A Phase 2, Multi-Center, Randomized, Double-Blind, Placebo-Controlled Parallel-Group Study to Evaluate the Safety, Tolerability, and Efficacy of Olorinab in Subjects With Irritable Bowel Syndrome Experiencing Abdominal Pain
Phase: PHASE2
Conditions: Irritable Bowel Syndrome
Sponsor: Arena Pharmaceuticals

CLINICAL STUDY PROTOCOL 
SUMMARY OF CHANGES 
Protocol title: 
A Phase 2, Multi-Center, Randomized, Double-Blind, Placebo-Controlled 
Parallel-Group Study to Evaluate the Safety, Tolerability, and Efficacy of 
Olorinab in Subjects with Irritable Bowel Syndrome Experiencing 
Abdominal Pain 
 
 
Protocol number: 
APD371-202 
Version: 
Amendment 3.0, dated 03 February 2020 
Replaces version: 
Amendment 2, dated 15 November 2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confidentiality Statement 
This document contains confidential information of Arena Pharmaceuticals, Inc. Unauthorized 
distribution, copying, or disclosure is strictly prohibited unless required by applicable law. Persons 
receiving this information must be notified that it is confidential and may not be further distributed, 
copied, or disclosed. 

Clinical Study Protocol Summary of Changes 
APD371-202 
Olorinab in IBS-C and IBS-D 
 
Amendment 3.0 
Arena Pharmaceuticals, Inc. 
Confidential 
Page 2 of 7 
PROTOCOL AMENDMENT SUMMARY OF CHANGES 
Amendment 3.0: 03 February 2020 
Overall Rationale for the Amendment 
The primary rationale for this amendment is to add an optional long-term extension period to the 
study. Additional minor updates have been made throughout the protocol to add clarity to 
intended study conduct. 
 

Clinical Study Protocol Summary of Changes 
APD371-202 
Olorinab in IBS-C and IBS-D 
 
Amendment 3.0 
Arena Pharmaceuticals, Inc. 
Confidential 
Page 3 of 7 
Summary of Changes 
Current Section No. and Name 
Description of Change 
Brief Rationale 
Throughout 
Minor editorial, formatting, and nomenclature revisions. 
Throughout the protocol, information about the new 
long-term extension (LTE) was added in new, separate 
subsections. 
The descriptor “Main Study” was added to text and section 
headings that apply to the original study. 
Section numbers were adjusted as needed for the addition 
of new sections describing the LTE. 
Updated amendment numbering scheme to 3.0. 
Minor updates for improved accuracy, clarity, readability, 
and consistency with current Arena standards. 
The descriptors “Long-Term Extension” and “Main Study” 
were added throughout for clarity. 
Numbering of the protocol amendment was adjusted 
 
 
Title Page 
Version information updated. 
Degrees for Sponsor’s Responsible Medical Officer added. 
Changes reflect the current protocol details. 
Medical Officer information was corrected. 
Protocol History 
Row added for Amendment 3.0. 
Changes reflect the current protocol details. 
Synopsis 
Updates throughout. 
Updated for consistency with changes made to the main 
body of the protocol (detailed below). 
Table of Contents 
Updated to reflect the addition of sections supporting the 
LTE. 
Changes support the addition of the LTE and the current 
outline of the protocol. 
List of Abbreviations and 
Definitions of Terms 
Updated. 
Per changes made throughout the protocol. 
1.1 Background 
Data from long-term repeated-dose oral toxicity studies 
were added. 
New long-term toxicity data to support long-term dosing in 
humans were needed. 
2.1 Main Study 
New subheading 2.1, Main Study, added above the Main 
Study Objectives. 
New subheading was added to clarify which objectives 
applied to the Main Study versus the LTE. 
2.2 Long-Term Extension 
New subheading 2.2, Long-Term Extension, was added 
and the new objectives of the LTE were added. 
New objectives were needed for the LTE and new 
subheadings were added for organization and clarity. 
3.1.1 Main Study 
New subheading 3.1.1, Main Study, added above the text 
describing the Main Study design. 
New subheading was added to clarify which study design 
text applied to the Main Study versus the LTE. 
Figure 1 
The descriptor “Main Study” was added to the study period 
headings within the figure. 
“Main Study” was added as a descriptor for clarity and to 
distinguish the figure from the new LTE figure. 

Clinical Study Protocol Summary of Changes 
APD371-202 
Olorinab in IBS-C and IBS-D 
 
Amendment 3.0 
Arena Pharmaceuticals, Inc. 
Confidential 
Page 4 of 7 
Current Section No. and Name 
Description of Change 
Brief Rationale 
3.1.2 Long-Term Extension 
New section and text describing the design of the LTE was 
added. 
New section needed to describe the design of the LTE. 
Figure 2 
New figure added showing design of LTE. 
New figure needed to show design of the LTE. 
3.2 Scientific Rationale for Study 
Design 
Text was added to describe the rationale for the LTE. 
New text needed to support the addition of the LTE. 
3.3.1 Main Study 
New subheading 3.3.1, Main Study, added above the text 
describing the justification for the doses used in the Main 
Study. 
New subheading was added to clarify which Justification 
for Dose text applied to the Main Study versus the LTE. 
3.3.2 Long-Term Extension 
New subheading 3.3.2, Long-Term Extension, was added 
and new text justifying the doses chosen for the LTE was 
added. 
New section needed to support the addition of the LTE. 
3.6 Main Study Treatment Period 
Text added to explain that the last day of the Run-in Period 
is Day 1 and the first day of the Treatment Period is 
Day 1. 
Clarified there is no Day 0 in the Main Study. 
3.8 Long-Term Extension 
Screening and Treatment Periods 
New section added to describe the LTE Screening and 
Treatment Periods. 
New section needed to support the addition of the LTE. 
3.9 Long-Term Extension 
Follow-Up/End of Study 
New section added to describe the LTE Follow-Up and 
End-of-Study procedures. 
New section needed to support the addition of the LTE. 
3.10 Early Termination Visit 
Text regarding the LTE Early Termination Visit was 
added. 
New text needed to support the addition of the LTE. 
3.11 Study Duration 
Text describing the duration of the LTE was added. 
New text needed to support the addition of the LTE. 
4.1 Main Study 
New subheading 4.1, Main Study, added above the list of 
inclusion criteria for the Main Study. 
New subheading was added to clarify which inclusion and 
exclusion criteria applied to the Main Study versus the 
LTE. 
 
 

Clinical Study Protocol Summary of Changes 
APD371-202 
Olorinab in IBS-C and IBS-D 
 
Amendment 3.0 
Arena Pharmaceuticals, Inc. 
Confidential 
Page 5 of 7 
Current Section No. and Name 
Description of Change 
Brief Rationale 
4.1 Main Study (Continued) 
Key exclusion criterion 3 was revised to allow history of 
cholecystectomy > 6 months prior to Screening for 
subjects with IBS-C. 
History of cholecystectomy in subjects with IBS-C is not 
expected to interfere for the scientific validity of the study 
or represent a safety concern for subjects. 
4.1.2.2 Other Exclusion Criteria 
(exclusion criterion 14) 
Clostridium difficile was updated to Clostridioides difficile.  Update was made due to the reclassification of Clostridium 
difficile to Clostridioides difficile based on the adoption by 
the US Centers for Disease Control and Prevention. 
4.2 Long-Term Extension 
New section heading added. 
New section heading needed to support the addition of the 
LTE. 
4.2.1 Inclusion Criteria 
New section added and inclusion criteria for LTE added. 
New section needed to support the addition of the LTE. 
4.2.2 Exclusion Criteria 
New section added and exclusion criteria for LTE added. 
New section needed to support the addition of the LTE. 
4.5 Screen Failures, Run-in 
Failures, and Rescreening 
Guidance 
Text added to define LTE screen failures and to describe 
circumstances under which subjects may be rescreened for 
the LTE. 
New text needed to support the addition of the LTE. 
Content regarding values recorded after Screening and 
before Baseline that fail eligibility thresholds were 
rewritten. 
Text was revised and shortened for clarity and readability. 
5 Study Treatment 
Information about the powder-in-capsule formulation was 
removed. 
The powder-in-capsule formulation is no longer needed. 
The formulation to be used during the LTE was described. 
New text needed to support the addition of the LTE. 
5.5 Measures to Minimize Bias: 
Randomization and Blinding 
The procedures for maintaining and breaking the blind 
during the LTE were added. 
New text needed to support the addition of the LTE. 
5.6 Study Treatment Compliance 
The study visits at which compliance will be calculated 
during the Main Study were changed from Visits 4 through 
7 to Visits 4 through 8. For the LTE, added Visits 3 
through 7 during which compliance will be calculated. 
The visits to be used to calculate compliance during the 
Main Study were corrected to Visits 4 through 8 and added 
for the LTE. 
5.7 Concomitant Therapy 
Text describing the concomitant therapy to be recorded 
during the LTE was added. 
New text needed to support the addition of the LTE. 
5.7.2 Allowed Concomitant 
Therapy 

Clinical Study Protocol Summary of Changes 
APD371-202 
Olorinab in IBS-C and IBS-D 
 
Amendment 3.0 
Arena Pharmaceuticals, Inc. 
Confidential 
Page 6 of 7 
Current Section No. and Name 
Description of Change 
Brief Rationale 
5.7.3 Rescue Medication for 
Constipation or Diarrhea 
Symptoms 
Text was revised to specify the study periods during which 
rescue medications for constipation or diarrhea symptoms 
may be administered, and to prohibit their use during the 
Screening Period. 
New text needed to support the addition of the LTE and to 
clarify that rescue medications for constipation or diarrhea 
are not allowed during the Screening or Run-in Periods.  
5.7.4 Prohibited Concomitant 
Therapy 
Table 1 Prohibited Concomitant 
Medications 
7.2 Informed Consent 
A sentence was added to specify that participation in the 
LTE is optional and subjects who participate in the LTE 
will sign an additional consent. 
New text needed to support the addition of the LTE. 
7.5 Efficacy Assessments 
Text describing when the eDiary should be completed 
during the LTE was added. 
New text needed to support the addition of the LTE. 
7.7.2 Vital Signs 
and  
Schedule of Assessments for Main 
Study, footnote e 
The words “at least” were added to the instruction that 
subjects must rest in the supine position for “at least” 
5 minutes before vital signs are measured.  
This change allows some flexibility to sites when 
performing vital signs measurements and is not expected to 
affect study results.  
7.7.4 Clinical Laboratory 
Assessments 
The maximum amount of blood to be collected from each 
subject during the LTE was added. 
New text needed to support the addition of the LTE. 
7.10 Pharmacokinetics 
The pharmacokinetic analysis to be performed during the 
LTE was added. 
New text needed to support the addition of the LTE. 
8.2 Analysis Sets 
The analysis sets for the LTE were added. 
New text and table needed to support the addition of the 
LTE. 
8.3 Statistical Analyses 
Text was added to describe when the SAPs for the Main 
Study and LTE will be finalized and how results will be 
reported. 
New text needed to support the addition of the LTE. 
8.3.1.1 Main Study Endpoints 
New subheading 8.3.1.1, Main Study Endpoints, added 
above the text describing the Main Study endpoints. 
New subheading was added to clarify which study 
endpoints apply to the Main Study versus the LTE. 

Clinical Study Protocol Summary of Changes 
APD371-202 
Olorinab in IBS-C and IBS-D 
 
Amendment 3.0 
Arena Pharmaceuticals, Inc. 
Confidential 
Page 7 of 7 
Current Section No. and Name 
Description of Change 
Brief Rationale 
8.3.1.2 Long-Term Extension 
Endpoints 
New section and text for LTE endpoints added. 
New section needed to support the addition of the LTE. 
8.3.6 Statistical Analyses for the 
Long-Term Extension 
New section added to describe the statistical analyses for 
the LTE. 
New section needed to support the addition of the LTE. 
9.2 Informed Consent Process 
New sentence added regarding informed consent for the 
LTE. 
New text needed to support the addition of the LTE. 
 

Name: Clinical Study Protocol: APD371-202 Amendment 3.0 - Summary of Changes
Description: A Phase 2, Multi‑Center, Randomized, Double‑Blind, Placebo‑Controll
User Nam
Capacity: 
Meaning: Approval Step
Date: 03-Feb-2020 23:14:59 GMT+0000

 
CLINICAL STUDY PROTOCOL 
 
Protocol title: 
A Phase 2, Multi-Center, Randomized, Double-Blind, Placebo-Controlled 
Parallel-Group Study to Evaluate the Safety, Tolerability, and Efficacy of 
Olorinab in Subjects with Irritable Bowel Syndrome Experiencing 
Abdominal Pain 
Protocol number: 
APD371-202 
Version: 
Amendment 3.0, dated 03 February 2020 
Compound: 
Olorinab (APD371) 
Study phase: 
Phase 2 
Short title: 
Olorinab in IBS-C and IBS-D 
Indication: 
Abdominal pain due to irritable bowel syndrome 
NCT number: 
NCT04043455 
Sponsor name: 
Arena Pharmaceuticals, Inc. 
Legal registered 
address: 
6154 Nancy Ridge Drive 
San Diego, California 92121 
Sponsor’s Responsible 
Medical Officer: 
, MD, MHS, FACC 
Chief Medical Officer & Head of Clinical Development 
Clinical lead: 
, PharmD, PhD 
Director, Clinical Development 
Arena Pharmaceuticals, Inc. 
Tel: +
E-mail:
SAE reporting: 
IQVIA Pharmacovigilance 
Tel:
Fax
E-mail: 
 
Sponsor approval: 
This protocol was approved by the Sponsor’s Responsible Medical 
Officer or delegate. The electronic signature manifest is appended. 
Confidentiality Statement 
This document contains confidential information of Arena Pharmaceuticals, Inc. Unauthorized 
distribution, copying, or disclosure is strictly prohibited unless required by applicable law. Persons 
receiving this information must be notified that it is confidential and may not be further distributed, 
copied, or disclosed. 

Clinical Study Protocol 
APD371-202 
Olorinab in IBS-C and IBS-D 
Amendment 3.0 
Arena Pharmaceuticals, Inc. 
Confidential 
Page 2 of 93 
PROTOCOL HISTORY 
 
Document 
Amendment Type 
Date 
Amendment 3.0 
Global 
03 February 2020 
Amendment 2 
Global 
15 November 2019 
Amendment 1 
Global 
15 May 2019 
Original Protocol 
Not applicable 
7 March 2019 
 

Clinical Study Protocol 
APD371-202 
Olorinab in IBS-C and IBS-D 
Amendment 3.0 
Arena Pharmaceuticals, Inc. 
Confidential 
Page 3 of 93 
PROTOCOL SYNOPSIS 
Sponsor: Arena Pharmaceuticals, Inc. 
Name of investigational study drug: Olorinab (APD371) 
Protocol title: A Phase 2, Multi-Center, Randomized, Double-Blind, Placebo-Controlled 
Parallel-Group Study to Evaluate the Safety, Tolerability, and Efficacy of Olorinab in Subjects with 
Irritable Bowel Syndrome Experiencing Abdominal Pain 
Protocol number: APD371-202 
Phase: 2 
Countries/regions (planned): United States 
Objectives: 
Main Study 
Primary Objectives 
 
To compare the efficacy of different doses of olorinab versus placebo on improvement in 
abdominal pain severity in subjects with irritable bowel syndrome (IBS) 
 
To compare the safety and tolerability of different doses of olorinab versus placebo in 
subjects with IBS 
Secondary Objectives 
 
To compare the proportion of abdominal pain treatment responders for different doses of 
olorinab versus placebo 
 
To compare change in pain frequency for different doses of olorinab versus placebo 
 
To characterize the pharmacokinetics (PK) of olorinab and its predominant metabolites 
, and 
 in subjects with IBS 
 
Long-Term Extension (LTE) 
Primary Objective 
 
To evaluate the safety and tolerability of long-term administration of olorinab in subjects with 
IBS 

Clinical Study Protocol 
APD371-202 
Olorinab in IBS-C and IBS-D 
Amendment 3.0 
Arena Pharmaceuticals, Inc. 
Confidential 
Page 4 of 93 
Study Design: 
Main Study 
The Main Study is designed to assess the efficacy, safety, and tolerability of olorinab in the treatment 
of abdominal pain in subjects with IBS with predominant constipation (IBS-C) or IBS with 
predominant diarrhea (IBS-D) who are not on concomitant treatment for IBS. This is a Phase 2, 
multi-center, randomized, double-blind, placebo-controlled, parallel-group study that includes a 
Screening Period (up to 4 weeks for subjects who consent to colonic biopsy, up to 2 weeks for all 
other subjects), a Run-in Period (2 weeks), a randomized Main Study Treatment Period (12 weeks), 
and a post-treatment Follow-Up Period (2 weeks), totaling 16-20 weeks. After the Run-in Period, 
eligible subjects will be equally randomized into 1 of 4 treatment groups (olorinab 10, 25, or 50 mg 
3 times per day [tid] or placebo tid). Randomization will be stratified by sex and IBS subtype. The 
number of subjects enrolled with IBS-C will be approximately equal to the number of subjects 
enrolled with IBS-D. 
 
LTE 
The LTE is an optional extension period that is designed to assess the safety, tolerability, population 
PK (Ctrough), and efficacy of long-term administration of olorinab in subjects who have completed the 
Main Study. The LTE will be conducted at the same study sites as the Main Study. Subjects who 
participate in the LTE will be subjects who complete LTE Visit 2 < 28 days after their Main Study 
Week 12 visit (“Continuing subjects”) or subjects who complete their Main Study Week 12 visit 
≥ 28 days prior to LTE Visit 2 (“Gap subjects”). Gap subjects will be required to have an LTE 
Screening visit approximately 14 days prior to randomization in the LTE. After completing eligibility 
assessments, subjects will enter a randomized LTE Treatment Period (52 weeks), and a post-treatment 
LTE Follow-Up Period (2 weeks). Gap subjects who are interested in participating in the LTE must 
enroll in the LTE within 8 weeks after the IRB approval date of Amendment 3.0. All subjects who 
meet LTE eligibility criteria will be assigned to olorinab treatment as follows: 
 
Subjects who received 25 mg or 50 mg olorinab during the Main Study will continue to 
receive the same dose. 
 
Subjects who received placebo or 10 mg olorinab during the Main Study will be 
re-randomized (1:1) in a double-blind manner to receive either 25 mg or 50 mg olorinab. 
Number of subjects (planned): 
Main Study subjects 
Subjects will be screened until approximately 60 subjects have been randomized per study group for a 
total of approximately 240 subjects. 
 
LTE subjects 
Subjects who participate in the LTE will include study subjects who completed the Main Study 
Treatment Period and who meet the applicable inclusion and exclusion criteria for the LTE. Subject 
enrollment in the LTE will not be capped. 
Eligibility criteria: 
Main Study 
Inclusion criteria: 
Subjects must meet the following inclusion criteria to be eligible for enrollment into the study: 
1. Male and female subjects ≥ 18 and ≤ 70 years of age at Visit 1 (Screening) 

Clinical Study Protocol 
APD371-202 
Olorinab in IBS-C and IBS-D 
Amendment 3.0 
Arena Pharmaceuticals, Inc. 
Confidential 
Page 5 of 93 
3. Clinical diagnosis of IBS-C or IBS-D according to Rome IV criteria at Visit 1 (Screening) 
4. Per the Rome IV diagnostic algorithm for IBS, subjects 50 years of age and over are to have 
had one of the following with a result that rules out causes of abdominal pain other than IBS: 
a. Colonoscopy (within 10 years of Visit 1 [Screening]) 
b. Flexible sigmoidoscopy and double contrast barium enema (within 5 years of Visit 1 
[Screening]) 
c. Computed tomography (CT) colonography (within 5 years of Visit 1 [Screening]) 

Clinical Study Protocol 
APD371-202 
Olorinab in IBS-C and IBS-D 
Amendment 3.0 
Arena Pharmaceuticals, Inc. 
Confidential 
Page 6 of 93 
Key exclusion criteria: 
Subjects are excluded from the study if they meet any of the following key exclusion criteria. 
Additional exclusion criteria are listed in Section 4.1.2. 
1. Diagnosis of IBS with mixed bowel habits (IBS-M) or unsubtyped IBS (IBS-U) 
2. Clinically relevant changes in dietary, lifestyle, or exercise regimen within 30 days prior to 
Visit 1 (Screening) that may confound efficacy assessments in the clinical judgment of the 
Investigator (or designee) 
3. Any colonic or major abdominal surgery (eg, bariatric surgery [including gastric banding], 
stomach surgery, small/large bowel surgery, or abdominal large vessel surgery). History of 
cholecystectomy is exclusionary for subjects with IBS-D. For subjects with IBS-C, a history 
of cholecystectomy more than 6 months prior to Visit 1 (Screening) is allowed. Procedures 
such as appendectomy, hysterectomy, caesarean section, or polypectomy are allowed as long 
as they have occurred at least 3 months prior to Visit 1 (Screening). 

Clinical Study Protocol 
APD371-202 
Olorinab in IBS-C and IBS-D 
Amendment 3.0 
Arena Pharmaceuticals, Inc. 
Confidential 
Page 7 of 93 
LTE 
Inclusion criteria: 
Subjects must meet the following inclusion criteria to be eligible for enrollment into the LTE: 
1. All subjects must have completed the Main Study (including both Visit 8 [Week 12] and 
Visit 9 [Week 14]). 
Exclusion criteria: 
Subjects are excluded from the LTE if they meet any of the following exclusion criteria: 
1. Subject meets any exclusion criteria from the Main Study, at the time of assessing eligibility 
for the LTE, unless approved by the Sponsor in advance. 
2. Subject had less than 75% overall compliance with eDiary entries during the Main Study. 
3. Subject deviated from the prescribed dosage regimen during the Main Study (ie, overall 
study treatment compliance less than 85% or more than 115%), unless approved by the 
Sponsor in advance. 

Clinical Study Protocol 
APD371-202 
Olorinab in IBS-C and IBS-D 
Amendment 3.0 
Arena Pharmaceuticals, Inc. 
Confidential 
Page 8 of 93 
Treatment groups and duration: 
Main Study 
This study will include a Screening Period (up to 4 weeks for subjects consenting to biopsy, up to 
2 weeks for all other subjects), a Run-in Period (2 weeks), a randomized Main Study Treatment 
Period (12 weeks), and a post-treatment Follow-Up Period (2 weeks) for a total duration of 
16 to 20 weeks. Throughout the Main Study Treatment Period, subjects will self-administer oral study 
treatment (olorinab 10, 25, or 50 mg, or placebo) tid with water. This study will not allow dose 
adjustments. 
 
LTE 
The LTE will include a 2-week LTE Screening Period for Gap subjects only; continuing subjects may 
enter the LTE without a separate LTE Screening Period. Once enrolled, all subjects will enter a 
52-week LTE Treatment Period followed by a 2-week LTE Follow-Up Period. Subjects who 
participate in the LTE will have a total study duration as follows: 
 
Gap Subjects: Main Study (16 to 20 weeks), an LTE Screening Period (2 weeks), an LTE 
Treatment Period (52 weeks), and an LTE Follow-Up Period (2 weeks), for a total duration of 
72 to 76 weeks. 
 
Continuing Subjects: Main Study (16 to 20 weeks), an LTE Treatment Period (52 weeks), and 
an LTE Follow-Up Period (2 weeks), for a total duration of 70 to 74 weeks. 
Subjects will self-administer oral study treatment (olorinab 25 or 50 mg) tid with water. This study 
will not allow dose adjustments. 
Endpoints 
Main Study 
Primary  
 
Change in average abdominal pain score (AAPS) from Baseline to Week 12 
 
Adverse events (AEs) and clinically relevant changes in vital signs and clinical laboratory 
results 
Secondary 
 
The proportion of subjects achieving a ≥ 30% improvement in AAPS from Baseline to 
Week 12 
 
The proportion of subjects achieving a ≥ 30% improvement in AAPS from Baseline for at 
least 6 of the 12 weeks during the Main Study Treatment Period 
 
Percent change in AAPS from Baseline to Week 12 
 
Change in number of pain free days per week from Baseline to Week 12 
 
PK parameters including, but not limited to, observed maximum concentration (Cmax), time of 
observed maximum (peak) concentration after drug administration (tmax), and observed trough 
(pre-dose) concentration (Ctrough) 

Clinical Study Protocol 
APD371-202 
Olorinab in IBS-C and IBS-D 
Amendment 3.0 
Arena Pharmaceuticals, Inc. 
Confidential 
Page 9 of 93 
 
LTE 
Primary 
 
AEs, clinically relevant changes in vital signs, and clinical laboratory results. 
Statistical methods: 
Main Study 
Sample size: 
It is assumed that change in AAPS from Baseline to Week 12 will be normally distributed with a 
standard deviation (SD) of 1.9. Assuming a 1:1:1:1 randomization, 240 subjects (60 per treatment 
group) is sufficient to achieve at least 80% power to detect a treatment effect of 1.0 between each of 
the olorinab treatment groups and placebo by a 2-sample t-test using a 2-sided significance level of 
0.05. 
Note, under the same assumptions there is at least 95% power to detect a treatment effect of 1.0 
between the pooled olorinab treatment group (180 subjects) and placebo (60 subjects). 
A blinded review of the data to evaluate the assumption regarding the SD of the change in AAPS 
from Baseline at Week 12 may be conducted. The planned sample size will not be reduced as a result 
of the sample size re-estimation. Details will be specified in the Main Study Statistical Analysis Plan 
(SAP). 
Testing strategy: 
No formal testing strategy or adjustments of the type I error will be employed for the primary, 
secondary, or exploratory endpoints. Estimates and confidence intervals (CI) for treatment groups and 
from pairwise comparisons will be used in an exploratory manner. 
Statistical analysis: 
The primary endpoint, change in AAPS from Baseline to Week 12, will be analyzed using a 
mixed-effects model repeated measures (MMRM) analysis with treatment, stratification factors, visit, 
and treatment-by-visit interaction as factors and Baseline AAPS as a covariate. Least squares means, 
standard errors (SEs), and 95% CIs for the treatments and their difference will be presented together 
with the p-values. 
Unless otherwise specified, continuous endpoints will be analyzed using a MMRM analysis with 
treatment, the stratification factors, visit, and treatment-by-visit interaction as factors and Baseline 
AAPS and Baseline value (if applicable) as covariates. Least squares means, SEs, and 95% CIs for the 
treatments and their difference will be presented together with the p-values. 
Categorical endpoints will be analyzed by either the Cochran-Mantel-Haenszel method, Fisher’s exact 
test, or by logistic regression with a model that includes treatment and stratification factors as factors 
and Baseline AAPS and Baseline value (if applicable) as covariates. The odds ratio of each olorinab 
treatment group relative to placebo and percentage of difference from placebo will be presented 
together with corresponding 95% CIs and the p-values. 
Time-to-event endpoints will be displayed using Kaplan-Meier plots and analyzed with Cox 
regression with a model that includes treatment and stratification factors as factors and Baseline 
AAPS and Baseline value (if applicable) as covariates. The hazard ratio will be presented together 
with 95% CIs and the p-values. 
Pairwise comparisons of each olorinab treatment group compared to placebo will be conducted. In 
addition, analyses of the pooled olorinab treatment groups compared placebo will be conducted. 
Where statistical assumptions (eg, proportional hazards, normality, proportional odds) are not met, 
alternative approaches will be evaluated (eg, non-parametric analysis, log transformation). 

Clinical Study Protocol 
APD371-202 
Olorinab in IBS-C and IBS-D 
Amendment 3.0 
Arena Pharmaceuticals, Inc. 
Confidential 
Page 10 of 93 
Pharmacokinetic analysis: 
A descriptive summary of observed plasma concentrations will be displayed by time and by treatment 
group. The Pharmacokinetic Set will be used to analyze plasma levels. Full details of PK analysis will 
be provided in the SAP for the Main Study. 
Safety analysis: 
All safety data will be listed and summarized by treatment group. All AEs will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA) and tabulated by System Organ Class and 
Preferred Term. Incidence of AEs, serious AEs (SAEs), and treatment-emergent AEs (TEAEs) 
leading to study treatment discontinuation will be summarized and presented in descending order of 
frequency. Laboratory parameters will be summarized by treatment group at each scheduled 
assessment timepoint using descriptive statistics. Associated laboratory parameters such as hepatic 
enzymes, renal function, and hematology values will be grouped and presented together. Individual 
subject values will be listed and values outside of the standard reference range will be noted. Shift 
tables and analyses of changes from Baseline will be produced. The change from Baseline for each of 
the vital signs and electrocardiogram (ECG) parameters will be summarized. Incidence of abnormal 
vital signs parameters and outlier ECG results will be tabulated. 
 
Interim analysis: 
No formal interim analyses are planned. 
 
LTE 
The LTE has 2 treatment groups, 25 mg and 50 mg. Based on subjects’ treatment assignment in the 
Main Study and the LTE, subjects can be classified into 6 unique treatment groups: “Placebo|25 mg”, 
“Placebo|50 mg”, “10 mg|25 mg”, “10 mg|50 mg”, “25 mg|25 mg”, and “50 mg|50 mg”. 
Safety analyses will be performed as described above for the Main Study. In addition, new AEs that 
occur after the first dose in the LTE or TEAEs which occurred in the Main Study period and increase 
in severity after the first dose of LTE study treatment will also be summarized by the 6 unique 
treatment groups. 
A descriptive summary of observed plasma concentrations will be provided by treatment group. 
Summary statistics will be provided for efficacy endpoints by unique treatment group. 
Proportion-based endpoints including responders will be summarized with frequency count and 
percentage. Continuous endpoints will be summarized with descriptive statistics including mean, 
median, standard deviation, minimum, and maximum. There is no formal between-treatment 
comparison for efficacy endpoints. 
Additional analyses may be performed in some subgroups of medical interest, such as sex, age, race, 
and IBS subtype. Details of the analyses will be provided in the SAP for LTE. 
 

Clinical Study Protocol 
APD371-202 
Olorinab in IBS-C and IBS-D 
Amendment 3.0 
Arena Pharmaceuticals, Inc. 
Confidential 
Page 11 of 93 
TABLE OF CONTENTS 
PROTOCOL HISTORY ..................................................................................................................2 
PROTOCOL SYNOPSIS ................................................................................................................3 
TABLE OF CONTENTS ...............................................................................................................11 
LIST OF APPENDICES ................................................................................................................15 
LIST OF TABLES .........................................................................................................................16 
LIST OF FIGURES .......................................................................................................................16 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................17 
1. 
INTRODUCTION ......................................................................................................21 
1.1. 
Background .................................................................................................................21 
1.2. 
Benefit/Risk Assessment ............................................................................................22 
2. 
OBJECTIVES .............................................................................................................24 
2.1. 
Main Study..................................................................................................................24 
2.2. 
Long-Term Extension .................................................................................................24 
3. 
STUDY DESIGN .......................................................................................................25 
3.1. 
Overall Design ............................................................................................................25 
3.1.1. 
Main Study..................................................................................................................25 
3.1.2. 
Long-Term Extension .................................................................................................25 
3.2. 
Scientific Rationale for Study Design ........................................................................26 
3.3. 
Justification for Dose ..................................................................................................27 
3.3.1. 
Main Study..................................................................................................................27 
3.3.2. 
Long-Term Extension .................................................................................................28 
3.4. 
Main Study Screening and Enrollment .......................................................................28 
3.5. 
Main Study Run-in Period ..........................................................................................29 
3.6. 
Main Study Treatment Period .....................................................................................29 
3.7. 
Main Study Follow-Up/End of Main Study ...............................................................29 
3.8. 
Long-Term Extension Screening and Treatment Periods ...........................................30 
3.9. 
Long-Term Extension Follow-Up/End of Study ........................................................30 
3.10. 
Early Termination Visit ..............................................................................................30 
3.11. 
Study Duration ............................................................................................................31 
4. 
STUDY POPULATION .............................................................................................32 
4.1. 
Main Study..................................................................................................................32 

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4.1.1. 
Inclusion Criteria ........................................................................................................32 
4.1.2. 
Exclusion Criteria .......................................................................................................33 
4.1.2.1. 
Key Exclusion Criteria ...............................................................................................33 
4.1.2.2. 
Other Exclusion Criteria .............................................................................................34 
4.2. 
Long-Term Extension .................................................................................................37 
4.2.1. 
Inclusion Criteria ........................................................................................................37 
4.2.2. 
Exclusion Criteria .......................................................................................................37 
4.3. 
Rome IV Criteria for IBS Diagnosis ..........................................................................38 
4.4. 
Lifestyle Considerations .............................................................................................38 
4.4.1. 
Meals and Dietary Restrictions ...................................................................................38 
4.4.2. 
Water Restrictions ......................................................................................................39 
4.4.3. 
Activity .......................................................................................................................39 
4.5. 
Screen Failures, Run-in Failures, and Rescreening Guidance ....................................39 
5. 
STUDY TREATMENT ..............................................................................................41 
5.1. 
Dosage and Administration ........................................................................................41 
5.2. 
Instructions for Missed Doses ....................................................................................41 
5.3. 
Dose Interruptions ......................................................................................................42 
5.4. 
Handling/Storage/Accountability ...............................................................................42 
5.5. 
Measures to Minimize Bias: Randomization and Blinding ........................................42 
5.6. 
Study Treatment Compliance .....................................................................................43 
5.7. 
Concomitant Therapy .................................................................................................43 
5.7.1. 
Required Concomitant Therapy ..................................................................................44 
5.7.2. 
Allowed Concomitant Therapy ...................................................................................44 
5.7.3. 
Rescue Medication for Constipation or Diarrhea Symptoms .....................................45 
5.7.4. 
Prohibited Concomitant Therapy ................................................................................45 
5.8. 
Dosing in Excess of Instructed Daily Treatment ........................................................46 
5.9. 
Dose Modification ......................................................................................................47 
5.10. 
Treatment After the End of the Study .........................................................................47 
6. 
DISCONTINUATION OF STUDY TREATMENT AND SUBJECT 
DISCONTINUATION/WITHDRAWAL ..................................................................48 
6.1. 
Discontinuation of Study Treatment ...........................................................................48 
6.2. 
Safety Criteria for Stopping Study Treatment ............................................................48 
6.3. 
Safety Criteria for Stopping the Study........................................................................49 

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6.4. 
Subject Discontinuation of Study ...............................................................................49 
6.5. 
Lost to Follow-Up.......................................................................................................49 
7. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................51 
7.1. 
General Instructions ....................................................................................................51 
7.2. 
Informed Consent .......................................................................................................51 
7.3. 
Eligibility ....................................................................................................................51 
7.4. 
Demography and Other Subject Characteristics .........................................................51 
7.4.1. 
Evaluation of Specific Ongoing Conditions of Interest ..............................................51 
7.5. 
Efficacy Assessments .................................................................................................52 
7.5.1. 
Abdominal Pain Score ................................................................................................52 
7.6. 
Order of Events and Priority for Timed Assessments ................................................54 
7.7. 
Safety Assessments .....................................................................................................54 
7.7.1. 
Physical Examinations ................................................................................................54 
7.7.2. 
Vital Signs ..................................................................................................................55 
7.7.3. 
Electrocardiography ....................................................................................................55 
7.7.4. 
Clinical Laboratory Assessments ...............................................................................56 
7.7.4.1. 
Clinical Chemistry, Hematology, and Coagulation ....................................................56 
7.7.4.2. 
Urinalysis ....................................................................................................................57 
7.7.5. 
Screening/Ongoing Study Eligibility ..........................................................................57 
7.7.5.1. 
Drugs of Abuse ...........................................................................................................57 
7.7.5.2. 
Pregnancy Testing ......................................................................................................58 

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7.7.5.4. 
Clinical Chemistry, Hematology, and Coagulation ....................................................58 
7.7.5.5. 
Urinalysis ....................................................................................................................58 
7.8. 
Adverse Events ...........................................................................................................58 
7.8.1. 
Definitions ..................................................................................................................58 
7.8.1.1. 
Adverse Event .............................................................................................................58 
7.8.1.2. 
Serious Adverse Event ................................................................................................59 
7.8.1.3. 
Adverse Drug Reaction ...............................................................................................59 
7.8.1.4. 
Adverse Events of Special Interest .............................................................................60 
7.8.1.5. 
Severity .......................................................................................................................60 
7.8.1.6. 
Relationship ................................................................................................................60 
7.8.2. 
Eliciting and Recording Adverse Events ....................................................................61 
7.8.2.1. 
Eliciting Adverse Events ............................................................................................61 
7.8.2.2. 
Recording Adverse Events .........................................................................................61 
7.8.2.3. 
Diagnosis Versus Signs or Symptoms ........................................................................62 
7.8.2.4. 
Reporting Serious Adverse Events .............................................................................62 
7.8.2.5. 
Serious Adverse Events ..............................................................................................62 
7.8.2.6. 
Serious, Unexpected Adverse Drug Reactions ...........................................................63 
7.9. 
Pregnancy ...................................................................................................................63 
7.10. 
Pharmacokinetics ........................................................................................................64 
7.11. 
Pharmacodynamics .....................................................................................................64 
7.12. 
Genetics ......................................................................................................................64 
7.13. 
Biomarkers ..................................................................................................................65 
7.13.1. 
RNA Transcriptome Research ....................................................................................65 
7.13.2. 
Proteome Research .....................................................................................................65 
7.13.3. 
Metabolomic Research ...............................................................................................65 
7.14. 
Medical Resource Utilization and Health Economics ................................................66 
8. 
STATISTICAL CONSIDERATIONS .......................................................................67 
8.1. 
Sample Size Determination ........................................................................................67 
8.2. 
Analysis Sets ...............................................................................................................67 
8.3. 
Statistical Analyses .....................................................................................................68 
8.3.1. 
Endpoints ....................................................................................................................69 
8.3.1.1. 
Main Study Endpoints ................................................................................................69 
8.3.1.2. 
Long-Term Extension Endpoints ................................................................................70 

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8.3.2. 
Main Study Efficacy Analyses ...................................................................................70 
8.3.3. 
Main Study Pharmacokinetic Analysis .......................................................................71 
8.3.4. 
Main Study Safety Analyses .......................................................................................71 
8.3.4.1. 
Adverse Events ...........................................................................................................71 
8.3.4.2. 
Extent of Exposure .....................................................................................................72 
8.3.4.3. 
Clinical Laboratory Results ........................................................................................72 
8.3.4.4. 
Vital Signs ..................................................................................................................72 
8.3.4.5. 
Physical Exams ...........................................................................................................72 
8.3.4.6. 
Electrocardiography ....................................................................................................72 
8.3.5. 
Other Analyses ............................................................................................................73 
8.3.6. 
Statistical Analyses for the Long-Term Extension .....................................................73 
8.4. 
Data Safety Monitoring Board ....................................................................................73 
8.5. 
Interim Analyses .........................................................................................................73 
8.6. 
Missing Data ...............................................................................................................73 
8.7. 
Testing Strategy/Multiplicity ......................................................................................74 
9. 
OPERATIONAL CONSIDERATIONS .....................................................................75 
9.1. 
Regulatory and Ethical Considerations ......................................................................75 
9.2. 
Informed Consent Process ..........................................................................................75 
9.3. 
Data Protection ...........................................................................................................76 
9.4. 
Protocol Compliance ..................................................................................................76 
9.5. 
Data Quality Assurance ..............................................................................................77 
9.6. 
Source Documents ......................................................................................................78 
9.7. 
Study and Site Closure................................................................................................78 
REFERENCES ..............................................................................................................................80 
 
LIST OF APPENDICES 
APPENDIX 2: INVESTIGATOR SIGNATURE .......................................................................93 
 

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LIST OF TABLES 
Table 1: 
Prohibited Concomitant Medications .........................................................................46 
Table 3: 
Clinical Laboratory Tests ...........................................................................................57 
Table 4: 
Analysis Sets for Main Study .....................................................................................67 
Table 5: 
Analysis Sets for Long-Term Extension .....................................................................68 
Table 6: 
Statistical Analysis Methods for Efficacy Analyses ...................................................71 
 
LIST OF FIGURES 
Figure 1: 
Schematic Diagram of Main Study Design ................................................................25 
Figure 2: 
Schematic Diagram of Long-Term Extension Design ................................................26 
 
 

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Amendment 3.0 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Explanation 
5-HT3 
5-hydroxytryptamine receptor 3 
5-HT4 
5-hydroxytryptamine receptor 4 
AAPS 
average abdominal pain score 
ADR 
adverse drug reaction 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
APS 
abdominal pain score 
AUCinf 
area under the plasma versus time concentration curve from time zero 
to the last quantifiable measure 
bpm 
beats per minute 
BUN 
blood urea nitrogen 
Cave 
average concentration 
CB1 (or 2) 
cannabinoid receptor 1 or 2 
CBD 
cannabidiol 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CIOMS 
Council for International Organizations of Medical Sciences 
Cmax 
observed maximum concentration 
CMH 
Cochran-Mantel-Haenszel 
CONSORT 
Consolidated Standards of Reporting Trials 
CT 
computed tomography 
CTCAE 
common terminology criteria for adverse events 
Ctrough 
observed trough (pre-dose) concentration 
DBP 
diastolic blood pressure 
DGP 
deamidated gliadin peptide 
DNA 
deoxyribonucleic acid 
DSMB 
Data Safety Monitoring Board 
ECG 
electrocardiogram 
eCRF 
electronic case report form 

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Abbreviation 
Explanation 
EDC 
electronic data capture 
eDiary 
electronic diary 
eGFR 
estimated glomerular filtration rate 
ELISA 
enzyme-linked immunosorbent assay 
EQ-5D 
European Quality of Life 5 
FAS 
Full Analysis Set 
GCP 
Good Clinical Practice 
GERD 
gastroesophageal reflux disease 
GI 
gastrointestinal 
HADS 
Hospital Anxiety and Depression Scale 
HBsAg 
hepatitis B surface antigen 
hCG 
human chorionic gonadotropin 
HCV 
hepatitis C virus 
HDPE 
high-density polyethylene 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human Immunodeficiency Virus 
HR 
heart rate 
IBD 
inflammatory bowel disease 
IBS 
irritable bowel syndrome 
IBS-C 
irritable bowel syndrome with predominant constipation 
IBS-D 
irritable bowel syndrome with predominant diarrhea 
IBS-M 
irritable bowel syndrome with mixed bowel habits 
IBS-QoL 
Irritable Bowel Syndrome-Quality of Life 
IBS-SSS 
Irritable Bowel Syndrome-Severity Scoring System 
IBS-U 
unsubtyped irritable bowel syndrome 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IgA 
immunoglobulin A 
IgG 
immunoglobulin G 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
IUD 
intrauterine device 

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Amendment 3.0 
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Abbreviation 
Explanation 
IUS 
intrauterine system 
IWRS 
Interactive Web Response System 
LDH 
lactate dehydrogenase 
M1 
 
M2 
 
M4 
 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCV 
mean corpuscular volume 
MDMA 
methylenedioxymethamphetamine 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
mixed-effects model repeated measures 
OTC 
over the counter 
PGIC 
Patient Global Impression of Change 
PIC 
powder in capsule 
PK 
pharmacokinetic 
PP 
Per Protocol 
PRO 
patient-reported outcome 
PROMIS 
Patient-Reported Outcomes Measurement Information System 
PT 
prothrombin time 
PTT 
activated partial thromboplastin time 
QTc 
corrected QT interval 
QTcB 
corrected QT interval by Bazzett 
QTcF 
corrected QT interval by Fridericia 
RBC 
red blood cell 
RNA 
ribonucleic acid 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SBP 
systolic blood pressure 
SD 
standard deviation 
SE 
standard error 
SNRI 
serotonin and norepinephrine reuptake inhibitor 

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Abbreviation 
Explanation 
SOP 
standard operating procedure 
SSRI 
selective serotonin reuptake inhibitors 
T3 
triiodothyronine 
T4 
thyroxine 
TEAE 
treatmentemergent adverse event 
THC 
tetrahydrocannabinol 
tid 
3 times per day 
tmax 
time of observed maximum (peak) concentration after drug 
administration 
TMF 
trial master file 
tTG 
tissue transglutaminase 
TSH 
thyroid-stimulating hormone 
ULN 
upper limit of normal 
WBC 
white blood cell 
 

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Amendment 3.0 
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1. 
INTRODUCTION 
Irritable bowel syndrome (IBS) is a functional gastrointestinal (GI) disease defined according to 
Rome IV criteria by recurrent abdominal pain associated with defecation or a change in bowel 
habits (Lacy 2016). Patients with IBS may also experience other abdominal symptoms of 
cramping, bloating, and abdominal distension and have lower scores in quality of life measures 
compared to others with chronic diseases (ten Berg 2006). There are 3 main subtypes of IBS: 
IBS-C (predominant constipation), IBS-D (predominant diarrhea), and IBS-M (mixed bowel 
habits). Research (Rey de Castro 2015) suggests that the frequency and severity of pain attacks 
has been shown to be generally similar across subtypes, but with some differences in duration 
and frequency of IBS symptomatic episodes (Hellstrom 2011, Weinland 2011). 
In Western countries, the prevalence of IBS has been estimated at approximately 10-15%, but 
with considerably greater country and region variability globally (Hungin 2005, Saito 2002, 
Sperber 2017). IBS accounts for more than 50% of referrals to GI specialists (Jones 2000, 
Sandler 1984). Although the underlying cause of IBS is unknown, evidence suggests that 
multiple biological factors, including motility, epithelial hyperpermeability, dysbiosis, 
inflammation and immune dysfunction, visceral hypersensitivity, epigenetics/genetics, altered 
brain-gut interactions, and various psychosocial factors (eg, response to past and present 
stressors, cognitive status, coping behaviors) may all contribute to the pathogenesis of this 
disorder (Drossman 2016, Enck 2016). 
Many patients with IBS report abdominal pain as their most severe IBS symptom (Drossman 
2009). Attempts to address IBS-related pain with centrally acting pain medications such as 
opioids, gabapentin, and tricyclic antidepressants has resulted in limited success, primarily due to 
the safety profile of these medications. Therefore, treatment of pain in this population remains 
under developed (Camilleri 2018). 
1.1. 
Background 
Cannabinoid receptors 1 and 2 (CB1 and CB2, respectively) play critical roles in pain perception. 
CB1/CB2 agonists have been shown to alleviate acute, chronic inflammatory, postsurgical, 
cancer, and neuropathic pain in animal models. However, the therapeutic potential of 
nonselective CB1/CB2 agonists is limited by the psychotropic effects resulting from activation of 
CB1 located in the brain. In well-validated rodent models of inflammatory, neuropathic pain and 
postoperative pain, CB2-selective agonists have been shown to exhibit analgesic, 
anti-hyperalgesic, and anti-allodynic activity without psychotropic consequences (Guindon 
2008). 
Supporting a role for CB2 in visceral pain in humans, CB2 are upregulated on inflamed intestinal 
epithelia, myenteric and submucosal plexi, and immune cells of patients with Crohn’s disease 
(Wright 2005, Wright 2008). Expression of CB2 is also increased on colonic mucosa in patients 
with IBS (Cremon 2017). 
Olorinab (APD371) is a peripherally acting, full agonist of CB2, with 1000-fold higher 
selectivity for CB2 over CB1 that is being developed for the treatment of abdominal pain in 
patients with IBS. A detailed description of the chemistry, pharmacology, efficacy, and safety of 
olorinab is provided in the Investigator’s Brochure. In various preclinical studies, olorinab has 

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Clinical Study Protocol 
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Olorinab in IBS-C and IBS-D 
Amendment 3.0 
Arena Pharmaceuticals, Inc. 
Confidential 
Page 23 of 93 
subject throughout the study. During the Phase 2a study, there was no apparent dose-dependent 
change in HR observed and there were no TEAEs related to changes in HR. 
In the single ascending dose study, the mean values for systolic blood pressure (SBP) and 
diastolic blood pressure (DBP) were within the normal range at Baseline and at all post-dose 
timepoints assessed, and there were no clinically significant changes in the mean values of the 
different treatment groups. In the multiple ascending dose study, all individual supine SBP and 
DBP measurements remained in a physiologically acceptable range for each subject throughout 
the study; all individual changes observed were asymptomatic and no AEs were reported that 
were related to changes in blood pressure. On Day 1, changes in mean supine SBP and DBP for 
the lowest olorinab dose group were generally comparable to the placebo group. Mean supine 
SBP and DBP exhibited a mild decrease from Baseline as early as 1 hour after the first dose on 
Day 1 in the two higher dose groups and reached a nadir at 6 hours. In general, mean changes in 
supine blood pressure in the Phase 2a study during the first day of dosing were variable and 
small. After Day 1, mean supine and orthostatic SBP and DBP values collected before the first 
daily dose over the course of the 8-week study remained relatively stable for both dose groups. 
Preliminary efficacy results from the Phase 2a study demonstrated significant decreases in 
abdominal pain (as measured by AAPS) starting on Week 1 and sustained through Week 8. 
The benefit-risk profile supports further clinical development of olorinab. 

Clinical Study Protocol 
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Olorinab in IBS-C and IBS-D 
Amendment 3.0 
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2. 
OBJECTIVES 
2.1. 
Main Study 
Primary Objectives 
 To compare the efficacy of different doses of olorinab versus placebo on 
improvement in abdominal pain severity in subjects with IBS 
 To compare the safety and tolerability of different doses of olorinab versus placebo in 
subjects with IBS 
Secondary Objectives 
 To compare the proportion of abdominal pain treatment responders for different doses 
of olorinab versus placebo 
 To compare change in pain frequency for different doses of olorinab versus placebo 
 To characterize the pharmacokinetics (PK) of olorinab and its predominant 
metabolites 
, and 
 in subjects with IBS 
2.2. 
Long-Term Extension 
Primary Objective 
 To evaluate the safety and tolerability of long-term administration of olorinab in 
subjects with IBS 

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Amendment 3.0 
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3. 
STUDY DESIGN 
3.1. 
Overall Design 
3.1.1. 
Main Study 
The Main Study is designed to assess the efficacy, safety, and tolerability of olorinab in the 
treatment of abdominal pain in subjects with IBS with IBS-C or IBS-D who are not on 
concomitant treatment for IBS. This study is a Phase 2, multi-center, randomized, double-blind, 
placebo-controlled, parallel-group study that includes a Screening Period (up to 4 weeks for 
subjects who consent to colonic biopsy, up to 2 weeks for all other subjects), a Run-in Period 
(2 weeks), a randomized Main Study Treatment Period (12 weeks), and a post-treatment Main 
Study Follow-Up Period (2 weeks), totaling 16-20 weeks (Figure 1). After the Run-in Period, 
eligible subjects will be equally randomized into 1 of 4 treatment groups (olorinab 10, 25, or 
50 mg tid or placebo tid). Randomization will be stratified by sex and IBS subtype. The number 
of subjects enrolled with IBS-C will be approximately equal to the number of subjects enrolled 
with IBS-D. An optional Long-Term Extension (LTE) is described in Section 3.1.2. 
Figure 1: 
Schematic Diagram of Main Study Design 
 
AAPS, average abdominal pain score; tid, 3 times per day; Wk, week 
Notes: 
The Screening Period may be extended to up to a total of 4 weeks for subjects who consent to colonic biopsy. The last 
day of the Run-in Period is Day 1 and the first day of the Treatment Period is Day 1. There is not a designated Day 0 in this 
study. For Continuing subjects, Visit 9 of the Main Study may take place on the same day as Visit 2 of the Long-Term Extension. 
3.1.2. 
Long-Term Extension 
The LTE is an optional extension period that is designed to assess the safety, tolerability, 
population PK (Ctrough), and efficacy of long-term administration of olorinab in subjects who 
have completed the Main Study. The LTE will be conducted at the same study sites as the Main 
Study. Subjects who participate in the LTE will be subjects who complete LTE Visit 2 < 28 days 

Clinical Study Protocol 
APD371-202 
Olorinab in IBS-C and IBS-D 
Amendment 3.0 
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after their Main Study Week 12 visit (“Continuing subjects”) or subjects who complete their 
Main Study Week 12 visit ≥ 28 days prior to LTE Visit 2 (“Gap subjects”). Gap subjects will be 
required to have an LTE Screening visit approximately 14 days prior to randomization in the 
LTE. After completing eligibility assessments, subjects will enter a randomized LTE Treatment 
Period (52 weeks), and a post treatment LTE Follow-Up Period (2 weeks) (Figure 2). 
Gap subjects who are interested in participating in the LTE must enroll in the LTE within 
8 weeks after the IRB approval date of Amendment 3.0. All subjects who meet LTE eligibility 
criteria will be assigned to olorinab treatment as follows: 
 Subjects who received 25 mg or 50 mg olorinab during the Main Study will continue 
to receive the same dose. 
 Subjects who received placebo or 10 mg olorinab during the Main Study will be 
re-randomized (1:1) in a double-blind manner to receive either 25 mg or 50 mg 
olorinab. 
Figure 2: 
Schematic Diagram of Long-Term Extension Design 
 
AAPS, average abdominal pain score, LTE, long-term extension; tid, 3 times per day; Wk, week 
a Gap subjects start the LTE at Visit 1. 
b Continuing subjects start the LTE at Visit 2. 
3.2. 
Scientific Rationale for Study Design 
IBS is a GI disorder characterized by abdominal pain associated with defecation or change in 
bowel habits (Lacy 2016). Symptoms are chronic and may be episodic in nature, varying widely 
among patients (Miller 2014, Weinland 2011). In clinical studies of IBS, a run-in period of 
1-3 weeks is recommended to monitor presence and consistency of symptoms according to study 
entry criteria (EMA 2014, FDA 2012, Miller 2014, Spiegel 2017). Accordingly, this study will 
incorporate a Main Study Run-in Period of at least 2 weeks (14-19 days), which will be used to 

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train subjects on the proper completion of patient-reported outcome (PRO) instruments, to 
confirm subject eligibility with respect to abdominal pain severity, and to establish baseline 
values of various assessments. 
Based on its mechanism of action as a selective CB2 agonist and data from previous nonclinical 
and clinical studies, it is anticipated that olorinab may have an effect on abdominal pain in 
patients with IBS, but will not have an effect on motility or bowel symptoms of constipation or 
diarrhea (Mathison 2004). Per FDA Guidance for Industry, Irritable bowel syndrome - clinical 
evaluation of drugs for treatment (FDA 2012), abdominal pain score (APS) is the recommended 
instrument for measuring pain in IBS. The instrument is a patient-reported outcome that uses an 
11-point numeric rating scale ranging from 0 (no abdominal pain) to 10 (worst possible 
abdominal pain). The scale has been validated and has been widely used in clinical studies on 
pain in IBS (Spiegel 2009). Subjects in this study will record their worst abdominal pain over the 
previous 24 hours in a daily electronic diary (eDiary). Abdominal pain in IBS can fluctuate daily. 
To better capture a summary of subject pain, the AAPS (for Baseline: the average of all APS 
scores during the Run-In Period; for post-baseline visits: the average of the APS score over the 
7 days before the scheduled visit) will be used to summarize subject pain and compare changes 
in pain over time. In the absence of significant safety findings, a greater decrease in AAPS in 
olorinab-treated subjects compared to placebo-treated subjects over the course of this study will 
provide supportive evidence that olorinab provides a direct benefit to subjects. 
This study has been designed as a randomized, double-blind, placebo-controlled, parallel-group, 
dose-ranging study to reduce bias and account for placebo effect in the evaluation of the safety 
and efficacy of multiple dose levels of olorinab. The addition of an LTE, during which subjects 
will receive olorinab 25 mg tid or 50 mg tid for approximately 1 year, is included to allow 
subjects access to olorinab for an extended period of time and for the collection of long-term 
safety data. 
3.3. 
Justification for Dose 
3.3.1. 
Main Study 
The safety, tolerability, and PK of olorinab have been evaluated in 2 Phase 1 dose escalation 
studies. Olorinab has also been evaluated in an 8-week Phase 2a, proof-of-concept study in 
subjects with quiescent to mildly active Crohn’s disease. In a single ascending dose study, single 
oral doses of 10 to 400 mg of olorinab were administered to healthy, adult volunteers. TEAEs 
were predominantly mild in severity and the majority of TEAEs occurred in subjects 
administered doses ≥ 120 mg. No TEAEs led to discontinuation and there were no serious AEs 
(SAEs). A dose-dependent trend of increases in supine HR was observed at doses ≥ 250 mg. 
Systemic exposure of olorinab (observed maximum concentration [Cmax] and area under the 
plasma versus time concentration curve from time zero to the last quantifiable measure [AUCinf]) 
increased with dose in a manner that was less than dose proportional. 
In a multiple ascending dose study, multiple oral doses of olorinab 50, 100, and 200 mg were 
administered tid for 10 days to healthy, adult volunteers. Most TEAEs were mild in severity. 
Olorinab was associated with mean decreases from baseline in supine SBP and DBP, 
respectively, that were evident beginning at 1-hour post-dose on Day 1 and Day 10, in the 100 
and 200 mg groups. Blood pressure values returned to baseline or above baseline values upon 

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discontinuation of treatment. The 200 mg dose was associated with mean decreases in supine HR 
of approximately 10 to 15 beats per minute (bpm) compared to baseline throughout the 
Treatment Period. In the 50 mg and 100 mg groups, changes in HR relative to baseline were 
small and variable. 
In a Phase 2a study, doses of 25 and 100 mg of olorinab were administered tid for 8 weeks in a 
randomized, open-label study in 14 subjects with quiescent to mildly active Crohn’s disease. PK 
results indicated that the systemic exposure of olorinab was dose proportional. 
Decreases in AAPS compared to baseline were similar for both olorinab treatment groups 
starting on Week 1 and sustained through Week 8 in the Phase 2a study. The lack of 
dose-dependency on AAPS may indicate possible pharmacological saturation of CB2 at 25 mg 
tid. Resultant Cmax and average concentration (Cave) plasma concentrations that were generally 
equal to or higher than those that achieved notable efficacy in rat models of pain are also 
consistent with a potential pharmacological saturation of CB2 at 25 mg tid and above. 
The absence of a placebo group in the Phase 2a study in combination with high placebo response 
rates reported in previous studies of patients with IBD and IBS confound the confirmation of 
clinical efficacy as it relates to a dose-response relationship. Therefore, the pharmacologically 
active 25 mg tid dose will be bracketed with 10 and 50 mg doses tid. 
PK modelling predicts that the 25 mg and 50 mg tid dose levels will provide mean Cave values 
that correspond to those that show efficacy in the rat. Similar modelling to predict mean Cmax and 
Cave after a 10 mg dose results in values lower than rat efficacious values. Therefore, inclusion of 
the 10 mg dose is intended to contribute to the characterization of the efficacy dose response for 
olorinab. 
In summary, olorinab doses of 10, 25, and 50 mg tid have been selected for the Main Study 
based on their safety and tolerability profile from prior studies. Furthermore, these doses are 
expected to result in a range of efficacies, which will inform dose selection in future clinical 
studies. 
3.3.2. 
Long-Term Extension 
Chronic abdominal pain is a common feature in patients with IBS. In the LTE, subjects will 
receive olorinab doses of 25 or 50 mg which are expected to be in the therapeutic range for pain 
relief, and were shown to be safe and well tolerated in previous Phase 1 and Phase 2 studies. 
3.4. 
Main Study Screening and Enrollment 
Potential subjects will provide written informed consent before any study-specific procedure is 
performed. The Screening Period will last for up to 2 weeks. For subjects who consent to 
collection of a colonic biopsy sample for biomarker analysis, the Screening Period may be 
extended 2 additional weeks for a total Screening Period of up to 4 weeks; collection of colonic 
biopsy tissue must be performed at least 1 week prior to entering the Run-in Period. A summary 
of screening and enrollment events is provided in the
). 
Inclusion and exclusion criteria are listed in Section 4.1.1 and Section 4.1.2, respectively. 
Eligible subjects meeting all inclusion and none of the exclusion criteria requirements may be 
enrolled. 

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3.5. 
Main Study Run-in Period 
Subjects who are enrolled in the study will enter the Run-in Period. The Run-in Period will last 
at least 2 weeks (14-19 days) and will end on Day 1. No study treatment will be administered 
during the Run-in Period. At the beginning of the Run-in Period, subjects will be trained on daily 
eDiary entry. Subjects will be instructed to complete daily eDiary entries in the evening, 
generally at the same time every day, throughout the Run-in Period. As a follow-up to training, 
study staff will attempt to contact subjects within approximately 3 days after Visit 2 (Day 1 of 
Run-in) to confirm whether subjects are able to see the eDiary questions, to confirm whether the 
eDiary devices are appropriately synchronizing, and to help troubleshoot any potential eDiary 
technical issues in a timely manner as appropriate. This contact attempt should be documented in 
the subject’s source document. At the end of the Run-in Period and prior to randomization at 
Visit 3 (Day 1), subject eligibility will be determined based on the following: 
 Compliance with eDiary completion requirements 
 AAPS score during the Run-in Period ≥ 4 
 Continued eligibility as defined by the inclusion/exclusion criteria 
 Subject did not use any rescue medication during the Run-in Period 
Subjects who do not meet the criteria listed above will be considered Run-in failures and will not 
progress in the study. Subjects who do meet the criteria listed above will move on to the Main 
Study Treatment Period. 
3.6. 
Main Study Treatment Period 
The Main Study Treatment Period will begin on Day 1. The last day of the Run-in Period is 
Day 1 and the first day of the Main Study Treatment Period is Day 1. There is not a designated 
Day 0 in this study. 
Subjects who have completed the Run-in Period and remain eligible for the study will be 
randomized to receive olorinab 10, 25, or 50 mg or placebo tid. All Main Study Treatment 
Period study visits (Visits 4, 5, 6, 7, and 8) that occur after Visit 3 (Day 1) should be scheduled 
relative to the actual date of Day 1. Subjects will receive study treatment for 12 weeks (± 3 days) 
and will continue to perform daily eDiary entries. Study visits and assessments will be conducted 
per the
. 
3.7. 
Main Study Follow-Up/End of Main Study 
Subjects who have completed the Main Study Treatment Period will return for a Main Study 
Follow-Up Visit at Week 14, approximately 2 weeks (± 3 days) after completion of the Main 
Study Treatment Period. When possible, subjects who have stopped taking study treatment prior 
to the end of the Main Study Treatment Period (Early Termination) will also conduct a 
Follow-Up visit approximately 2 weeks (± 3 days) after discontinuation of study treatment. 
Subjects will complete daily eDiary entries throughout the Main Study Follow-Up Period. Visit 
assessments are detailed in the 
). 

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3.8. 
Long-Term Extension Screening and Treatment Periods 
Subjects who complete the Main Study (including both Visit 8 [Week 12] and Visit 9 [Week 14]) 
and meet eligibility criteria for the LTE may continue to receive olorinab at doses of 25 mg or 
50 mg for approximately 52 weeks starting as soon as approximately 2 weeks after their last dose 
of study drug in the Main Study Treatment Period. Subjects will provide written informed 
consent before any procedures specific to the LTE are performed. 
For Continuing subjects who enter the LTE (ie, subjects who completed Visit 8 [Week 12] 
< 28 days before LTE Visit 2), the first visit in the LTE period (LTE Visit 2) may take place on 
the same day as the Main Study Follow-Up Visit 9 [Week 14]. Eligibility for Continuing subjects 
for the LTE will be confirmed as indicated in Section 4.2. 
For Gap subjects (ie, subjects who completed Visit 8 [Week 12] ≥ 28 days before LTE Visit 2), 
an additional 14-day LTE Screening Period will be required before LTE dosing can commence. 
During the LTE Screening visit (LTE Visit 1), eligibility for the LTE will be confirmed as 
indicated in Section 4.2. At the LTE Screening visit, subjects will be re-trained on daily eDiary 
entry as described in Section 3.5. 
Subjects will complete the eDiary daily throughout the LTE. 
 
. During the LTE Treatment Period, the site staff will contact each subject by 
telephone approximately 3 weeks before each study visit to remind them of the importance of 
their eDiary entries and of their upcoming visit. 
3.9. 
Long-Term Extension Follow-Up/End of Study 
Subjects who have completed the LTE Treatment Period will return for a Follow-Up Visit at 
LTE Week 54, approximately 2 weeks (± 7 days) after completion of the LTE Treatment Period. 
When possible, subjects who have stopped taking study treatment prior to the end of the LTE 
Treatment Period (Early Termination) will return for an LTE Follow-Up Visit approximately 
2 weeks (± 7 days) after discontinuation of study treatment. 
 
 
3.10. 
Early Termination Visit 
Subjects who stop taking study treatment prior to the end of the Main Study Treatment Period 
will return to the clinic for a Main Study Early Termination Visit. Subjects enrolled in the LTE 
who stop taking olorinab prior to the end of the LTE Treatment Period will return to the clinic 
for an LTE Early Termination Visit. Early Termination Visit assessments are detailed in the 
 Every effort should be made to schedule Early 
Termination procedures within 3 days of the last dose of study treatment and before initiation of 
any new treatments which could affect endpoints. After completion of the Early Termination 
Visit, subjects should also return (when possible) for a Follow-Up Visit approximately 2 weeks 
(± 3 days [for the Main Study] or ± 7 days [for the LTE]) after discontinuation of study 
treatment. Site staff will work with subjects who withdraw early to obtain as much follow-up 
data as possible. 

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3.11. 
Study Duration 
For subjects who participate only in the Main Study, study duration from the time of consent to 
the last visit for each subject will be 16 to 20 weeks. A subject is considered to have completed 
the Main Study if they complete all phases of the study including Visit 8 (Week 12) and the 
Follow-Up Visit at Week 14. 
For Continuing subjects who participate in the LTE, study duration from the time of consent to 
the last visit for each subject will be 70 to 74 weeks. 
For Gap subjects who participate in the LTE, the duration of time that the subject participates in 
the study will be 72 to 76 weeks, not including the time that the subject is not enrolled in the 
study after completion of the Follow-Up Visit (Week 14) in the Main Study and before the 
subject returns for the LTE Screening Visit. 
The end of the study is defined as the date of the last clinic visit (scheduled or unscheduled) of 
the last subject in the study. 

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4. 
STUDY POPULATION 
Prospective approval of protocol deviations from recruitment and enrollment criteria, also known 
as protocol waivers or exemptions, is not permitted. 
4.1. 
Main Study 
4.1.1. 
Inclusion Criteria 
Subjects must meet the following inclusion criteria to be eligible for enrollment into the study: 
1. Male and female subjects ≥ 18 and ≤ 70 years of age at Visit 1 (Screening) 
 
 
 
3. Clinical diagnosis of IBS-C or IBS-D according to Rome IV criteria at Visit 1 
(Screening) 
4. Per the Rome IV diagnostic algorithm for IBS, subjects 50 years of age and over are to 
have had one of the following with a result that rules out causes of abdominal pain other 
than IBS: 
a. Colonoscopy (within 10 years of Visit 1 [Screening]) 
b. Flexible sigmoidoscopy and double contrast barium enema (within 5 years of 
Visit 1 [Screening]) 
c. Computed tomography (CT) colonography (within 5 years of Visit 1 [Screening]) 

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4.1.2. 
Exclusion Criteria 
Subjects are excluded from the study if any of the following exclusion criteria apply. 
4.1.2.1. 
Key Exclusion Criteria 
1. Diagnosis of IBS-M or unsubtyped IBS (IBS-U) 
2. Clinically relevant changes in dietary, lifestyle, or exercise regimen within 30 days prior 
to Visit 1 (Screening) that may confound efficacy assessments in the clinical judgment of 
the Investigator (or designee) 
3. Any colonic or major abdominal surgery (eg, bariatric surgery [including gastric 
banding], stomach surgery, small/large bowel surgery, or abdominal large vessel 
surgery). History of cholecystectomy is exclusionary for subjects with IBS-D. For 
subjects with IBS-C, a history of cholecystectomy more than 6 months prior to Visit 1 
(Screening) is allowed. Procedures such as appendectomy, hysterectomy, caesarean 
section, or polypectomy are allowed as long as they have occurred at least 3 months prior 
to Visit 1 (Screening). 

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4.1.2.2. 
Other Exclusion Criteria 

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Clinical Study Protocol 
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Amendment 3.0 
Arena Pharmaceuticals, Inc. 
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Amendment 3.0 
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4.2. 
Long-Term Extension 
4.2.1. 
Inclusion Criteria 
Subjects must meet the following inclusion criteria to be eligible for enrollment into the LTE: 
1. All subjects must have completed the Main Study (including both Visit 8 [Week 12] and 
Visit 9 [Week 14]). 
4.2.2. 
Exclusion Criteria 
Subjects are excluded from the LTE if they meet any of the following exclusion criteria: 
1. Subject meets any exclusion criteria from the Main Study at the time of assessing 
eligibility for the LTE, unless approved by the Sponsor in advance. 
2. Subject had less than 75% overall compliance with eDiary entries during the Main Study. 
3. Subject deviated from the prescribed dosage regimen during the Main Study (ie, overall 
study treatment compliance less than 85% or more than 115%), unless approved by the 
Sponsor in advance. 

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Amendment 3.0 
Arena Pharmaceuticals, Inc. 
Confidential 
Page 39 of 93 
(Main Study Visit 5), which include post-dose blood samples, subjects can be 
provided a snack to be consumed between the 0.5 and 1 hour PK blood sample. At all 
visits, caffeine is restricted until after the last vital signs have been taken. 
 Subjects will be instructed to refrain from the use of alcohol within 24 hours of study 
visits. 
 Subjects will be instructed to refrain from making significant dietary changes 
throughout the duration of the study. 
4.4.2. 
Water Restrictions 
There are no water restrictions. 
4.4.3. 
Activity 
 Subjects will be instructed to refrain from strenuous exercise (relative to the subject’s 
fitness level and typical exercise routine) within 24 hours prior to each study visit. 
 Subjects will be instructed to refrain from making significant changes to their activity 
levels and exercise routines throughout the duration of the study. 
 On Day 1 and Week 4, which include post-dose blood samples, strenuous exercise 
should be avoided until all blood samples have been collected. 
 On Day 1 and Week 4, which include post-dose blood samples, subjects should not 
assume a supine position after administration of study treatment, except as needed for 
vital sign assessments, until the completion of the blood sample at 2 hours post-dose. 
4.5. 
Screen Failures, Run-in Failures, and Rescreening Guidance 
Main Study screen failures are defined as subjects who consent to participate in the Main clinical 
study but are not subsequently enrolled into the study at Visit 2 (Run-in). LTE screen failures are 
defined as subjects who consent to participate in the LTE but are not subsequently enrolled into 
the LTE. Run-in failures are defined as subjects who are enrolled at Main Study Visit 2 (Run-in) 
but do not randomize at Visit 3 (Day 1). A minimal set of screen failure information is required 
to ensure transparent reporting of screen failure subjects to meet the Consolidated Standards of 
Reporting Trials (CONSORT) publishing requirements and to respond to queries from regulatory 
authorities. Minimal information includes demography, reason for screen failure, eligibility 
criteria, any concomitant medications, and any SAEs. If a screen failure occurs because of a 
restricted concomitant medication, the medication should be documented in the eCRF. 
Individuals may re-qualify for study enrollment in the Main Study or LTE within 2 weeks of 
Main Study Visit 1 (Screening) or LTE Visit 1 (Screening), as applicable, following an abnormal 
laboratory test, vital signs, or ECG finding by having that test repeated once with acceptable 
results as judged by the Investigator (or designee). The Investigator may consult with the 
Medical Monitor as needed. 
If a result for laboratory, vital signs, or ECG obtained after Screening but before randomization 
fails eligibility thresholds outlined below as applicable, the subject must be withdrawn unless the 
value is assessed and documented as not a clinically significant change from the qualifying 
Screening value by the Investigator (or designee). 

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Subjects who have not been randomized and do not meet the remaining inclusion and exclusion 
criteria may be rescreened for the Main Study with a new screening number if the Investigator 
assesses that the subject is an appropriate candidate for re-screening. The Investigator may 
consult with the Medical Monitor if there are any questions related to rescreening a subject. 
Subjects may not be rescreened more than once without prior approval of the Medical Monitor 
and rescreening must occur at least 2 weeks after the date of screen failure. Subjects who do not 
meet the minimum pain requirements for study entry, as defined in Inclusion Criterion 10, and 
subjects who have been randomized are not eligible for rescreening. 

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5. 
STUDY TREATMENT 
Olorinab (APD371) is a highly selective, full agonist of CB2. 
Olorinab is provided in 2 formulations: powder in capsule (PIC) and tablet. Both tablets and 
capsules are immediate-release formulations, therefore the same bioavailability is expected. Both 
formulations include the following strengths: 10 mg, 25 mg, and 50 mg. 
 
 
 
 
 
 
 
 
 
 
 
 
 
Olorinab drug substance, drug product (capsules and tablets), and matching placebo (capsules 
and tablets) are manufactured in compliance with current Good Manufacturing Practices. 
Capsules and tablets are packaged in the following configuration: 63 count in 100-cc 
high-density polyethylene (HDPE) bottles heat-induction sealed with child-resistant screw cap. 
Bottles will be labeled in compliance with local country requirements and shipped to 
participating clinical study sites for study use. 
Although 2 different dosage forms (capsules and tablets) of study treatment will be used in this 
study, individual subjects will remain on the same dosage form assigned at the time of 
randomization throughout the Main Study Treatment Period. During the LTE, all subjects will 
receive the tablet dosage form, regardless of which dosage form they were assigned to during the 
Main Study. 
5.1. 
Dosage and Administration 
5.2. 
Instructions for Missed Doses 
Subjects should be instructed that if they forget to take a dose, they should take their missed dose 
as soon as they realize the dose has been missed as long as the next planned dose is at least 
3 hours away; otherwise, they should skip their missed dose and they should take their next dose 
at the regular time. Subjects should be instructed to contact the Investigator if they miss more 
than 9 consecutive doses (ie, all doses have been missed for at least a 72-hour period). If the 

Clinical Study Protocol 
APD371-202 
Olorinab in IBS-C and IBS-D 
Amendment 3.0 
Arena Pharmaceuticals, Inc. 
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subject vomits the study treatment, he/she should be instructed not to take another dose in the 
same dosing period, but to take the next dose at the regular time. 
5.3. 
Dose Interruptions 
All study treatment interruptions of greater than 5 consecutive days will be noted in the 
electronic case report form (eCRF) with the start date, duration, and reason for the interruption 
(if known) specified. If the interruption was caused by an AE, only the primary AE leading to 
interruption of study treatment, per the judgment of the Investigator, should have an action taken 
of study treatment interrupted. If a study treatment interruption greater than 5 days is required for 
a medical reason, the Investigator must contact the Medical Monitor. 
5.4. 
Handling/Storage/Accountability 
Sufficient study treatment will be provided to participating clinical study sites to support study 
conduct. All study treatment must be stored in a secure, limited access area. 
 
 
Procedures for reporting any shipment damage or temperature excursions are specified in the 
Pharmacy Manual. 
The Investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit and storage for all study treatments received. Any discrepancies must 
be reported to Sponsor or designee. All issues must be resolved before use of the study treatment. 
Only subjects randomized in the study may receive study treatment and only authorized site staff 
are permitted to supply or administer study treatment. 
The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study treatment accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records). 
At completion of the study, all study treatment will be reconciled and either retained or destroyed 
according to direction from the Sponsor and applicable country regulations. On-site destruction 
may be permitted under the guidance of local regulations and applicable site standard operating 
procedures (SOPs). Prior to taking any action with study treatment, the Investigator or designee 
will contact the Sponsor or designee for approval of such action. Final reconciliation will be 
performed at study completion. Further guidance and information for the final disposition of 
used and unused study treatment will be provided in a separate Pharmacy Manual. 
5.5. 
Measures to Minimize Bias: Randomization and Blinding 
This is a double-blind study with limited access to the randomization code. All study treatment 
bottles will be identical in appearance, and olorinab and placebo will be identical in appearance 
within each type of formulation (capsules or tablets). The treatment each subject receives will 
not be disclosed to the Investigator, study site staff, subject, study vendors, or Sponsor personnel 
involved with the conduct of the study (with the exception of the clinical supply staff and safety 
staff). The Interactive Web Response System (IWRS) will store treatment codes and maintain kit 
numbers for dispensed study treatment. All subjects will be centrally assigned to randomized 
study treatment group using an IWRS. Before the study is initiated, the login information and 
directions for the IWRS will be provided to each site. 

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Amendment 3.0 
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The IWRS will be programmed with blind-breaking instructions. In case of an emergency, the 
Investigator has the sole responsibility for determining if unblinding of a subject’s treatment 
assignment is warranted. Subject safety must always be the first consideration in making such a 
determination. If the Investigator decides that unblinding is warranted, the Investigator should 
make every effort to contact the Sponsor prior to unblinding a subject’s treatment assignment 
unless this could delay emergency treatment of the subject. If a subject’s treatment assignment is 
unblinded, the subject should immediately stop taking all study treatment and the Sponsor must 
be notified within 24 hours after breaking the blind. The date and reason that the blind was 
broken must be recorded in the source documentation and eCRF, as applicable. 
After the Main Study has completed and the database for that portion of the study has been 
locked, that database will be unblinded for analysis. However, the investigators (except as 
necessary for data review), sites, and subjects will remain blinded to the treatment assignments 
throughout study conduct (including conduct of the LTE). 
5.6. 
Study Treatment Compliance 
Study treatment will be dispensed at the study visits scheduled in the 
 
. 
Subjects will document study treatment administration once daily in the subject eDiary. At 
Visit 3, subjects will be instructed on how to record treatment administration in the subject 
eDiary. 
Starting with Visit 4, subjects will be instructed to bring unused study treatment and used study 
treatment packaging to each study visit to assess compliance with study treatment administration. 
Returned study treatment should be counted at each visit. Compliance with the scheduled dose 
should be assessed based on the following: 
 Study treatment accountability 
 Non-directed verbal questioning 
 Review of eDiary responses regarding study treatment administration 
Deviation(s) from the prescribed dosage regimen will be recorded in the eCRF. If compliance is 
not between 85% and 115%, inclusive, at Main Study Visits 4 through 8 or LTE Visits 3 
through 7, the subject will be counseled by the Investigator or designee about the importance of 
compliance with the regimen. 
Subjects with administration compliance greater than 115% and subjects who do not return any 
study treatment or study treatment packaging will be asked for the reason for the overcompliance 
or missing study treatment and their response will be recorded in the eCRF. 
The Sponsor retains the right to require the withdrawal of any subject who violates the protocol. 
5.7. 
Concomitant Therapy 
Medication restrictions are outlined in the inclusion and exclusion criteria (Section 4.1.1 and 
Section 4.1.2 for the Main Study and Section 4.2.1 and Section 4.2.2 for the LTE) and in the 
lifestyle considerations (Section 4.4). Restrictions apply until study completion or 
discontinuation from randomized study treatment. 

Clinical Study Protocol 
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Olorinab in IBS-C and IBS-D 
Amendment 3.0 
Arena Pharmaceuticals, Inc. 
Confidential 
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Dosages for allowed background concomitant medications should be stable prior to screening 
and maintained constant during the study (ie, until study completion or discontinuation from 
randomized study treatment) unless otherwise specified in this protocol or instructed by the 
Investigator (who will contact the Medical Monitor for consultation prior to any such changes). 
The Medical Monitor must be informed in a timely manner if study site personnel are informed 
of any use of restricted medications or treatments which could affect safety of the subject or 
study endpoints during the study (until study completion or Early Termination). The Sponsor, in 
consultation with the Medical Monitor, will decide whether a subject with such medication 
changes will be allowed to continue randomized study treatment. 
Any medication or vaccine (including OTC or prescription medicines, vitamins, and/or herbal 
supplements) other than study treatment that the subject has received within the 3 months prior 
to Screening, is receiving at the time of Screening, or receives during the study must be recorded 
in the concomitant medication log along with: 
 Reason for use 
 Dates of administration including start and end dates 
 Dosage information including dose and frequency 
For Gap subjects who enroll in the LTE, any medication or vaccine (as described above) that the 
subject has received during the Gap period between Main Study Visit 9 (Week 14) and LTE 
Visit 1 must be recorded in the concomitant medication log. 
The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
5.7.1. 
Required Concomitant Therapy 
Not applicable 
5.7.2. 
Allowed Concomitant Therapy 
The following concomitant medications, sometimes used to treat IBS symptoms, are allowed 
throughout the course of this study provided that doses are unchanged for at least 90 days prior 
to screening and that the subject agrees to maintain the same dose of the medication throughout 
the study: 
 Tricyclic antidepressants, tetracyclic antidepressants, SSRIs, SNRIs, or 
anticonvulsants (eg, pregabalin or gabapentin) for conditions other than IBS pain 
 Benzodiazepines or non-benzodiazepine hypnotics, administered at bedtime for 
conditions other than IBS pain 
The following concomitant medications are allowed throughout the course of this study as long 
as doses are stable for at least 30 days prior to Visit 1 (Screening) of the Main Study or the LTE, 
as applicable, and the subject agrees to maintain stable doses (within ± 20% total daily dose), or 
approximate frequency of ‘as needed’ use of medication throughout study participation: 

Clinical Study Protocol 
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Amendment 3.0 
Arena Pharmaceuticals, Inc. 
Confidential 
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5.7.3. 
Rescue Medication for Constipation or Diarrhea Symptoms 
Rescue medications for constipation or diarrhea symptoms may not be taken for more than 
3 days within any 30-day period. Subjects who do not comply with requirements will be 
reassessed on a case-by-case basis for continuing study eligibility by the Investigator in 
consultation with the Sponsor. The following medications will be permitted as rescue medication 
for constipation or diarrhea symptoms after a minimum of 3 days of increased symptoms during 
the Main Study Treatment Period, Main Study Follow-Up Period, LTE Screening Period, LTE 
Treatment Period, or LTE Follow-Up Period: 
 Loperamide, for diarrhea, restricted to no more than 8 mg in a 24-hour period and no 
more than 14 mg in a 48-hour period 
 Bisacodyl, for constipation, restricted to no more than 15 mg administered orally or 
10 mg suppository in cases of severe constipation 
The study restrictions regarding the use of rescue medication will be explained to subjects during 
informed consent. Rescue medications for constipation and diarrhea symptoms are not permitted 
during the Screening or Run-in Periods. Subjects who require rescue medication for constipation 
and diarrhea symptoms during the Run-in Period will be considered Run-in failures and may be 
eligible for re-screening. 
All rescue medication will be documented in the concomitant medication log. 
5.7.4. 
Prohibited Concomitant Therapy 
Restricted or prohibited concomitant treatments are summarized below. Restrictions and 
prohibitions are effective from the time of informed consent through the final Follow-Up Visit 
(Main Study Visit 9 or LTE Visit 9) or Early Termination. 

Clinical Study Protocol 
APD371-202 
Olorinab in IBS-C and IBS-D 
Amendment 3.0 
Arena Pharmaceuticals, Inc. 
Confidential 
Page 46 of 93 
Table 1: 
Prohibited Concomitant Medications 
Interaction 
Drugs 
Moderate or strong 
CYP3A4 inducers and 
inhibitorsa 
https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-
interactions-table-substrates-inhibitors-and-inducers 
IBS medication 
Note: The medications list at the linked website is not exhaustive. The Medical Monitor may be consulted for questions related to 
restricted medication. 
5.8. 
Dosing in Excess of Instructed Daily Treatment 
Subjects will be instructed to contact the Investigator if they take more than 6 capsules or tablets 
of study treatment (> 2 times the recommended daily dose) within a 24-hour time period. Once 
notified, the Investigator should document the event in the subject’s source documents. The 
Sponsor does not recommend specific treatment for an overdose; there is no known antidote to 
the study treatment. In the absence of associated AEs as assessed per the clinical judgement of 
the Investigator, no further action is required. 
If a subject reports receiving > 2 times the recommended daily dose within a 24-hour period, and 
if symptoms are present, the Investigator or designee should: 
1. Contact the Medical Monitor immediately. 
2. Closely monitor the subject to assess for any AEs/SAEs and laboratory abnormalities. 
3. Obtain a plasma sample for PK analysis of the last dose of study treatment if requested by 
the Medical Monitor (determined on a case-by-case basis). 
4. Document the quantity of the excess dose as well as the duration of the excess dose in the 
eCRF. 
Subjects who do not comply with study treatment instructions will be counseled on correct 
dosing and administration of study treatment as soon as possible after a non-compliance with 
study treatment administration is identified. Decisions regarding dose interruptions, or 
withdrawal of the subject from the study will be made by the Investigator in consultation with 
the Medical Monitor based on the clinical evaluation of the subject. 

Clinical Study Protocol 
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Olorinab in IBS-C and IBS-D 
Amendment 3.0 
Arena Pharmaceuticals, Inc. 
Confidential 
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5.9. 
Dose Modification 
Dose modification is not permitted in this study. 
5.10. 
Treatment After the End of the Study 
Additional treatment will not be available after completion of the Main Study Treatment Period 
for subjects who participate only in the Main Study, or after the LTE Treatment Period for 
subjects who participate in the LTE. Investigators (or designees) will consult with subjects to 
determine appropriate care for their condition upon completion of the study. 

Clinical Study Protocol 
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Olorinab in IBS-C and IBS-D 
Amendment 3.0 
Arena Pharmaceuticals, Inc. 
Confidential 
Page 48 of 93 
6. 
DISCONTINUATION OF STUDY TREATMENT AND SUBJECT 
DISCONTINUATION/WITHDRAWAL 
6.1. 
Discontinuation of Study Treatment 
A subject’s study treatment may be discontinued early for any of the following reasons: 
 AE 
 Withdrawal by subject 
 Investigator decision 
 Study termination by Sponsor (the study may be terminated early if, in the opinion of 
the Sponsor, Medical Monitor, data safety monitoring board (DSMB), Investigator, or 
Institutional Review Board [IRB] an unacceptable risk to the safety and welfare of 
subjects is posed by the continuation of the study) 
 Death 
 Protocol deviation 
 Pregnancy (Section 7.9) 
 Other 
6.2. 
Safety Criteria for Stopping Study Treatment 
A subject’s study treatment may be interrupted or discontinued if any of the following conditions 
are met: 

Clinical Study Protocol 
APD371-202 
Olorinab in IBS-C and IBS-D 
Amendment 3.0 
Arena Pharmaceuticals, Inc. 
Confidential 
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If the study treatment is interrupted due to any of the criteria listed above, the subject may be 
evaluated as part of an unscheduled visit to assess their status. Additional subsequent visits may 
be scheduled as required to assess event outcomes. The Investigator, in consultation with the 
Medical Monitor, and Sponsor will determine the next course of action, which may include 
allowing the subject to resume treatment with the study treatment. 
Subjects that are discontinued from the study will be followed up by the Investigator until event 
resolution. 
6.3. 
Safety Criteria for Stopping the Study 
The recommended study stopping criteria are defined in a separate DSMB charter. 
6.4. 
Subject Discontinuation of Study 
Subjects will be free to withdraw from the study at any time should they wish to do so. Any 
subject may be discontinued early from the study for any of the following reasons: 
 AE 
 Withdrawal by subject 
 Investigator decision 
 Lost to follow-up (Section 6.5) 
 Study termination by Sponsor 
 Death 
 Protocol deviation 
 Pregnancy 
 Other 
Subjects who withdraw from the study will be encouraged to return to the site to complete an 
Early Termination visit 
 Subjects who withdraw from the study will not be 
replaced by additional subjects. 
6.5. 
Lost to Follow-Up 
A subject will be considered lost to follow-up if he/she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site. 
The following actions must be taken if a subject fails to return to the clinic for a required study 
visit: 
 The site must attempt to contact the subject and reschedule the missed visit as soon as 
possible, counsel the subject on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the subject wishes to and/or should continue in 
the study. 

Clinical Study Protocol 
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Olorinab in IBS-C and IBS-D 
Amendment 3.0 
Arena Pharmaceuticals, Inc. 
Confidential 
Page 50 of 93 
 Before a subject is deemed lost to follow-up, the Investigator or designee must make 
every effort to regain contact with the subject (where possible, 3 telephone calls and, 
if necessary, a certified letter to the subject’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the subject’s 
source document. 
 Should the subject continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 
Closure of specific sites or termination of the study as a whole will be addressed as described in 
Section 9.7. 

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Clinical Study Protocol 
APD371-202 
Olorinab in IBS-C and IBS-D 
Amendment 3.0 
Arena Pharmaceuticals, Inc. 
Confidential 
Page 52 of 93 
 Migraine 
 Fibromyalgia 
 Other chronic pain (to be specified) 
 Endometriosis 
 Interstitial cystitis/ bladder pain syndrome 
 Chronic pelvic pain 
7.5. 
Efficacy Assessments 
All patient-reported efficacy data, including daily eDiary data will be captured electronically 
using hand-held devices. Daily eDiary entry will include: APS, 
 
 
and treatment administration. Subjects will be instructed to complete daily eDiary entries in the 
evening, generally at the same time each day. eDiary entries will be completed at the times 
shown in the 
 
7.5.1. 
Abdominal Pain Score 
The APS is a single-question, 11-point numeric rating scale in which 0 represents no abdominal 
pain and 10 represents the worst possible abdominal pain. Once per day, subjects will use the 
APS to report their worst abdominal pain over the previous 24 hours. AAPS values collected 
during the Run-in Period will be used to determine subject eligibility for randomization. Daily 
APS will be collected throughout the study at the times shown in the 
 
. 

Clinical Study Protocol 
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Olorinab in IBS-C and IBS-D 
Amendment 3.0 
Arena Pharmaceuticals, Inc. 
Confidential 
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Clinical Study Protocol 
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Olorinab in IBS-C and IBS-D 
Amendment 3.0 
Arena Pharmaceuticals, Inc. 
Confidential 
Page 54 of 93 
7.6. 
Order of Events and Priority for Timed Assessments 
Every effort should be made to perform procedures as closely as possible to the scheduled times 
indicated in the 
. In chronological order, the order for 
completing visit procedures is pre-dose assessments (orthostatic vital signs or supine vital signs 
[as applicable] followed by body temperature and respiratory rate, physical examination, blood 
draw for trough PK and clinical laboratory assessments, and urine sample; ECG may be 
collected during the resting period prior to orthostatic vital signs or after the collection of 
respiratory rate), subject questionnaires, drug accountability and dispensing, study treatment 
administration, and all other assessments. For timed post-dose procedures scheduled at the same 
nominal timepoint, ECG may be collected during the resting period prior to orthostatic vital 
signs or after the collection of respiratory rate; blood draws should be collected after the 
completion of vital signs and ECG. 
7.7. 
Safety Assessments 
 
 
7.7.1. 
Physical Examinations 
A full physical examination (including examination of general appearance, skin/dermatologic, 
lymph nodes, head, eyes, ears, nose and throat, neck, chest, thorax/lungs, and the following 
systems: cardiovascular, GI, neurologic, hematologic, and musculoskeletal) will be performed by 
medically qualified personnel at the timepoints specified in the 
 
. 
An abbreviated physical examination (including examination of general appearance, 
thorax/lungs, cardiovascular system, and abdomen as well as assessments of any changes in the 
subject’s health since the last visit) will per performed at the timepoints specified in the 
 All findings will be documented in subject source 
documents. 

Clinical Study Protocol 
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Olorinab in IBS-C and IBS-D 
Amendment 3.0 
Arena Pharmaceuticals, Inc. 
Confidential 
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A symptom-driven physical examination will be performed at the timepoints specified in the 
 and at unscheduled timepoints if deemed necessary by 
the Investigator. Any new abnormalities or worsening may be recorded as AEs at the 
Investigator’s discretion. 
7.7.2. 
Vital Signs 
Vital signs measurements will include blood pressure, HR, body temperature, and respiratory 
rate. Vital signs measures will be collected as defined in the 
 
 
Vital signs will be measured prior to any blood draw that occurs at the same timepoint. 
Blood pressure and HR should be measured by an automated device. Proper technique should be 
utilized during the measurement of blood pressure and HR to include the following: 
 Subjects should be allowed a 5-minute rest period before each assessment 
 Readings should be taken on the subject’s non-dominant arm consistently throughout 
the study 
 The subject’s arm should be bare and supported at heart level 
 An appropriately sized cuff (cuff bladder encircling at least 80% of the arm) should 
be utilized. Subject’s legs should not be crossed during the evaluation 
Supine HR and blood pressure are measured after the subject has been resting in the supine 
position for at least 5 minutes. Orthostatic HR and blood pressure are measured after the subject 
has been resting in the supine position for at least 5 minutes and then after 1 and 3 minutes of 
standing. Supine vital signs and orthostatic measures will be collected at the timepoints indicated 
in the 
 
The Investigator or designee will be responsible for interpretation of vital signs at the time of the 
subject’s visit. Clinically significant abnormalities will be documented in the eCRF and may be 
reported as AEs at the Investigator’s discretion. Occurrence of orthostatic hypotension (defined 
as a decrease in SBP of 20 mm Hg relative to supine or a decrease in DBP of 10 mm Hg relative 
to supine) or postural tachycardia (defined as an increase of 30 bpm relative to supine or a 
maximum of 120 bpm) that occur at 1 or 3 minutes of standing will be documented on the eCRF. 
If orthostatic hypotension or postural tachycardia events are associated with symptoms they may 
also be documented as AEs at the discretion of the Investigator. 
7.7.3. 
Electrocardiography 
All ECGs will be recorded from a 12-lead ECG machine. Every attempt should be made to 
ensure the subject ECG readings are obtained using the same machine throughout the study at 
timepoints indicated in the 
 
It is recommended to collect ECGs at least 30 minutes after the end of the subject’s most recent 
meal. All ECGs will be recorded with subjects in supine position. Supine rest time prior to ECGs 
should be at least 5 minutes. 
Parameters to be provided on the confirmed read for each safety ECG are HR, and the following 
intervals: RR, PR, QRS, QT, QTc (QTcF required, QTcB optional). The ECGs will be read and 

Clinical Study Protocol 
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Amendment 3.0 
Arena Pharmaceuticals, Inc. 
Confidential 
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interpreted by the central ECG laboratory and the Investigator (or qualified designee) will be 
responsible for assessment of the clinical significance of ECGs. Clinically significant 
abnormalities will be documented in the eCRF and may be reported as AEs at the Investigator’s 
discretion. 
7.7.4. 
Clinical Laboratory Assessments 
All laboratory assessments required by the protocol will be performed by a central laboratory 
unless otherwise stated. The maximum amount of blood collected from each subject at a single 
visit will not exceed 85 mL. The maximum amount of blood collected from each subject over the 
duration of the Main Study, including any extra assessments that may be required will not exceed 
350 mL. The maximum amount of blood collected from each subject over the duration of the 
LTE will not exceed 135 mL. Repeat or unscheduled samples may be taken for safety reasons or 
for technical issues with samples. Additional details regarding clinical laboratory sample 
collection, preparation, and shipment are provided in the Laboratory Manual. 
Clinical safety laboratory tests should be completed pre-dose after the subject has fasted 
overnight (at least 8 hours). Clinical laboratory tests, including basic metabolic panel, and 
screening for drugs of abuse will be conducted at timepoints specified in the 
 
 
The Investigator must review the laboratory report and document their review. Clinically 
significant worsening from baseline occurring during the study may be recorded as AEs at the 
Investigator’s discretion. The laboratory reports must be filed with the source documents. 
Clinically significant abnormal laboratory findings are those that are not associated with the 
underlying disease, unless judged by the Investigator to be more severe than expected for the 
subject’s condition. 
All laboratory tests with values considered clinically significantly abnormal during participation 
in the study should be repeated until the values return to normal or baseline (Main Study Visit 3 
or LTE Visit 2, as applicable) or are no longer considered clinically significant by the 
Investigator or Medical Monitor. 
 If such values do not return to normal/baseline within a period of time judged 
reasonable by the Investigator, the etiology should be identified, and the Sponsor 
should be notified. 
 All protocol-required laboratory assessments, as defined in the 
 
 must be conducted in accordance with the Laboratory 
Manual. 
 If laboratory values from non-protocol-specified laboratory assessments performed at 
the institution’s local laboratory require a change in subject management or are 
considered clinically significant by the Investigator (eg, AE), then the results must be 
recorded in the eCRF. 
7.7.4.1. 
Clinical Chemistry, Hematology, and Coagulation 
Clinical chemistry, hematology, and coagulation parameters that will be assessed during the 
study are identified in Table 3. 

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Subjects will be in a seated or supine position during blood collection. 
7.7.4.2. 
Urinalysis 
Urinalysis parameters that will be assessed during the study are identified in Table 3. 
Table 3: 
Clinical Laboratory Tests 
Virology 
HIV, HBsAg, and HCV 
Pregnancy Testing 
Serum or urine pregnancy test 
human chorionic gonadotropin 
(hCG) 
Drugs of Abuse 
Amphetamine, barbiturates, benzodiazepines, cocaine, marijuana, 
methadone, methamphetamine, methylenedioxymethamphetamine, opioid, 
oxycodone, phencyclidine, THC, and THC derivatives 
Hematology 
Serum Chemistry 
Urinalysis 
Hematocrit 
Hemoglobin 
MCH 
MCHC 
MCV 
Platelet count 
RBC count 
WBC count with differential 
 
Albumin 
ALP 
ALT 
AST 
Bicarbonatea 
BUNa 
Calciuma 
Chloridea 
Creatininea 
Creatine kinase 
Glucosea 
LDH 
Phosphorus 
Potassiuma 
Sodiuma 
Total bilirubin 
Direct bilirubin 
Total cholesterol 
Total protein 
Triglycerides 
Uric acid 
Appearance 
Bilirubin 
Color 
Glucose 
Ketones 
Microscopic examination of 
sediment  
Nitrite 
Occult blood 
pH 
Protein 
Specific gravity 
Urine drug screen 
Urobilinogen 
Coagulation 
PT 
PTT 
INR 
Additional Thyroid Chemistry 
TSH 
T4 free 
T3 free 
Thyroid binding protein 
a Assessments included in the basic metabolic panel. 
ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BUN, blood urea nitrogen; hCG, 
human chorionic gonadotropin; HIV, human immunodeficiency virus; INR, international normalized ratio; HBsAg, hepatitis B 
surface antigen; HCV, hepatitis C virus; LDH, lactate dehydrogenase; MCH, mean corpuscular hemoglobin; MCHC, mean 
corpuscular hemoglobin concentration; MCV, mean corpuscular volume; PT, prothrombin time; PTT, activated partial 
thromboplastin time; RBC, red blood cell; T3, triiodothyronine; T4, thyroxine; TSH, thyroid-stimulating hormone; THC, 
tetrahydrocannabinol; WBC, white blood cell 
7.7.5. 
Screening/Ongoing Study Eligibility 
Laboratory tests conducted at Main Study and LTE Screening are detailed in Table 3. Some 
assessments may be repeated at specified visits in the 
 to 
confirm continuing eligibility. 
7.7.5.1. 
Drugs of Abuse 
A standard urine drug screen will be performed to determine subject eligibility. Subjects who test 
positive for amphetamine, barbiturates, cocaine, marijuana, methadone, methamphetamine, 

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methylenedioxymethamphetamine, opioid, oxycodone, phencyclidine, THC, and THC 
derivatives will not be eligible for study participation (ie, considered Screen Failures 
[Section 4.5]). If a subject has a positive result on a urine drug screen as a result of a prescribed 
medication that treats a concomitant illness that is not excluded or restricted per the protocol 
(Section 5.7.4), it is not required to exclude the subject from the study. Additional urine drug 
screening will be performed at every scheduled visit throughout the study. Positive urine drug 
screening results during the Treatment Period will be assessed on a case by case basis. 
7.7.5.2. 
Pregnancy Testing 
A serum human chorionic gonadotropin (hCG) pregnancy test will be performed on female 
subjects of childbearing potential to determine eligibility. Additional urine pregnancy tests 
(hCG) will be conducted at visits as specified in the 
 
Any subject with a positive pregnancy test at any time during the study must stop taking study 
treatment immediately. Refer to Section 7.9 for additional information on pregnancy events. 
Negative pregnancy test results must be documented for all female subjects of childbearing 
potential prior to dosing at applicable study visits. Women who are surgically sterile or those 
who are postmenopausal are not considered to be of childbearing potential; otherwise women are 
considered to be of childbearing potential. 
7.7.5.4. 
Clinical Chemistry, Hematology, and Coagulation 
Clinical chemistry, hematology, coagulation parameters, and basic metabolic panel that will be 
assessed during the study are identified in Table 3. 
Subjects will be in a seated or supine position during blood collection. All laboratory samples 
other than post-dose lab collections specified in the Schedule of Assessments should be collected 
prior to the administration of study treatment at applicable visits (
 
). 
7.7.5.5. 
Urinalysis 
Urinalysis parameters that will be assessed during the study are identified in Table 3. 
7.8. 
Adverse Events 
7.8.1. 
Definitions 
7.8.1.1. 
Adverse Event 
An AE is any untoward medical occurrence in a subject or clinical investigational subject 
administered a medicinal product and which does not necessarily have a causal relationship with 
this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or 
disease temporally associated with the use of a medicinal product, whether or not considered 
related to the medicinal product. 

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AEs can include, but are not limited to, any of the following: 
 Unfavorable changes in general condition 
 Subjective or objective signs/symptoms 
 Concomitant disease or accidents 
 Clinically relevant adverse changes in laboratory parameters over the course of the 
study 
 Pre-existing conditions that worsen in severity or frequency or that have new 
signs/symptoms associated with them 
Planned elective procedures or planned procedures not resulting from any worsening from a 
baseline condition are not considered AEs; however, any associated concomitant medications, 
contrast dyes, blood loss or blood transfusions must be reported in the clinical database as 
described in Section 7.8.2.2. 
7.8.1.2. 
Serious Adverse Event 
An AE should be classified as an SAE if it meets one of the following criteria: 
7.8.1.3. 
Adverse Drug Reaction 
An adverse drug reaction (ADR) in the pre-approval clinical experience with a new medicinal 
product or its new usages, particularly as the therapeutic dose(s) may not be established, is any 
Fatal: 
AE resulted in death. 
Life-threatening: 
The AE placed the subject at immediate risk of death. This 
classification does not apply to an AE that hypothetically might cause 
death if it were more severe. 
Hospitalization: 
The AE required or prolonged an existing inpatient hospitalization. 
Hospitalizations for elective medical or surgical procedures or 
treatments planned before the signing of informed consent in the study 
or routine check-ups are not SAEs by this criterion. Admission to a 
palliative unit or hospice care facility is not considered to be a 
hospitalization. Hospitalizations or prolonged hospitalizations for 
scheduled therapy of the underlying cancer or study target disease 
need not be captured as SAEs. 
Disabling/ 
incapacitating: 
Resulted in a persistent or significant incapacity or substantial 
disruption of the subject’s ability to conduct normal life functions. 
Congenital anomaly 
or birth defect: 
An adverse outcome in a child or fetus of a subject exposed to the 
molecule or study treatment regimen before conception or during 
pregnancy. 
Medically significant: The AE did not meet any of the above criteria but could have 
jeopardized the subject and might have required medical or surgical 
intervention to prevent one of the outcomes listed above or involves 
suspected transmission via a medicinal product of an infectious agent. 

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noxious and unintended response to a medicinal product related to any dose. The phrase 
“responses to a medicinal product” means that a causal relationship between a medicinal product 
and an AE is at least a reasonable possibility (ie, the relationship cannot be ruled out). 
7.8.1.4. 
Adverse Events of Special Interest 
Based on the mechanism of action of olorinab and prior experience with other agents acting via a 
similar mechanism, potential AEs of special interest may be identified. In addition to appropriate 
reporting of these events as an AE or SAE, supplementary detailed information may be collected. 
7.8.1.5. 
Severity 
The severity of each AE will be assessed at the onset by a nurse/or physician. When recording 
the outcome of the AE the maximum severity of the AE experienced will also be recorded. The 
severity of each AE will be graded according to CTCAE, version 5.0: 
Grade 1: 
Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated 
Grade 2: 
Moderate; minimal, local or noninvasive intervention indicated; 
limiting age-appropriate instrumental activities of daily living 
Grade 3: 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling, 
limiting self-care activities of daily living (eg, preparing meals, 
shopping for groceries or clothes, using the telephone, managing 
money) 
Grade 4: 
Life-threatening consequences, urgent intervention indicated 
Grade 5: 
Death related to AE 
7.8.1.6. 
Relationship 
The Investigator is obligated to assess the relationship (causal relationship) between the study 
treatment and each occurrence of each AE/SAE. The AE relationship (causal relationship) to 
study treatment must be characterized as one of the following categories: 
Not Related: 
The AE does not follow a reasonable temporal sequence from 
administration of the study treatment, does not abate upon 
discontinuation of the study treatment, does not follow a known or 
hypothesized cause-effect relationship, and (if applicable) does not 
reappear when the study treatment is reintroduced, furthermore, there 
may exist a clear alternative medical explanation (eg, underlying 
disease state) or association with study procedure or study conduct. 
Unlikely Related: 
The temporal association between the AE and the study treatment is 
such that the study treatment is not likely to have any reasonable 
association with the AE. 

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Probably Related: 
The AE follows a reasonable temporal sequence from administration of 
the study treatment and cannot be reasonably explained by the known 
characteristics of the subject’s clinical state, environmental, or toxic 
factors, or other modes of therapy administered to the subject. 
Related: 
The AE follows a reasonable temporal sequence from administration of 
the study treatment, abates upon discontinuation of the study treatment, 
follows a known or hypothesized cause-effect relationship, and (if 
appropriate) reappears when the study treatment is reintroduced. 
The Investigator will use clinical judgment to determine the relationship (causal relationship). 
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk factors, as 
well as the temporal relationship of the event to the study treatment administration should be 
considered and investigated. The Investigator should consult the Investigator’s Brochure and the 
Product Information of marketed products within the drug class, when applicable. For each 
AE/SAE, the Investigator must document in the source documents that he/she has reviewed the 
AE/SAE and has provided an assessment of causality. There may be situations in which an SAE 
has occurred and the Investigator has minimal information to include in the initial report to the 
Sponsor; however, it is very important that the Investigator always makes an initial assessment 
of causality for every event before the initial transmission of the SAE to the Sponsor. The 
Investigator may change his/her opinion of causality based on subsequent receipt of information 
and send an SAE follow-up report with the updated causality assessment. The causality 
assessment is one of the criteria used when determining regulatory reporting requirements. 
7.8.2. 
Eliciting and Recording Adverse Events 
7.8.2.1. 
Eliciting Adverse Events 
Subjects will be instructed that they may report AEs at any time. An open-ended or nondirected 
method of questioning should be used at each study visit to elicit the reporting of AEs. 
7.8.2.2. 
Recording Adverse Events 
The AE reporting period for safety surveillance begins when the subject is initially included in 
the study (date of first signature of informed consent) and continues up to 30 days after the last 
study treatment administration. If an AE is not resolved or stabilized by this time, the Sponsor in 
consultation with the Investigator will decide whether to continue to monitor the AE or closeout 
the event in the database if no further follow-up is necessary. 
Any SAE suspected to be related to the study treatment must be reported whenever it occurs, 
irrespective of the time elapsed since the last administration. 
Investigator and study personnel will record all AEs and SAEs whether received through an 
unsolicited report by a subject, elicited during subject questioning, discovered during physical 
examination, laboratory testing, and/or other means by recording them on the eCRF as 
appropriate. To avoid vague, ambiguous, or colloquial expressions, the AE should be recorded 
on the source documents and/or eCRFs using standard medical terminology that is as specific as 
possible, rather than the subject’s own words. Whenever the Investigator is confident in making 

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a unifying diagnosis, all related signs, symptoms, and abnormal test results should be grouped 
together as a single AE in the source document and/or eCRF (eg, cough and rhinitis should be 
reported as an “upper respiratory tract infection”). 
The Investigator should assess when it may be appropriate for intermittent events of the same 
type to be grouped together as a single AE in the source document and/or eCRF (eg, 
“intermittent headache”). 
The following information should be recorded on the AE eCRF: 
 Description including onset and resolution dates 
 Whether it met SAE criteria 
 Severity 
 Relationship to study treatment or other causality 
 Outcome 
For SAEs, events occurring secondary to the primary event should be described on the eCRF in 
the narrative description field. 
The following should be considered when recording SAEs: 
 Death is an outcome of an event. The event that resulted in the death should be 
recorded and reported on the eCRF 
 For hospitalizations, surgical, or diagnostic procedures, the illness leading to the 
surgical or diagnostic procedure should be recorded as the SAE, not the procedure 
itself. The procedure should be captured in the narrative as part of the action taken in 
response to the illness. 
7.8.2.3. 
Diagnosis Versus Signs or Symptoms 
In general, the use of a unifying diagnosis is preferred to the listing out of individual symptoms. 
Grouping of symptoms into a diagnosis should generally be limited to occasions when each 
component sign and/or symptom is a medically confirmed component of a diagnosis as 
evidenced by standard medical textbooks. If an aspect of a sign or symptom does not fit into a 
classic pattern of the diagnosis in the clinical judgement of the investigator, the individual 
symptom should generally be reported as a separate AE. 
7.8.2.4. 
Reporting Serious Adverse Events 
All SAEs are subject to reporting requirements. 
7.8.2.5. 
Serious Adverse Events 
All SAEs, whether or not considered related to study treatment, must be reported to the 
designated Sponsor Contact within 24 hours of becoming aware of the event. Enter the SAE 
information into the electronic data capture (EDC) system, and send other available pertinent 
information (eg, hospital records, laboratory results) to the designated Sponsor Contact:  

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IQVIA Pharmacovigilance 
Phone: 
 
Fax: 
 
Email: 
 
If additional follow-up information is required or becomes available for a previously reported 
SAE, entry of the new information into EDC should be completed within 24 hours of 
awareness. 
Elective hospitalization and/or surgery for clearly preexisting conditions (eg, a surgery that has 
been scheduled prior to the subject’s entry into the study) will not be reported as an SAE. All 
other hospitalizations, including elective hospitalizations for any condition that was not 
preexisting, will be reported as an SAE. 
Any SAE that is ongoing when the subject completes the study or discontinues the study will be 
followed by the Investigator until the event resolved, stabilized or returned to baseline (Main 
Study Visit 3 or LTE Visit 2, as applicable) status. 
7.8.2.6. 
Serious, Unexpected Adverse Drug Reactions 
All ADRs that are both serious and unexpected are subject to expedited reporting to regulatory 
agencies. An unexpected ADR is one for which the nature or severity is not consistent with 
information in the relevant source documents. 
The following documents or circumstances will be used to determine whether an AE/ADR is 
expected: 
1. For a medicinal product not yet approved for marketing in a country, the reference safety 
information section of a company’s Investigator’s Brochure will serve as the source 
document in that country 
2. Reports that add significant information on specificity or severity of a known, already 
documented serious ADR constitute unexpected events. For example, an event more 
specific or more severe than described in the Investigator’s Brochure would be 
considered “unexpected” 
7.9. 
Pregnancy 
If at any point a urine or serum hCG pregnancy test is positive, the subject will be withdrawn 
from the study treatment. 
Details of all pregnancies that occur in female subjects and female partners of male subjects after 
the start of study treatment and until 30 days after the last dose will be collected. 
Pregnancy (during maternal or paternal exposure to study treatment) does not meet the definition 
of an AE; however, to fulfill regulatory requirements, any pregnancy should be reported via the 
Pregnancy Report Form to the designated Sponsor Contact within 24 hours of awareness to 
collect data on the outcome of the birth for both the mother and the fetus. 
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs and should be reported as such even if 
outside the SAE reporting period. 

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7.10. 
Pharmacokinetics 
Blood samples of approximately 4 mL will be collected for measurement of plasma 
concentrations of olorinab and its metabolites as specified in the 
 
. Fasting requirements and other restrictions for blood sampling are described in 
Section 4.4. Additional samples may be collected at additional timepoints or sampling days 
during the study if warranted and agreed upon between the Investigator and the Sponsor. A 
Laboratory Manual will be provided to instruct on material supplies, and sample collection, 
processing, storage, and shipping procedures. The actual date and time (24-hour clock time) of 
each sample will be recorded. 
Samples will be used to evaluate the PK of olorinab and its predominant metabolites 
 
. Samples collected for analyses of these olorinab 
plasma concentrations may also be used for profiling of drug binding proteins, bioanalytical 
method validation, stability assessments, metabolite assessments, to assess other actions of 
olorinab (and/or its metabolites) with plasma constituents, or for context pertaining to safety 
events arising during or after the study. 
During the Main Study, calculated plasma PK parameters of olorinab and its metabolites will 
include but not necessarily be limited to the following: 
 Cmax – observed maximum concentration 
 tmax – time of observed maximum (peak) concentration after drug administration 
 Ctrough – observed trough (pre-dose) concentration  
During the LTE, only Ctrough will be calculated. 
Subject confidentiality will be maintained. 
Drug concentration information that would unblind the study will not be reported to investigative 
sites or blinded personnel until the study has been unblinded. Detailed instructions regarding 
sample collection, processing, and shipping will be provided in a separate Laboratory Manual. 
7.11. 
Pharmacodynamics 
Pharmacodynamic parameters are not evaluated in this study. 
7.12. 
Genetics 
A blood sample for deoxyribonucleic acid (DNA) isolation will be collected from subjects who 
have consented to participate in the genetic analysis component of the study. Participation is 
optional. Subjects who do not wish to participate in the genetic research may still participate in 
the study. 
In the event of DNA extraction failure, a replacement genetic blood sample may be requested 
from the subject. Signed informed consent will be required to obtain a replacement sample 
unless it was included in the original consent. 
Details on processes for collection and shipment and destruction of these samples can be found 
in the Laboratory Manual. 

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Samples may be stored for a maximum of 20 years (or according to local regulations) following 
the last subject’s last visit for the study at a facility selected by the Sponsor to enable further 
analysis of genetic samples. 
7.13. 
Biomarkers 
Colonic biopsy and blood biomarker samples will be collected from subjects who have 
consented to participate in the colonic biopsy and blood biomarker component of the study. 
Collection of blood samples for exploratory biomarker assessments will be collected at all sites. 
Blood samples may be tested for cytokines and chemokines. Collection of colonic biopsy 
samples for exploratory biomarker assessments will be collected at select sites only. Colonic 
biopsy tissue may be tested for components of the endocannabinoid system. Additional 
biomarkers in blood or colonic biopsies as deemed relevant to assess efficacy and mechanism of 
action of olorinab may be evaluated. Collection of colonic biopsy and biomarker samples will be 
conducted 
 
Details for collection, processing, and storage will be provided in the Laboratory Manual. 
Residual samples will be stored and may be used for additional analyses to further explore 
efficacy and mechanism of action of olorinab if the subject has granted optional consent for such 
testing. These additional analyses will only be conducted where allowed by the regulatory 
authorities and local ethics committees. 
Samples may be stored for a maximum of 20 years (or according to local regulations) following 
the last subject’s last visit for the study at a facility selected by the Sponsor to enable further 
analysis of biomarker responses to olorinab. 
7.13.1. 
RNA Transcriptome Research 
Transcriptome studies of blood samples and colonic biopsies will be conducted using ribonucleic 
acid (RNA)-Seq, and/or alternative equivalent technologies. This will enable the evaluation of 
changes in transcriptome profiles that may correlate with biological response relating to IBS and 
pain or the action of olorinab. 
The same samples may also be used to confirm findings by application of alternative 
technologies. 
7.13.2. 
Proteome Research 
The biomarker blood sample and colonic biopsy samples will be collected to enable proteome 
studies performed by enzyme-linked immunosorbent assay (ELISA), mass spectrometry, or an 
alternative equivalent procedure. This will enable the evaluation of changes in proteome profiles 
that may correlate with biological response related to IBS and the mechanism of action of 
olorinab. 
The samples may also be used to confirm findings by application of alternative technologies. 
7.13.3. 
Metabolomic Research 
Blood and colonic biopsy metabolome studies will be performed by mass spectrometry, liquid 
chromatography-mass spectrometry, gas chromatography-mass spectrometry, and/or 
Fourier-transform mass spectrometry, and equivalent methods. This may include analysis of 

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identified or uncharacterized metabolites and lipids that are known to be or emerge in the future 
as important in the pathogenesis of IBS and may be impacted by treatment with olorinab. 
7.14. 
Medical Resource Utilization and Health Economics 
Health Economics/Medical Resource Utilization and Health Economics parameters are not 
evaluated in this study. 

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8. 
STATISTICAL CONSIDERATIONS 
8.1. 
Sample Size Determination 
It is assumed that change in AAPS from Main Study Baseline to Week 12 will be normally 
distributed with a standard deviation (SD) of 1.9. Assuming a 1:1:1:1 randomization, 
240 subjects (60 per treatment group) is sufficient to achieve at least 80% power to detect a 
treatment effect of 1.0 between each of the olorinab treatment groups and placebo by a 2-sample 
t-test using a 2-sided significance level of 0.05. 
Note, under the same assumptions, there is at least 95% power to detect a treatment effect of 1.0 
between the pooled olorinab treatment group (180 subjects) and placebo (60 subjects). 
A blinded review of the data to evaluate the assumption regarding the SD of the change in AAPS 
from Baseline at Week 12 may be conducted. The planned sample size will not be reduced as a 
result of the sample size re-estimation. Details will be specified in the Statistical Analysis Plan 
(SAP) for the Main Study. 
8.2. 
Analysis Sets 
For purposes of analysis, the following analysis sets are defined for the Main Study (Table 4). 
Table 4: 
Analysis Sets for Main Study 
Analysis Set 
Definition 
Screened 
The Screened Set will include all subjects who sign the ICF. 
Enrolled 
The Enrolled Set will include all subjects who are enrolled in the Run-in Period. 
Full Analysis 
The Full Analysis Set (FAS) will include all randomized subjects, irrespective of whether 
they received study treatment. 
Per Protocol 
The Per Protocol Set will include all subjects in the FAS without major protocol violations 
that might affect the evaluation of the effect of the study treatment on the primary 
endpoint. These violations will be pre-defined in the SAP and the Per Protocol Set will be 
specified prior to unblinding. 
Pharmacokinetic 
The Pharmacokinetic Set will include all subjects in the FAS with at least 1 post-dose PK 
measurement. 
Safety 
The Safety Set will include subjects randomly assigned to study treatment and who take at 
least one dose of study treatment. 
 

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For purposes of analysis, the following analysis sets are defined for the LTE (Table 5). 
Table 5: 
Analysis Sets for Long-Term Extension 
Analysis Set 
Definition 
Screened 
The Screened Set will include all Gap subjects who signed the ICF for LTE. 
Full Analysis 
The Full Analysis Set (FAS) will include all randomized subjects in LTE, irrespective of 
whether they received study treatment. 
Pharmacokinetic 
The Pharmacokinetic Set will include all subjects in the FAS with at least 1 post-dose 
PK measurement in LTE. 
Safety 
The Safety Set will include subjects randomly assigned to study treatment and who take 
at least one dose of study treatment in LTE. 
8.3. 
Statistical Analyses 
Details regarding the statistical analyses will be provided in the SAPs. The SAP for the Main 
Study will be finalized prior to database lock (unblinding) of the Main Study and the SAP for the 
LTE will be finalized prior to database lock for the LTE. Results of the Main Study and the LTE 
may be reported in 2 separate clinical study reports. 
Continuous variables will be summarized using the number of observations, mean, SD, median, 
minimum, and maximum. Categorical variables will be summarized using frequency counts and 
percentages. For time-to-event variables, the number of subjects at risk over time, as well as the 
cumulative percentage of subjects experiencing the event of interest will be presented, based on 
Kaplan-Meier methodology. 
Unless otherwise specified, continuous endpoints will be analyzed using a mixed-effects model 
repeated measures (MMRM) analysis with treatment, the stratification factors, visit, and 
treatment-by-visit interaction as factors and Baseline AAPS and Baseline value (if applicable) as 
covariates. Visit will include all scheduled visits except Visit 9 (Week 14). Least squares means, 
standard errors (SEs), and 95% confidence intervals (CIs) for the treatments and their difference 
will be presented together with the p-values. 
Continuous endpoints derived from the eDiary (eg, score in abdominal pain, bloating, 
discomfort, number of bowel movements), will be analyzed using the MMRM above that 
includes scheduled visit, as well as a second MMRM model that includes treatment, the 
stratification factors, week, and treatment-by-week interaction as factors and Baseline AAPS and 
Baseline value (if applicable) as covariates. Week will include each week from Week 1 to 
Week 12. Least squares means, standard errors (SEs), and 95% confidence intervals (CIs) for the 
treatments and their difference will be presented together with the p-values. 
Categorical endpoints will be analyzed by either the Cochran-Mantel-Haenszel (CMH) method, 
Fisher’s exact test, or by logistic regression with a model that includes treatment and 
stratification factors as factors and Baseline AAPS and Baseline value (if applicable) as 
covariates. The odds ratio relative to placebo and percentage of difference from placebo will be 
presented together with corresponding 95% CIs and the p-values. 
Time-to-event endpoints will be displayed using Kaplan-Meier plots and analyzed with Cox 
regression with a model that includes treatment and the stratification factors as factors and 

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Baseline AAPS and Baseline value (if applicable) as covariates. The hazard ratio will be 
presented together with 95% CIs and the p-values. 
Where statistical assumptions (eg, proportional hazards, normality, proportional odds) are not 
met, alternative approaches will be evaluated (eg, non-parametric analysis, log transformation). 
Pairwise comparisons of each olorinab treatment group compared to placebo will be conducted. 
In addition, analyses of the pooled olorinab treatment groups compared placebo will be 
conducted. 
Efficacy data will be analyzed by randomized treatment, while safety data will be analyzed by 
actual treatment. 
8.3.1. 
Endpoints 
8.3.1.1. 
Main Study Endpoints 
Primary 
 Change in average abdominal pain score (AAPS) from Baseline to Week 12 
 Adverse events and clinically relevant changes in vital signs and clinical laboratory 
results 
Secondary 
 The proportion of subjects achieving a ≥ 30% improvement in AAPS from Baseline to 
Week 12 
 The proportion of subjects achieving a ≥ 30% improvement in AAPS from Baseline for at 
least 6 of the 12 weeks during the Main Study Treatment Period 
 Percent change in AAPS from Baseline to Week 12 
 Change in number of pain free days per week from Baseline to Week 12 
 PK parameters including, but not limited to, Cmax, tmax, and Ctrough 
Exploratory 

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8.3.1.2. 
Long-Term Extension Endpoints 
Primary 
 AEs, clinically relevant changes in vital signs, and clinical laboratory results 
 
8.3.2. 
Main Study Efficacy Analyses 
Statistical analysis methods for efficacy analyses in the Main Study are listed in Table 6. 

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Table 6: 
Statistical Analysis Methods for Efficacy Analyses 
Endpoint 
Statistical Analysis Methods 
Primary 
The primary endpoint, change in AAPS from Baseline to Week 12, will be analyzed using a 
MMRM analysis with treatment, stratification factors, visit, and treatment-by-visit interaction as 
factors and Baseline AAPS as a covariate. An unstructured variance-covariance matrix will be 
used for the MMRM analysis. Least squares means, SEs, and 95% CIs for the treatments and 
their difference will be presented together with the p-values. 
The primary analysis will be conducted in the FAS. Sensitivity analyses will be detailed in the 
SAP. 
Secondary 
The proportion of subjects achieving a ≥ 30% improvement in AAPS from Baseline to Week 12 
will be analyzed using the CMH test stratified by the stratification factors. The odds ratio relative 
to placebo and percentage of difference from placebo will be presented together with 
corresponding 95% CIs and the p-values. 
The proportion of subjects achieving a ≥ 30% improvement in AAPS for at least 6 of the 
12 weeks during the Treatment Period will be analyzed using the CMH test stratified by the 
stratification factors. The odds ratio relative to placebo and percentage of difference from 
placebo will be presented together with corresponding 95% CIs and the p-values. 
The percent change in AAPS from Baseline to Week 12 and Change from Baseline to Week 12 
in number of pain free days will be analyzed using the same MMRM analysis as specified for the 
primary endpoint above. 
The change and percent change in AAPS from Baseline to Week 12 and change from Baseline to 
Week 12 in number of pain-free days per week will be analyzed using another MMRM model 
with treatment, stratification factors, week, and treatment-by-week interaction as factors and 
Baseline AAPS as a covariate. An unstructured variance-covariance matrix will be used for the 
MMRM analysis. Least squares means, SEs, and 95% CIs for the treatments and their difference 
will be presented together with the p-values. 
A detailed description of PK analyses will be provided in the SAP. 
Additional details regarding the statistical methods for secondary endpoints will be described in 
the SAP. 
8.3.3. 
Main Study Pharmacokinetic Analysis 
A descriptive summary of observed plasma concentrations will be displayed by time and by 
treatment group. The Main Study Pharmacokinetic Set will be used to analyze plasma levels. 
Full details of PK analysis will be provided in the SAP for the Main Study. 
8.3.4. 
Main Study Safety Analyses 
All safety analyses will be performed on the Main Study Safety Population. All safety data will 
be listed and summarized by treatment group. Additional statistical analysis methods for safety 
analyses are listed below. 
8.3.4.1. 
Adverse Events 
AEs will be coded using Medical Dictionary for Regulatory Activities (MedDRA). 
For each treatment group, the proportion of subjects with TEAEs will be summarized overall, by 
severity, and by relationship to olorinab. A TEAE is defined as: 

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 An AE that occurs after initiation of olorinab that was not present at the time of 
treatment start. 
 An AE that increases in severity after the initiation of olorinab, if the event was 
present at the time of treatment start. 
Incidence of AEs, SAEs, and TEAEs leading to study treatment discontinuation will be 
summarized and presented in descending order of frequency. AEs occurring before the first dose 
of olorinab will be summarized separately. 
8.3.4.2. 
Extent of Exposure 
The duration of time on study and time on study treatment will be summarized for each treatment 
using descriptive statistics. The number of subjects on treatment for certain time intervals will 
also be summarized. The total subject-years and total subject-years on study will also be 
included in this summary. 
8.3.4.3. 
Clinical Laboratory Results 
Laboratory parameters will be summarized by treatment group at each scheduled assessment 
timepoint using descriptive statistics. Associated laboratory parameters such as hepatic enzymes, 
renal function, and hematology values will be grouped and presented together. Individual subject 
values will be listed and values outside of the standard reference range will be noted. Shift tables 
and analyses of changes from Baseline will be produced. 
8.3.4.4. 
Vital Signs 
The change from Baseline for each of the vital signs (blood pressure, HR, respiratory rate, body 
temperature) will be presented by treatment group. The incidence of abnormal vital signs 
parameters will be tabulated. 
8.3.4.5. 
Physical Exams 
Clinically significant physical examination abnormalities will be included in medical history or 
recorded and summarized as an AE. 
8.3.4.6. 
Electrocardiography 
The change from Baseline Descriptive statistics for each of the ECG parameters will be 
presented by treatment group. The incidence of outlier ECG results will be tabulated. Individual 
ECG values will be listed by visit and summarized using descriptive statistics. Parameters to be 
provided on the confirmed read for each safety ECG are HR and the following intervals: RR, PR, 
QRS, QT, and QTc (QTcF required, QTcB optional). The ECGs will be read and interpreted by 
the central ECG laboratory. Post-Baseline ECGs for each subject will be compared with the 
Baseline ECG. Any clinically significant change from Baseline may be recorded as an AE if 
deemed appropriate by the Investigator, or Investigator in consultation with the Medical Monitor. 
Outlier analysis will be performed on all subjects with QTcF values greater than 500 ms or 
change from Baseline > 60 ms in the absence of Baseline ECG abnormalities that preclude 
accurate surface ECG assessment of ventricular repolarization (eg, bundle branch block). 

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8.3.5. 
Other Analyses 
8.3.6. 
Statistical Analyses for the Long-Term Extension 
The LTE has 2 treatment groups, 25 mg and 50 mg. Based on subjects’ treatment assignments in 
the Main Study and the LTE study, subjects can be classified into 6 unique treatment groups: 
“Placebo|25 mg”, “Placebo|50 mg”, “10 mg|25 mg”, “10 mg|50 mg”, “25 mg|25 mg”, and 
“50 mg|50 mg”. 
Safety analyses will be performed as described above for the Main Study. In addition, new AEs 
that occur after the first dose in the LTE or TEAEs which occurred in the Main Study period and 
increase in severity after the first dose of LTE study treatment will also be summarized by the 
6 unique treatment groups. Exposure will also be summarized by unique treatment group. 
A descriptive summary of observed plasma concentrations will be provided by treatment group. 
Summary statistics will be provided for efficacy endpoints by unique treatment group. 
Proportion-based endpoints including responders will be summarized with frequency count and 
percentage. Continuous endpoints will be summarized with descriptive statistics including mean, 
median, standard deviation, minimum, and maximum values. There is no formal between-
treatment comparison for efficacy endpoints. 
Additional analyses may be performed in some subgroups of medical interest, such as sex, age, 
race, and IBS subtype. Details of the analyses will be provided in the SAP for LTE. 
8.4. 
Data Safety Monitoring Board 
An independent data safety monitoring board (DSMB) has been established for the regular and 
ad hoc review of aggregate safety data. Membership of the DSMB, meeting frequency, and 
safety review criteria are defined in a separate DSMB charter. Recommendations for specific 
study stopping criteria are described in the DSMB charter. The DSMB will have access to 
aggregate blinded data but may also request to review unblinded data at their discretion as 
needed. At the conclusion of each meeting, the DSMB will provide a recommendation to the 
Sponsor’s Safety Lead and the Study Lead Investigator. 
8.5. 
Interim Analyses 
No formal interim analyses are planned. 
8.6. 
Missing Data 
The efficacy analyses will be conducted on the FAS. The robustness of the primary endpoint 
result will be assessed using various sensitivity analyses (eg, complete-case, multiple 
imputation). In addition, sensitivity analyses may be used to assess the robustness of results for 
the secondary and exploratory endpoint using various methodology (eg, MMRM, complete-case, 
worst-case, non-responder, multiple imputation). 

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8.7. 
Testing Strategy/Multiplicity 
No formal testing strategy or adjustments of the type I error will be employed for the primary, 
secondary or exploratory endpoints. Estimates and CIs for treatment groups and from pairwise 
comparisons will be used in an exploratory manner. 

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9. 
OPERATIONAL CONSIDERATIONS 
9.1. 
Regulatory and Ethical Considerations 
 This study will be conducted in accordance with the protocol and with the following: 
 Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) international ethical guidelines 
 Applicable International Council for Harmonisation (ICH) Good Clinical Practice 
(GCP) guidelines 
 Applicable laws and regulations 
 The protocol, protocol amendments, ICF, Investigator’s Brochure, and any other 
patient-facing documents (eg, advertisements) must be submitted to an IRB by the 
Investigator and reviewed and approved by the IRB before the study is initiated. 
 Any amendments to the protocol will require IRB approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an 
immediate hazard to study subjects. 
 The Investigator will be responsible for the following: 
 Providing written summaries of the status of the study to the IRB annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB 
 Notifying the IRB of SAEs or other significant safety findings as required by IRB 
procedures 
 Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB, European regulation 536/2014 
for clinical studies (if applicable), and all other applicable local regulations 
 The Sponsor is responsible for compliance with applicable sections of 21 CFR 
Part 312, SubPart D (Responsibilities of Sponsors). 
9.2. 
Informed Consent Process 
The Investigator or his/her representative will explain the nature of the study and review 
protocol-specific subject requirements including requirements regarding background 
medications. The Investigator or his/her representative will answer any questions the subject has 
regarding study participation. 
Subjects must be informed that their participation is voluntary. Subjects will be required to sign a 
statement of informed consent that meets the requirements of 21 CFR Part 50, local regulations, 
ICH guidelines, HIPAA requirements, where applicable, and the IRB or study center. 
Informed consent will also include permission for the Investigator to obtain information on the 
subject’s health status from next of kin, health care professionals, or public registries in the event 

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the subject withdraws early from randomized study treatment and fails to respond to attempts to 
schedule the Follow-Up Visit. 
The informed consent process may also include additional consent for collection of colonic 
biopsy and blood samples for genetic analysis. The source document must include a statement 
that written informed consent was obtained before the subject was enrolled in the study and the 
date the written consent was obtained. The authorized person obtaining the informed consent 
must also sign the ICF. 
If the ICF is updated, subjects must be re-consented to the most current version of the ICF(s) 
during their participation in the study. 
A copy of the ICF(s) must be provided to the subject. 
Subjects who are rescreened are required to sign a new ICF. 
Subjects who participate in the LTE will be required to sign a separate ICF. 
9.3. 
Data Protection 
All information generated in this study is considered highly confidential and must not be 
disclosed to any person or entity not directly involved with the study unless prior written consent 
is provided from the Sponsor. 
Subjects will be assigned a unique identifier by the Sponsor. Any subject records or datasets that 
are transferred to the Sponsor will contain the identifier only; subject names or any information 
which would make the subject identifiable will not be transferred. 
The subject must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the subject. 
The subject must be informed that his/her medical records may be examined by Clinical Quality 
Assurance auditors or other authorized personnel appointed by the Sponsor, by appropriate IRB 
members, and by inspectors from regulatory authorities. 
In addition, prior to study participation, the subject must be informed that the records identifying 
the subject will not be made publicly available. 
9.4. 
Protocol Compliance 
The Investigator/institution will conduct the study in compliance with the protocol agreed to by 
the Sponsor and regulatory authorities (if applicable) and that was approved by the IRB. The 
Investigator/institution and the Sponsor should sign the protocol, or an alternative contract, to 
confirm agreement. 
The Investigator should not implement any deviation from, or changes to, the protocol without 
agreement by the Sponsor and prior review and documented approval from the IRB of an 
amendment, except where necessary to eliminate immediate hazard(s) to study subjects or when 
the change involves only logistical or administrative aspects of the study (eg, change in monitor, 
change of telephone number). 

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When an important deviation from the protocol is deemed necessary for an individual subject, 
the Investigator must contact the Sponsor. Such contact must be made as soon as possible to 
permit a review by the Sponsor to determine the impact of the deviation on the subject’s 
participation and/or the assessment of safety or efficacy in the study. Any significant protocol 
deviations affecting subject eligibility and/or safety must be reviewed and/or approved by the 
IRB and regulatory authorities, as applicable, prior to implementation. 
The Investigator should document and explain any deviation from the approved protocol. 
9.5. 
Data Quality Assurance 
Quality systems shall be implemented and maintained with written SOPs to ensure that the study 
is conducted and data are generated, documented (recorded), and reported in compliance with the 
protocol, GCP, and the applicable regulatory requirement(s). Quality control shall be applied to 
each stage of data handling to ensure that all data are reliable and have been processed correctly. 
Prior to study activities being initiated at the site(s), the Sponsor or designee will train study site 
personnel on the protocol and applicable procedures. If new study site personnel are assigned to 
the study after the initial training, study sites should contact the study monitor in a timely manner 
as appropriate to coordinate training. All training should be documented. 
All subject data relating to the study will be recorded on eCRFs unless transmitted to the Sponsor 
or designee electronically (eg, laboratory data). The Investigator is responsible for verifying that 
data entries are accurate and correct by physically or electronically signing the eCRF. 
The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF. 
The Investigator must permit study-related monitoring, audits, IRB review, and regulatory 
agency inspections and provide direct access to source data documents. 
Monitoring details describing strategy (eg, risk-based initiatives in operations and quality such as 
Risk Management and Mitigation Strategies and Analytical Risk-Based Monitoring), methods, 
responsibilities, and requirements, including handling of noncompliance issues and monitoring 
techniques (central, remote, or onsite monitoring) are provided in the Monitoring Plan.  
The Sponsor or designee is responsible for the data management of this study, including quality 
checking of the data. 
The Sponsor assumes accountability for actions delegated to other individuals (eg, Contract 
Research Organizations). 
Study monitors will perform ongoing source data verification to confirm that data entered into 
the eCRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of subjects are being protected; and that the study is being 
conducted in accordance with the currently approved protocol and any other study agreements, 
ICH GCP, and all applicable regulatory requirements. 
Records and documents, including signed ICFs, pertaining to the conduct of this study must be 
retained by the Investigator for 2 years after the last marketing application approval, or if the 
application is not approved or never submitted, 2 years after the appropriate regulatory 
authorities have been notified of the discontinuation of clinical development of the 

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investigational product. No records may be destroyed during the retention period without the 
written approval of the Sponsor. No records may be transferred to another location or party 
without written notification to the Sponsor. 
9.6. 
Source Documents 
Source documents provide evidence for the existence of the subject and substantiate the integrity 
of the data collected. Source documents are filed at the Investigator’s site. Source documents 
include information contained in original records and certified copies of results, observations or 
other facets required for the reconstruction and evaluation of the study that is contained in source 
documents. Examples of source documents may include (but are not limited to) hospital records, 
clinical and office charts, laboratory data/information, subjects’ diaries or evaluation checklists, 
pharmacy dispensing and other records, recorded data from automated instruments, ECGs, 
X-rays, ultrasounds, right heart catheterization reports, ECHO, and PFTs. Data collected during 
the study must be recorded on the appropriate source documents. 
Data reported on the eCRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
Investigator may need to request previous medical records or transfer records, depending on the 
study. Also, current medical records must be available. 
eCRFs must be completed for each subject screened/enrolled in this study. These forms will be 
used to transmit information collected during the study to the Sponsor and regulatory authorities, 
as applicable.  
The Investigator will document subject data in his/her own subject files. These subject files will 
serve as source data for the study. All eCRF data required by this protocol will be recorded by 
investigative site personnel. All data entered into the eCRF will be supported by source 
documentation. 
The Investigator or an authorized member of the Investigator’s staff will make any necessary 
corrections to the eCRF. All changed information, including the date and person performing the 
corrections, will be available via the audit trail, which will be part of the electronic data capture 
system. For any correction, a reason for the alteration will be provided. The eCRFs will be 
reviewed periodically for completeness and acceptability by Sponsor personnel (or their 
representatives). The Sponsor (or their representatives) will also be allowed access to all source 
documents pertinent to the study in order to verify eCRF entries. The Investigator will review the 
eCRFs for completeness and accuracy and provide his or her electronic signature and date to 
eCRFs as evidence thereof. 
The documentation related to the validation of the eCRFs will be maintained in the Trial Master 
File (TMF). The TMF will be maintained by the Contract Research Organization during the 
course of the clinical study and by the Sponsor upon completion of the study. 
9.7. 
Study and Site Closure 
The Sponsor or their designee reserves the right to close the study site or terminate the study at 
any time for any reason at the sole discretion of the Sponsor. Study sites will be closed after 
study completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed. 

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The Investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the Sponsor or Investigator may include, but are 
not limited to: 
 Failure of the Investigator to comply with the protocol, the requirements of the IRB 
or local health authorities, the Sponsor’s procedures, or GCP guidelines 
 Inadequate recruitment of subjects by the Investigator 
 Discontinuation of further study treatment development 
 

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Clinical Study Protocol 
APD371-202 
Olorinab in IBS-C and IBS-D 
Amendment 3.0 
Arena Pharmaceuticals, Inc. 
Confidential 
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Clinical Study Protocol 
APD371-202 
Olorinab in IBS-C and IBS-D 
Amendment 3.0 
Arena Pharmaceuticals, Inc. 
Confidential 
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Clinical Study Protocol 
APD371-202 
Olorinab in IBS-C and IBS-D 
Amendment 3.0 
Arena Pharmaceuticals, Inc. 
Confidential 
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Clinical Study Protocol 
APD371-202 
Olorinab in IBS-C and IBS-D 
Amendment 3.0 
Arena Pharmaceuticals, Inc. 
Confidential 
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Clinical Study Protocol 
APD371-202 
Olorinab in IBS-C and IBS-D 
Amendment 3.0 
Arena Pharmaceuticals, Inc. 
Confidential 
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Clinical Study Protocol 
APD371-202 
Olorinab in IBS-C and IBS-D 
Amendment 3.0 
Arena Pharmaceuticals, Inc. 
Confidential 
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Clinical Study Protocol 
APD371-202 
Olorinab in IBS-C and IBS-D 
Amendment 3.0 
Arena Pharmaceuticals, Inc. 
Confidential 
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Clinical Study Protocol 
APD371-202 
Olorinab in IBS-C and IBS-D 
Amendment 3.0 
Arena Pharmaceuticals, Inc. 
Confidential 
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Clinical Study Protocol 
APD371-202 
Olorinab in IBS-C and IBS-D 
Amendment 3.0 
Arena Pharmaceuticals, Inc. 
Confidential 
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Clinical Study Protocol 
APD371-202 
Olorinab in IBS-C and IBS-D 
Amendment 3.0 
Arena Pharmaceuticals, Inc. 
Confidential 
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APPENDIX 2: 
INVESTIGATOR SIGNATURE 
 
Study title: 
A Phase 2, Multi-Center, Randomized, Double-Blind, 
Placebo-Controlled Parallel-Group Study to Evaluate the Safety, 
Tolerability, and Efficacy of Olorinab in Subjects with Irritable Bowel 
Syndrome Experiencing Abdominal Pain 
 
 
I have read the protocol described above. I agree to comply with all applicable regulations and to 
conduct the study as described in the protocol. 
 
 
 
 
 
 
 
 
 
Investigator Signature 
 
Date 
 
 
 
 
 
 
Investigator Name and Credentials - Printed 
 
 
 
 
 
 
 
 
Institution Name – Printed 
 
 
 
 
 
 
 
 
 
 

Name: Clinical Study Protocol: APD371-202 Amendment 3.0
Description: A Phase 2, Multi‑Center, Randomized, Double‑Blind, Placebo‑Controll
User Nam
Capacity:
Meaning: Approval
Date: 03-Feb-2020 23:11:40 GMT+0000