worst possible]), with minimal intestinal inflammation, confirmed 
with a simple endoscopic score (-CD) score <10 or fecal calprotectin 
(FCP) <500 mcg/g. Endoscopy results obtained within 1 month prior 
to screening may be utilized. 
Concomitant therapy may include all anti-inflammatory therapy for 
CD, including 5-aminosalicylates, antibiotics, immunomodulators, 
and oral or topical corticosteroids (prednisone ≤20 mg/day, 
budesonide at a dose ≤9 mg/day, or equivalent steroid) on stable 
maintenance doses. Subjects who have received/are currently 
receiving anti-tumor necrosis factor- or other biologic therapy will 
be allowed to continue on these therapies if the dose/regimen has 
been stable for at least 8 weeks prior to screening and no intended 
change in these therapies during the study is anticipated.   
Inclusion criteria 
 
 
 
 
 
 
 
 
 
  
6. A clinical diagnosis of CD for at least 3 months prior to 
screening corroborated by prior endoscopic and histopathologic 
documentation consistent with CD.  
7. Quiescent to mildly active inflammatory CD defined with a total 
SES-CD score of < 10 or FCP < 500 mcg/g within 4 weeks 
before screening. 
8. Moderate to severe abdominal pain as defined by average 
abdominal pain score (AAPS) of ≥ 4 points on 7 consecutive 
days of the screening period up to Day -2. AAPS will be based 
on the 11-point numeric rating scale where 0 (no abdominal pain) 
to 10 (worst possible abdominal pain)  
  


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Clinical Trial Protocol: APD371-004 
 
 
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APD371 
 
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Exclusion criteria 
General Exclusion Criteria  
 
2. Female subjects who are lactating or have a positive serum 
pregnancy test during the screening period or a positive urine 
pregnancy test on Day 1 prior to study drug administration 
 
 
 
 
 
 
 
 
 
 


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Clinical Trial Protocol: APD371-004 
 
 
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8. Recent history (within 6 months of screening visit) of 
cerebrovascular disease, Acute Coronary Syndrome, 
Cerebrovascular accident, Transient ischemic attack, Myocardial 
infarction, unstable angina  
 
 
  
 
 
 
 
 
 
 
 
12. Other significant chronic pain conditions that in the opinion of 
the investigator may influence the abdominal pain score 
 
 
Gastrointestinal Exclusion Criteria  
  
15. Extensive colonic resection, subtotal or total colectomy  
 
17. History of >3 small bowel resections or diagnosis of short bowel 
syndrome or who have undergone bowel resection within 6 
months prior to randomization 
 
 
 
  
 
 
 
 
 
 
 


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Clinical Trial Protocol: APD371-004 
 
 
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Infectious Disease Exclusion Criteria  
30. Chronic active hepatitis B within the last year (unless shown at 
the time of study entry to be hepatitis B antigen negative) or any 
history of hepatitis C  
 
 
 
 
 
 
  
33. Evidence of current GI infection (bacterial or parasitic) or 
significant infection within 45 days of Screening  
 
 
 
 
 
 
 
 
 
Duration per 
Subject: 
Each subject will receive study treatment for up to 8 weeks 
Subject 
Assignment: 
Eligible subjects will be randomized in a 1:1 ratio to receive APD371 
25 mg TID or 100 mg TID.  
 


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Clinical Trial Protocol: APD371-004 
 
 
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Sample Size:  
It is planned to treat and complete safety and tolerability assessments 
in approximately 16 subjects. Since subjects maybe replaced if they 
are withdrawn due to major protocol violations, it is estimated a 
maximum of 20 subjects maybe be dosed.  These numbers will be 
appropriate for a preliminary evaluation of safety and tolerability, 
provision of PK profiles of APD371 at two doses and exploratory 
analysis of efficacy end points.  
Safety 
Assessments: 
• Adverse event reporting to include; Treatment Emergent Adverse 
Events (TEAEs), Serious Adverse Events (SAEs) and Suspected 
Unexpected Serious Adverse Reaction (SUSARs) 
• Clinical laboratory tests to include; hematology, serum chemistry, 
and urinalysis  
• Physical examinations  
• Vital sign measurements 
• 12-lead electrocardiograms (ECGs) 
Pharmacokinetic 
Assessments: 
Blood samples for the assay of APD371 and metabolites M1 
, M2 
, and M4 
 will be 
collected at the following time points: 
• Wk 0 (Day 1): prior to and 0.5, 1, 2, 4, 6, 8 (prior to second daily 
dose), 9, 10 and 24 hours post first daily dose. 
• Wk 2, 4, and 6: prior to first daily dose 
• Wk 8 (Day -1, last day dosing): prior to and 0.5, 1, 2, 4, 6, 8 (prior 
to second daily dose),.  
• An additional blood sample for PK analysis will be collected, if 
possible, at the time of any intolerable AE or SAE. 
Efficacy 
assessments: 
• The analgesic effect of APD371 on abdominal pain will be scored 
by subjects in a diary using the APS.  The score will be based on 
the 11-point numeric rating scale from 0 [no abdominal pain] to 
10 [worst possible abdominal as follows; 
During Screening Twice daily for at least 7 consecutive days; 
1. Early morning, approximately 06:00 - 08:00 
2. Late evening, approximately 20:00 - 22:00. 
During Treatment Three times a day every day (Day1 to 56);  
1. Before the morning dose and any other study procedures  
2. At 1.5 hours after the morning dose  
3. Before the evening dose.  
• Additional efficacy assessments will include achievement of 
clinical improvement [defined as a two- component PRO score 
(Stool frequency and abdominal pain) of <11], clinical response 
from baseline to Wk 8, and change from baseline in CRP and fecal 
calprotectin at week 4 and 8. 
 
 


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Data Analyses: 
Safety and tolerability data reported will include incidence of 
withdrawals and incidence and proportion of subjects with TEAEs, 
SAEs and SUSARs by dose and by duration of treatment. 
Compliance with treatment will be determined by tablet counts. 
The following parameters will be calculated from APD371 plasma 
concentrations on Wk 0 (Day 1) and Wk 8 (Day -1, last day): 
Cmax, tmax and AUC0-8 
Plasma concentration data from predose samples collected during Wk 
2, 4, 6, and 8 will be used to determine Ctrough. 
Parameter estimates for Cmax and AUC0-8 will be evaluated to assess 
dose-proportionality. 
The following parameters will be calculated from plasma 
concentration data for M1 
, M2 
, and 
M4 
 on Wk 0 (Day 1) and Wk 8 (Day -1): 
Cmax, tmax and AUC0-8 
The ratio of each metabolite to APD371 will be calculated for Cmax, 
AUC0-8. The analgesic effect of two doses of APD371 will be 
reported using summary statistics as a change from baseline in AAPS 
at each week for trough, peak and combined assessments. Differences 
between trough and peak APS scores will also be assessed by 
summary statistics and appropriate non-parametric methods. 
The proportion of subjects with clinical improvement/response will 
be determined for each dose and combined at Wk 8 and be compared 
between 2 doses.  
 
Date 
10 August 2017 
 


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Clinical Trial Protocol: APD371-004 
 
 
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TABLE OF CONTENTS 
SYNOPSIS .................................................................................................................................2 
TABLE OF CONTENTS .........................................................................................................11 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..........................................15 
1 
INTRODUCTION ...........................................................................................................17 
1.1 
Rationale for Proposed Clinical Study ...................................................................18 
1.2 
Ethics and Regulatory Considerations ...................................................................19 
2 
STUDY OBJECTIVES ....................................................................................................20 
2.1 
Primary Objective ..................................................................................................20 
2.2 
Exploratory Objectives ..........................................................................................20 
3 
INVESTIGATIONAL PLAN ..........................................................................................21 
3.1 
Overall Study Design and Plan ..............................................................................21 
3.2 
Study Duration and Dates ......................................................................................22 
3.3 
Rationale for Study Design ....................................................................................22 
3.4 
Study Population ....................................................................................................26 
3.5 
Inclusion Criteria ...................................................................................................26 
3.6 
Exclusion Criteria ..................................................................................................28 
4 
STUDY TREATMENTS .................................................................................................31 
4.1 
Test Article.............................................................................................................31 
4.2 
Treatments Administered .......................................................................................31 
4.3 
Packaging, Labeling and Storage ...........................................................................31 
4.4 
Test Article Accountability ....................................................................................31 
4.5 
Investigational Product Retention at Study Site ....................................................32 
4.6 
Dosage and Administration....................................................................................32 
4.6.1 
Dose Interruption and Stopping Rules .........................................................32 
4.7 
Method of Assigning Subjects to Treatment Groups .............................................34 
4.8 
Randomization and Blinding .................................................................................35 
4.8.1 
Randomization .............................................................................................35 
4.8.2 
Blinding........................................................................................................35 
4.8.3 
Maintenance of Randomization Codes ........................................................35 
4.9 
Concomitant Medications ......................................................................................35 
4.9.1 
Not permitted ...............................................................................................35 
4.9.2 
Permitted ......................................................................................................36 
4.10 
Restrictions ............................................................................................................36 
4.10.1 
Fluid and Food Intake ..................................................................................36 
4.10.2 
Activity ........................................................................................................37 
5 
STUDY PROCEDURES .................................................................................................38 
5.1 
Informed Consent...................................................................................................38 


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5.2 
Medical History .....................................................................................................38 
5.3 
Physical Examination.............................................................................................38 
5.4 
Vital Signs ..............................................................................................................38 
5.5 
Abdominal Pain assessment ...................................................................................39 
5.5.1 
Abdominal Pain Score and Average Abdominal Pain Score .......................39 
 
 
 
 
5.8 
Electrocardiography ...............................................................................................40 
5.8.1 
12-lead Safety Electrocardiograms ..............................................................40 
5.9 
Clinical Laboratory Tests .......................................................................................41 
5.9.1 
Laboratory Parameters .................................................................................41 
5.9.2 
Virology .......................................................................................................42 
5.9.3 
Drugs of Abuse Screen ................................................................................42 
5.9.4 
C-reactive Protein and other Biomarkers .....................................................42 
5.9.5 
Sample Collection, Storage, and Shipping ..................................................42 
5.9.6 
Blood Volume ..............................................................................................42 
5.10 
Stool Sample ..........................................................................................................42 
5.11 
Pharmacokinetic Assessments ...............................................................................42 
5.12 
Adverse Events Assessments .................................................................................43 
5.12.1 
Adverse Event Reporting .............................................................................43 
5.12.2 
Serious Adverse Events and Expedited Reporting of Adverse Events ........44 
5.12.3 
Assessment of Adverse Event Severity .......................................................46 
5.12.4 
Assessment of Adverse Event Relationship to Study Medication ...............46 
5.12.5 
Assessment of Adverse Event Outcome ......................................................47 
5.12.6 
Action Taken for Adverse Event .................................................................47 
5.12.7 
Action Taken for Study Drug ......................................................................47 
5.12.8 
Collection of Extra Laboratory Samples/Investigations ..............................47 
5.12.9 
Follow-up of Adverse Events Present at Last Scheduled Study Visit .........47 
5.13 
Concomitant Medications and Procedures.............................................................48 
5.14 
Removal of Subjects from the Trial or Study Drug ...............................................48 
5.14.1 
Handling of Withdrawals .............................................................................48 
5.14.2 
Replacements ...............................................................................................49 
5.15 
Allowable Visit and Procedure Windows ..............................................................49 
6 
STUDY ACTIVITIES .....................................................................................................50 
6.1 
Screening Visits Wk -4 to Wk -1 (Days –28 to -1)................................................50 
6.2 
Screening Failures ..................................................................................................51 
6.3 
Treatment Period Wk 0 to 8 (Day 1 to Day 56) .....................................................51 
6.3.1 
Wk 0 (Day 1) Pre-treatment .........................................................................51 


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6.3.2 
Wk 0 (Day 1) Post treatment .......................................................................51 
6.3.3 
Wk 0 (Day 2) ...............................................................................................52 
6.3.4 
Wk 0 to 8 (Day -1) (Days 1 to 56) ...............................................................52 
6.3.5 
End of Wk 1, 2, 4, 6 .....................................................................................52 
6.3.6 
Wk 8 (Day -1) ..............................................................................................53 
6.3.7 
Wk 8 End of Treatment................................................................................53 
6.4 
Early Termination Procedures ...............................................................................54 
6.5 
Wk 10 Follow-up Visit Procedures........................................................................54 
7 
DATA MANAGEMENT.................................................................................................55 
7.1 
Data Collection ......................................................................................................55 
7.2 
Data Coding ...........................................................................................................55 
7.2.1 
Adverse Events ............................................................................................55 
7.2.2 
Concomitant Medications ............................................................................55 
7.2.3 
Medical History ...........................................................................................55 
8 
PLANNED STATISTICAL METHODS ........................................................................56 
8.1 
General Considerations ..........................................................................................56 
8.2 
Determination of Sample Size ...............................................................................56 
8.3 
Analysis Populations ..............................................................................................56 
8.4 
Demographics and Baseline Characteristics ..........................................................56 
8.4.1 
Demographics ..............................................................................................57 
8.5 
Pharmacokinetic Variables ....................................................................................57 
8.6 
Safety Analysis ......................................................................................................58 
8.6.1 
Adverse Events ............................................................................................58 
8.6.2 
Physical Examinations .................................................................................58 
8.6.3 
Vital Signs ....................................................................................................58 
8.6.4 
Clinical Laboratory Values ..........................................................................58 
8.6.5 
12-lead ECGs ...............................................................................................58 
8.7 
Efficacy Analysis ...................................................................................................59 
8.7.1 
Abdominal pain score (APS) .......................................................................59 
8.7.2 
Average abdominal pain score (AAPS) .......................................................59 
8.7.3 
Pain relief responders ...................................................................................59 
 
 
8.7.5 
C-reactive Protein ........................................................................................59 
8.7.6 
Fecal calprotectin .........................................................................................60 
9 
REGULATORY REQUIREMENTS...............................................................................61 
9.1 
Pre-study Documentation.......................................................................................61 
9.2 
Investigator Obligations .........................................................................................61 
9.3 
Subject Confidentiality ..........................................................................................61 


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9.4 
Informed Consent...................................................................................................61 
9.5 
Institutional Review Board ....................................................................................62 
10 PROTOCOL MANAGEMENT AND ADMINISTRATIVE CONSIDERATIONS ......63 
10.1 
Study Documentation.............................................................................................63 
10.2 
Protocol Interpretation and Compliance ................................................................63 
10.3 
Study Monitoring ...................................................................................................63 
11 PRINCIPAL INVESTIGATOR SIGNATURE PAGE ...................................................64 
12 REFERENCES ................................................................................................................66 
 
 
LIST OF IN-TEXT TABLES 
 
 
  
 
Table 3. 
Pharmacokinetic sampling ...........................................................................42 
 
LIST OF IN-TEXT FIGURES 
Figure 1. 
APD371-004 Study plan ..............................................................................21 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
AAPS 
ADL 
average abdominal pain score 
activities of daily living 
AE 
adverse event 
APS 
abdominal pain score 
ASA 
acetyl salicylic acid 
AUC 
area under the plasma concentration-time curve 
AUC0-8 
area under the plasma concentration-time curve from time zero to 8 hr 
postdose 
CB1  
cannabinoid-1 (receptor) 
CB2  
cannabinoid-2 (receptor) 
CD 
Crohn’s Disease 
 
 
CFR 
Code of Federal Regulations 
Cmax 
maximum plasma concentration 
CRO 
contract research organization 
CRP 
C-Reactive Protein 
CTCAE 
Common Terminology Criteria for Adverse Events 
Ctrough 
plasma concentration observed before treatment administration during 
repeated dosing 
CV 
coefficient of variation 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
FCP 
fecal calprotectin 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GI 
gastrointestinal 
GPCR 
G protein-coupled receptor 
HBsAg 
hepatitis B surface antigen 
hCG 
human chorionic gonadotropin 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation  


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IND 
Investigational New Drug  
IRB 
Institutional Review Board 
IV 
intravenous 
LLOQ 
lower limit of quantification 
MedDRA 
Medical Dictionary for Regulatory Activities 
MIA 
monosodium iodoacetate 
min 
minute 
6-MP 
6 mercaptopurine 
MTD 
maximum tolerated dose 
NSAID 
non-steroidal anti-inflammatory 
OTC 
over-the-counter 
 
 
PI 
Principal Investigator 
PK 
pharmacokinetic(s) 
PRO 
patient reported outcome 
QTc 
Q and T wave (interval) 
RDC 
remote data capture 
SAE 
serious adverse event 
SC 
subcutaneous 
SD 
standard deviation 
SES 
simple endoscopic score  
SOP 
standard operating procedures 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment-emergent adverse event 
THC 
Tetrahydro cannabinol 
TID 
3 times a day 
tmax 
time of maximum plasma concentration 
TNF 
tumor necrosis factor 
UC 
ulcerative colitis 
ULN 
upper limit of normal 
USA 
United States of America 
WBC 
white blood cell (count) 
WHO 
World Health Organization 
WK 
week 


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1 
INTRODUCTION 
The two main types of inflammatory bowel disease (IBD) are ulcerative colitis (UC), 
which is limited to the colon, and Crohn’s disease (CD), which can affect any 
segment of the gastrointestinal tract. In both types the most common symptoms are 
diarrhea and abdominal pain. Treatments for pain associated with IBD that are 
currently available have been borrowed from other pain conditions and are not 
specific for abdominal pain. They include opioids that have the potential for 
developing tolerance/tachyphylaxis, addiction and abuse, and potentially fatal 
respiratory depression, gabapentinoids that are safer than opioids but also produce 
adverse cognitive effects, tricyclic antidepressants that show some efficacy but can 
also produce somnolence, hypotension, and arrhythmias, and non-steroidal anti-
inflammatories (NSAIDs; drugs such as ibuprofen and naproxen) which when 
administered long term may be associated with an increased risk of gastrointestinal 
injury/bleeding, cardiac events, hypertension, kidney injury, and death. Due to the 
limitations and side-effects of currently available treatments for abdominal pain, there 
is a need for an alternative approach to targeted pain management, especially for 
abdominal pain, that is poorly managed in IBD due to limited specific options. New 
research suggests the etiology of abdominal pain in IBD arises from dysregulation of 
the endocannabinoid system, offering the promise of a novel therapeutic target. 
APD371 is a new chemical entity developed by Arena Pharmaceuticals, Inc. for the 
treatment of abdominal pain due to IBD which includes CD. APD371 is an orally 
available, selective cannabinoid-2 (CB2) receptor agonist.  
The CB2 receptor is a member of a family of G protein-coupled receptors (GPCRs) 
that mediate the effects of several structurally related endocannabinoids such as 
anandamide and 2-arachidonolglycerol.1,2 Although expression of CB2 was initially 
thought to be predominantly restricted to immune cells in the periphery, recent data 
suggests that this receptor is also expressed in the nervous system in perivascular 
microglial cells and in brainstem neurons. CB2 is up-regulated in both dorsal root 
ganglia and peripheral neurons following injury.3 Preclinical data using CB2 agonists 
and receptor knockout mice has validated the receptor as a potential target for the 
treatment of pain and neuro-inflammation.4,5 However, the therapeutic utility of non-
selective, brain penetrable cannabinoid agonists is limited by undesirable 
psychotropic effects associated with activation of the cannabinoid-1 receptor (CB1). 
Such side-effects are not apparent upon CB2 receptor activation. Selectivity for CB2 
activation over CB1 activation is thus an essential feature needed for therapeutic 
compounds directed at CB2.  
The binding affinity, potency, and selectivity of APD371 for recombinant CB2 
receptors were determined using radioligand binding assays and GPCR signaling 
assays. APD371 was shown to be a full agonist of the CB2 receptor with a Ki of 6 nM 
for human CB2 and EC50 values between 6 nM and 8 nM for the human, rat, and dog 
receptors.6,7 At test concentrations up to 10 μM, APD371 did not interact with 
recombinant human, rat, or dog CB1 receptors, indicating a >1000-fold selectivity 
across these species.8,9 


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The efficacy of APD371 in alleviating pain was evaluated in multiple rodent models 
of chronic pain, including the monosodium iodoacetate (MIA)-induced model of 
osteoarthritic joint pain, which shares similar pathophysiology with clinical 
osteoarthritis in humans. When administered to rats by acute and subchronic oral 
dosing or by continuous subcutaneous infusion, APD371 significantly suppressed 
allodynia induced with MIA. APD371-induced analgesia was maintained after 
animals were pretreated with rimonabant (CB1 receptor antagonist) or naloxone 
(µ-opioid receptor inverse agonist) but not with 
(CB2 receptor antagonist), 
demonstrating on-target selectivity of APD371 in vivo.6 Subchronic and continuous-
infusion dosing with APD371 did not induce tachyphylaxis. The efficacy of APD371 
in alleviating pain was also demonstrated in the paclitaxel-induced rodent model of 
neuropathic pain and the painful peripheral neuropathy rodent models of type 1 and 
type 2 diabetes. 
 
1.1 
Rationale for Proposed Clinical Study 
The Cannabinoid system in IBD is dysregulated1 and the enzymes that breakdown 
endocannabinoids (e.g., fatty acid amide hydrolase -FAAH) are increased in active 
inflammatory Crohn’s disease. The enzymes that synthesize endocannabinoids (e.g., 
N -acyl-phosphatidylethanolamine-specific phospholipase -NAPE-PLD) are 
decreased in active inflammatory Crohn’s disease and some endocannabinoids are 
decreased in active inflammatory IBD. 
The CB2 receptors are located in the target tissue gastrointestinal (GI) cells and local 
immune cells in both humans and in rodents10 and are found in epithelial cells, 
immune cells, and in enteric neurons where CB2 mediated sensitivity is observed at 
visceral afferent nerve endings10. 
The CB2 receptor is increased in the ulcerative margin in Crohn’s disease,10 and 
cannabinoids have been shown to be effective in clinical trials for Crohn’s pain. For 
example, cannabis has been demonstrated to induce a clinical response in patients 
with Crohn's disease in a prospective placebo-controlled study,11 and treatment of 
Crohn's disease with cannabis in an observational study showed improvements in the 
pain score.12 
Several preclinical animal studies support these observations which suggest that CB2 
activation can alleviate abdominal pain without the unwanted cognitive effects of 
CB1 receptor activation. A CB2 agonist has been shown to block mesenteric nerve 
firing and this effect is blocked in CB2 knockouts13. Similarly, a reduction of 
intestinal pain by probiotic Lactobacillus Acidophophilis (LCFM) administration in a 
butyrate-induced model of colonic hypersensitivity is blocked by a CB2 receptor 
Antagonist14. 
 
Arena has completed two phase 1 studies with APD371. The aim of both studies was 
to assess the safety, tolerability, and pharmacokinetics of APD371 across a range of 


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escalating doses in healthy subjects aged 18-45.
 
 
 
 
Based on these two safety studies in human volunteers, a safety and tolerability study 
in CD subjects with abdominal pain treated with maintenance doses of APD371 
ranging from 25 mg to 100 mg TID for 8 weeks is proposed.  
 
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 22 of the 
United States (US) Code of Federal Regulations (CFR) Part 50 (21CFR §50 
[Protection of Human Subjects], 22 CFR §56 [Institutional Review Boards (IRB)], 
and 22 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 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 must be notified promptly by the Investigator of the following: 
• Deviations from, or changes to, the protocol to eliminate immediate hazards to 
the trial subjects; 
• Changes increasing the risk to subjects and/or affecting significantly the 
conduct of the trial; 
• All adverse events (AE)s that meet the definition of a serious adverse event 
(SAE); 
• New information that may adversely affect the safety of the subjects or the 
conduct of the trial. 
 
Any changes to the protocol will be made by means of a formal written protocol 
amendment. All amendments will require IRB approval before implementation except 
when changes to the protocol are required immediately to eliminate hazards to the 
trial subjects. 


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2 
STUDY OBJECTIVES 
2.1 
Primary Objective  
To assess the tolerability and safety of two doses of APD371 in subjects with Crohn’s 
Disease (CD) experiencing abdominal pain treated for up to 8 weeks.  
2.2 
Exploratory Objectives  
• To determine pharmacokinetic (PK) profiles (including metabolites) and 
average PK parameters (Cmax, tmax, AUC0-8) of two doses of APD371 TID. 
• To assess change in abdominal pain score (APS) from pre-dose (trough) to 1.5 
hr post-dose (peak) following the first of 3 daily doses of APD371; assessed 
daily to Day 56 and averaged weekly to Wk 8 
• To assess change in average abdominal pain score (AAPS) from Screening to 
Wk 8 (averaged weekly to Wk 8) 
• To determine the proportion of subjects who are weekly responders 
• To determine the proportion of subjects who are end-of-treatment responders 
• To determine the number of pain-free days per week in each treatment cohort, 
based on responses to the APS 
 
 
 
 
 
• To assess pain medication use in each treatment cohort 
• To assess the effect of APD371 treatment on reduction in CRP and other 
biomarkers at week 4 and week 8 
• To assess the effect of APD371 treatment on reduction in fecal calprotectin at 
week 4 and week 8 
 
 
 
 
 


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3 
INVESTIGATIONAL PLAN 
3.1 
Overall Study Design and Plan 
This is a Phase 2a study in subjects diagnosed with abdominal pain due to quiescent to 
mildly active CD.  The study design is a randomized, multi center, open-label, group 
comparison consisting of two cohorts dosed with APD371 in approximately 16 
subjects (8 subjects in each cohort). Randomization will be stratified by sex. A study 
plan is provided in Figure 1. 
Figure 1. 
APD371-004 Study plan 
 
Subjects will enter a screening period of up to 28 days during which they will record 
their APS on a diary card.  If their AAPS is >4 and they satisfy all other eligibility 
criteria, they will be randomized in a 1:1 ratio to receive APD371 doses of 25 mg or 
100 mg capsules TID for 8 weeks (until Day 56).  
Eligible subjects will be randomized and on Day 1 subjects will arrive at the study 
site in the early morning will undertake study evaluations and will stay overnight for 
safety monitoring until discharge 6 hrs after first dose on Day 2. Following the first 
day of treatment subjects will return for weekly safety and tolerability assessments for 
the first two weeks and then once every other week until the end of the treatment 
period. Safety assessments will include physical examinations, AE reporting, vital 
signs, 12-lead electrocardiograms (ECGs) and clinical laboratory tests including 
blood sampling.  
 
Subjects will record their APS during Screening twice daily for at least 7 consecutive 
days within the Screening period (Day -28 to Day-1); early morning and late evening, 


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approximately (06:00 - 08:00 and 20:00 - 22:00). During treatment, subjects will 
record their APS three times a day on each treatment Day (Day 1 to Wk 8), before the 
morning dose, at 1.5 hours after the morning dose and before the evening dose.  
They will also record their stool frequency on a daily basis. 
 
There will be two serial PK assessments; one at the beginning of the study Wk 0 (Day 
1, 2) and another at the end of the study Wk 8 (Day -1) and Wk 8. A single PK 
collection will be performed in the clinic prior to the subject’s first daily dose on Wks 
2, 4 and 6.  A final PK sample collection will be performed at the follow-up visit will 
occur on Wk 10.  If subjects discontinue the study (Early Termination), a final PK 
sample will be collected.  
  
3.2 
Study Duration and Dates  
 
For each subject, the study duration will last a total of approximately 14 weeks 
consisting of a screening period of up to 4 weeks, a treatment period of 8 weeks and a 
follow-up period of two weeks.  
Subjects will undergo Screening procedures within 29 days prior to dosing. If 
eligibility is confirmed, subjects will be checked-in at the study site early morning on 
Day 1, they will overnight at the study site on Day 1 during which they will be 
randomized, treated with their first dose of APD371 and assessed for safety, 
tolerability, PK and efficacy. They will then be allowed to return home 6 hours after 
the first dose of APD371 on Day 2.  
The schedule of procedures and visits for the study is provided in Table 1. 
3.3 
Rationale for Study Design 
As described in Section 1.1, APD371 has previously been administered to healthy 
adult subjects at single doses of up to 400 mg and in multiple dose of up to 200 mg 
for 10 days TID. This proposed multiple-dose study is primarily designed to evaluate 
the safety, tolerability, and PK of two oral doses of APD371 in patients with CD with 
abdominal pain in order to provide reliable safety, tolerability, and PK data that will 
guide drug dose and therapeutic regimen choices in subsequent clinical studies. 
 
 
 
 
 


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3.4 
Study Population 
The study population will consist of adult male and female subjects aged 18-80 years 
who are diagnosed with abdominal pain due to quiescent to mildly active CD, as 
defined by an AAPS ≥4 over one week (0 [no pain] to 10 [worst possible]), with 
minimal intestinal inflammation, confirmed with a total simple endoscopic score 
(SES-CD) score < 10 or ileal SES-CD < 4 or fecal calprotectin (FCP) < 500. 
Endoscopy results obtained within 4 weeks prior to screening may be utilized. 
 
Eligible subjects must meet all entry criteria prior to being randomized to receive 
study medication as outlined below.  
Exceptions to eligibility criteria will not be granted by the Investigator unless 
approved in advance by the Sponsor. 
3.5 
Inclusion Criteria 
Each subject must meet the following criteria to be enrolled in this study. 
 
 
 
 
 
 
 
 
 
  


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6. A clinical diagnosis of CD for at least 3 months prior to screening 
corroborated by prior endoscopic and histopathologic documentation 
consistent with CD.  
7. Quiescent to mildly active inflammatory CD defined with a total SES-CD 
score of < 10 or FCP < 500 mcg/g within 4 weeks before Screening 
8. Moderate to severe abdominal pain as defined by average abdominal pain 
score (AAPS) of ≥4 points on 7 consecutive days of the screening period up to 
Day -2. AAPS will be based on the 11-point numeric rating scale where 0 (no 
abdominal pain) to 10 (worst possible abdominal pain)  
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 


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3.6 
Exclusion Criteria 
Subjects who meet any of the following criteria will be excluded from the study. 
General Exclusion Criteria  
 
 
2. Female subjects who are lactating or have a positive serum pregnancy test 
during the screening period or a positive urine pregnancy test on Day 1 prior 
to study drug administration 
 
 
 
 
 
 


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8. Recent history (within 6 months of screening visit) of cerebrovascular disease, 
Acute Coronary Syndrome, Cerebrovascular accident, Transient ischemic 
attack, Myocardial infarction, unstable angina  
 
 
  
 
 
 
13. Other significant chronic pain conditions that in the opinion of the Investigator 
may influence the abdominal pain score 
 
 
Gastrointestinal Exclusion Criteria  
 
  
16. 
Extensive colonic resection, subtotal or total colectomy  
 
 
18. 
History of >3 small bowel resections or diagnosis of short bowel 
syndrome or who have undergone bowel resection within 6 months prior 
to randomization 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
  
 
  
 
 


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Infectious Disease Exclusion Criteria  
31. 
Chronic active hepatitis B within the last year (unless shown at the time of 
study entry to be hepatitis B antigen negative) or any history of hepatitis C  
 
 
 
 
 
 
 
34. 
Evidence of current GI infection (bacterial or parasitic) or significant 
infection within 45 days of Screening  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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4 
STUDY TREATMENTS 
4.1 
Test Article 
The Sponsor will provide adequate supplies of APD371 25 mg, 50 mg and 100 mg active 
drug capsules. APD371 25 mg and 100 mg strengths will have the same appearance, as 
will 50 mg strength If subjects in the 100 mg cohort require a 75 mg dose they will be 
administered one 50 mg and one 25 mg capsule, and a 50 mg dose will include dosing of 
one 50 mg capsule only. 
4.2 
Treatments Administered 
 
 
APD371 drug substance (active) and bulk drug product (capsules) were manufactured 
under Current Good Manufacturing Practice compliance at Arena Pharmaceuticals, San 
Diego, CA. Bulk drug product will be packaged and labeled 
 
and shipped to participating clinical study sites prior to the study start.  
4.3 
Packaging, Labeling and Storage 
25 mg and 100 mg APD371 capsules will be packaged 30 count in 60-cc HDPE bottles 
with a heat induction seal and child resistant screw cap. Each subject will be provided 
with 8 bottles of APD371 packaged drug product for the duration of the study, two 
bottles being dispensed on Day 1, Day 15, Day 29 and Day 43, respectively. If subjects in 
the 100 mg cohort are titrated down to a 50 mg dose they may receive additional bottles.   
The 50 mg APD371 capsules will also be packaged 30 count in 60-cc HDPE bottles with 
heat induction seal and child resistant screw cap. 
Subjects returning for assessment at the end of Wks 2, 4, 6 should take their morning 
APD371 medication from their newly dispensed bottles for treatment periods Wks 3-4, 5-
6 and 7-8, respectively. 
4.4 
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 subject in the study. Reasons for deviation from the expected 
dispensing regimen must also be recorded. Study medication will be reconciled by the 
Sponsor 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. 


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4.5 
Investigational Product Retention at Study Site 
At completion of the study, all study medication will be reconciled by the Sponsor’s 
monitor and then returned at the direction of the Sponsor to be retained or destroyed 
according to applicable USA regulations. Prior to any action being taken with study 
medication after the study is completed, the Investigator will contact the Sponsor Contact 
listed in the Synopsis for approval of such action. 
4.6 
Dosage and Administration 
Investigational product will be dispensed to the subjects under the supervision of the 
Investigator or his/her designee as determined by the randomization schedule. Dispensing 
will occur every two weeks at Wks 0, 2, 4 and 6.  
Subjects should not crush, break, chew, or dissolve the capsules. There are no food 
restrictions around dosing with the exception of ingestion of grapefruit juice or prune 
juice. 
For each of the planned dose cohorts (APD371 25 mg and 100 mg) subjects will self-
administer study treatment TID 
 
 on Days 1 to 56. Subjects will be requested not to take their morning dose 
of study medication on the day of a planned study visit schedule 
 
 until instructed to do so by the Investigator or his/her 
designee. There will be a total of 8 subjects randomized to each dose cohort.   
4.6.1 Dose Interruption and Stopping Rules 
Adverse Events (AEs) of supine SBP decrease, supine DBP decrease, postural BP 
decrease, HR increase and HR decrease will be closely monitored.  If such an AE occurs 
in patients taking the study drug, the Investigator must assess whether the AE meets the 
study drug interruption/stopping rules and proceed as recommended in the below table.     
If the study drug is interrupted due to the criteria described in the table, the patient will be 
evaluated as part of an unscheduled visit to assess their status and the Investigator will 
determine next course of action.  If necessary, subsequent visits to assess the outcome of 
the event will be scheduled.  Once the re-start criteria are met, study drug will be re-
started under medical supervision.  Additional visits may be scheduled at the 
investigator’s discretion to more closely monitor patient status. 
Any patient that develops postural hypotension will not be discharged from the study site 
with study drug until the event completely resolves and safety and tolerability of the 
reduced dose in the patient is confirmed. 
 
 
 


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4.7 
Method of Assigning Subjects to Treatment Groups 
A computer-generated block randomization schedule generated by the Sponsor. or a 
nominated designee will randomly assign 
 in a 1:1 ratio to 
either the APD371 25 mg or APD371 100 mg treatment groups.  The randomization code 
will be held by the hospital pharmacist who will use this to sequentially randomize 
eligible subjects.  


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4.8 
Randomization and Blinding 
4.8.1 Randomization 
Subjects will be randomized after the Investigator has verified that they are eligible per 
criteria in Section 3.5 and Section 3.6.  Subjects will then be enrolled into this study and 
assigned to APD371 25 mg TID or 100 mg TID according to a randomization schedule.  
Subjects will be randomized based on gender.   
Randomization will take place across all study sites using a centralized master list held by 
the study manager.  When a site is ready to enroll a subject, they will contact the study 
manager to get the appropriate dose group assignment and unique subject number.  The 
subject’s identification number will be used on all of that subject’s case report forms 
(CRF). Any subject identification numbers that are assigned will not be reused even if the 
subject does not receive treatment. All subjects must start treatment within 1 week of 
randomization. 
4.8.2 Blinding 
For each dose cohort, the Sponsor, CRO, Study safety medical monitors, subjects, and 
personnel involved with the conduct of the study will be unblinded to the identity of 
study medication.  
4.8.3 Maintenance of Randomization Codes  
All personnel directly related to this study (i.e., Investigators, site personnel, monitors, 
CRO personnel, Sponsor personnel) will remain unblinded.  
   
4.9 
Concomitant Medications  
All concomitant medications (over-the-counter [OTC] and prescribed) that are taken by 
subjects and all procedures that are performed during the Screening period and during the 
study will be documented in the electronic case report form (eCRF) with start date/time 
and stop date/time, if known. 
Stable doses of non-narcotic prescription medications required for treatment of current 
medical conditions other than pain (e.g., hypertension, thyroid disease, diabetes) may be 
continued during the screening and study period.   Doses may be adjusted as appropriate 
per usual standards of care. 
4.9.1 Not permitted  
• Hormonal contraceptives for pain relief within 30 days prior to the Screening Visit, 
during the Screening period, and for the duration of the study.  
• Moderate or strong CYP3A4/5 inducers or inhibitors  
 


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4.9.2 Permitted 
• Pain rescue medications during screening or the treatment period including: 
• For an inflammatory flare: prednisone at a dose of 40 mg orally daily, to be 
tapered by 5 mg per week. 
• For severe pain:  hyoscyamine at a dose of 0.25 mg tid prn pain 
• Pain relief medications such as NSAIDs, narcotic analgesics, or 
acetaminophen/paracetamol given at stable doses for at least 2 weeks prior to 
screening and for the duration of the study 
• Stable dose of oral or topical 5-ASA for at least two* weeks prior to randomization; 
stable dose to be maintained on the 5-ASA compound at a constant dose at least 
through end of study 
• Mesalamine or sulfasalazine for at least 4 weeks prior to randomization  
• Azathioprine or 6-MP, or methotrexate for at least 8 weeks prior to screening 
• Oral corticosteroid therapy (prednisone at a stable dose of 30 mg/day, budesonide at a 
dose ≤ 9 mg/day, or equivalent steroid) provided that the dose has been stable for the 
2 weeks immediately prior to screening or for the two weeks immediately prior to 
randomization if corticosteroids are being tapered 
• Dose regimens within the ranges approved by the FDA and stable for at least 8 weeks 
prior to screening for the following monoclonal anti-inflammatory drugs:   
• Infliximab 
• Adalimumab 
• Certolizumab pegol  
• Ustekinumab 
• Vedolizumab 
• Probiotics (e.g., Culturelle, Saccharomyces boulardii) provided that the dose has been 
stable for the 2 weeks immediately prior to randomization  
• Antidiarrheals (eg, loperamide, diphenoxylate with atropine) for control of chronic 
diarrhea 
• Antibiotics used for the treatment of CD (i.e., ciprofloxacin, metronidazole) provided 
that the dose has been stable for the two weeks immediately prior to randomization 
and will remain stable throughout study participation 
 
 
4.10 
Restrictions 
4.10.1 
Fluid and Food Intake 
There are no food restrictions around dosing with the exception of grapefruit and prune juice. 
Subjects will be provided standardized meals (breakfast, lunch, dinner, snacks) per the 
Investigating site’s SOPs while housed in the clinic. 240 mL of water will be administered 
with study medication in the clinic at the time of dosing on Day 1 and Week 8 when the PK 
profile will be obtained.  Water may be provided at all other times as needed. 


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4.10.2 
Activity 
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5 
STUDY PROCEDURES 
5.1 
Informed Consent 
For any subject to be screened the Investigator will obtain a signed Informed Consent Form 
(ICF). The ICF must be reviewed and approved by the Investigator’s designated IRB and by 
the Sponsor. The ICF should include all the elements as outlined in Section 4.8.10 of the ICH 
guideline for GCP (E6). 
All subjects will be informed in writing of the nature of the protocol and investigational 
therapy and its possible hazards, and of their right to withdraw at any time, before they will 
be permitted to sign the ICF. The subject’s medical record should contain written 
documentation indicating that informed consent was obtained.  
5.2 
Medical History 
During the Screening Visit, a complete medical history and a social history, including 
smoking, caffeine, and alcohol use, will be collected by subject interviewer. Concomitant 
medications, recent blood donations, illnesses, and participation in other investigational drug 
studies will also be recorded. A review of the subjects screening medical history will be 
performed at the time of presentation on Day 1 (pre-treatment) to update findings including 
the requirement for a AAPS ≥ 4 (from a subject diary) and to document any pre-treatment 
AEs. 
5.3 
Physical Examination 
Body measurements (height and weight) will be taken at the timepoints indicated in the 
Schedule of Events (Table 1). A complete physical examination including weight will be 
performed at the initial Screening visit. Abbreviated physical examinations (includes body 
weight and evaluation of changes to previously observed abnormal findings) will be 
completed at the time of presentation to the clinic prior to initial dose administration, at the 
Follow-up Visit Wk 10 and at early termination noting changes in any body system since the 
previous examination. 
5.4 
Vital Signs 
Supine blood pressure, pulse rate, temperature, and respiratory rate will be measured after the 
subject has been resting in the supine position for 5 minutes at the timepoints indicated in the 
Schedule of Events (Table 1). All once daily vital sign assessments are take place before 
morning dosing or equivalent times when not dosed at approximately 08:00.  Vitals signs 
will be measured after any 12-lead ECG measurement but prior to any blood draw that is 
scheduled at the same timepoint. Pulse rate will be measured with a pulse oximeter.  
Active-Standing Test 
The Active-Standing Test15 that measures BP and heart rate before and after changing the 
position from supine to standing will also be performed. The test will be performed by the 


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bedside by measuring blood pressure (BP) and heart rate after the subject has been resting in 
the supine position for 5 minutes and then after 1 and 3 minutes of standing.    
The test will be performed at the following timepoints: 
• Day 1: pre-dose, 2, 4, 6, 8 and 10 hours after first dose 
• Day 2: 2, 4 and 6 hours after the first dose 
• Week 1, 2, 4, 6, and 8 visits 2 hours after the first dose  
The active-standing test will be performed if subjects discontinue the study (Early 
Termination). 
 
5.5 
Abdominal Pain assessment 
5.5.1 
Abdominal Pain Score and Average Abdominal Pain Score 
The abdominal pain score (APS) is a PRO using an NCR rating scale which is recorded in a 
subject diary.  The 11 point NCR scale ranges from 0 [no abdominal pain] to 10 [worst 
possible abdominal pain] will be recorded by subjects in a diary as follows; 
During Screening. Twice daily for at least 7 consecutive days within the initial Screening 
period (Day -28 to Day-1), at the following times; 
1. Early morning, approximately 06:00 - 08:00 
2. Late evening, approximately 20:00 - 22:00. 
 
The Screening assessment of AAPS will be based on the average of the last (most recent) 7 
days of morning and evening diary records within the screening period.  
During Treatment. Three times a day on each treatment Day (Day 1 to 56) at the following 
times;  
1. Before the morning dose and before any other morning dose study procedures  
2. Approximately at 1.5 hours after the morning dose  
3. Before the evening dose.  
Note: Subjects will also be required to complete the diary before their first morning dose on 
Wk 0 (Day 1), and at the End-of-Treatment Visit at Wk 8 in the early morning (06:00 - 
08:00).  If a subject discontinues the study, Early Termination, the APS score will be 
assessed. 
The average abdominal pain Score (AAPS) is the average of the APS score over each weekly 
assessment period (Wk 1 to Wk 8). These average scores will be determined automatically in 
the eCRF from the diary cards records inserted into the eCRF. 


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If a subject changes dose during the course of the study, they will maintain their daily APS 
scoring. 
 
 
 
  
 
 
 
  
 
5.8 
Electrocardiography  
5.8.1 
12-lead Safety Electrocardiograms 
Safety 12-lead ECGs will be recorded from an ECG machine and will be printed and 
reviewed on site by the Investigator or designee. Typically, all 12-lead ECGs will be 
obtained as single tracings, with the exception of the pre-treatment ECG obtained on Day -1, 
which will be a triplicate recording. If a 12-lead ECG shows an abnormality, then 
two additional ECGs should be obtained as soon as possible for confirmation. Abnormalities 
of particular interest include increased PR or corrected QT (QTc) intervals, either absolute 
prolongations or clinically noteworthy increases from baseline values. 
Electrocardiograms will be recorded with subjects resting in the supine position. Subjects 
will have been in the supine position for 10 minutes prior to ECG recording, which will be 
performed prior to any vital sign measurement and/or blood draw that may be scheduled at 
the same time point. 
Intervals to be provided on the confirmed read for each 12-lead ECG are: RR, PR, QRS, QT, 
QTc, QTcB, and QTcF. All interval measurements will be made from a single lead (lead II). 
If lead II is unsuitable for measurement, the following lead progression will be used: I, V4, 
V5, V3, any suitable lead. 
The Investigator will be responsible for review and interpretation of 12-lead ECGs on site 
and for determining if the ECG is normal, abnormal clinically insignificant, or abnormal 
clinically significant. Findings will be documented in the eCRF. This information will be 
used in the ongoing safety review during the conduct of the study. 
A 12-lead ECGs will be collected at Screening; at the start of Wk 0 (Day 1) and at Wk 8 
(Day -1) prior to and 1.5 hours after the first daily dose; and at the Follow-up Visit at Wk 10. 
12-lead ECGs will be collected prior to any vital sign measurement and/or blood draw that is 
scheduled at the same time point.  


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5.9 
Clinical Laboratory Tests 
Protocol-required laboratory testing will be collected during initial screening to determine 
eligibility.  Clinical laboratory tests will be repeated at pre-treatment on Wk 0 (Day 1), pre-
treatment at the end of Wk 4 and 8 (Day -1), at the Follow-up visit (Wk 10) and in the event 
of early termination. 
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 PK 
sample collection manual provided by the Sponsor. 
In the event of abnormal clinical laboratory values, the Investigator will make a judgment 
whether or not the abnormality is clinically significant. 
5.9.1 
Laboratory Parameters 
Clinical laboratory tests will include the following:  
Serum Chemistry 
Aspartate transaminase  
Alanine transaminase 
Alkaline phosphatase 
Gamma-glutamyl transferase 
Bicarbonate 
Magnesium 
Sodium 
Potassium 
Chloride 
Calcium 
Inorganic phosphate 
Glucose 
Amylase 
Bilirubin (total) 
Creatinine 
Blood urea nitrogen 
Total protein 
Albumin 
Creatine kinase and MB subtype (if 
elevated) 
Lactate dehydrogenase 
Lipase 
Total Cholesterol 
Triglycerides 
 
Other 
Serum/urine pregnancy test (females 
only), Thyroid function tests [(TSH, T4, 
and free T4) - Screening only], Hs CRP 
Hematology  
White blood cell count (WBC) 
Red blood cell count 
Hemoglobin 
Hematocrit 
Mean cell volume 
Mean cell hemoglobin 
Platelet count 
Differential WBC 
  
Urinalysis 
Appearance 
Color 
Specific gravity 
pH 
Protein 
Glucose 
Ketones 
Leukocyte esterase 
Blood 
Bilirubin 
Urobilinogen 
 
Coagulation 
Prothrombin time 
Activated partial thromboplastin time 
 
 


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5.9.2 
Virology 
Human immunodeficiency virus (HIV) antibody, hepatitis B surface antigen (HBsAg), and 
hepatitis C virus (HCV) Screening tests will be performed at the Screening Visit only. 
5.9.3 
Drugs of Abuse Screen 
A drugs of abuse screen will be completed according to the laboratory manual provided by 
the local or central laboratory and according to the Schedule of Events (Table 1). 
The drugs of abuse screen will include cotinine, alcohol, amphetamines, barbiturates, cocaine 
metabolites, opiates, benzodiazepines, and cannabinoids. 
5.9.4 
C-reactive Protein and other Biomarkers 
Separate blood samples (a total of 20 mL) for high sensitivity analysis of CRP will be 
collected at screening, pre-dose at Day 1, Week 4 and Week 8 (Day -1), and Week 10 
(Follow-up).
 
 
 
5.9.5 
Sample Collection, Storage, and Shipping 
Blood samples for hematology, serum chemistry, coagulation, HIV and hepatitis screens, 
drugs of abuse screens, and serum hCG will be collected according to the laboratory manual 
provided by the local or central laboratory and according to the Schedule of Events (Table 1). 
5.9.6 
Blood Volume 
Total blood volume for clinical laboratory tests will be approximately 205 mL. 
5.10 
Stool Sample 
A stool sample will be collected during screening and at Weeks 4 and 8 (Day -1) for the 
analysis of fecal calprotectin, a biomarker of intestinal inflammatory activity. 
5.11 
Pharmacokinetic Assessments 
Pharmacokinetic samples for the assay of APD371 and metabolites M1 
, M2 
, and M4 
 will be collected will be collected at the visit time points 
indicated in the Schedule of Events (Table 1) and detailed in Pharmacokinetic sampling, 
Table 3. 
 
Table 3. Pharmacokinetic sampling 
Study Day 
Blood sampling assessments* 
Wk 0 (Day 1) 
Prior to and 0.5, 1, 2, 4, 6, 8 (prior to second daily dose), 9 
and 10 hours post first daily dose. 
Wk 0 (Day 2) 
24 hours post dose first daily dose on Day 1 


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Wk 2 
Prior to first daily dose 
Wk 4 
Prior to first daily dose 
Wk 6 
Prior to first daily dose 
Wk 8 (Day -1) 
Prior to and 0.5, 1, 2, 4, 6, 8 (prior to second daily dose). 
Wk 8 (End-of-Treatment) 
8 hours post dose first daily dose on Wk 8 (Day-1) 
* Allowable windows for sample collection: 
- 
time points up to 4 hours: ± 5 mins  
- 
time points after 4 hours: ± 15 mins  
 
Approximately 4 mL of blood will be collected at each timepoint. Blood samples will be 
processed for collection of plasma fractions for determination of APD371 and metabolite M1 
, M2 
, and M4 
 plasma concentrations. In addition, a 
blood sample for PK analysis should be collected if possible at the time of any SAE. 
Total blood volume collected for PK samples will be approximately 100 ml.  
A PK sample collection manual will be provided to instruct on the type of anticoagulant to be 
used, the material supplies, and the sample processing, storage, and shipping procedures. 
Plasma samples will be stored at the local laboratory and shipped to the analytical lab for 
analysis. 
At the end of each cohort, biological samples (e.g. plasma) should be packed, labeled, and 
shipped on dry ice to the designated bioanalytical CRO for analysis. Samples should be 
shipped in accordance with the hospital SOPs or guidance, and only on a Monday, Tuesday 
or Wednesday, to minimize the possibility of the samples being in transit over a weekend. If 
duplicate samples are being shipped, confirmation should be obtained of arrival at the 
analytical lab of one set of samples before the second set is shipped.  
5.12 
Adverse Events Assessments 
Adverse events will be recorded and reported in accordance with ICH GCP and 
22 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.”  
5.12.1 
Adverse Event Reporting 
Subjects will be instructed that they may report AEs at any time. Adverse events will be 
regarded as ‘pre-treatment’ if they occur between the Screening Visit and the time of 
administration of the first dose of study medication. All events reported following study 
medication administration will be recorded as TEAEs. 
Monitoring of AEs will be continued up to 30 days after the last 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. 


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For this study, an AE is defined as: “Any untoward medical occurrence in a study subject 
administered any dose of study medication (APD371) and which does not necessarily have to 
have a causal relationship with this treatment.” An AE can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of the study medication, whether or not related to the product. AEs 
can be any of the following: 
• Unfavorable changes in general condition; 
• Subjective or objective signs/symptoms; 
• Concomitant disease or accident; 
• Clinically relevant adverse changes in laboratory parameters observed in a subject 
in the course of a clinical study; 
• Pre-existing conditions which worsen in severity or frequency or which have new 
signs/symptoms associated with them. 
Adverse events may be elicited 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 AE Form including details of severity, onset, 
duration, outcome and relationship to the drug as determined by the Investigator. 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). Adverse 
events may also be reported at any time. The type and duration of follow-up of subjects after 
AEs will be documented. 
5.12.2 
Serious Adverse Events and Expedited Reporting of Adverse Events 
An 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. 
All SAEs will be captured from the time of Screening to 30 days after the 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 an SAE when, based upon appropriate medical judgment, 
it may jeopardize the subject 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 


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dyscrasias, or convulsions that do not result in in-subject 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 subject’s entry into the study) will not be 
reported as an SAE. All other hospitalizations, including elective hospitalizations for any 
condition that was not 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) 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: 
 
PPD PVG Fax line: 
 
In the event that the 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).  
Other situations as defined in ICH Topic E2A, ICH Guideline, 22 CFR§ 312.32, and EU 
Volume 10, may 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 including Suspected Unexpected Serious Adverse 
reactions (SUSARs) 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.  
Subjects who become pregnant during the study will be discontinued immediately. Although 
not considered an SAE or AE, pregnancies occurring during the period of study drug 
administration (Day 1 to Day 11) until 30 days after the last dose of study drug should be 
reported to the Sponsor Contact and IRB in the same manner as an SAE. 
Pregnancies will be followed every trimester through the first well baby visit. For female 
partners who become pregnant by male study subjects 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 subject. 


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5.12.3 
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 Common Terminology 
Criteria for Adverse Events (CTCAE) v4.0317 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. 
*Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using 
the telephone, managing money, etc. 
**Self-care ADL refer to bathing, dressing and undressing, feeding self, using the 
toilet, taking medications, and not bedridden. 
 
5.12.4 
Assessment of Adverse Event Relationship to Study Medication  
The relationship of an AE to investigational product(s) will be classified using modified 
World Health Organization (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. 
 


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5.12.5 
Assessment of Adverse Event Outcome 
Outcome of AEs will be defined based on ICH Topic E2B, ICH Guideline. 
• Recovered/Resolved 
• Recovered/Resolved with Sequelae 
• Recovering/Resolving 
• Not Recovered/Not Resolved 
• Fatal 
• Unknown 
 
5.12.6 
Action Taken for Adverse Event 
Action taken for AEs will be documented in the eCRF according to the following: 
• Concomitant medication or other treatment 
• Withdrawal from study 
 
5.12.7 
Action Taken for Study Drug 
Any action taken with study drug will be defined based on ICH Topic E2B, ICH Guideline 
and documented in the eCRF according to the following: 
• Drug Withdrawn 
• None (not changed) 
• Dose Reduced   
• Unknown 
• Not Applicable 
 
5.12.8 
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 subjects 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 Sponsor (or designee) may suggest special tests based on expert 
advice. 
5.12.9 
Follow-up of Adverse Events Present at Last Scheduled Study Visit 
Adverse events present at the last study day (Wk8) that require follow-up or a repeat 
laboratory test will be assessed at the last Follow-up visit (Wk 10) and if still present will 


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continue to be followed-up for 30 days after the last day of study treatment, according to the 
CRO’s procedures for AE follow-up.  
Adverse events that have not resolved or stabilized at 30 days after the last subject’s last 
study dose, will be reviewed with the Sponsor on an individual basis to determine if the 
database will be locked and subsequently updated once the events of ongoing AEs are 
resolved or if database lock will be held. 
5.13 
Concomitant Medications and Procedures 
All medications (OTC and prescribed) that are taken by subjects and all procedures that are 
performed during the Screening period and during the study must be recorded in the eCRF 
with start date/time and stop date/time, if known. 
5.14 
Removal of Subjects from the Trial or Study Drug 
The study will be terminated early if, in the opinion of the Sponsor, Investigator, or IRB, an 
unacceptable risk to the safety and welfare of subjects is posed by the continuation of the 
study in light of review of the key safety data. 
Subjects will be informed that they are free to withdraw from the study at any time for any 
reason should they so wish. The Investigator may remove a subject if, in his/her opinion, it is 
in the best interest of the subject. A subject may be withdrawn from the study for any of the 
following reasons: 
• Deviation/noncompliance with the protocol; 
• A serious or intolerable AE occurs; 
• The Sponsor or Investigator terminates the study; or 
• Withdrawal of consent - any subject 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 is withdrawn. 
 
5.14.1 
Handling of Withdrawals 
Although a subject 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 
subject’s rights. If there is a medical reason for withdrawal, the subject will remain under the 
supervision of the study physician until in satisfactory health. Reasonable efforts will be 
made to contact a subject who fails to attend any follow-up appointments, in order to ensure 
that he/she is in satisfactory health.  
If a subject is prematurely discontinued from this study, the procedures described in 
Section 6.4 must be followed. 


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5.14.2 
Replacements 
Randomized and treated subjects who discontinue the study will not be replaced. Subjects 
who are randomized but are not treated or are withdrawn due to non-compliance or a major 
protocol deviation may be replaced.  
5.15 
Allowable Visit and Procedure Windows 
The following are allowable windows for study visits and procedures: 
 
• Study visits: 
 Wks 2, 4, 6, 8 and 10 (Follow-up):  ± 2 days 
 
• Vital signs and Active-Standing Test: 
 Pre-dose timepoint:  - 15 mins 
 Post-dose timepoints:  ± 15 min 
 


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6 
STUDY ACTIVITIES 
6.1 
Screening Visits Wk -4 to Wk -1 (Days –28 to -1) 
Subjects with a signed ICF and undergoing planned screening will be allocated a sequential 
4 digit screening number starting X001 by the investigator or designee.  
Within 29 days and up to Day -1 before administration of the first dose of study medication, 
all Screening activities necessary to define eligibility for entry into the study will be 
conducted and consist of the following: 
• Collection of demographic data (sex, age, race/ethnicity) 
• Completion of medical and social history (to include tobacco, alcohol, and caffeine 
use) 
• Body measurements 
• Physical examination (complete examination) at initial screening visit 
• Abbreviated physical exam (includes body weight and evaluation of changes to 
previously observed abnormal findings) at final screening visit  
• Vital signs 
• 12-lead ECG 
• Virology screen (HBsAg, HIV antibodies, and HCV antibodies) 
• Drugs of abuse screen 
• Serum hCG pregnancy test (females only) at the initial screening visit 
• Urine pregnancy test (females only) at the final screening visit 
• Clinical laboratory tests to include hematology, serum chemistry, coagulation, 
HsCRP, thyroid function tests (TSH, T4, and free T4 at initial Screening visit only) 
and urinalysis. 
• Stool sample for fecal calprotectin 
• Total Simple Endoscopic Score (SES-CD) score < 10 or FCP < 500 mcg/g. 
Endoscopy results obtained within 1 month prior to screening may be utilized 
• Abdominal Pain Assessment scores to be conducted on at least 7 consecutive days 
twice daily 
 
 
• Monitor and document any pre-treatment AEs  
• Concomitant medications assessment 
 
At the end of Day -1 all subjects will have undergone screening assessments and final 
confirmation or otherwise of eligibility. 


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Subjects who are deemed eligible for the study will be randomized and then report to the 
study site on the morning of Wk 0 (Day 1) ready for an overnight stay. They will undergo 
pre-treatment assessments and then the first dose of study medication will be given in the 
morning at the study site.  
 
6.2 
Screening Failures 
A Screening failure is defined as a subject who has signed the ICF, but does not meet all the 
entry criteria as outlined in this protocol and has not been randomized or received study 
medication. A Screening log will be maintained by the Investigator or designee, indicating 
the reason for the Screening failure. 
6.3 
Treatment Period Wk 0 to 8 (Day 1 to Day 56) 
Subjects will self-administer APD371 TID for 56 consecutive days according to the 
randomization schedule. Study procedures will be conducted at the time points indicated in 
the Schedule of Events (Table 1) and include the following assessments; 
6.3.1 
Wk 0 (Day 1) Pre-treatment  
• Vital signs and Active-Standing Test 
• 12-lead ECG 
• Abdominal Pain Score within 60 min prior to first morning dose  
• PK Blood sample for the analysis of APD371 and metabolite plasma concentrations 
will be collected within 60 min prior to the first morning dose 
• Clinical laboratory tests (to include hematology, serum chemistry, coagulation, 
HsCRP, 
and urinalysis) 
 
 
• Record AEs 
• Record concomitant medications 
• Study medication will be dispensed before the first dose (Week 1-2) 
 
6.3.2 
Wk 0 (Day 1) Post treatment  
• Vital signs and Active-Standing Test 
• 
12-lead ECG at 1.5 hours after initial Day 1 dose 
• Abdominal Pain Score at 1.5 hr after first morning dose  


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• PK Blood samples for the analysis of APD371 and metabolite plasma concentrations 
0.5, 1, 2, 4, 6 and 8 hr after the first daily dose (prior to second daily dose) and 9 and 
10 hr. 
• 
Record AEs; 
• Record concomitant medications 
6.3.3 
Wk 0 (Day 2)  
• Vital signs and Active-Standing Test 
• Abdominal Pain Scores  
• A PK Blood sample for the analysis of APD371 and metabolite plasma 
concentrations will be collected 24 hr post first daily dose on Day 1 and before the 
first daily dose on Day 2 
• 
Record AEs 
• Record concomitant medications 
 
6.3.4 
Wk 0 to 8 (Day -1) (Days 1 to 56) 
• Abdominal Pain Scores will be determined three times a day. 
 
6.3.5 
End of Wk 1, 2, 4, 6 
• Vital signs and Active-Standing Test 
• Abdominal Pain Scores  
• PK blood samples will also be taken immediately before the first daily dose (Week 2, 
4 and 6 only) 
• 
Clinical laboratory tests (to include hematology, serum chemistry, coagulation, 
HsCRP, 
 and urinalysis) prior to first morning dose, Wk 4 
only 
• Study medication will be dispensed before the first daily dose for Wk 0 (Day 1), 2, 4 
and 6 
• Compliance will be assessed based on all returned bottles and treatment duration at 
Wks 2, 4, 6 and 8 
• 
Record AEs 
• Record concomitant medications 
• 
Stool sample for fecal calprotectin (Wk 4 only) 
 
 
 


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It is important that subjects do not take their morning study medication prior to instruction by 
the investigation team on Wk 0 (Day 1 and Day 2), 2, 4 and 6.   
6.3.6 
Wk 8 (Day -1) 
• Vital signs and Active-Standing Test 
• 12-lead ECG 
• Clinical laboratory tests (to include hematology, serum chemistry, coagulation, 
HsCRP, 
 and urinalysis) prior to first morning dose  
• Abdominal Pain Score  
• 
PK Blood samples for the analysis of APD371 and metabolite plasma concentrations 
will be collected prior to and at 0.5, 1, 2, 4, 6 and 8 hr after the first daily dose (prior 
to second daily dose)  
• Stool sample for fecal calprotectin 
 
 
• Colonoscopy for total Simple Endoscopic Score (SES-CD) score (optional) 
• 
Record AEs 
• Record concomitant medications 
 
6.3.7 
Wk 8 End of Treatment  
• Vital signs and Active-Standing Test 
• Abdominal Pain Score 
 
 
• A PK Blood samples for the analysis of APD371 and metabolite plasma 
concentrations will be collected 8 hr post first daily dose on Wk 8 (Day -1) 
• 
Record AEs 
• Record concomitant medications 
Each subject will be evaluated continuously by the Investigator and Sponsor with regards to 
safety, and then the decision will be made on a case-by-case basis on whether the subject 
needs to stay overnight at Week 8 to be assessed for safety, including blood pressure and 
heart rate.  If the decision to remove the Visit 8 (Wk 8) overnight stay has been determined, 
all scheduled evaluations still must be done, including serial PK collections vital signs, 
active-standing test, APS,
 
detailed in the diary cards. 
 


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6.4 
Early Termination Procedures 
• Physical examination (abbreviated examination including body weight and evaluation 
of changes to previously observed abnormal findings) 
• Vital signs and Active-Standing Test 
• 12-lead ECG 
• Serum hCG pregnancy test (females only) 
• Final PK blood sample 
• Clinical laboratory tests (to include hematology, serum chemistry, coagulation, 
HsCRP, 
 and urinalysis)  
• Abdominal Pain Score 
 
 
• Record AEs 
• Record concomitant medications 
 
6.5 
Wk 10 Follow-up Visit Procedures 
Subjects will return to the study site on an outpatient basis for a Follow-up Visit. 
 
• Physical exam (abbreviated examination including body weight and evaluation of 
changes to previously observed abnormal findings) 
• Vital signs and Active-Standing Test 
• 12-lead ECG  
• Serum hCG pregnancy test (females only) 
• Clinical laboratory tests (to include hematology, serum chemistry, coagulation, 
HsCRP, 
 and urinalysis) 
• Record AEs 
• Record concomitant medications 
 
The Principal Investigator and study site staff should exert every effort to secure subject 
attendance to the Follow-Up visit.  Three attempted telephone contacts should be 
documented by study personnel before a subject can be considered lost to follow-up.  
Furthermore, key research personnel should mail a certified letter to the subject’s address if 
no response to 3 telephone contacts remain unanswered.  If the subject or a family member 
does not respond, the certified letter receipt should be filed in the individual’s research record 
with a copy of the letter sent. 


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7 
DATA MANAGEMENT 
7.1 
Data Collection 
All data will be collected according to the Sponsor or CRO’s SOPs. 
Upon database lock, to include resolution of all queries, the CRO, if applicable, will provide 
SAS Transport Files (SAS XPT) datasets to the Sponsor and to the biostatistician for analysis 
using secure electronic data transfer per the Sponsor’s specifications. 
7.2 
Data Coding 
7.2.1 
Adverse Events 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(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. 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). Adverse events will 
be regarded as ‘pre-treatment’ if they occur between Screening and the time of 
administration of the first dose of study medication. All other AEs that occur after the first 
dose of study medication will be considered to be ‘treatment-emergent’. 
7.2.2 
Concomitant Medications 
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 WHO Drug Dictionary, Format C. 
7.2.3 
Medical History 
Medical history will be coded using MedDRA (version 18.0 or later). 
 
 


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8 
PLANNED STATISTICAL METHODS 
The statistical analysis of the data obtained from this study will be the responsibility of the 
Sponsor or designated CRO. Full details of the statistical analyses will be written in a 
separate statistical analysis plan (SAP) which will be finalized prior to database lock. Any 
changes made to the pre-specified statistical analysis plan, will be listed in the Clinical Study 
Report along with an explanation as to why they occurred. 
8.1 
General Considerations 
This is a proof-of-concept study design and there are no formal hypothesis tests being 
specified, Descriptive statistics for proportion based and continuous variables will be 
reported. Subgroup analysis by randomization stratification factor sex will be performed to 
assess potential safety and efficacy differences between males and females. Non-inferential 
between dose cohort comparisons for main study endpoint measures will be performed using 
parametric or non-parametric methods as appropriate and nominal p-values (2-sided) will be 
reported. The 95% confidence intervals for main study endpoint measures will also be 
reported. 
8.2 
Determination of Sample Size 
No formal sample size and power calculation were performed. For this initial study in 
subjects it is planned to treat and complete safety and tolerability assessments in 
approximately 16 subjects, which is reasonable to assess the main study endpoints. Since 
subjects maybe replaced if they are withdrawn due to major protocol violations, a maximum 
of 20 subjects will be randomized in the study.  It is expected that this number of subjects 
will provide guidance for the assessment of tolerability in this population and quantify the 
extent of abdominal pain relief. 
8.3 
Analysis Populations 
The Safety Population will include all randomized subjects who received at least 1 dose of 
study medication. 
The PK Completers Population will be defined as all subjects who receive APD371 and have 
at least 5 of the 9 scheduled PK collections on Wk 0 (Day 1), Wk 0 (Day 2) - 2 or Wk 8 (Day 
-1) and Wk 8, including the pre-dose sample.  
The Efficacy population will include all randomized subjects who received at least 1 dose of 
study medication and have completed at least one consecutive week of APS up to Week 4. 
 
8.4 
Demographics and Baseline Characteristics 
All screening subject characteristics of demographic data (age, height, weight, 
race/ethnicity), social history (smoking status, caffeine intake, alcohol intake), medical 


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history (abnormalities only), physical examination (abnormalities only), and concomitant 
medications at study entry will be listed for all subjects. 
8.4.1 
Demographics 
Demographic data will be summarized and tabulated. Continuous variables will be 
summarized using number of observations (n), mean, standard deviation, median, minimum, 
and maximum. Frequencies and percentages will be reported for all categorical data. 
8.5 
Pharmacokinetic Variables 
The PK analysis will be conducted by the Sponsor’s representative or designated CRO 
employing noncompartmental methods 
 
 
. Only subjects who are given active APD371 drug and have evaluable 
plasma concentration-time profiles will be included in the analysis. 
Individual APD371 and metabolites M1 
, M2 
, and M4 (
 
plasma concentrations at specified timepoints will be listed for each subject and will be 
summarized by dose level. Individual plasma concentration-time profiles of APD371 and 
metabolites M1, M2 and M4 will be plotted on both a linear and a semi-logarithmic scale for 
each dose level. Mean values will also be presented graphically for each dose level.  
Pharmacokinetic parameters of APD371 and metabolites M1, M2, and M4 may be listed for 
each subject and summarized by dose level. The following PK parameters may be 
determined for APD371 and metabolites unless otherwise specified: 
Wk 0 (Day 1) and Wk 8 (Day -1) 
Cmax 
maximum plasma concentration 
tmax 
time of maximum plasma concentration 
AUC0-8 
area under the plasma concentration-time curve over dosing 
interval (8 hours) 
Wk 0 (Day 2), 2, 4, 6, 8 
Ctrough 
plasma concentration observed before treatment administration 
during repeated dosing 
 
The individual elapsed sampling times will be used for all plasma PK parameters. For the 
purpose of calculating descriptive statistics and PK parameters, plasma concentrations below 
the lower limit of quantification (LLOQ) will be set to zero. After the peak, any measurable 
concentrations observed after two or more consecutive concentrations below the LLOQ will 
be considered anomalous and excluded from the PK analyses. Any quantifiable 
concentrations at pre-treatment on Day 1 will be set to zero. 
Unrounded data will be used for estimation of summary statistics and PK analysis. Data will 
be rounded for reporting purposes only, with data presented to 3 significant figures for 


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Clinical Trial Protocol: APD371-004 
  
 
Amendment 02 (10 August 2017) 
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numbers less than or equal to 1,000 and to the nearest integer for numbers greater than 1,000. 
Fold increases will be reported to two decimal places. 
The ratio of each metabolite to APD371 will be calculated for Cmax and AUC0-8. 
Summary statistics for continuous variables will include arithmetic mean, arithmetic SD, 
coefficient of variation, geometric mean, median, minimum and maximum; tmax will be 
summarized using median, minimum and maximum values. The effect of multiple doses of 
APD371 on PK parameters will be assessed with an analysis of variance model with 
treatment as factor. Appropriate transformations will be applied to the variables. 
Ctrough APD371 will be summarized by treatment period for each subject. 
8.6 
Safety Analysis 
8.6.1 
Adverse Events 
Adverse events will be coded using MedDRA v18.0 and tabulated by dose cohort, 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 study medication. 
8.6.2 
Physical Examinations 
Physical examination results (abnormalities only) will be listed and summarized by dose 
cohort. 
8.6.3 
Vital Signs 
Individual vital sign measurements will be listed by treatment and measurement time, and 
summarized using descriptive statistics. Summary statistics will also be provided for change 
from baseline in vital sign measurements by dose cohort.  
8.6.4 
Clinical Laboratory Values 
Individual lab values will be listed by treatment and visit, and summarized by dose cohort 
using descriptive statistics. Summary statistics will also be provided for change from baseline 
in lab values. Shift tables from baseline to the last visit will also be produced for the 
laboratory assessments based on the categories of Low, Normal, and High.  
8.6.5 
12-lead ECGs 
Individual 12-lead ECG values will be listed by dose cohort and visit, and summarized using 
descriptive statistics by dose cohort. Intervals to be provided for each ECG are: RR, PR, 
QRS, QT, QTc, QTcB, and QTcF. Any clinically significant change from baseline may be 
recorded as an AE if deemed appropriate by the Investigator or Sponsor.  
 


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Clinical Trial Protocol: APD371-004 
  
 
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8.7 
Efficacy Analysis 
8.7.1 
Abdominal pain score (APS) 
The change in APS scores between morning dose (trough) and 1.5 hr post-treatment first 
daily dose (peak) assessments will be summarized across all days of treatment and compared 
by dose cohort and overall. Difference between dose cohort will be reported. 
 
8.7.2 
Average abdominal pain score (AAPS) 
AAPS will be summarized for the screening period and for each week of treatment before 
morning dose (trough) assessments and 1.5 hr post-treatment first daily dose (peak) 
assessments, by study cohort. Statistical comparisons of AAPS will be made between 
screening and WK 4 and at Wk 8, trough and peak assessments, by dose cohort and overall. 
Difference between dose cohort will be reported. 
 
8.7.3 
Pain relief responders 
Proportion of subjects in each treatment cohort who are weekly responders will be 
summarized and difference between dose cohort will be reported. 
Proportion of subjects in each treatment arm who are end-of-treatment responders will be 
summarized and difference between dose cohort will be reported. 
 
 
 
 
Other exploratory efficacy measure listed in Section 2.2 will be summarized and difference 
between dose cohort will be reported: 
• The number of pain-free days per week in each treatment cohort, based on 
responses to the APS 
• Pain rescue medication use in each dose arm 
 
8.7.5 
C-reactive Protein 
Change from baseline in level of CRP at week 4 and week 8 (Day-1) will be measured by a 
high-sensitivity assay (HsCRP), summarized and difference between dose cohort will be 
reported. 


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Clinical Trial Protocol: APD371-004 
  
 
Amendment 02 (10 August 2017) 
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8.7.6 
Fecal calprotectin 
Change from baseline in level of fecal calprotectin at week 4 and week 8 (Day-1) will be 
summarized and difference between dose cohort will be reported. 


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Clinical Trial Protocol: APD371-004 
  
 
Amendment 02 (10 August 2017) 
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9 
REGULATORY REQUIREMENTS 
9.1 
Pre-study Documentation 
The Sponsor or designee must receive the following documentation prior to initiation of the 
study: 
• Protocol signature page signed by the PI  
• Food and Drug Administration (FDA) form 1572 signed by the PI 
• Curriculum vitae of the PI and Sub-investigators, updated within two years 
• Current medical licenses for the PI and all Sub-investigators 
• Financial disclosure form signed by the PI and all Sub-investigators listed on the FDA 
Form 1572 
• Copy of the IRB approval letter for the study and approved voluntary ICF 
• IRB Membership List. 
 
 
9.2 
Investigator Obligations 
The PI is responsible for ensuring that all study site personnel, including Sub-investigators 
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 subject’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 22 CFR §312.64. 
9.3 
Subject Confidentiality 
All information obtained during the conduct of the study with respect to the subjects’ state of 
health will be regarded as confidential. This is detailed in the written information provided to 
the subject. An agreement for disclosure of any such information will be obtained in writing 
and is included in both copies of the ICF signed by the subject. The study data shall not be 
disclosed to a third party without the written consent of the Sponsor.  
9.4 
Informed Consent 
According to the ICH guideline for GCP (E6), the PI (or designee) will obtain and document 
informed consent for each subject screened for this study. All subjects 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 subject’s medical record should contain 
written documentation indicating that informed consent was obtained. The ICF must be 
reviewed and approved by the Investigator’s designated IRB and by the Sponsor. The ICF 


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Clinical Trial Protocol: APD371-004 
  
 
Amendment 02 (10 August 2017) 
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should include all the elements as outlined in Section 4.8.10 of the ICH guideline for GCP 
(E6). 
9.5 
Institutional Review Board 
This protocol and relevant supporting data are to be submitted to the appropriate IRB for 
review and approval before the study can be initiated. Amendments to the protocol will also 
be submitted to the IRB prior to implementation of the change. The Sponsor must receive a 
letter documenting the IRB approval prior to initiation of the study. The PI is also responsible 
for informing the IRB of the progress of the study and for obtaining annual IRB 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 in writing of any 
SAE or any unexpected AE according to ICH guidelines. 


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Clinical Trial Protocol: APD371-004 
  
 
Amendment 02 (10 August 2017) 
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Page 63 of 67 
10 PROTOCOL MANAGEMENT AND ADMINISTRATIVE 
CONSIDERATIONS 
10.1 
Study Documentation 
The PI and study staff have the responsibility of maintaining a comprehensive and 
centralized filing system containing all study-related documentation. These files must be 
available for inspection by the Sponsor, representatives of the Sponsor, the IRB, and 
regulatory authorities (i.e., FDA or international regulatory authorities) at any time, and 
should consist of the following elements: 
Subject files, containing the completed eCRFs, supporting source documentation from the 
medical record including laboratory data and the ICF. 
Regulatory files, containing the protocol with all amendments and Investigator signature 
pages, copies of all other regulatory documentation, and all correspondence between the site 
and the IRB 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 two years after marketing application approval, or if the 
application is not approved or never submitted, two 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. 
10.2 
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. 
10.3 
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 subjects’ complete medical 
records, laboratory data, and other source documentation as needed to monitor the study 
appropriately. 


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Clinical Trial Protocol: APD371-004 
  
 
Amendment 02 (10 August 2017) 
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Page 64 of 67 
11 PRINCIPAL INVESTIGATOR SIGNATURE PAGE 
I agree to conduct the study as outlined in the protocol entitled, “A Randomized, Open-label, 
Parallel, Phase 2a Study to Determine the Tolerability, Pharmacokinetics, and Efficacy of 
APD371 in Subjects with Crohn’s disease experiencing Abdominal Pain” 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 regulatory 
agencies to inspect study facilities and pertinent records at reasonable times and in a 
reasonable manner that ensures subject 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 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. 
• Submission of any proposed change in the protocol to the IRB 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.  
• Documentation and explanation of individual protocol deviations on the appropriate 
eCRF page or in letters to the Sponsor. 
• Submission of reports of SAEs to PPD Medical Affairs/ Pharmacovigilance within 
24 hours after the Investigator’s initial receipt of the information.  
• Submission of written reports of SAEs, as outlined in the protocol, to the IRB within 
15 calendar days of their disclosure. 
• Submission of timely progress reports to the IRB and Sponsor at appropriate intervals 
on a schedule determined by the IRB.  
• Maintenance of appropriate records: Federal regulations require an Investigator to 
prepare and maintain adequate and an accurate case history 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 two 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 two 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 eCRF in a manner to 
assure legibility and accuracy. To this end, I shall carefully follow the instructions for 
completing eCRFs. 


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Clinical Trial Protocol: APD371-004 
  
 
Amendment 02 (10 August 2017) 
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Page 65 of 67 
I also agree that all information provided to me by the Sponsor, including protocols, eCRFs, 
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. 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 or to the FDA or other legally constituted authority. 
 
 
Principal Investigator 
 
 
Date 
 
Printed Name 
 


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Clinical Trial Protocol: APD371-004 
  
 
Amendment 02 (10 August 2017) 
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12 REFERENCES 
1. Matsuda LA, Lolait SJ, Brownstein MJ, Young AC, Bonner TI. Structure of a 
cannabinoid receptor and functional expression of the cloned cDNA. Nature 1990 August 
9;346(6284):561-4. 
2. Munro S, Thomas KL, Abu-Shaar M. Molecular characterization of a peripheral receptor 
for cannabinoids. Nature 1993;365:61-5. 
3. Anand P, Whiteside G, Fowler CJ, Hohmann AG. Targeting CB2 receptors and the 
endocannabinoid system for the treatment of pain. Brain Res Rev 2009;60:255-66. 
4. Atwood BK, Mackie K. CB2: a cannabinoid receptor with an identity crisis. Br J 
Pharmacol 2010;160:167-479. 
5. Cheng Y, Hitchcock SA. Targeting cannabinoid agaonists for inflammatory and 
neuropathic pain. Expert Opin Investig Drugs 2007;16:951-65. 
6. 
 
 
 
7. 
 
 
 
8. 
 
9. 
 
 
10. Wright KL, Duncan M, Sharkey KA. Cannabinoid CB2 receptors in the gastrointestinal 
tract: a regulatory system in states of inflammation. Br J Pharmacol 2008;153(2):263-70. 
11. Naftali T, Bar-Lev Schleider L, Dotan I, et al. Cannabis induces a clinical response in 
patients with Crohn's disease: a prospective placebo-controlled study. Clin Gastroenterol 
Hepatol 2013;11(10):1276-80 e1. 
12. Naftali T, Lev LB, Yablecovitch D, et al. Treatment of Crohn's disease with cannabis: an 
observational study. Isr Med Assoc J 2011;13(8):455-8. 
13. Hillsley K, McCaul C, Aerssens J, et al. Activation of the cannabinoid 2 (CB2) receptor 
inhibits murine mesenteric afferent nerve activity. Neurogastroenterol Motil 
2007;19(9):769-77. 
14. Rousseaux C, Thuru X, Gelot A, et al. Lactobacillus acidophilus modulates intestinal 
pain and induces opioid and cannabinoid receptors. Nat Med 2007;13(1):35-7. 


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Clinical Trial Protocol: APD371-004 
  
 
Amendment 02 (10 August 2017) 
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15. Shibao C, Lipsitz LA, Biaggioni I. ASH Position Paper:  Evaluation and Treatment of 
Orthostatic Hypotension. The Journal of Clinical Hypotension 2013; (15):147-153. 
16. Vilela EG, Gama Tores, HO, et. al. Evaluation of inflammatory activity in Crohn's 
disease and ulcerative colitis. World J Gastroenterol 2012; 18(9):872-881. 
17. Common Terminology Criteria for Adverse Events v4.03 (CTCAE). 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-15_QuickReference_5x7.pdf. 
[Accessed October 2010]. 6-15-2010. 2010.  
 
 
 
 
 


 
This is a representation of an electronic record that was signed electronically, and this 
page is the manifestation of the electronic signature. 
 
UserName: 
 
Title:  Sr. Manager, Medical Writer 
Date: Thursday, 10 August 2017, 02:22 PM   Pacific Daylight Time 
Meaning: Author Approval 
================================================
UserName: 
 
Title:  Vice President, Regulatory Affairs and Quality  
Date: Thursday, 10 August 2017, 04:19 PM   Pacific Daylight Time 
Meaning: Approval 
================================================
UserName: 
 
Title:  EVP, Research & Development 
Date: Thursday, 10 August 2017, 04:43 PM   Pacific Daylight Time 
Meaning: Approval 
================================================
UserName:
 
Title:  Vice President, Clinical Development 
Date: Friday, 11 August 2017, 07:45 AM   Pacific Daylight Time 
Meaning: Approval 
================================================


APD371-004 Amendment 02 (10 August 2017)  
 
APD371 
Summary of Changes 
 
Page 1 of 15 
Confidential and/or proprietary information of Arena Pharmaceuticals, Inc. 
 
 
APD371-004 AMENDMENT 02  
SUMMARY OF CHANGES 
 
Protocol Number: APD371-004 Protocol Amendment 02 
 
Protocol Title: A Randomized, Open-label, Parallel, Phase 2a Study to Determine the 
Tolerability, Pharmacokinetics, and Efficacy of APD371 in Subjects with Crohn’s 
disease experiencing Abdominal Pain 
 
Amendment Date:  10 August 2017 
 
 
 
 
 
 
 
 


APD371-004 Amendment 02 (10 August 2017) 
 
APD371 
Summary of Changes 
 
Page 2 of 15 
Confidential and/or proprietary information of Arena Pharmaceuticals, Inc. 
PAGE(S) 
PROTOCOL CHANGE DESCRIPTION 
RATIONALE 
Throughout 
Minor administrative and formatting changes were made 
Not applicable 
1 
TITLE PAGE –Sponsor Contact 
Previously read: 
 
Associate Director, Clinical Operations 
Arena Pharmaceuticals, Inc. 
6154 Nancy Ridge Drive 
San Diego, CA 92121, USA 
Phone: 
 
Email:
 
 
Now reads: 
 
Head of Clinical Operation 
Arena Pharmaceuticals, Inc. 
6154 Nancy Ridge Drive 
San Diego, CA 92121, USA 
Phone: 
 
Email:
 
 
Administrative change 
1 
TITLE PAGE  
Added: 
Amendment 02     08 August 2017 
 
Administrative change 
2 
SYNOPSIS – Name of Sponsor Medical Contact 
Previously read: 
 MD 
Arena Pharmaceuticals Development GmbH 
Gotthardstrasse 3 
6300 Zug, Switzerland 
Phone: 
 
Email:
 
 
 
Administrative change 


APD371-004 Amendment 02 (10 August 2017) 
 
APD371 
Summary of Changes 
 
Page 3 of 15 
Confidential and/or proprietary information of Arena Pharmaceuticals, Inc. 
Now reads: 
, MD, PhD 
Arena Pharmaceuticals, Inc. 
6154 Nancy Ridge Drive 
San Diego, California 92121 
United States of America (USA) 
Phone: 
 
Email: 
 
 
3 
and 
20 
SYNOPSIS – Objectives, Exploratory Objectives 
and 
2.2 Exploratory Objectives 
Added: 
 
 
 
 
 
 
 
  
3 
and 
20 
SYNOPSIS – Objectives, Exploratory Objectives 
and 
2.2 Exploratory Objectives 
Previously read: 
• 
Pain rescue medication use  
Now reads: 
• 
Pain medication use 
Use of standard of care pain 
medication, including narcotics, is 
being allowed in this protocol 
amendment (see Inclusion 
Criteria #9). A decrease in the use 
of pain medication will be 
considered one of the exploratory 
efficacy endpoints for APD371.  
3 
and 
20 
SYNOPSIS – Objectives, Exploratory Objectives 
and 
2.2 Exploratory Objectives 
Previously read: 
• Effect of APD371 treatment on reduction in C-reactive protein (CRP) at week 4 and week 8 
Now reads: 
• Effect of APD371 treatment on reduction in C-reactive protein (CRP) and other biomarkers at week 4 and week 8 
 
Since the CB2 receptor is mainly 
expressed in immune cells, 
additional immune and 
inflammation-related biomarkers 
will be evaluated to help 
understand the mechanism of 
action of APD371. 
3 
and 
SYNOPSIS – Objectives, Exploratory Objectives 
and 
2.2 Exploratory Objectives 
Added: 
 


APD371-004 Amendment 02 (10 August 2017) 
 
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Summary of Changes 
 
Page 4 of 15 
Confidential and/or proprietary information of Arena Pharmaceuticals, Inc. 
20 
 
 
 
 
3 
and 
20 
SYNOPSIS – Objectives, Exploratory Objectives 
and 
2.2 Exploratory Objectives 
Added: 
 
 
 
 
 
 
 
 
 
4 
SYNOPSIS – Study Population 
Previously read: 
The study population will consist of adult male and female subjects aged 18 to 80 years who are diagnosed with 
abdominal pain due to quiescent to mildly active CD, as defined by a weekly average abdominal pain score (AAPS) 
>5 over one week (0 [no pain] to 10 [worst possible]), with minimal intestinal inflammation, confirmed with a simple 
endoscopic score (-CD) score <6 or ileal SES-CD <4 or fecal calprotectin <300 mcg/g.  
Now reads: 
The study population will consist of adult male and female subjects aged 18 to 80 years who are diagnosed with 
abdominal pain due to quiescent to mildly active CD, as defined by a weekly average abdominal pain score (AAPS) 
≥4 over one week (0 [no pain] to 10 [worst possible]), with minimal intestinal inflammation, confirmed with a simple 
endoscopic score (-CD) score <10 or fecal calprotectin (FCP) <500 mcg/g.  
 
The study entry criteria have been 
amended to revise inclusion and 
exclusion criteria that were 
unnecessarily restrictive.  
4 
and 
26 
SYNOPSIS – Inclusion Criteria 
and 
3.5 Inclusion Criteria #7 
Previously read: 
7. Quiescent to mildly active inflammatory CD defined with a total SES-CD score of < 6 or ileal SES-CD < 4 or FCP 
< 300 mcg/g at Screening 
 
Now reads: 
7. Quiescent to mildly active inflammatory CD defined with a total SES-CD score of < 10 or FCP < 500 mcg/g within 
4 weeks before screening 
 
The study entry criteria have been 
amended to revise inclusion and 
exclusion criteria that were 
unnecessarily restrictive. 


APD371-004 Amendment 02 (10 August 2017) 
 
APD371 
Summary of Changes 
 
Page 5 of 15 
Confidential and/or proprietary information of Arena Pharmaceuticals, Inc. 
4 
and 
27  
SYNOPSIS – Inclusion Criteria 
and 
3.5 Inclusion Criteria #8 
Previously read: 
8. Moderate to severe abdominal pain as defined by average abdominal pain score (AAPS) of >5 points on 7 
consecutive days of the screening period up to Day -2. AAPS will be based on the 11-point numeric rating scale where 
0 (no abdominal pain) to 10 (worst possible abdominal pain)  
Now reads: 
8. Moderate to severe abdominal pain as defined by average abdominal pain score (AAPS) of ≥ 4 points on 7 
consecutive days of the screening period up to Day -2. AAPS will be based on the 11-point numeric rating scale where 
0 (no abdominal pain) to 10 (worst possible abdominal pain)  
 
The study entry criteria have been 
amended to revise inclusion and 
exclusion criteria that were 
unnecessarily restrictive. 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
. 


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Summary of Changes 
 
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Confidential and/or proprietary information of Arena Pharmaceuticals, Inc. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 


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APD371 
Summary of Changes 
 
Page 7 of 15 
Confidential and/or proprietary information of Arena Pharmaceuticals, Inc. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9 
SYNOPSIS – Sample size 
And 
3.5 Overall study design and plan 
Previously read: 
It is planned to treat and complete safety and tolerability assessments in at least 16 subjects. 
 
Now reads: 
It is planned to treat and complete safety and tolerability assessments in approximately 16 subjects. 
 
Clarification of sample size. 
9 
SYNOPSIS – Pharmacokinetic Assessments 
Previously read: 
Blood samples for the assay of APD371 and metabolites M1 
, M2 
, and M4
 
will be collected at the following time points: 
• 
Wk 8 (Day -1, last day dosing): prior to and 0.5, 1, 2, 4, 6, 8 (prior to second daily dose), 9, 10 and 24 hr post first 
daily dose.  
Now reads: 
Blood samples for the assay of APD371 and metabolites M1 
, M2 
, and M4 
 
will be collected at the following time points: 
• 
Wk 8 (Day -1, last day dosing): prior to and 0.5, 1, 2, 4, 6, 8 (prior to second daily dose).  
 
Based on PK analysis, AUC0-8 
will be an important index for 
comparison between Week 0 
(Day 1) and Week 8 (Day -1) as 
per section 8.5 (Pharmacokinetic 
Variables). Samplings at 9, 10 
and 24 hours are not required.  
15-16 
List of Abbreviations and Definitions of Terms 
Added: 
     
 
 
Addition of abbreviations 


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Summary of Changes 
 
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Confidential and/or proprietary information of Arena Pharmaceuticals, Inc. 
THC      Tetrahydro cannabinol 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
. 


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Summary of Changes 
 
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Confidential and/or proprietary information of Arena Pharmaceuticals, Inc. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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26 
3.4 Study Population 
Previously read: 
The study population will consist of adult male and female subjects aged 18-80 years who are diagnosed with 
abdominal pain due to quiescent to mildly active CD, as defined by an AAPS >5 over one week (0 [no pain] to 10 
The study entry criteria have been 
amended to revise inclusion and 
exclusion criteria that were 
unnecessarily restrictive. 


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Summary of Changes 
 
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[worst possible]), with minimal intestinal inflammation, confirmed with a total simple endoscopic score (SES-CD) 
score < 6 or ileal SES-CD < 4 or fecal calprotectin (FCP) < 300. Endoscopy results obtained within 4 weeks prior to 
screening may be utilized. 
 
Now reads: 
The study population will consist of adult male and female subjects aged 18-80 years who are diagnosed with 
abdominal pain due to quiescent to mildly active CD, as defined by an AAPS ≥4 over one week (0 [no pain] to 10 
[worst possible]), with minimal intestinal inflammation, confirmed with a total simple endoscopic score (SES-CD) 
score < 10 or ileal SES-CD < 4 or fecal calprotectin (FCP) < 500. Endoscopy results obtained within 4 weeks prior to 
screening may be utilized. 
 
 
26 
3.4 Study Population 
Previously read: 
Exceptions to eligibility criteria will not be granted by the Investigator or the Sponsor. 
 
Now reads: 
Exceptions to eligibility criteria will not be granted by the Investigator unless approved in advance by the Sponsor. 
 
Revised to allow for exceptions to 
eligibility criteria.  
32 
4.6 Dosage and Administration 
Previously read: 
There are no food restrictions around dosing with the exception of ingestion of grapefruit juice, prune juice or 
poppy seeds or poppy seed containing items. 
Now reads: 
There are no food restrictions around dosing with the exception of ingestion of grapefruit juice or prune juice. 
The restriction on ingestion of 
poppy seeds or poppy seed 
containing items was 
unnecessarily restrictive and has 
been removed. 
35 
4.9 Concomitant Medications 
Previously read: 
Stable doses of non-narcotic prescription medications required for treatment of current medical conditions other than 
pain (e.g., hypertension, thyroid disease, diabetes) may be continued during the screening and study period with the 
exception of medications known to be moderate or strong CYP3A4/5 inducers or inhibitors.   Doses may be adjusted 
as appropriate per usual standards of care. 
 
Now reads: 
Administrative change (see 4.9.1 
Not Permitted) 
 
 


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Stable doses of non-narcotic prescription medications required for treatment of current medical conditions other than 
pain (e.g., hypertension, thyroid disease, diabetes) may be continued during the screening and study period.   Doses 
may be adjusted as appropriate per usual standards of care. 
35 
4.9 Concomitant Medications – 4.9.1 Not Permitted 
Previously read: 
• 
Prescription and OTC medications for pain relief (for exceptions, see Section 4.9.2 – Permitted)  
• 
Hormonal contraceptives for pain relief within 30 days prior to the Screening visit, during the Screening 
period, and for the duration of the study.   
• 
Dietary supplements (vitamin, herbal, and mineral supplements), unless deemed appropriate by the 
Investigator for the treatment of an AE. 
 
Now reads: 
• 
Hormonal contraceptives for pain relief within 30 days prior to the Screening Visit, during the Screening 
period, and for the duration of the study.  
• 
Moderate or strong CYP3A4/5 inducers or inhibitors  
 
Not permitted Medications have 
been amended to revise criteria 
that were unnecessarily 
restrictive.  
36 
4.9 Concomitant Medications – 4.9.2 Permitted 
Previously read: 
• 
Pain relief medications such as NSAIDs or acetaminophen/paracetamol given at stable doses for at least 2 
weeks prior to screening and for the duration of the study 
Now reads: 
• 
Pain relief medications such as NSAIDs, narcotic analgesics, or acetaminophen/paracetamol given at stable 
doses for at least 2 weeks prior to screening and for the duration of the study 
 
Patients with moderate to severe 
abdominal pain need to be on 
standard-of-care pain 
medications, including narcotics, 
during the study. 
36 
4.10 Restrictions – 4.10.1 Fluid and Food Intake 
Previously read: 
There are no food restrictions around dosing with the exception of grapefruit, prune juice and poppy seeds or poppy 
seed containing items. 
Now reads: 
There are no food restrictions around dosing with the exception of grapefruit and prune juice. 
 
The restriction on ingestion of 
poppy seeds or poppy seed 
containing items was 
unnecessarily restrictive and has 
been removed. 
37 
4.10 Restrictions – 4.10.2 Smoking 
Removed: 
It is common that Crohn’s 
Disease patients that experience 
abdominal pain are smokers - 
therefore this restriction was 


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Subjects who smoke, have a history of smoking or nicotine use, or use of nicotine-containing products within 90 days 
prior to dosing will not be allowed into the study. Smoking or use of nicotine-containing products is not allowed 
during study participation. 
 
unnecessarily restrictive and has 
been removed. 
41 
5.9 Clinical Laboratory Tests – 5.9.4 C-Reactive Protein and other Biomarkers 
Previously read: 
Blood samples for analysis of C-reactive protein (CRP) will be collected at screening, pre-dose at Day 1, Week 4 and 
Week 8 (Day -1), and Week 10 (Follow-up). 
Now reads: 
Separate blood samples (a total of 20 mL) for analysis of C-reactive protein (CRP) will be collected at screening, pre-
dose at Day 1, Week 4 and Week 8 (Day -1), and Week 10 (Follow-up).
 
 
 
 
 
 
42 
5.9 Clinical Laboratory Tests – 5.9.6 Blood Volume 
Previously read: 
Total blood volume for clinical laboratory tests will be approximately 185 mL. 
Now reads: 
Total blood volume for clinical laboratory tests will be approximately 205 mL. 
 
Blood volume increased to 
accommodate additional 
biomarker testing 
42 
5.11 Pharmacokinetic sampling 
Previously read: 
Pharmacokinetic samples for the assay of APD371 and metabolites M1 
M2 
, and M4 
 will be collected will be collected at the visit time points indicated in the Schedule of Events (Table 1) 
and detailed in Pharmacokinetic sampling, Table 3. 
 
Table 3. 
Pharmacokinetic sampling 
Study Day 
Blood sampling assessments* 
Wk 0 (Day 1) 
Prior to and 0.5, 1, 2, 4, 6, 8 (prior to second daily dose), 9 and 10 hours 
post first daily dose. 
Wk 0 (Day 2) 
24 hours post dose first daily dose on Day 1 
Wk 2 
Prior to first daily dose 
Wk 4 
Prior to first daily dose 
Based on PK analysis, AUC0-8 
will be an important index for 
comparison between Week 0 
(Day 1) and Week 8 (Day -1) as 
per section 8.5 (Pharmacokinetic 
Variables). Sampling at 9, 10 and 
24 hours is not required. 


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Wk 6 
Prior to first daily dose 
Wk 8 (Day -1) 
Prior to and 0.5, 1, 2, 4, 6, 8 (prior to second daily dose), 9, 10 post first 
daily dose. 
Wk 8 (End-of-Treatment) 
24 hours post dose first daily dose on Wk 8 (Day-1) 
 
 Now reads: 
Pharmacokinetic samples for the assay of APD371 and metabolites M1 
, M2 
, and M4 
 will be collected will be collected at the visit time points indicated in the Schedule of Events (Table 1) 
and detailed in Pharmacokinetic sampling, Table 3. 
 
Table 3. 
Pharmacokinetic sampling 
Study Day 
Blood sampling assessments* 
Wk 0 (Day 1) 
Prior to and 0.5, 1, 2, 4, 6, 8 (prior to second daily dose), 9 and 10 hours 
post first daily dose. 
Wk 0 (Day 2) 
24 hours post dose first daily dose on Day 1 
Wk 2 
Prior to first daily dose 
Wk 4 
Prior to first daily dose 
Wk 6 
Prior to first daily dose 
Wk 8 (Day -1) 
Prior to and 0.5, 1, 2, 4, 6, 8 (prior to second daily dose) 
Wk 8 (End-of-Treatment) 
8 hours post dose first daily dose on Wk 8 (Day-1) 
* Allowable windows for sample collection: 
- 
time points up to 4 hours: ± 5 mins  
- 
time points after 4 hours: ± 15 mins 
 
50 
6 STUDY ACTIVITIES – 6.1 Screening Visits Wk -4 to Wk -1 (Days -28 to -1) 
Previously read: 
• 
Total Simple Endoscopic Score (SES-CD) score < 6 or ileal SES-CD < 4 or FCP < 300 mcg/g. Endoscopy 
results obtained within 1 month prior to screening may be utilized.  
Now reads: 
• 
Total Simple Endoscopic Score (SES-CD) score < 10 or FCP < 500 mcg/g. Endoscopy results obtained 
within 1 month prior to screening may be utilized. 
The study entry criteria have been 
amended to revise inclusion and 
exclusion criteria that were 
unnecessarily restrictive. 
53 
6 STUDY ACTIVITIES – 6.3.6 Wk 8 (Day -1) 
Previously read: 
• 
PK Blood samples for the analysis of APD371 and metabolite plasma concentrations will be collected prior 
to and at 0.5, 1, 2, 4, 6 and 8 hr after the first daily dose (prior to second daily dose) and 9 and 10 hr 
Based on PK analysis, AUC0-8 
will be an important index for 
comparison between Week 0 
(Day 1) and Week 8 (Day -1) as 
per section 8.5 (Pharmacokinetic 


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Now reads: 
• 
PK Blood samples for the analysis of APD371 and metabolite plasma concentrations will be collected prior 
to and at 0.5, 1, 2, 4, 6 and 8 hr after the first daily dose (prior to second daily dose)  
Variables). Sampling at 9, 10 and 
24 hours is not required. 
53 
6 STUDY ACTIVITIES – 6.3.7 Wk 8 End of Treatment 
Previously read: 
• 
A PK Blood samples for the analysis of APD371 and metabolite plasma concentrations will be collected 24 
hr post first daily dose on Wk 8 (Day -1) 
Now reads: 
• 
A PK Blood samples for the analysis of APD371 and metabolite plasma concentrations will be collected 8 hr 
post first daily dose on Wk 8 (Day -1) 
Based on PK analysis, AUC0-8 
will be an important index for 
comparison between Week 0 
(Day 1) and Week 8 (Day -1) as 
per section 8.5 (Pharmacokinetic 
Variables). Sampling at 9, 10 and 
24 hours is not required. 
 


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APD371-004 AMENDMENT 1 SUMMARY OF CHANGES 
 
Protocol Number: APD371-004 Protocol Amendment 01 
 
Protocol Title:  A Randomized, Open-label, Parallel, Phase 2a Study to Determine the Tolerability, 
Pharmacokinetics, and Efficacy of APD371 in Subjects with Crohn’s disease 
experiencing Abdominal Pain 
 
Amendment Date:  24 March 2017 
 
 
 
 
 
 
 
 


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APD371-004 Protocol Amendment 01 Summary of Changes 
 
Page(s) 
Protocol Change Description 
Rationale 
Throughout 
Minor administrative and formatting changes were made 
Not applicable 
1 
TITLE PAGE – Title 
Previously read: 
A Randomized, Open-label, Parallel Group, Phase 2a Study to Determine the Tolerability, Pharmacokinetics, and 
Efficacy of APD371 in Subjects with Crohn’s disease experiencing Abdominal Pain 
Now reads: 
A Randomized, Open-label, Parallel, Phase 2a Study to Determine the Tolerability, Pharmacokinetics, and Efficacy of 
APD371 in Subjects with Crohn’s disease experiencing Abdominal Pain  
 
Consistency with protocol title 
1 
and 
2 
TITLE PAGE - Indication 
and 
SYNOPSIS 
Previously read: 
Acute and chronic inflammatory and neuropathic pain 
Now reads: 
Acute and chronic inflammatory pain 
The company decided to focus on 
inflammatory visceral pain and 
remove neuropathic pain as a 
target for the study. 
1 
TITLE PAGE –Sponsor Contact 
Previously read: 
 
Director, Clinical Operations 
Arena Pharmaceuticals, Inc. 
6154 Nancy Ridge Drive 
San Diego, CA 92121, USA 
Phone : 
, ext. 
 
Email: 
 
Now reads: 
 
Associate Director, Clinical Operations 
Arena Pharmaceuticals, Inc. 
Administrative change 


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6154 Nancy Ridge Drive 
San Diego, CA 92121, USA 
Phone: 
 
Email: 
 
1 
TITLE PAGE  
Added: 
Amendment 01     24 March 2017 
Administrative change 
2 
SYNOPSIS – Name of Sponsor Medical Contact 
Previously read: 
 MD, CPI 
Principal, Pacific Pharma Group, LLC 
1402 S. Brookside Terrace 
Tacoma, WA 98465-1210, USA. 
Phone: 
 
Mobile: 
 
Email: 
 
Now reads: 
 MD 
Arena Pharmaceuticals Development GmbH 
Gotthardstrasse 3 
6300 Zug, Switzerland 
Phone:
 
Email: 
 
Administrative change 
2 
SYNOPSIS – Medical Monitor 
Added: 
 MD, CPI 
Principal, Pacific Pharma Group, LLC 
1402 S. Brookside Terrace 
Tacoma, WA 98465-1210, USA. 
Phone: 
 
Mobile: 
 
Email: 
 
Administrative change 
3 
and 
SYNOPSIS – Objectives, Exploratory Objectives 
and 
2.2 Exploratory Objectives 
Previously read: 
Simplification and wording 
consistency with other objectives  


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20 
• 
Proportion of subjects in each treatment cohort who are weekly responders  
Now reads: 
• 
Proportion of subjects who are weekly responders 
3 
and 
20 
SYNOPSIS – Objectives, Exploratory Objectives 
and 
2.2 Exploratory Objectives 
Previously read: 
• 
Proportion of subjects in each treatment cohort who are end-of treatment responders  
Now reads: 
• 
Proportion of subjects who are end-of-treatment responders 
Simplification and wording 
consistency with other objectives 
3 
SYNOPSIS – Study Design 
Previously read: 
A randomized, open label, parallel group, multi center, comparison of two doses of APD371. 
Eligible subjects will enter a screening period of up to 4 weeks and will then be randomized into an open-label, study, 
receiving APD371 in doses of 25 mg or 100 mg capsules for 8 weeks.  
Treatment cohorts will consist of daily doses of 25 mg or 100 mg APD371 TID. Subjects will be randomized in a 1:1 
ratio, with random assignment to active study drug 25 mg or 100 mg. 
 
Randomization will be stratified by sex. 
Now reads: 
A randomized, open label, parallel group, multi center, comparison of two doses of APD371. 
Eligible subjects will enter a screening period of up to 4 weeks and will then be randomized in a 1:1 ratio to receive 
APD371 in doses of 25 mg or 100 mg TID for 8 weeks. 
Randomization will be stratified by sex. 
To remove redundancy and 
incorrect information 
4 
SYNOPSIS – Section descriptor 
Previously read: 
Subject Population 
Now reads: 
Study Population 
Consistency throughout the 
protocol. 
4 
SYNOPSIS – Subject Population 
Previously read: 
Revised for consistency with 
Section 3.4 and provide the 


APD371-004 Amendment 01 Summary of Changes  
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The study population will consist of adult male and female subjects aged 18 to 80 years who are diagnosed with 
abdominal pain due to quiescent to mildly active CD, as defined by a weekly average abdominal pain score (AAPS) 
>5 over one week (0 [no pain] to 10 [worst possible]), with minimal intestinal inflammation, confirmed with a simple 
endoscopic score (-CD) score <5 or fecal calprotectin <300. Endoscopy results obtained within 1 month prior to 
screening may be utilized. 
Now reads: 
The study population will consist of adult male and female subjects aged 18 to 80 years who are diagnosed with 
abdominal pain due to quiescent to mildly active CD, as defined by a weekly average abdominal pain score (AAPS) 
>5 over one week (0 [no pain] to 10 [worst possible]), with minimal intestinal inflammation, confirmed with a simple 
endoscopic score (-CD) score <6 or ileal SES-CD <4 or fecal calprotectin <300 mcg/g. Endoscopy results obtained 
within 1 month prior to screening may be utilized. 
appropriate units for fecal 
calprotectin. 
4 
and 
26 
SYNOPSIS – Inclusion Criteria 
and 
3.5 Inclusion Criteria 
Previously read: 
7. Quiescent to mildly active inflammatory CD defined with a total SES-CD score of < 6 or ileal SES-CD < 4 or FCP 
< 300 at Screening 
Now reads: 
7. Quiescent to mildly active inflammatory CD defined with a total SES-CD score of < 6 or ileal SES-CD < 4 or FCP 
< 300 mcg/g at Screening 
Addition of appropriate units for 
FCP assessment results 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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. 


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. 


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7 
and 
29 
SYNOPSIS – Exclusion Criteria 
and 
3.5 Exclusion Criteria – General Exclusion Criteria 
Previously read: 
13.  Other significant chronic pain conditions that in the opinion of the investigator may influence the pain score 
Now reads: 
13.  Other significant chronic pain conditions that in the opinion of the Investigator may influence the abdominal pain 
score 
Clarification of which pain score.    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
   
 
 
 
 
 
 
 
  


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8 
SYNOPSIS – Subject Assignment 
Previously read: 
Eligible subjects will be randomized in a 1:1 ratio to receive APD371 25 mg TID or 100 mg TID. 
If subjects on 100 mg TID experience hypotensive symptoms of SBP <90 or DBP<50 mmHg, they will be titrated 
down to 75 mg TID, or to 50 mg TID if this recurs. 
Now reads: 
Eligible subjects will be randomized in a 1:1 ratio to receive APD371 25 mg TID or 100 mg TID. 
Deleted original dose reduction 
parameters and added more 
defined dose reduction parameters 
in Section 3.1 Overall Study 
Design and Plan. 
14 
List of In-Text Tables 
Previously read: 
Now reads: 
Table 3. 
Pharmacokinetic sampling .................................................................................................. 42 
16 
List of Abbreviations and Definitions of Terms 
Added: 
PRO   Patient Reported Outcome 
Clarification 
18  
1.1 Rationale for Proposed Clinical Study 
Previously read: 
Revised to correct protocol 
number for the second study, the 
minimal dose tested in that study 


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Now reads: 
 
 
 
 
 
 
 
and add units to the lowest dose 
in this study. 
19 
1.2 
Ethics and Regulatory Considerations   
Previously read: 
 
The IRB must be notified promptly by the Investigator of the following: 
• 
Deviations from, or changes to, 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 adverse events (AE)s that meet the definition of a serious adverse event (SAE); 
• 
New information that may adversely affect the safety of the volunteers or the conduct of the trial. 
 
Any changes to the protocol will be made by means of a formal written protocol amendment. All amendments will 
require IRB approval before implementation except when changes to the protocol are required immediately to 
eliminate hazards to the volunteer. 
Now reads: 
The IRB must be notified promptly by the Investigator of the following: 
• 
Deviations from, or changes to, the protocol to eliminate immediate hazards to the trial subjects; 
• 
Changes increasing the risk to subjects and/or affecting significantly the conduct of the trial; 
• 
All adverse events (AE)s that meet the definition of a serious adverse event (SAE); 
• 
New information that may adversely affect the safety of the subjects or the conduct of the trial. 
 
Any changes to the protocol will be made by means of a formal written protocol amendment. All amendments will 
require IRB approval before implementation except when changes to the protocol are required immediately to 
eliminate hazards to the trial subjects. 
Revised to correctly identify the 
study population (e.g., volunteers 
vs subjects) in this study. 


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20 
2.2 Exploratory Objectives 
Previously read: 
• 
To assess change in abdominal pain score (APS) from pre-dose (trough) to 1.5 hr post-dose (peak) following 
the first of 3 daily doses of APD371; assessed daily to Day 56 
Now reads: 
• 
To assess change in abdominal pain score (APS) from pre-dose (trough) to 1.5 hr post-dose (peak) following 
the first of 3 daily doses of APD371; assessed daily to Day 56 and averaged weekly to Wk 8 
Revised for consistency with 
synopsis exploratory objectives. 
21 
3.1 Overall Study Design and Plan – Figure 1. APD371-004 Study Plan 
Previously read: 
 
Now reads: 
Figure revised to reflect 
clarification of dose adjustment 
parameters. 


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21 
3.1 Overall Study Design and Plan 
Previously read: 
Subjects will enter a screening period of up to 28 days during which they will record their APS on a diary card.  If 
their AAPS is >5 and they satisfy all other eligibility criteria, they will be randomized in a 1:1 ratio to receive 
APD371 doses of 25 mg or 100 mg capsules TID for 8 weeks (until Day 56). If subjects on APD371 100 mg TID 
experience hypotensive symptoms (SBP <90 or DBP<50 mmHg) at any stage during the course of study treatment, 
they will be titrated down to APD371 75 mg TID, or to 50 mg TID if this recurs. 
Now reads: 
Subjects will enter a screening period of up to 28 days during which they will record their APS on a diary card.  If 
their AAPS is >5 and they satisfy all other eligibility criteria, they will be randomized in a 1:1 ratio to receive 
APD371 doses of 25 mg or 100 mg capsules TID for 8 weeks (until Day 56).  
Deleted original dose reduction 
parameters and added more 
defined dose reduction parameters 
in Section 3.1 Overall Study 
Design and Plan. 
22 
3.1 Overall Study Design and Plan 
Previously read: 
There will be two PK assessment days at the beginning of the study Wk 0 (Day 1, 2) and two at the end of the study 
Wk 8 (Day -1) and Wk 8. A final follow-up visit will occur on Wk 10. 
Now reads: 
There will be two serial PK assessments; one at the beginning of the study Wk 0 (Day 1, 2) and another at the end of 
the study Wk 8 (Day -1) and Wk 8. A single PK collection will be performed in the clinic prior to the subject’s first 
daily dose on Wks 2, 4 and 6.  A final PK sample collection will be performed at the follow-up visit will occur on Wk 
10.  If subjects discontinue the study (Early Termination), a final PK sample will be collected. 
Revised for additional 
clarification on composition of 
the PK sample collections and 
timing of the collections. 
22 
3.1 Overall Study Design and Plan 
Deleted: 
Removed option for discontinuing 
overnight stay parameters and 


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Following review of safety and tolerability of the first 6 subjects the Investigator may at 
their discretion; 
 
1. Remove the Day 1 CRU overnight stay following TID treatment and discharge subjects from the CRU 
following completion of the last 10 hr post first dose (2hr post second dose) PK sample and vital sign 
evaluation. 
2. Remove Visit 2 (Wk 0, Day 2); including all evaluations with the exception of APS assessments detailed by 
the subject at home in diary cards. 
3. Remove Visit 8 (Wk 8); including all evaluations with the exception of APS and CDActivity index/stool 
frequency assessments (morning only) detailed in diary cards by the subject at home. These evaluations 
should be collected at a later date up to the follow-up visit, together with the return of study drug for 
compliance assessment. 
noted clarification in Table 1, 
Schedule of Events.   
22 
3.2 Study Duration and Dates 
Previously read: 
Subjects will undergo Screening procedures within 29 days prior to dosing. If eligibility is confirmed, subjects will be 
checked-in at the clinical research unit (CRU) early morning on Day 1 they will overnight at the CRU on Day 1 
during which they will be randomized, treated with their first dose of APD371 and assessed for safety, tolerability, PK 
and efficacy. They will then be allowed to return home 4 hours after the first dose of APD371 on Day 2. 
Now reads: 
Subjects will undergo Screening procedures within 29 days prior to dosing. If eligibility is confirmed, subjects will be 
checked-in at the clinical research unit (CRU) early morning on Day 1, they will overnight at the CRU on Day 1 
during which they will be randomized, treated with their first dose of APD371 and assessed for safety, tolerability, PK 
and efficacy. They will then be allowed to return home 6 hours after the first dose of APD371 on Day 2. 
Revised to update time when 
subject may return home on Day 
2. 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 


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26 
3.4 Study Population 
Added: 
Exceptions to eligibility criteria will not be granted by the Investigator or the Sponsor. 
 
Clarification of no exceptions for 
eligibility.   
31 
4.3 Packaging, Labeling and Storage 
Previously read: 
25 mg and 100 mg APD371 capsules will be packaged 30 count in 60cc HDPE bottles with a heat induction seal and 
child resistant screw cap. Each subject will be provided with 8 bottles of APD371 packaged drug product for the 
duration of the study, two bottles being dispensed on Day 1, Day 15, Day 29 and Day 43, respectively. If subjects in 
the 100 mg cohort are titrated down to a 75mg dose or to a 50 mg dose they may receive additional bottles. 
The 75 mg dose will be supplied by a combination of 50 mg and 25 mg capsules. A two week dispensation will 
consist of two bottles of 25 mg and two bottles of 50 mg APD371 drug product (4 bottles in total). 50 mg APD371 
capsules will also be packaged 30 count in 40-cc HDPE bottles with heat induction seal and child resistant screw cap. 
Subjects returning for assessment at the end of Wk 2, 4, 6 should take their morning APD371 medication from their 
newly dispensed bottles for treatment periods Week 3-4, 5-6 and 7-8 respectively. 
Now reads: 
Revised to accommodate 
potential dose reductions and 
clarification of 50 mg packaging 
size. 


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25 mg and 100 mg APD371 capsules will be packaged 30 count in 60-cc HDPE bottles with a heat induction seal and 
child resistant screw cap. Each subject will be provided with 8 bottles of APD371 packaged drug product for the 
duration of the study, two bottles being dispensed on Day 1, Day 15, Day 29 and Day 43, respectively. If subjects in 
the 100 mg cohort are titrated down to a 50 mg dose they may receive additional bottles. 
 
The 50 mg APD371 capsules will also be packaged 30 count in 60-cc HDPE bottles with heat induction seal and child 
resistant screw cap. 
 
Subjects returning for assessment at the end of Wks 2, 4, 6 should take their morning APD371 medication from their 
newly dispensed bottles for treatment periods Wks 3-4, 5-6 and 7-8, respectively. 
 
32 
4.6 Dosage and Administration 
Previously read: 
Investigational product will be dispensed to the subjects under the supervision of the Investigator or his/her designee 
as determined by the randomization schedule. Dispensing will occur every two weeks at Wk 0, 2, 4 and 6.  
Subjects should not crush, break, chew, or dissolve the capsules. There are no food restrictions around dosing with the 
exception of ingestion of grapefruit juice, prune juice or poppy seeds. 
For each of the planned dose cohorts (APD371 25 mg and 100 mg) subjects will self-administer study treatment TID 
(at approximately 07:00 ± 2 hr, 15:00 ± 2 hr and 23:00 ± 2 hr for 8 Wk) on Days 1 to 56. Subjects will be requested 
not to take their morning dose of study medication on the day of a planned study visit schedule (Wk 0 (Day 1 and Day 
2), 2, 4, 6 and Wk 8 (Day-1)) until instructed to do so by the Investigator or his/her designee. There will be a total of 
8 subjects randomized to each dose cohort. If subjects in the APD371 100 mg TID cohort experience hypotension, 
they will be titrated down to APD371 75 mg TID, or to 50 mg TID if this recurs. 
Now reads: 
Investigational product will be dispensed to the subjects under the supervision of the Investigator or his/her designee 
as determined by the randomization schedule. Dispensing will occur every two weeks at Wks 0, 2, 4 and 6.  
Subjects should not crush, break, chew, or dissolve the capsules. There are no food restrictions around dosing with the 
exception of ingestion of grapefruit juice, prune juice or poppy seeds or poppy seed containing items. 
For each of the planned dose cohorts (APD371 25 mg and 100 mg) subjects will self-administer study treatment TID 
(at approximately 07:00 ± 2 hr, 15:00 ± 2 hr and 23:00 ± 2 hr for 8 Wk) on Days 1 to 56. Subjects will be requested 
not to take their morning dose of study medication on the day of a planned study visit schedule (Wk 0 (Day 1 and Day 
2), 2, 4, 6 and Wk 8 (Day-1)) until instructed to do so by the Investigator or his/her designee. There will be a total of 
8 subjects randomized to each dose cohort.   
Section amended to include dose 
adjustments, study drug stopping 
rules and safety measures to 
address adverse events, including 
hypotension and pulse.   


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4.6.1 Dose Interruption and Stopping Rules 
Adverse Events (AEs) of supine SBP decrease, supine DBP decrease, postural BP decrease, HR increase and HR 
decrease will be closely monitored.  If such an AE occurs in patients taking the study drug, the Investigator must 
assess whether the AE meets the study drug interruption/stopping criteria and proceed as recommended in the below 
table.     
If the study drug is interrupted due to the criteria described in the table, the patient will be evaluated as part of an 
unscheduled visit to assess their status and the Investigator will determine next course of action.  If necessary, 
subsequent visits to assess the outcome of the event will be scheduled.  Once the re-start criteria are met, study drug 
will be re-started under medical supervision.  Additional visits may be scheduled at the investigator’s discretion to 
more closely monitor patient status. 
Any patient that develops postural hypotension will not be discharged from the clinical research unit with study drug 
until the event completely resolves and safety and tolerability of the reduced dose in the patient is confirmed. 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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35 
4.8.1 Randomization  
Previously read: 
A sealed envelope containing the randomization code stratified by sex will be held by the Principal Investigator (PI) 
and the Arena Medical monitor in a secure yet accessible environment in case of emergency. 
Now reads: 
Subjects will be randomized after the Investigator has verified that they are eligible per criteria in Section 3.5 and 
Section 3.6.  Subjects will then be enrolled into this study and assigned to APD371 25 mg TID or 100 mg TID 
according to a randomization schedule.  Subjects will be randomized based on gender.   
 
Randomization will take place across all study sites using a centralized master list held by the study manager.  When a 
site is ready to enroll a subject, they will contact the study manager to get the appropriate dose group assignment and 
unique subject number.  The subject’s identification number will be used on all of that subject’s case report forms 
Revised to clarify the 
randomization process across 
multiple sites. 


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(CRF). Any subject identification numbers that are assigned will not be reused even if the subject does not receive 
treatment. All subjects must start treatment within 1 week of randomization. 
35 
4.8.3 Maintenance of Randomization Codes 
Previously read: 
All personnel directly related to this study (i.e., Investigators, site personnel, monitors, CRO personnel, Sponsor 
personnel) will remain unblinded.  
 
If a subject experiences hypotensive symptoms (SBP <90 or DBP<50 mmHg) during the course of study drug 
treatment the investigator can instruct the pharmacy to dispense a APD371 75 mg dose.  If hypotension still persists 
after treatment a APD371 50 mg dose can be dispensed.  In either situation all other study medication should be 
returned to the pharmacy 
Now reads: 
All personnel directly related to this study (i.e., Investigators, site personnel, monitors, CRO personnel, Sponsor 
personnel) will remain unblinded.  
 
Deleted dose reduction specifics 
now incorporated in 4.6.1. 
35 
4.9 Concomitant Medications 
Added: 
Stable doses of non-narcotic prescription medications required for treatment of current medical conditions other than 
pain (e.g., hypertension, thyroid disease, diabetes) may be continued during the screening and study period with the 
exception of medications known to be moderate or strong CYP3A4/5 inducers or inhibitors.   Doses may be adjusted 
as appropriate per usual standards of care. 
 
Amended to clarify acceptable 
use of non-narcotic medications 
during screening and study period 
and allowed adjustments.  
35 
4.9 Concomitant Medications – 4.9.1 Not Permitted 
Previously read: 
The following concomitant medication restrictions will apply: 
 
• 
No prescription medications or hormonal contraceptives are allowed within 30 days prior to the 
Screening Visit, during the Screening period, and for the duration of the study. 
• 
No OTC medications are allowed, including analgesics or dietary supplements (vitamin, herbal, and mineral 
supplements) during the Screening period and for the duration of the study unless deemed appropriate by the 
Investigator for the treatment of an AE 
Now reads: 
• 
Prescription and OTC medications for pain relief (for exceptions, see Section 4.9.2 – Permitted)  
• 
Hormonal contraceptives for pain relief within 30 days prior to the Screening visit, during the Screening 
period, and for the duration of the study.   
Amended to provide clarification 
on the use of medications for pain 
relief and hormonal 
contraceptions. 
 


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• 
Dietary supplements (vitamin, herbal, and mineral supplements), unless deemed appropriate by the 
Investigator for the treatment of an AE. 
36 
4.9 Concomitant Medications – 4.9.2 Permitted 
Previously read: 
The following medications are allowed in addition to pain relief medications for subjects who still have a AAPS>5; 
Now reads: 
• 
Pain rescue medications during screening or the treatment period including: 
• 
For an inflammatory flare: prednisone at a dose of 40 mg orally daily, to be tapered by 5 mg per 
week. 
• 
For severe pain:  hyoscyamine at a dose of 0.25 mg tid prn pain 
• 
Pain relief medications such as NSAIDs or acetaminophen/paracetamol given at stable doses for at least 2 
weeks prior to screening and for the duration of the study 
 
Amended to clarify the permitted 
use of pain relief medications and 
consistency with synopsis. 
36 
4.9 Concomitant Medications – 4.9.2 Permitted 
 
Moved: 
• 
Stable doses of NSAIDs or acetaminophen/paracetamol for at least 2 weeks prior to screening and to remain 
stable for the duration of the study 
 
Removed pain relief medications 
from list of rescue mediations.  
Information added to section 
introduction. 
36 
4.9 Concomitant Medications – 4.9.2 Permitted 
Previously read: 
• 
Oral corticosteroid therapy (prednisone at a stable dose ≤ 20 mg/day, budesonide at a dose ≤ 9 mg/day, or 
equivalent steroid) provided that the dose has been stable for the 2 weeks immediately prior to screening or for 
the two* weeks immediately prior to randomization if corticosteroids are being tapered 
Now reads: 
• 
Oral corticosteroid therapy (prednisone at a stable dose of 30 mg/day, budesonide at a dose ≤ 9 mg/day, or 
equivalent steroid) provided that the dose has been stable for the 2 weeks immediately prior to screening or for 
the two weeks immediately prior to randomization if corticosteroids are being tapered. 
Clarification of stable dose for 
prednisone that is more in-line 
with the clinical setting and 
removal of asterisk (*) 
referencing deleted comment. 
36 
4.9 Concomitant Medications – 4.9.2 Permitted 
Deleted: 
Corticosteroids ,Immunosuppressive agents, TNF α- antagonists, Integrin antagonists: See Appendix A for further 
details of use in screening 
 
Information included in previous 
bullet points 
36 
4.9 Concomitant Medications – 4.9.2 Permitted 
Deleted: 
*All AAPS should be based on a stable dose of pain relief medication for the screening and treatment periods. 
Clarification for stable doses 
incorporated into the individual 
bullet points.  


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36 
4.10 Restrictions – 4.10.1 Fluid and Food Intake 
Previously read: 
There are no food restrictions around dosing with the exception of grapefruit, prune juice and poppy seeds. Subjects 
will be provided standardized meals (breakfast, lunch, dinner, snacks) per the Investigating site SOPs while housed in 
the clinic. Water, other than 240 mL administered with study medication, will not be permitted from 1 hour before 
until 1 hour after dosing, but will be allowed at all other times. 
Now reads: 
There are no food restrictions around dosing with the exception of grapefruit, prune juice and poppy seeds or poppy 
seed containing items. Subjects will be provided standardized meals (breakfast, lunch, dinner, snacks) per the 
Investigating site SOPs while housed in the clinic. 240 mL of water will be administered with study medication in the 
clinic at the time of dosing on Day 1 and Week 8 when the PK profile will be obtained.  Water may be provided at all 
other times as needed. 
Provide clarification on ingestion 
of poppy seed containing items 
and hydration during PK 
assessments and while on study. 
37 
4.10 Restrictions – 4.10.2 Smoking 
Previously read: 
Subjects who smoke, have a history of smoking or nicotine use, or use of nicotine containing products within 90 days 
prior to dosing will not be allowed into the study. Smoking or use of nicotine-containing products is not allowed 
during the inpatient period. 
Now reads: 
Subjects who smoke, have a history of smoking or nicotine use, or use of nicotine-containing products within 90 days 
prior to dosing will not be allowed into the study. Smoking or use of nicotine-containing products is not allowed 
during study participation. 
Clarifying duration of smoking 
restriction. 
37 
4.10 Restrictions – 4.10.3 Activity 
Previously read: 
Subjects will not engage in strenuous activity at any time during the inpatient period. 
Now reads: 
Subjects will not engage in strenuous activity at any time during study participation. 
Clarifying duration of activity 
restriction. 
38 
5.2 Medical History 
Previously read: 
During the Screening Visit, a complete medical history and a social history, including smoking, caffeine, and alcohol 
use, will be collected by subject interviewer. 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 the CRU to update findings since the Screening Visit including the requirement for a AAPS >5 from a 
subject diary and to document any pre-treatment AEs. 
Now reads: 
Clarification identifying review of 
subjects status prior to 
randomization. 


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During the Screening Visit, a complete medical history and a social history, including smoking, caffeine, and alcohol 
use, will be collected by subject interviewer. Concomitant medications, recent blood donations, illnesses, and 
participation in other investigational drug studies will also be recorded. A review of the subjects screening medical 
history will be performed at the time of presentation on Day 1 (pre-treatment) to update findings including the 
requirement for a AAPS > 5 (from a subject diary) and to document any pre-treatment AEs. 
38 
5.3 Physical Examination 
 
Previously read: 
Body measurements (height and weight) will be taken at the timepoints indicated in the Schedule of Events (Table 1). 
A complete physical examination including weight will be performed at the initial Screening visit. Abbreviated 
physical examinations will be completed at the final Screening visit and at the Follow-up Visit Wk 10. 
 
Now reads: 
Body measurements (height and weight) will be taken at the timepoints indicated in the Schedule of Events (Table 1). 
A complete physical examination including weight will be performed at the initial Screening visit. Abbreviated 
physical examinations (includes body weight and evaluation of changes to previously observed abnormal findings) 
will be completed at the time of presentation to the clinic prior to initial dose administration, at the Follow-up Visit 
Wk 10 and at early termination noting changes in any body system since the previous examination. 
Amended to clarify timing of full 
and abbreviated examinations and 
review requirements for post 
initial screening exam. 
38 
5.4 Vital Signs 
 
Previously read: 
Supine blood pressure, pulse rate, temperature, and respiratory rate will be measured after the subject has been resting 
in the supine position for 5 minutes at the timepoints indicated in the Schedule of Events (Table 1). Vitals signs will 
be measured after any 12-lead ECG measurement but prior to any blood draw that is scheduled at the same timepoint. 
Pulse rate will be measured with a pulse oximeter. 
 
Now reads: 
Supine blood pressure, pulse rate, temperature, and respiratory rate will be measured after the subject has been resting 
in the supine position for 5 minutes at the timepoints indicated in the Schedule of Events (Table 1). All once daily 
vital sign assessments are to take place before morning dosing or equivalent times when not dosed at approximately 
08:00.  Vitals signs will be measured after any 12-lead ECG measurement but prior to any blood draw that is 
scheduled at the same timepoint. Pulse rate will be measured with a pulse oximeter.  
Active-Standing Test 
 
The Active-Standing Test that measures BP and heart rate before and after changing the position from supine to 
standing will also be performed.  The test will be performed by the bedside by measuring blood pressure (BP) and 
heart rate after the subject has been resting in the supine position for 5 minutes and then after 1 and 3 minutes of 
standing.   
 
Amended to include assessments 
of orthostatic parameters.   


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The test will be performed at the following timepoints: 
 
• 
Day 1:  pre-dose, 2, 4, 6, 8 and 10 hours after first dose  
• 
Day 2:  2, 4 and 6 hours after the first dose 
• 
Weeks 1, 2 4, 6 and 8 visits 2 hours after the first dose.   
 
The active-standing test will be performed if subjects discontinue the study (Early Termination). 
39 
5.5 Abdominal Pain Assessment – 5.5.1 Abdominal Pain Score and Average Abdominal Pain Score 
Previously read: 
Note: Subjects will also be required to complete the diary before their first morning dose on Wk 0 (Day 1), and at the 
End-of-Treatment Visit at Wk 8 in the early morning (06:00 - 08:00).   
Now reads: 
Note: Subjects will also be required to complete the diary before their first morning dose on Wk 0 (Day 1), and at the 
End-of-Treatment Visit at Wk 8 in the early morning (06:00 - 08:00).  If a subject discontinues the study, Early 
Termination, the APS score will be assessed. 
Amended to include assessment 
at time of early termination.  
40 
 
 
 
 
 
 
 
 
 
 
 
 
 
41 
5.9 Clinical Laboratory Tests 
Added: 
Protocol-required laboratory testing will be collected during screening to determine eligibility.  Clinical laboratory 
tests will be repeated at pre-treatment on Wk 0 (Day 1), pre-treatment at the end of Wk 4 and 8 (Day -1), at the 
Follow-up visit (Wk 10) and in the event of early termination. 
Clarification on laboratory 
assessments from screening 
through study conduct, including 
early termination. 
41 
5.9 Clinical Laboratory Tests – 5.9.1 Laboratory Parameters 
Previously read: 
Other 
Serum/urine pregnancy test (females only), Thyroid function tests (TSH, T4, and free T4), C-reactive Protein 
Now reads: 
Other 
Clarifying collection period for 
Thyroid function tests.  


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Serum/urine pregnancy test (females only), Thyroid function tests [(TSH, T4, and free T4) - Screening only], C-
reactive Protein 
42 
5.11 Pharmacokinetic sampling 
Previously read: 
Pharmacokinetic samples for the assay of APD371 and metabolites M1 
, M2 
, and M4 
 will be collected will be collected at the visit time points indicated in the Schedule of Events (Table 1) 
and detailed in Pharmacokinetic sampling, Table 2. 
 
Table 2. 
Pharmacokinetic sampling 
Study Day 
Blood sampling assessments* 
Wk 0 (Day 1) 
Prior to and 0.5, 1, 2, 4, 6, 8 (prior to second daily dose), 9 and 10 hours 
post first daily dose. 
Wk 0 (Day 2) 
24 hours post dose first daily dose on Day 1 
Wk 2 
Prior to first daily dose 
Wk 4 
Prior to first daily dose 
Wk 6 
Prior to first daily dose 
Wk 8 (Day -1) 
Prior to and 0.5, 1, 2, 4, 6, 8 (prior to second daily dose), 9, 10 post first 
daily dose. 
Wk 8 (End-of-Treatment) 
24 hours post dose first daily dose on Wk 8 (Day-1) 
 
 Now reads: 
Pharmacokinetic samples for the assay of APD371 and metabolites M1 
, M2 
, and M4 
will be collected will be collected at the visit time points indicated in the Schedule of Events (Table 1) 
and detailed in Pharmacokinetic sampling, Table 3. 
 
Table 1. 
Pharmacokinetic sampling 
Study Day 
Blood sampling assessments* 
Wk 0 (Day 1) 
Prior to and 0.5, 1, 2, 4, 6, 8 (prior to second daily dose), 9 and 10 hours 
post first daily dose. 
Wk 0 (Day 2) 
24 hours post dose first daily dose on Day 1 
Wk 2 
Prior to first daily dose 
Wk 4 
Prior to first daily dose 
Wk 6 
Prior to first daily dose 
Wk 8 (Day -1) 
Prior to and 0.5, 1, 2, 4, 6, 8 (prior to second daily dose), 9, 10 post first 
daily dose. 
Wk 8 (End-of-Treatment) 
24 hours post dose first daily dose on Wk 8 (Day-1) 
* Allowable windows for sample collection: 
Correction of Table numbering 
and addition of collection 
windows. 


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- 
time points up to 4 hours: ± 5 mins  
- 
time points after 4 hours: ± 15 mins 
49 
5.15 Allowable Visit and Procedure Windows 
Previously read: 
All visit and procedure windows are detailed in Table 1 study schedule. 
Now reads: 
The following are allowable windows for study visits and procedures: 
• 
Study visits: 
- 
Wks 2, 4, 6, 8 and 10 (Follow-up):  ± 2 days 
• 
Vital signs and Active-Standing Test: 
- 
Pre-dose timepoint:  - 15 mins 
- 
Post-dose timepoints:  ± 15 min 
Amended to include visit and 
procedure windows. 
50 
6 STUDY ACTIVITIES – 6.1 Screening Visits Wk -4 to Wk -1 (Days -28 to -1) 
Previously read: 
• 
Physical examination (complete examination)  
Now reads: 
• 
Physical examination (complete examination) at initial screening visit  
Amended to clarify timing for 
examination. 
50 
6 STUDY ACTIVITIES – 6.1 Screening Visits Wk -4 to Wk -1 (Days -28 to -1) 
Added: 
• 
Abbreviated physical exam (includes body weight and evaluation of changes to previously observed 
abnormal findings) at final screening visit 
Amended to clarify type and 
timing for examination. 
50 
6 STUDY ACTIVITIES – 6.1 Screening Visits Wk -4 to Wk -1 (Days -28 to -1) 
Previously read: 
• 
Serum hCG pregnancy test (females only)  
Now reads: 
• 
Serum hCG pregnancy test (females only) at the initial screening visit 
Amended to clarify timing for 
examination. 
50 
6 STUDY ACTIVITIES – 6.1 Screening Visits Wk -4 to Wk -1 (Days -28 to -1) 
Added: 
• 
Urine pregnancy test (females only) at the final screening visit 
Amended to clarify type and 
timing for examination. 
50 
6 STUDY ACTIVITIES – 6.1 Screening Visits Wk -4 to Wk -1 (Days -28 to -1) 
Previously read: 
• 
Clinical laboratory tests (hematology, serum chemistry, coagulation, CRP, thyroid function tests 
[TSH, T4, and free T4] and urinalysis)  
Now reads: 
Amended to clarify timing for 
assessment. 


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• 
Clinical laboratory tests to include hematology, serum chemistry, coagulation, CRP, thyroid 
function tests (TSH, T4, and free T4 at initial Screening visit only) and urinalysis 
50 
6 STUDY ACTIVITIES – 6.1 Screening Visits Wk -4 to Wk -1 (Days -28 to -1) 
Previously read: 
• 
total Simple Endoscopic Score (SES-CD) score < 6 or ileal SES-CD < 4 or FCP < 300. Endoscopy results 
obtained within 1 month prior to screening may be utilized 
Now reads: 
• 
Total Simple Endoscopic Score (SES-CD) score < 6 or ileal SES-CD < 4 or FCP < 300 mcg/g. Endoscopy 
results obtained within 1 month prior to screening may be utilized  
Clarified units associated with 
FCP result. 
51 
6 STUDY ACTIVITIES – 6.3.1 Wk 0 (Day 1) Pre-treatment 
Previously read: 
• 
Vital signs 
Now reads: 
• 
Vital signs and Active-Standing Test 
Addition of Active-Standing Test 
to scheduled procedures 
51 
6 STUDY ACTIVITIES – 6.3.2 Wk 0 (Day 1) Post treatment 
Previously read: 
• 
Vital signs 
• 
12-lead ECG 
• 
Abdominal Pain Score before dosing and 1.5 hr after first morning dose  
Now reads: 
• 
Vital signs and Active-Standing Test 
• 
12-lead ECG at 1.5 hours after initial Day 1 dose 
• 
Abdominal Pain Score at 1.5 hr after first morning dose 
Clarification of assessments and 
times. 
52 
6 STUDY ACTIVITIES – 6.3.3 Wk 0 (Day 2) 
Previously read: 
• 
Vital signs 
Now reads: 
• 
Vital signs and Active-Standing Test 
Addition of Active-Standing Test 
to scheduled procedures 
52 
6 STUDY ACTIVITIES – 6.3.3 Wk 0 (Day 2) 
Deleted: 
If there are no immediate safety concerns, the subject will be discharged from the CRU approximately 4 hours after 
the morning dose. 
Deleted as protocol requires all 
subjects to stay overnight on Day 
1. 


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Following review of the safety and tolerability of first 6 subjects the Investigator may at their discretion, remove the 
Wk 0 (Day 1) CRU overnight stay and discharge subjects from the CRU following completion of the last 10 hr post 
first-dose PK sample. On Day 2 subjects will continue with their three times daily APS assessments, but an 
assessment visit will not be required. 
 
52 
6 STUDY ACTIVITIES – 6.3.4  
Previously read: 
6.3.4  Wk 0 to 8 (Day -1) (Days 3 to 56)  
Now reads: 
6.3.4  Wk 0 to 8 (Day -1) (Days 1 to 56)  
Clarification on start day. 
52 
6 STUDY ACTIVITIES – 6.3.5 End of Wk 1, 2, 4, 6  
Previously read: 
• 
Vital signs 
Now reads: 
• 
Vital signs and Active-Standing Test 
 
Clarification for addition for 
active-standing assessment 
52 
6 STUDY ACTIVITIES – 6.3.5 End of Wk 1, 2, 4, 6  
Added: 
Compliance will be assessed based on all returned bottles and treatment duration at Wks 2, 4, 6 and 8   
Inclusion of dose administration 
compliance to visit schedule.   
53 
6 STUDY ACTIVITIES – 6.3.6 Wk 8 (Day -1) 
Previously read: 
• 
Vital signs 
Now reads: 
• 
Vital signs and Active-Standing Test 
 
Clarification for addition for 
active-standing assessment 
53 
6 STUDY ACTIVITIES – 6.3.6 Wk 8 (Day -1) 
Added: 
 
   
Inclusion of 
to visit 
schedule.   
53 
6 STUDY ACTIVITIES – 6.3.7 Wk 8 End of Treatment 
Previously read: 
• 
Vital signs 
Now reads: 
• 
Vital signs and Active-Standing Test 
Clarification for addition for 
active-standing assessment 


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53 
6 STUDY ACTIVITIES – 6.3.7 Wk 8 End of Treatment  
 
Previously read: 
Following review of safety and tolerability of the first 6 subjects the Investigator may at their discretion remove Visit 
8 (Wk 8); including all evaluations with the exception of APS and 
 
 detailed in diary cards by the subject at home. These evaluations should be collected at a later date up 
to the follow-up visit, together with the return of study drug for compliance assessment 
 
Now reads: 
Each subject will be evaluated continuously by the Investigator and Sponsor with regards to safety, and then the 
decision will be made on a case-by-case basis on whether the subject needs to stay overnight at Week 8 to be assessed 
for safety, including blood pressure and heart rate.  If the decision to remove the Visit 8 (Wk 8) overnight stay has 
been determined, all scheduled evaluations still must be done, including serial PK collections vital signs, active-
standing test, APS, 
 detailed in the diary cards. 
Amended to clarify the safety 
review of each subject for 
determination of Visit 8 overnight 
stay and procedures to be 
performed if overnight stay is not 
required. 
54 
6 STUDY ACTIVITIES – 6.4 Early Termination Procedures 
Previously read: 
• 
Physical examination (abbreviated examination including body weight measurement) 
• 
Vital signs 
• 
12-lead ECG 
• 
Serum hCG pregnancy test (females only) 
• 
Final PK blood sample 
• 
Clinical laboratory tests (to include hematology, serum chemistry, coagulation, and urinalysis)  
• 
Record AEs 
• 
Record concomitant medications 
Now reads: 
• 
Physical examination (abbreviated examination including body weight and evaluation of changes to 
previously observed abnormal findings) 
• 
Vital signs and Active-Standing Test 
• 
12-lead ECG 
• 
Serum hCG pregnancy test (females only) 
• 
Final PK blood sample 
• 
Clinical laboratory tests (to include hematology, serum chemistry, coagulation, and urinalysis)  
• 
Abdominal Pain Score 
• 
 
• 
Record AEs 
Amended to include Active-
Standing Test, Abdominal Pain 
Score,
 
for subject who 
terminate the study early.   


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• 
Record concomitant medications 
54 
6 STUDY ACTIVITIES – 6.5 Wk 10 Follow-up Visit Procedures  
Previously read: 
• 
Physical exam (abbreviated examination including body weight and evaluation of changes to previously 
observed abnormal findings) 
• 
Vital signs 
• 
12-lead ECG  
• 
Serum hCG pregnancy test (females only) 
• 
Clinical laboratory tests (to include hematology, serum chemistry, coagulation, CRP and urinalysis) 
• 
Record AEs 
• 
Record concomitant medications 
Now reads: 
• 
Physical exam (abbreviated examination including body weight measurement) 
• 
Vital signs and Active-Standing Test 
• 
12-lead ECG  
• 
Serum hCG pregnancy test (females only) 
• 
Clinical laboratory tests (to include hematology, serum chemistry, coagulation, CRP and urinalysis) 
• 
Record AEs 
• 
Record concomitant medications 
 
The Principal Investigator and study site staff should exert every effort to secure subject attendance to the Follow-Up 
visit.  Three attempted telephone contacts should be documented by study personnel before a subject can be 
considered lost to follow-up.  Furthermore, key research personnel should mail a certified letter to the subject’s 
address if no response to 3 telephone contacts remain unanswered.  If the subject or a family member does not 
respond, the certified letter receipt should be filed in the individual’s research record with a copy of the letter sent. 
Amended to clarify abbreviated 
physical examination, include 
Active-Standing Test and provide 
clarification on process to 
appropriately document subject 
lost to follow-up. 
61 
9 REGULATORY REQUIREMENTS – 9.1 Pre-study Documentation 
Previously read: 
The Sponsor must receive the following documentation prior to initiation of the study:  
Now reads: 
The Sponsor or designee must receive the following documentation prior to initiation of the study: 
Clarify responsibility may be 
assigned to sponsor designee. 
61 
9 REGULATORY REQUIREMENTS – 9.1 Pre-study Documentation  
Deleted: 
Documents should be faxed or mailed to the Sponsor Contact at the following address: 
 
Director, Clinical Operations  
Not required for this study. 


APD371-004 Amendment 01 Summary of Changes  
APD371 
 
Summary of Changes 
Page 34 of 34 
Confidential and/or proprietary information of Arena Pharmaceuticals, Inc. 
Arena Pharmaceuticals, Inc. 
6154 Nancy Ridge Drive 
San Diego, California 92121 
Phone: 
 ext. 
 
Fax:  
 
email: 
 
66 
12 REFERENCES 
 
Added: 
15.  Shibao C, Lipsitz LA, Biaggioni I. ASH Position Paper:  Evaluation and Treatment of Orthostatic Hypotension. 
The Journal of Clinical Hypotension 2013; (15):147-153. 
16.  Vilela EG, Gama Tores, HO, et. al. Evaluation of inflammatory activity in Crohn's disease and ulcerative colitis. 
World J Gastroenterol 2012; 18(9):872-881. 
Additional references  
77 
Appendix A 
Deleted 
 
Information clarified in main 
body of the protocol.   
 

SAP_001.pdf: 
Statistical Analysis Plan 
Arena Pharmaceuticals, Inc. 
APD371-004 
27 March 2019 
Statistical Analysis Plan 
A Randomized, Open-label, Parallel, Phase 2a Study to Determine the Tolerability, 
Pharmacokinetics, and Efficacy of APD371 in Subjects with Crohn’s Disease 
Experiencing Abdominal Pain 
Protocol Number: 
APD371-004 
Product Name: 
APD371 
Sponsor: 
Arena Pharmaceuticals, Inc. 
6154 Nancy Ridge Drive 
San Diego, CA  92121 
Author: 
, PhD 
Arena Pharmaceuticals, Inc. 
Date: 
14 September 2018 (Original) 
27 March 2019 (Amendment 1) 
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: NCT03155945
This NCT number has been applied to the document for 
purposes of posting on Clinicaltrials.gov
-
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Statistical Analysis Plan 
APD371-004 
APPROVAL SIGNATURES 
Arena Pharmaceuticals, lnc. 
27 March2019 
Study Tide: 
A Randomized, Open-label, Parallel, Phase 2a Study to Determine the 
Tolerability, Phannacokinetics, and Efficacy of APD37 l in Subjects with 
Crohn's Disease Experiencing Abdominal Pain 
Vice resi ent, Biostatistics and Data Management 
Arena Phannaceuticals, Inc. 
Confidential
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Statistical Analysis Plan 
APD371-004 
Arena Pharmaceuticals, Inc. 
27 March 2019 
 
Confidential 
Page 1 of 28 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS...................................................................................................... 4 
1. 
INTRODUCTION .................................................................................................... 8 
2. 
STUDY OBJECTIVES............................................................................................. 8 
2.1. 
Primary Objective ..................................................................................................... 8 
2.2. 
Exploratory Objectives ............................................................................................. 8 
3. 
INVESTIGATIONAL PLAN ................................................................................... 9 
3.1. 
Overall Study Design and Plan ................................................................................. 9 
3.2. 
Study Duration and Dates ....................................................................................... 10 
3.3. 
Study Endpoints ..................................................................................................... 10 
3.3.1. 
Primary Endpoints .................................................................................................. 10 
3.3.2. 
Exploratory Endpoints ............................................................................................ 10 
3.3.2.1. 
Abdominal Pain Score (APS) and Average Abdominal Pain Score (AAPS) ............ 10 
3.3.2.2. 
Pain relief responders ............................................................................................. 11 
 
 
 
 
3.3.2.5. 
C-reactive protein (CRP) ........................................................................................ 12 
3.3.2.6. 
Fecal calprotectin.................................................................................................... 12 
 
 
3.3.2.8. 
Number of pain-free days ....................................................................................... 12 
3.3.2.9. 
Pain rescue medication ........................................................................................... 12 
4. 
GENERAL STATISTICAL CONSIDERATIONS ................................................. 13 
4.1. 
Determination of Sample Size................................................................................. 13 
4.2. 
Methods of Assigning Study Participants to Treatment Groups ............................... 13 
4.3. 
Randomization and Stratification ............................................................................ 13 
4.4. 
Blinding.................................................................................................................. 14 
4.5. 
Analysis Populations .............................................................................................. 14 
4.6. 
Multiple Comparisons/Multiplicity ......................................................................... 14 
4.7. 
Data Handling ........................................................................................................ 14 
4.7.1. 
Baseline Definitions or Conventions ....................................................................... 14 
4.7.2. 
Time Points and Day Ranges .................................................................................. 14 
4.7.3. 
Missing Data .......................................................................................................... 15 
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27 March 2019 
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5.
SUBJECT DISPOSITION ...................................................................................... 16 
5.1. 
Study Populations ................................................................................................... 16 
5.2. 
Disposition ............................................................................................................. 16 
5.3. 
Protocol Violations ................................................................................................. 16 
6.
DEMOGRAPHICS AND BASELINE CHARACTERISTICS ................................ 16 
6.1. 
Demographics......................................................................................................... 16 
6.2. 
Medical History ...................................................................................................... 17 
7.
TREATMENT AND MEDICATIONS ................................................................... 17 
7.1. 
Prior and Concomitant Medications ........................................................................ 17 
7.2. 
Study Treatments .................................................................................................... 17 
7.3. 
Study Treatment Compliance .................................................................................. 18 
8.
EFFICACY ANALYSES ....................................................................................... 18 
8.1. 
Abdominal pain score (APS) .................................................................................. 18 
8.2. 
Average abdominal pain score (AAPS) ................................................................... 18 
8.3. 
Pain relief responders ............................................................................................. 19 
 
 
 
 
8.6. 
C-reactive protein (CRP) ........................................................................................ 20 
8.7. 
Fecal calprotectin.................................................................................................... 20 
 
 
8.9. 
Number of pain-free days ....................................................................................... 20 
8.10. 
Use of rescue medication ........................................................................................ 21 
9.
SAFETY ANALYSES ........................................................................................... 21 
9.1. 
Adverse Events ....................................................................................................... 21 
9.2. 
Physical Examinations ............................................................................................ 21 
9.2.1. 
Vital Signs .............................................................................................................. 22 
9.2.2. 
Active-Standing Test .............................................................................................. 22 
9.3. 
Clinical Laboratory Values ..................................................................................... 23 
9.4. 
12-lead ECGs ......................................................................................................... 23 
10.
OTHER ANALYSES ............................................................................................. 23 
10.1. 
Interim Analyses ..................................................................................................... 23 
10.2. 
Subgroup Analyses ................................................................................................. 23 
11.
CHANGES IN PLANNED ANALYSES ................................................................ 23 
■ 
■ 
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27 March 2019 
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12.
REFERENCES ....................................................................................................... 24 
13.
TABLES, LISTINGS, AND FIGURES .................................................................. 25 
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Statistical Analysis Plan 
APD371-004 
LIST OF ABBREVIATIONS 
AAPS 
average abdominal pain score 
adverse event 
analysis of covariance 
abdominal pain score 
Arena Phrumaceuticals, hlc. 
27 Mru·ch 2019 
AE 
ANCOVA 
APS 
AUCo_g 
area under the plasma concentration-time curve from time zero to 8 
hours post-dose 
BP 
BMI 
bpm I. 
CI 
Cmax 
CRP 
CTCAE 
DBL 
DBP 
I 
ET 
ECG 
eCRF 
EOT 
HR 
ICH 
IFN-g 
MedDRA 
mmHg 
NRS -
PK 
PR 
PRN 
PRO 
PT 
QTc 
RR 
SAE 
Confidential 
blood pressure 
body mass index 
beats per minute 
confidence interval 
maximum plasma concentration 
C-reactive protein 
Cornmon Terminology Criteria for Adverse Events 
database lock 
diastolic blood pressure 
-
early termination 
electrocardiogram 
electronic case repo11 form 
end-of-treatment 
heart rate 
International Conference on Harmonization 
interferon garnma 
Medical Dictionary for Regulato1y Activities 
millimeters of mercmy 
numerical rating scale 
pharmacokinetic( s) 
PR interval 
as needed 
patient-repo1ied outcome 
preferred term 
conected QT interval 
inter-beat interval 
serious adverse event 
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Statistical Analysis Plan 
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27 March 2019 
 
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Page 5 of 28 
SAP 
statistical analysis plan 
SBP 
systolic blood pressure 
SD 
standard deviation 
SES-CD  
simple endoscopic score Crohn’s disease 
SOC 
system organ class 
TEAE 
treatment-emergent adverse event 
TID 
3 times a day 
t max 
time of maximum plasma concentration 
TNF 
tumor necrosis factor 
WHO 
World Health Organization 
Wk 
week 
 
 
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Statistical Analysis Plan 
APD37 1-004 
Arena Phrumaceuticals, hlc. 
27 Mru·ch 2019 
Statistical Analysis Plan Amendment 1: Summary of Changes 
The original statistical analysis plan (SAP) was approved on 12 September 2018, prior to the 
database lock (DBL) on 14 September 2018. This SAP amendment reflects the following changes, 
which are being incorporated after the DBL (original 14 September 2018, relock 
19 November 2018): 
• 
Co1Tect minor typographical errors and inconsistencies regarding the footnotes on the 
tables, figures, and listings. 
• 
The evaluation of the pharmacokinetics of APD371 is outlined in a standalone 
pharmacokinetics SAP (dated 23 January 2019). 
I 
• 
The definitions of 01i hostatic hypotension and postural tachycardia (Section 9.2.2) 
have been clarified and impacted table and listing footnotes have been updated. 
• 
The analysis populations have been added to titles of listings in Section 13. 
• 
All tables, figures, and listings have been renumbered per ICH E3 "Strncture and 
Content of Clinical Study Reports." 
• 
Nine new tables, 4 new listings, and 5 new figures have been added: 
o Table 14.1.6.2. Crohn's Disease Medical History (Safety Population) 
o Table 14.2.4. Summary of Daily Abdominal Pain Scores (Efficacy Population) 
o Table 14.2.5. Summaiyof Average Abdominal Pain Score (AAPS) Analyses (Efficacy 
Population) 
o Table 14.2.6.3. Summary of Propo1iion of Pain Responders (Observed data) (Efficacy 
Population) 
o Table 14.2.6.4. Summai·y of Propo1i ion of Pain Responders (Observed data) (Per 
Protocol Population) 
I 
o Table 14.3.4.3.4. Summai·y of Categorical Change from Supine in Active Standing 
Test Vital Signs by Visit (Safety Population) 
o Table 14.3.4.3.5. Summai·y of Categorical Change from Supine in Active Standing 
Test Vital Signs by Visit - Alternative Categories (Safety Population) 
o 
Table 14.3.4.3.6. Summaiy of Categorical Change from Baseline in Active Standing 
Test Vital Signs by Visit (Safety Population) 
o Listing 16.2.2.1. Protocol Deviations - Site Related (Emolled Subjects) 
o Listing 16.2.2.2. Protocol Deviations - Subject Related (Emolled Subjects) 
o Listing 16.2.6.8. Phai·macokinetic Blood Samples & Logs (Safety Population) 
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Statistical Analysis Plan 
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• 
0 
o Figme 14.2.3. Weekly Responders (%) by Treatment and Visit (Observed Data) 
(Efficacy Population) 
o Figme 14.3.4.1. Active Standing Test Vital Signs by Treatment and Visit (Safety 
Population) 
o Figme 14.3.4.2. Active Standing Test Vital Signs by Treatment and Visit - Alternate 
(Safety Population) 
o Figme 14.3.4.3. Individual Subject Active Standing Test Vital Sign Profiles (Safety 
Population) 
o Figme 14.3.4.4. Individual Subject Active Standing Test Vital Sign Profiles - Day 1 
(Safety Population) 
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Statistical Analysis Plan 
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27 Mru·ch 2019 
1. 
INTRODUCTION 
This statistical analysis plan (SAP) provides the statistical rationale and methods to be 
implemented during the analysis of data collected within the scope of clinical trial protocol 
APD371-004 to assess the tolerability and efficacy of APD371 in subjects with Crohn's disease 
(CD) experiencing abdominal pain. 
The evaluation of the phannacokinetics (PK) of APD371 is outlined in a standalone PK SAP 
(dated 
23 January 2019) 
This SAP has been written according to protocol APD371-004 Amendment 2, dated 10 August 
2017. 
2. 
STUDY OBJECTIVES 
2.1. 
Primary Objective 
To assess the tolerability and safety of two doses of APD371 in subjects with Crohn's disease 
(CD) experiencing abdominal pain treated for up to 8 weeks (Wks). 
2.2. 
Exploratory Objectives 
• 
To determine pharmacokinetic (PK) profiles (including metabolites) and 
average PK parameters (Cmax, tmax, AUC0_8) of two doses of APD371 tlll'ee 
times aday(fID) 
• 
To assess change in abdominal pain score (APS) from pre-dose (trough) to 1.5 
hours post-dose (peak) following the first of3 daily doses of APD371 ; assessed 
daily to Day 56 and averaged weekly to Wk 8 
• 
To assess change in average abdominal pain score (AAPS) from Screening to 
Wk 8 (averaged weekly to Wk 8) 
• 
To determine the propo1tion of subjects who are weekly responders 
• 
To determine the prop01tion of subjects who are end-of-treatment (EOl) 
responders 
• 
To determine the number of pain-free days per week in each treatment cohoit, 
based on responses to the APS 
I 
I 
Confidential 
• 
To assess pain medication use in each treatment coho1t 
• 
To assess the effect of APD371 treatment on reduction in C-Reactive 
Protein (CRP) and other biomarkers at Wk 4 and Wk 8 
• 
To assess the effect of APD371 treatment on reduction in fecal calprotectin at 
Wk4and Wk8 
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Statistical Analysis Plan 
APD37 1-004 
I 
I 
3_ 
INVESTIGATIONAL PLAN 
3-L 
Overall Study Design and Plan 
Arena Phrumaceuticals, hlc. 
27 Mru·ch 2019 
This is a Phase 2a study in subjects diagnosed with abdominal pain due to quiescent to mildly active 
CD. The study design is a randomized, multi center, open-label, parallel group comparison 
consisting of two cohorts dosed with APD371 in up to a total of 16 subjects (8 subjects in each 
coho11). Randomization will be stratified by sex. A study plan is provided in Figure 1. 
Figure 1. 
APD371-004 Study Plan 
SCREENING 
TREATMENT 
FU I 
VISIT I SVl 
SV2 
I Vl V2 
V3 
V4 
vs 
V6 
V7 V8 I V9 I 
WEEK I W-4 
W•l 
I wowo 
Wl 
W2 
W4 
W6 
ws ws I WlO I 
DAY ·D-28 to O·l •07 to •Ol 
01 02 
·01 
~-----------------·····I APD371 100 mg TIO 
---t-- --~--- ----+ --------,-------r+·····I APD371 50 mg TIO 
------------------•·•···I 
APD37125 mg TIO 
1---t----~--- ----+------ -7-------r+·-··-I APD37125 mg8/D 
Subjects will enter a Screening period of up to 28 days during which they will record their APS 
on a diary card. If their AAPS is ~4 and they satisfy all other eligibility criteria, they will be 
randomized in a 1:1 ratio to receive APD371 doses of25 mg or 100 mg capsules TID for 8 
weeks ( until Day 56). If subjects on APD3 71 100 mg TID experience hypo tensive symptoms 
(systolic blood pressure [SBP] <90 or diastolic blood pressure [DBP] <50 mmHg) at any stage 
during study treatment, they will be titrated down to 50 mg TID. 
Following the first day of treatment subjects will return for weekly safety and tolerability 
assessments for the first two weeks and then once every other week until the end of the treatment 
period. Safety assessments will include physical examinations, adverse event (AE) repo11ing, 
vital signs, 12-lead electrocardiograms (ECGs) and clinical laborato1y tests including blood 
sampling. 
Subjects will record their APS during Screening twice daily for at least 7 consecutive days 
within the Screening period (Day -28 to Day-1); early morning and late evening (approximately 
06:00 - 08:00 and 20:00 - 22:00). During Treatment subjects will record their APS three times a 
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APD371-004 
Arena Pharmaceuticals, Inc. 
27 March 2019 
 
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Page 10 of 28 
day on each treatment Day (Day 1 to Wk 8), before the morning dose, at 1.5 hours after the 
morning dose and before the evening dose. 
Subjects will also record their stool frequency on a daily basis. 
3.2. 
Study Duration and Dates 
For each subject, the study duration will last a total of approximately 14 weeks consisting of a 
Screening period of up to 4 weeks, a Treatment period of 8 weeks and a follow-up period of two 
weeks. 
Subjects will undergo screening procedures within 29 days prior to dosing. If eligibility is 
confirmed, subjects will be checked-in at the study site early morning on Day 1, they will 
overnight at the study site on Day 1 during which they will be randomized, treated with their first 
dose of APD371 and assessed for safety, tolerability, PK, and efficacy. They will then be 
allowed to return home 6 hours after the first dose of APD371 on Day 2. 
3.3. 
Study Endpoints 
3.3.1. 
Primary Endpoints 
There is no primary endpoint in this study. 
3.3.2. 
Exploratory Endpoints 
3.3.2.1. 
Abdominal Pain Score (APS) and Average Abdominal Pain Score (AAPS) 
The APS is a PRO using a numerical rating scale (NRS) which is recorded in a subject diary. 
The 11-point NRS scale ranges from 0 (no abdominal pain) to 10 (worst possible abdominal 
pain) will be recorded by subjects in a diary as follows; 
During Screening Period 
APS is recorded twice daily for at least 7 consecutive days within the Screening period (Day -28 
to Day -1), at the following times: 
 
1. Early morning, approximately 06:00 - 08:00 
2. Late evening, approximately 20:00 - 22:00 
 
To establish a baseline for AAPS the following procedure will be adopted: 
The last diary entry prior to treatment will be identified. The 7 consecutive days that terminate 
with this last data point constitute the Screening reference period. Baseline for AAPS is the mean 
of non-missing pain scores within the Screening reference period. 
During Treatment Period 
APS is recorded three times a day on each treatment Day (Day 1 to 56) at the following times: 
 
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1. Before the morning dose and before any other morning dose study procedures (i.e., at 
trough APD371 concentration) 
2. Approximately 1.5 hours after the morning dose (i.e., at peak APD371 concentration) 
3. Before the evening dose (i.e., at evening trough ADP371 concentration) 
 
Note: Subjects will also be required to complete the diary before their first morning dose on 
Wk 0 (Day 1), and at the EOT Visit at Wk 8 in the early morning (06:00 - 08:00). If a subject 
discontinues the study, ET, the APS score will be assessed. 
 
It should be noted that: 
• The AAPS is derived for each assessment period (Wks 1, 2, 4, 6, 8). For Wks 4, 6, and 8 
scores are collected from the previous 7 days of diary entries prior to the visit day. 'Peak 
AAPS' is the mean of non-missing APS recorded at the time of peak concentration for 
those 7 days. Likewise, 'Trough APS' is the mean of non-missing APS recorded at the 
time of trough concentration for those 7 days. Similarly, 'Evening Trough APS' is the 
mean of non-missing APS recorded at the time of evening trough concentration for those 
7 days. Wk 1 and Wk 2 peak, trough, evening trough, and overall AAPS are derived in a 
similar manner but note that: 
o For Wk 1, as Day 1 is neither peak nor trough, and APS scores cannot be 
accurately identified as pre-dose or post-dose, scores on Day 1 are disregarded. 
Hence, AAPS scores may be obtained from fewer than 7 days.  
o No APS score will contribute to more than 1 visit. Therefore, Wk 2 scores may be 
derived from fewer than 7 days (if the Wk 1 and Wk 2 Visits are less than 7 days 
apart).  
o Summary pain scores were auto-calculated and entered in the database. However, 
AAPS has been programmatically derived directly from the raw diary data using 
the above rules. 
If a subject changes dose during the study, they will maintain their daily APS scoring. 
3.3.2.2. 
Pain Relief Responders 
Pain relief responders are defined as follows: 
• A weekly pain relief responder at peak is defined as a subject who, in each week, has 
≥30% reduction in peak AAPS from their Baseline AAPS.  
• A weekly pain relief responder at trough is defined as a subject who, in each week, has 
≥30% reduction in trough AAPS from their Baseline AAPS.  
• A weekly pain relief responder at evening trough is defined as a subject who, in each 
week, has ≥30% reduction in evening trough AAPS from their Baseline AAPS.  
• A weekly pain relief responder for average daily pain is defined as a subject who, in each 
week, has ≥30% reduction in average daily AAPS (averaged over peak, trough and 
evening trough diary entries) from their Baseline AAPS.   
• An EOT pain relief responder at peak, trough, evening trough, and daily average is 
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defined as ~30% reduction in peak, trough and average daily AAPS respectively from 
Baseline at EOT. 
3.3.2.5. 
C-Reactive Protein (CRP) 
CRP is measured at Baseline, Wk 4, and Wk 8. 
3.3.2.6. 
Fecal Calprotectin 
A stool sample is collected at Screening, Wk 4, and Wk 8. Fecal calprotectin level is recorded. 
3.3.2.8. 
Number of Pain-Free Days 
The number of pain-free days per week is recorded by visit (Screening, Wks 1, 2, 4, 6, 8). The 
screening score will be derived from the last 7 days of the Screening period. 
3.3.2.9. 
Pain Rescue Medication 
Pain rescue medication use during Screening or the Treatment period is defined as prednisone at 
a dose of 40 mg orally daily or hyoscyamine at a dose of 0.25 mg TID or as needed (PRN). 
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4. 
GENERAL STATISTICAL CONSIDERATIONS 
This SAP was developed based on International Council on Harmonization (ICH) E3 and E9 
Guidelines. This SAP should be read in conjunction with the study protocol and electronic case 
report forms. 
Unless otherwise noted, the summary of continuous variables will include the number of non-
missing observations (n), arithmetic mean, median, standard deviation (SD), minimum, and 
maximum. Percentages will be calculated using the number of subjects within group and overall 
as the denominator. 
All statistical analyses will be conducted using SAS® software (Version 9.4 or higher, SAS 
Institute Inc., Cary, NC). 
4.1. 
Determination of Sample Size 
No formal sample size or power calculations were performed. For this initial study in subjects, it 
is planned to treat and complete safety and tolerability assessments in approximately16 subjects, 
which is reasonable to assess the primary and exploratory study endpoints. Since subjects may be 
replaced if they are withdrawn due to major protocol violations, a maximum of 20 subjects will 
be randomized in the study. It is expected that this number of subjects will provide guidance for 
the assessment of tolerability in this population and quantify the extent of abdominal pain relief. 
4.2. 
Methods of Assigning Study Participants to Treatment Groups 
Subjects who meet all the entry criteria and are eligible for the study will report to the 
investigator to be randomized on Day 1. Eligible subjects will be randomly assigned to receive 1 
of 2 study treatments, either APD371 100 mg TID or APD371 25 mg TID in a 1:1 ratio. The 
investigator will randomize up to 20 subjects for entry from a sealed envelope held by the 
Sponsor clinical trial manager.  
If a subject in the APD371 100 mg TID group experiences hypotensive symptoms (SBP <90 or 
DBP <50 mmHg) during the course of study drug treatment, the investigator can instruct the 
pharmacy to dispense an APD371 50 mg dose. In this situation all other study medication should 
be returned to the pharmacy. 
The analyses for all safety outcomes will use the Safety population which consists of all 
randomized subjects who received at least 1 dose of study drug; in addition, if a subject is found 
to have taken a study therapy for the entire duration of the study different from that to which they 
was randomized, then the subject is counted in the treatment group of the drug they actually 
received. 
4.3. 
Randomization and Stratification 
Subjects will be randomized after the Investigator has verified that they are eligible per criteria in 
Section 3.5 and Section 3.6 of the protocol. Subjects will then be enrolled into this study and 
assigned to APD371 25 mg TID or 100 mg TID according to a randomization schedule. 
Randomization will be stratified by sex. 
Randomization will take place across all study sites using a centralized master list held by the 
Sponsor clinical trial manger, in consultation with the Medical Monitor. When a site is ready to 
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enroll a subject, they will contact the study manager to get the appropriate dose group 
assignment and unique subject number. The subject’s identification number will be used on all of 
that subject’s electronic case report forms (eCRF). Any subject identification numbers that are 
assigned will not be reused even if the subject does not receive treatment. All subjects must start 
treatment within 1 week of randomization. 
4.4. 
Blinding 
This is an open-label study. For each dose cohort, the Sponsor, contract research organization 
(CRO), study safety medical monitors, subjects, and personnel involved with the conduct of the 
study will be unblinded to the identity of study medication. 
4.5. 
Analysis Populations 
The following analysis sets are defined in this study: 
• 
The Randomized population will include all randomized subjects. 
• 
The Efficacy population will include all randomized subjects who received at least 1 dose 
of study medication and have completed at least 7 days of assessments of APS on 
treatment up to Wk 4. The analyses of all efficacy variables will use the Efficacy 
population. 
• 
The Per Protocol population will comprise all members of the Efficacy population 
without a major protocol violation that could affect the validity of efficacy assessments. 
The Per Protocol population will be used for the analysis of selected endpoints indicated 
in Section 8. The Per Protocol population will be identified prior to database lock.  
• 
The Safety population will include all randomized subjects who received at least one 
dose of study medication. The analyses of all safety variables will use Safety population.   
4.6. 
Multiple Comparisons/Multiplicity 
Since this is an exploratory proof of concept study, no formal testing strategy or adjustments of 
p-values will be employed. Estimates and confidence intervals (CIs) for treatment groups and 
from pairwise comparisons will be used in an exploratory manner. 
4.7. 
Data Handling 
4.7.1. 
Baseline Definitions or Conventions 
Unless, as specified in Section 3.3.2.1, the Screening period is used to derive a Baseline value, 
then Baseline value is defined as the Day 1 (randomization) measurement. If the Day 1 
measurement is not available, the last non-missing pre-randomization measurement will be used 
as the Baseline value. For vital signs, where the time of the assessment is available, the last pre-
treatment assessment on Day 1 will be the Baseline value. 
4.7.2. 
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 subject’s visit will be defined by 
the relative day ranges described in Tables 1 to 3.  
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Table 1. 
Mapping for Endpoints Measured at Day 1, Wk 4, and Wk 8 
Time Point 
Target 
Study Days 
Baseline 
Day 1 
:5 Day 1 
Wk: 4 
Day29 
2 ::; Day::; 42 
Wk:8 
Day56 
> Day 42 
Table 2. 
Mapping for Endpoints Measured at Day 1 and Wk 8 or Wk 8 EOT 
Time Point 
Target 
Study Days 
Baseline 
Day l 
:5 Day 1 
Wk: 8 
Day56 
> Day 1 
Wk: 8 EOT 
Day57 
> Day 1 
Table 3. 
Mapping for Endpoints Measured at Day 1 and Wk 1 to Wk 8 
Time Point 
Target 
Study Days 
Baseline 
Day l 
:5 Day 1 
Wkl 
Day8 
2 :S Day::; 11 
Wk: 2 
Day 15 
12 :S Day::; 18 
Wk: 3 
Day22 
19 :S Day :S 25 
Wk:4 
Day29 
26 :S Day :S 32 
Wk:5 
Day36 
33 :S Day :S 39 
Wk:6 
Day 43 
40 :S Day :S 46 
Wk: 7 
Day50 
47 :S Day :S 53 
Wk: 8 
Day56 
> Day 53 
If a subject has more than one assessment in a window, the assessment date closest to the target 
date will be selected. If a subject has 2 assessments that are equidistant from the target date, the 
later assessment will be selected. 
4.7.3. 
Missing Data 
As described in Section 8.3, in responder analyses, subjects with missing data will be classified 
as non-responders. Othe1wise, there will be no imputation of missing data. 
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5. 
SUBJECT DISPOSITION 
5.1. 
Study Populations 
The number and percentage of subjects in each analysis population will be summarized by 
treatment group. Subject inclusion in each analysis population will be presented in a subject 
listing.  
Reasons for exclusion from the Per Protocol population will be listed. 
5.2. 
Disposition 
The number of subjects enrolled in the study by investigator and treatment group will be 
tabulated. Subject disposition will be summarized by treatment group and will include the 
number of subjects who were randomized into the study, the number of subjects who completed 
the study, and the number of subjects who discontinued prematurely (ET) for any of the 
following reasons:  
• Deviation/noncompliance with the protocol or study drug  
• Adverse event(s) 
• Investigator decision 
• Sponsor decision 
• Subject withdrawal of consent 
• Subject lost to follow up 
• Death 
• 
Other 
5.3. 
Protocol Violations 
Significant protocol violations will be tabulated displaying frequencies and percentages of the 
Efficacy population falling into the following categories: 
• 
Treated despite violating inclusion criterion 8 (i.e., screening AAPS of ≥ 4) 
• 
Treated with dose other than the dose the subject was randomized to receive 
• 
Developed withdrawal criterion but was not discontinued from treatment 
• 
Less than 80% compliance 
6. 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS 
6.1. 
Demographics 
Demographic and baseline characteristics data (age, height, weight, BMI), social history 
(smoking, caffeine, alcohol use), medical history (abnormalities only), physical examination 
(abnormalities only), and concomitant medications at study entry will be listed for all subjects. 
Demographic and Baseline Characteristics of the Safety and Efficacy populations will be 
summarized by treatment group and for the overall population.  
Baseline for the demographic and baseline characteristic variables will be the last pre-
randomization value.  
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Continuous variables will be summarized using number of observations (n), mean, 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 and overall: 
Continuous demographic and Baseline characteristic variables: age (years), height (cm), weight 
(kg), body mass index (BMI; kg/m2), and simple endoscopic score Crohn’s disease (SES-CD). 
Categorical demographic and Baseline characteristic variables: sex (female or male), ethnicity 
(Hispanic/Latino or Not Hispanic/Not Latino) and race (American Indian or Alaska Native; 
Asian; Black or African American; Native Hawaiian or Other Pacific Islander; White; Other, 
specify) nicotine consumption (never, former, current), and alcohol consumption (never, former, 
current). 
Baseline SES-CD, an optional assessment by colonoscopy, will be presented in subject listing.  
6.2. 
Medical History 
During the Screening Visit, a complete medical history will be collected by subject interviewer. 
Concomitant medications, recent blood donations, illnesses, and participation in other 
investigational drug studies will also be recorded. A review of the subject’s screening medical 
history will be performed at the time of presentation on Day 1 (pre-treatment) to update findings 
including the requirement for an AAPS ≥4 (from a subject diary) and to document any pre-
treatment AEs. Medical history will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA; Version 21.0). 
A summary of medical history, which includes the number (%) of subjects in each treatment 
group classified according to MedDRA system organ class (SOC) and preferred term (PT) will 
be provided, as well as a subject listing.  
7. 
TREATMENT AND MEDICATIONS 
7.1. 
Prior and Concomitant Medications 
Medications administered prior to but not during study treatment were considered as prior 
medications. Medications initiated prior to start of study treatment and maintained during the 
study, or taken during the course of the study, were considered as concomitant medications. 
Medications with partial or missing start dates were assumed to be concomitant medications, 
unless there was clear evidence) to suggest that the medications were not taken during study. 
Prior and concomitant medications will be coded using the World Health Organization (WHO) 
Drug Dictionary (March 2018). 
7.2. 
Study Treatments 
The duration of treatment for each subject will be assessed by descriptively summarizing the 
number of weeks on drug, both as a continuous and categorical variable (e.g., <1 week). In 
addition, the average daily dose (mg), total exposure (mg), and total duration of treatment in 
subject-weeks will be summarized by treatment group and overall. 
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7.3. 
Study Treatment Compliance 
Compliance will be assessed using subject data recorded in the drug accountability form of the 
eCRFs. On each day, a subject should take their assigned treatment. The compliance rate for 
each subject will be computed as 100% × (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 subject has been in the active treatment phase of 
the trial. Compliance rates will be summarized for each treatment group and overall. 
8. 
EFFICACY ANALYSES 
Complete specifications given below assume that the final sample size will allow for inferential 
statistical analysis. If the number of subjects analyzed is very low some, or all, inferential 
procedures will no longer be appropriate. 
8.1. 
Abdominal Pain Score (APS) 
For each subject, APS score measured at peak will be averaged over the entire treatment period. 
Likewise, the APS score measured at trough will be averaged for each subject. The difference 
(peak - trough) will be calculated, per subject, as mean (peak) - mean (trough).  
Mean peak, trough, and peak - trough will be summarized by treatment and overall. The peak - 
trough differences will be analyzed between treatments using an analysis of covariance 
(ANCOVA) model with treatment as a factor and Baseline score as a covariate. The 95% CI for 
the adjusted treatment difference will be presented together with the p-value. For the pooled data, 
a 1-sample t-test will be conducted testing against the hypothesis of zero difference between 
peak and trough. The 95% CI for the overall difference between peak and trough assessments 
will be presented. 
Additionally, the APS score measured prior to evening dose (evening trough) will be averaged 
for each subject. The difference (peak - evening trough) will be calculated, per subject, as mean 
(peak) - mean (evening trough). The analysis will be repeated using mean peak, evening trough, 
and peak - evening trough and will be summarized by treatment and overall.  
8.2. 
Average Abdominal Pain Score (AAPS) 
AAPS is the average of the APS score over each weekly assessment period (Wks 1, 2, 4, 6, 8). 
The Baseline value of AAPS will be derived as the average of the last (most recent) non-missing 
7 days of morning and evening diary records within the Screening period prior to Day 1 of 
treatment. During the treatment period, summaries for a nominal week will be derived from the 
last 7 days within that period that contain a non-missing assessment. Summaries may be derived 
from fewer than 7 days (e.g., if the Wk 1 and Wk 2 Visits are less than 7 days apart). AAPS will 
be summarized for the Screening period and for each assessment week of treatment before 
morning dose (trough) assessments and 1.5 hours post-treatment first daily dose (peak) 
assessments, by treatment group and overall. Statistical comparisons of AAPS will be made 
between Screening and Wk 4 and Wk 8, trough and peak assessments, by treatment and overall. 
Change scores from Baseline for peak and trough at Wk 4 and Wk 8 will be derived. Treatment 
comparisons of the change scores will be analyzed using ANCOVA as for AAPS. The adjusted 
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treatment effect, 95% CI, and p-value will be presented. Overall changes from Baseline at Wk 4 
and Wk 8 will be assessed using I-sample t-tests as for AAPS. These analyses will be repeated 
for the Per Protocol population. 
Peak and trough AAPS by treatment and visit will be plotted displaying treatment means and 
95% Cls for the efficacy population only. 
These analyses will be repeated where AAPS will be summarized for the Screening period and 
for each assessment week of treatment before evening dose (evening trough) assessments and 1.5 
hours post first daily dose (peak) assessments, by treatment group and overall. 
8-3_ 
Pain Relief Responders 
For each ofWks 1, 2, 4, 6, 8 a subject with a missing AAPS will be coded to non-responder. The 
number and propo1iion of responders for Wks 1 to 8 and at EOT will be tabulated by treatment 
group and overall. The difference in propo1iions of peak, trough, evening trough, and average 
daily pain weekly responders between the treatment groups at Wk 8 and EOT will be tested by 
Fisher's exact test and the p-value presented. 
These analyses will be repeated for the Per Protocol population. 
The percentage of peak, trough, evening trough, and average daily pain weekly responders will 
be plotted by treatment and visit for the Efficacy population only. 
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Statistical Analysis Plan 
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8-6_ 
C-reactive protein (CRP) 
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27 Mru·ch 2019 
CRP will be summarized by visit (Baseline, Wk 4, Wk 8). Within subject changes from Baseline 
at Wk 4 and Wk 8 will be analyzed by treatment and overall using dependent means t-tests. 
Mean change, 95% Cls and p-values will be presented. Changes from Baseline at Wk 4 and Wk 
8/EOT will be analyzed using an ANCOV A model with treatment as a factor and Baseline value 
as a covariate. Adjusted treatment effects with p-values and 95% Cls will be presented. CRP by 
treatment and visit will be plotted for the Efficacy population displaying treatment means and 
95% Cls. A scatterplot will be produced of change from Baseline in CRP and change from 
Baseline in peak AAPS at Wk 8 for all subjects (irrespective of treatment) in the Efficacy 
population. A regression line will be fitted. 
8.7. 
Fecal Calprotectin 
Fecal calprotectin will be summarized by visit (Baseline, Wk 4, Wk 8). Within subject changes 
from Baseline at Wk 4 and Wk 8 will be analyzed by treatment and overall using dependent 
means t-tests. Mean change, 95% Cls and p-values will be presented. Changes from Baseline at 
Wk 4 and Wk 8 EOT will be analyzed using an ANCOV A model with treatment as a factor and 
Baseline value as a covariate. Adjusted treatment effects with p-values and 95% Cls will be 
presented. Fecal calprotectin by treatment and visit will be plotted for the efficacy population 
displaying treatment means and 95% Cls. A scatte1plot will be produced of change from 
Baseline in fecal calprotectin and change from Baseline in peak AAPS at Wk 8 for all subjects 
( irrespective of treatment) in the Efficacy population. A regression line will be fitted. 
8.9. 
Number of Pain-Free Days 
The number of pain-free days per week will be summarized by visit (Screening, Wks 1 to 8). The 
Screening score will be derived from the screening reference period as defined in Section 3.3.2.1. 
Because few subjects had pain-free days either at Screening or post-baseline, no inferential 
analyses will be conducted. 
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8.10. 
Use of Rescue Medication  
The number of subjects using rescue medication during the Screening period and at any time 
during active treatment will be tabulated by treatment group and overall by shift table. Because 
of the paucity of data with respect to changes, no inferential analyses will be conducted. 
9. 
SAFETY ANALYSES 
Safety and tolerability will be assessed by a review of all safety parameters including AEs, 
laboratory safety parameters, vital signs, and ECG. Only summary tabulations (N, n, mean [or 
median], SD, mean [or median] change/percent change, percentage) and 95% CIs for between-
group differences will be obtained. AEs will be presented as summary tabulations and listed. 
9.1. 
Adverse Events 
AEs will be coded using MedDRA (Version 21.0) 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 APD371 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 subject 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 v4.032 definitions) 
and relatedness to study medication. 
Summaries of the number (%) of subjects in each treatment group with at least one TEAE, 
classified according to MedDRA system organ class (SOC) and preferred term (PT), will also be 
provided for: 
• 
Drug-related TEAE 
• 
TEAEs leading to permanent discontinuation of study medication (study 
medication discontinued or withdrawal from study). 
• 
Serious adverse events (SAEs) 
SAEs will be listed by subject 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. 
9.2. 
Physical Examinations 
Physical examination results (abnormalities only) will be listed and summarized by treatment 
group. 
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9.2.1. 
Vital Signs 
Arena Phrumaceuticals, hlc. 
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Supine vital sign measurements (blood pressure, pulse rate, respirato1y rate, and oral body 
temperature) are taken at the following timepoints: 
• 
Initial and final Screenings 
• 
Wk 0 (Day 1) prior to and 0.5, 1, 2, 4, 6 and 8 hours after the first daily dose (prior to 
second daily dose) and 9 and 10 hours (1 and 2 hours after the second daily dose). 
• 
Once a day on Wk 0 (Day 2), at the end of Wk 1 (Day 8), 2, 4, 6 and 8 and at the Follow-
up Visit at Wk 10 
• 
Wk 8 (Day-1) prior to and 0.5, 1, 2, 4, 6 and 8 hours after the first daily dose (prior to 
second daily dose) and 9 and 10 hours (1 and 2 hours after the second daily dose). 
All vital sign measurements will be listed by treatment. Assessments and changes from Baseline 
will be summarized for blood pressure (BP), pulse rate, respirato1y rate, and temperature by 
treatment at all timepoints. Baseline is defined as the last pre-treatment measurement. 
9.2.2. 
Active-Standing Test 
The Active Standing Test measures BP and heali rate (HR) before and after changing the 
position from supine to standing. The test will be performed by the bedside by measuring BP and 
HR after the subject has been resting in the supine position for 5 minutes and then after 1 and 3 
minutes of standing. The test will be perfo1med at the following timepoints: 
• 
Day 1: pre-dose, 2, 4, 6, 8 and 10 hours after first dose 
• 
Day 2: 2, 4 and 6 homs after the first dose 
• 
Wks 1, 2, 4, 6 and 8: 2 hours after the first dose 
The active-standing test will be performed if subjects discontinue the study (ET). 
At each time point, differences between active-standing and supine assessments will be derived 
for SBP, DBP, and HR: 
• 
Active Standing (1 minute) - Supine-
• 
Active Standing (3 minute) - Supine-
These derived variables and their changes from baseline will be summarized by treatment at all 
timepoints throughout the trial. 
Individual subject profiles will be produced presenting the following data points on a single plot 
per subject at all timepoints: 
• 
Supine DBP (mmHg) 
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• Active Standing DBP (1 minute) (mmHg) 
• Active Standing DBP (3 minutes) (mmHg) 
• Supine SBP (mmHg) 
• Active Standing SBP (1 minute) (mmHg) 
• Active Standing SBP (3 minutes) (mmHg) 
• Supine HR (bpm) 
• Active Standing HR (1 minute) (bpm) 
• Active Standing HR (3 minutes) (bpm) 
 
In addition, a summary of orthostatic hypotension and postural tachycardia will be presented. 
Specifically, the number of subjects (%) that have orthostatic hypotension (defined as a decrease 
in SBP of 20 mmHg or greater relative to supine or a decrease in DBP of 10 mmHg or greater 
relative to supine), postural tachycardia (defined as an increase in heart rate of 30 bpm or greater 
relative to supine or a maximum of 120 bpm), or both will be presented by treatment at all 
timepoints and summarized by treatment group and overall. 
9.3. 
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 on-treatment visit will also be produced for the laboratory 
assessments based on the categories of Low, Normal, and High.  
9.4. 
12-lead ECGs 
Individual safety ECG values will be listed by treatment and visit and summarized using 
descriptive statistics. Intervals to be provided for each ECG are: RR, PR, QRS, QT, QTc, QTcB, 
and QTcF. Summary statistics will be provided for change from Baseline in ECG values.  
10. 
OTHER ANALYSES 
10.1. 
Interim Analyses 
No interim analyses are planned for this study. 
10.2. 
Subgroup Analyses 
Subgroup analyses based upon sex (and other subgroups) may be conducted on an exploratory 
basis. 
11. 
CHANGES IN PLANNED ANALYSES 
Following the database lock, additional analyses were conducted, and the Summary of changes is 
provided at the beginning of the SAP. 
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12. 
REFERENCES 
 
1. 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 
 
2. Guideline on Structure and Content of Clinical Study Reports, International Conference on 
Harmonisation, Section ICH E3, 1996. 
 
3. Guideline on Statistical Principles for Clinical Trials, International Conference on 
Harmonisation, Section ICH E9, 1998. 
 
 
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TABLES, LISTINGS, AND FIGURES 
Tables 
Table 14.1.1. Subject Evaluation Groups (All Subjects) 
Table 14.1.2. Subject Emollment by Center (Randomized Population) 
Table 14.1.3. Subject Disposition (All Subjects) 
Table 14.1.4. Major Protocol Deviations (Efficacy Population) 
Arena Phrumaceuticals, hlc. 
27 Mru·ch 2019 
Table 14.1.5.1. Demographics and Baseline Characteristics (Safety Population) 
Table 14.1.5.2. Demographics and Baseline Characteristics (Per Protocol Population) 
Table 14.1.6.1. Medical Histo1y (Safety Population) 
Table 14.1.6.2. Crohn's Disease Medical History (Safety Population) 
Table 14.1.7. Prior Medication Use (Safety Population) 
Table 14.1.8. Concomitant Medications (Safety Population) 
Table 14.1.9. Treatment Exposure (Efficacy Population) 
Table 14.1.10. Treatment Compliance (Efficacy Population) 
Table 14.2.1.1. Abdominal Pain Score at Peak and Trough (Efficacy Population) 
Table 14.2.1.2. Abdominal Pain Score at Peak and Trough (Per Protocol Population) 
Table 14.2.1.3. Abdominal Pain Score at Peak and Evening Trough (Efficacy Population) 
Table 14.2.1.4. Abdo1ninal Pain Score at Peak and Evening Trough (Per Protocol Population) 
Table 14.2.2.1. Average Abdominal Pain Score All Subjects (Efficacy Population) 
Table 14.2.2.2. Average Abdominal Pain Score All Subjects (Per Protocol Population) 
Table 14.2.2.3. Average Abdominal Pain Score All Subjects by Sex (Efficacy Population) 
Table 14.2.3.1. Average Abdominal Pain Score by Treatment (Efficacy Population) 
Table 14.2.3.2. Average Abdominal Pain Score by Treatment (Per Protocol Population) 
Table 14.2.4. Summaiy of Daily Abdominal Pain Scores (Efficacy Population) 
Table 14.2.5. Summaiy of Average Abdominal Pain Score Analyses (Efficacy 
Population) 
Table 14.2.6.1. Summary of Propo1tion of Pain Responders (Efficacy Population) 
Table 14.2.6.2. Summary of Propo1tion of Pain Responders (Per Protocol Population) 
Table 14.2.6.3. Smnmai·y of Propo1tion of Pain Responders (Observed data) (Efficacy 
Population) 
Table 14.2.6.4. Smnmary of Propo1tion of Pain Responders (Observed data) (Per Protocol 
Population) 
Table 14.2.7.1. Number of Pain-Free Days per Week by Treatment (Efficacy Population) 
Table 14.2.7.2. Number of Pain-Free Days per Week, Overall (Efficacy Population) 
Table 14.2.8. Use of Pain Rescue Medication 
fficac Po ulation 
Table 14.2.10. Change from Baseline in C-Reactive Protein by Treatment (Efficacy Population) 
Table 14.2.11. Change from Baseline in Fecal Calprotectin by Treatment (Efficacy Population) 
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Table 14.3.1.1. Overall Summary of Treatment-Emergent Adverse Events: Safety Population 
Table 14.3.1.2. Incidence of Treatment-Emergent Adverse Events by System Organ Class and 
Prefe1Ted Term (Safety Population) 
Table 14.3.1.3. Incidence of Treatment-Emergent Adverse Events by System Organ Class, 
Prefe1Ted Term and Maximum Severity (Safety Population) 
Table 14.3.1.4. Incidence of Treatment-Emergent Adverse Events by System Organ Class, 
Prefe1Ted Term and Causality (Safety Population) 
Table 14.3.1.5. Incidence of Serious Adverse Events by System Organ Class and Preferred Term 
(Safety Population) 
Table 14.3.1.6. Incidence of Treatment-Emergent Adverse Events with Outcome of Death 
(Safety Population) 
Table 14.3.4.1.1. Laborato1y Results by Visit: Hematology (Safety Population) 
Table 14.3.4.1.2. Laborato1y Results by Visit: Chemistry (Safety Population) 
Table 14.3.4.1.3. Laborato1y Results by Visit: Urinalysis (Safety Population) 
Table 14.3.4.1.4. Shift Table for Hematological Tests (Safety Population) 
Table 14.3.4.1.5. Shift Table for Chemistry Tests (Safety Population) 
Table 14.3.4.1.6. Shift Table for Urinal sis Tests Safet Po ulation 
Table 14.3.4.2. Summary of Change from Baseline at Week 8 in ECG Parameters by Visit 
(Safety Population) 
Table 14.3.4.3.1. Summary of Change from Baseline in Vital Signs by Visit (Safety 
Population) 
Table 14.3.4.3.2. Summary of Change from Baseline in Active Standing Test Vital Signs by 
Visit (Safety Population) 
Table 14.3.4.3.3. Incidence of O1thostatic Hypotension and Postural Tachycardia by Visit 
(Safety Population) 
Table 14.3.4.3.4. Summary of Categorical Change from Supine in Active Standing Test Vital 
Signs by Visit (Safety Population) 
Table 14.3.4.3.5. Summary of Categorical Change from Supine in Active Standing Test Vital 
Signs by Visit - Alternative Categories (Safety Population) 
Table 14.3.4.3.6. Summary of Categorical Change from Baseline in Active Standing Test Vital 
Signs by Visit (Safety Population) 
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Listings 
Listing 16.2.1.1. Subject Populations (Emolled Subjects) 
Listing 16.2.1.2. Inclusion/Exclusion Criteria (Emolled Subjects) 
Listing 16.2.1.3. Subject Visits (Emolled Subjects) 
Listing 16.2.1.4. Subject Disposition (Emolled Subjects) 
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27 Mru·ch 2019 
Listing 16.2.2.1. Protocol Deviations - Site Related (Emolled Subjects) 
Listing 16.2.2.2. Protocol Deviations - Subject Related (Emolled Subjects) 
Listing 16.2.4.1. Demographics (Safety Populations) 
Listing 16.2.4.2. Social History (Safety Populations) 
Listing 16.2.4.3. Medical Histo1y (Safety Populations) 
Listing 16.2.4.4. Prior Medications (Safety Populations) 
Listing 16.2.4.5. Concomitant Medications (Safety Populations) 
Listing 16.2.4.6. Crohn's Disease Prior and Concomitant Treatment (Safety Populations) 
Listing 16.2.4.7. Concomitant Non Dmg Treatment (Safety Populations) 
Listing 16.2. 5 .1. On Site Dosing (Safety Population) 
Listing 16.2.5.2. Dmg Accountability (Safety Populations) 
Listing 16.2.6.1. Average Abdominal Pain Score (Efficacy Population) 
Listin 16.2.6.2. Rescue medication Safet Po ulations 
Listing 16.2.6.8. Pharmacokinetic Blood Sample & Logs 
Listing 16.2.7. Adverse Events (Safety Populations) 
Listing 14.3.2.1. Serious Adverse Events (Safety Populations) 
Listing 14.3.2.2. Deaths (Safety Populations) 
Listing 14.3.3. Serious Adverse Events Information (Safety Populations) 
Listing 16.2.8.1. Laborato1y Results Hematology (Safety Populations) 
Listing 16.2.8.2. Laborato1y Results Chemistry (Safety Populations) 
Listin 16.2.8.3. Laborato1 Results Urinal sis Safet Po ulations 
Listing 16.2.8.5. Coagulation Local Lab (Safety Populations) 
Listing 16.2.8.6. Virology Local Lab (Safety Populations) 
Listing 16.2.8.7. Urine Dmg/Pregnancy Screen (Safety Populations) 
Listing 16.2.9.1. 12-Lead ECG (Safety Populations) 
Listing 16.2.9.2. Vital Signs (Safety Populations) 
Listing 16.2.9.3. Oithostatic Hypotension and Postural Tachycardia (Safety Population) 
Listing 16.2.9.4. Pregnancy Test (Safety Populations) 
Listing 16.2.9.5. Physical Exam (Safety Populations) 
Listing 16.2.9.6. Stool Sample (Safety Populations) 
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Figures 
Figme 14.2.1. Mean Trough and Peak AAPS by Treatment and Visit 
(Efficacy Population) 
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27 Mru·ch 2019 
Figme 14.2.2. Weekly Responders(%) by Treatment and Visit (Efficacy Population) 
Figme 14.2.3. Weekly Responders(%) by Treatment and Visit (Observed Data) (Efficacy 
Po ulation 
Figme 14.2.5. Mean C-Reactive Protein by Treatment and Visit (Efficacy Population) 
Figme 14.2.6. Mean Fecal Calprotectin by Treatment and Visit (Efficacy Population) 
Figme 14.2.7. Scatterplot of Changes from Baseline in Peak AAPS and Fecal Calprotectin at 
Week 8 (Efficacy Population) 
Figme 14.2.8. Scatterplot of Changes from Baseline in Peak AAPS and C-Reactive 
Protein at Week 8 (Efficacy Population) 
Figme 14.3.4.1. Active Standing Test Vital Signs by Treatment and Visit (Safety Population) 
Figme 14.3.4.2. Active Standing Test Vital Signs by Treatment and Visit- Alternate (Safety 
Population) 
Figme 14.3.4.3. Individual Subject Active Standing Test Vital Sign Profiles (Safety 
Population) 
Figme 14.3.4.4. Individual Subject Active Standing Test Vital Sign Profiles - Day 1 (Safety 
Population) 
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