Clinical trial NCT04043455
Conditions: Irritable Bowel Syndrome
Keywords: Abdominal pain Olorinab APD371 Irritable bowel syndrome (IBS) IBS-C (IBS with predominant constipation) IBS-D (IBS with predominant diarrhea)
Sponsor: Arena Pharmaceuticals
Start date: 2019-07-24; Completion date: 2021-04-29
Enrollment: 273 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to determine whether olorinab is a safe and effective treatment for abdominal pain in participants with irritable bowel syndrome (IBS).

Detailed description:

Arms: arm 1: None arm 2: None arm 3: None arm 4: None arm 5: Participants will receive olorinab based on their treatment assignment in the Main Study.
Interventions: intervention 1: Olorinab intervention 2: Olorinab intervention 3: Olorinab intervention 4: Placebo intervention 5: Olorinab intervention 6: Olorinab
Intervention descriptions: intervention 1: Olorinab Dose 1 capsule or tablet by mouth, 3 times per day up to 12 weeks intervention 2: Olorinab Dose 2 capsule or tablet by mouth, 3 times per day up to 12 weeks intervention 3: Olorinab Dose 3 capsule or tablet by mouth, 3 times per day up to 12 weeks intervention 4: Olorinab matching placebo capsule or tablet by mouth, 3 times per day up to 12 weeks intervention 5: Olorinab Dose 2 capsule or tablet by mouth, 3 times per day up to 52 weeks intervention 6: Olorinab Dose 3 capsule or tablet by mouth, 3 times per day up to 52 weeks

Protocol documents:
Prot_000.pdf: 
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 
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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 
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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 
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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 
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Olorinab in IBS-C and IBS-D 
Amendment 3.0 
Arena Pharmaceuticals, Inc. 
Confidential 
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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 
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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. 
 


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Amendment 3.0 
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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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Amendment 3.0 
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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 


Clinical Study Protocol 
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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 


Clinical Study Protocol 
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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 


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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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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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(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 
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Olorinab in IBS-C and IBS-D 
Amendment 3.0 
Arena Pharmaceuticals, Inc. 
Confidential 
Page 42 of 93 
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. 
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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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Olorinab in IBS-C and IBS-D 
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 
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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 
 
. 


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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 
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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 


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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 
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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 
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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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seeking behavior in subjects with bowel dysfunction. Gastroenterology. 1984;87(2):314-318.  
Schmulson MJ, Drossman DA. What is new in Rome IV. J Neurogastroenterol Motil. 
2017;23(2):151-163. On file at Arena. 
Snaith RP. The Hospital Anxiety And Depression Scale. Health Qual Life Outcomes. 2003;1:29.  
Sperber AD, Dumitrascu D, Fukudo S, et al. The global prevalence of IBS in adults remains 
elusive due to the heterogeneity of studies: A Rome Foundation working team literature review. 
Gut. 2017;66(6):1075-1082.  
Spiegel B, Bolus R, Harris LA, et al. Measuring irritable bowel syndrome patient-reported 
outcomes with an abdominal pain numeric rating scale. Aliment Pharmacol Ther. 2009;30(11-
12):1159-1170.  
Spiegel B, Irvine JE, Tack J, et al. Rome IV design of treatment trials for functional 
gastrointestinal disorders. In: Drossman D, Chang L, Chey WD, et al., eds. ROME IV. 
Functional Gasterointestinal Disorders. Disorders of Gut-Brain Interaction. Vol II. ROME 
Foundation; 2017:573-644. On file at Arena. 


Clinical Study Protocol 
APD371-202 
Olorinab in IBS-C and IBS-D 
Amendment 3.0 
Arena Pharmaceuticals, Inc. 
Confidential 
Page 83 of 93 
Spiegel BM, Hays RD, Bolus R, et al. Development of the NIH Patient-Reported Outcomes 
Measurement Information System (PROMIS) gastrointestinal symptom scales. Am J 
Gastroenterol. 2014;109(11):1804-1814.  
ten Berg MJ, Goettsch WG, van den Boom G, Smout AJPM, Herings RMC. Quality of life of 
patients with irritable bowel syndrome is low compared to others with chronic diseases. Eur J 
Gastroenterol Hepatol. 2006;18(5):475-481.  
Weinland SR, Morris CB, Hu Y, Leserman J, Bangdiwala SI, Drossman DA. Characterization of 
episodes of irritable bowel syndrome using ecological momentary assessment. Am J 
Gastroenterol. 2011;106(10):1813-1820.  
Wright K, Rooney N, Feeney M, et al. Differential expression of cannabinoid receptors in the 
human colon: Cannabinoids promote epithelial wound healing. Gastroenterology. 
2005;129(2):437-453.  
Wright KL, Duncan M, Sharkey KA. Cannabinoid CB2 receptors in the gastrointestinal tract: A 
regulatory system in states of inflammation. Br J Pharmacol. 2008;153(2):263-270.  
 
 


Clinical Study Protocol 
APD371-202 
Olorinab in IBS-C and IBS-D 
Amendment 3.0 
Arena Pharmaceuticals, Inc. 
Confidential 
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Olorinab in IBS-C and IBS-D 
Amendment 3.0 
Arena Pharmaceuticals, Inc. 
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Olorinab in IBS-C and IBS-D 
Amendment 3.0 
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Olorinab in IBS-C and IBS-D 
Amendment 3.0 
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Olorinab in IBS-C and IBS-D 
Amendment 3.0 
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Olorinab in IBS-C and IBS-D 
Amendment 3.0 
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Olorinab in IBS-C and IBS-D 
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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

SAP_001.pdf: 
PROTOCOL APD371-202 
Analysis Plan – Main Study 
Page 1 of 77
STATISTICAL ANALYSIS PLAN 
APD371-202 
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 
AUTHORS: 
 AND 
 
VERSION NUMBER AND DATE: 1.0 15JAN2021 


PROTOCOL APD371-202 
Analysis Plan – Main Study 
Page 2 of 77
STATISTICAL ANALYSIS PLAN SIGNATURE PAGE 
Statistical Analysis Plan V1.0 (Dated 15JAN2021) for Protocol APD371-202 
Amendment 3.
Name 
Signature 
Date 
Author: 
 
 
Position: 
Associate Director 
Company: 
IQVIA 
Name 
Signature 
Date 
Author: 
 
 
Position: 
Associate Research Pharmacokinetics Director 
Company: 
IQVIA 
Upon review of this document, the undersigned approves this version of the Statistical 
Analysis Plan, authorizing that the content is acceptable for the reporting of this study. 
Name 
Signature 
Date 
Approved By: 
 
 
Position: 
Sr. Director 
Company: 
Arena Pharmaceuticals 
Approved By: 
 
 
Position: 
VP, Biostatistics & Data Management 
Company: 
Arena Pharmaceuticals 


PROTOCOL APD371-202 
Analysis Plan – Main Study 
Page 3 of 77
MODIFICATION HISTORY 
Unique 
Identifier 
for this 
Version 
Date of the 
Document 
Version 
Author 
Significant Changes from  
Previous Authorized Version 
1.0 
15JAN2021 
 and 
 
Not Applicable – First Version 
Copyright © 2009, 2010, 2012, 2016, 2018 IQVIA. All rights reserved. The contents of this document are confidential and proprietary 
to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly proh bited. 
Document: 
\\quintiles.net\enterprise\Apps\sasdata\SASb\SAS\Arena\APD371\FZA87549\Biostatistics\Documentati
on\SAP\APD371-202_Main_Study_SAP_Final.docx 
Author: 
 and 
 
Version 
Number:
1.0 
Version Date:  
15JAN2021
Template No.:  CS_TP_BS016 Revision 5 
Reference:  CS_WI_BS005 
Effective Date: 01Apr2018 


PROTOCOL APD371-202 
Analysis Plan – Main Study 
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TABLE OF CONTENTS 
1.
LIST OF ABBREVIATIONS ......................................................................................... 8 
2.
INTRODUCTION ......................................................................................................... 11 
3.
STUDY OBJECTIVES ................................................................................................. 11 
3.1. 
Primary Objectives ........................................................................................................................................ 11 
3.2. 
Secondary Objectives .................................................................................................................................... 11 
4.
STUDY DESIGN ........................................................................................................... 12 
4.1. 
General Description ....................................................................................................................................... 12 
4.2. 
Schedule of Events ......................................................................................................................................... 13 
4.3. 
Changes to Analysis from Protocol .............................................................................................................. 14 
5.
PLANNED ANALYSES ............................................................................................... 14 
5.1. 
Data Safety Monitoring Board (DSMB) ...................................................................................................... 14 
5.2. 
Final Analysis ................................................................................................................................................. 14 
6.
ANALYSIS SETS .......................................................................................................... 15 
6.1. 
Screened Set ................................................................................................................................................... 15 
6.2. 
All Subjects Enrolled Set ............................................................................................................................... 15 
6.3. 
Full Analysis Set [FAS] ................................................................................................................................. 15 
6.4. 
Per Protocol Set ............................................................................................................................................. 15 
6.5. 
Safety Set ........................................................................................................................................................ 15 
6.6. 
Pharmacokinetic Analysis Set ....................................................................................................................... 16 
7.
GENERAL CONSIDERATIONS ................................................................................ 16 
7.1. 
Reference Start Date and Study Day ........................................................................................................... 16 
7.2. 
Baseline/Post-Baseline ................................................................................................................................... 16 
7.3. 
Retests, Unscheduled Visits and Early Termination Data ......................................................................... 18 


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7.4. 
Windowing Conventions ............................................................................................................................... 18 
7.5. 
Statistical Tests .............................................................................................................................................. 19 
7.6. 
Common Calculations ................................................................................................................................... 19 
7.7. 
General Study Information ........................................................................................................................... 20 
8.
SAMPLE SIZE JUSTIFICATION .............................................................................. 20 
9.
STATISTICAL CONSIDERATIONS ......................................................................... 21 
9.1. 
Adjustments for Covariates and Factors to be Included in Analyses ....................................................... 21 
9.2. 
Multicenter Studies ........................................................................................................................................ 21 
9.3. 
Missing Data ................................................................................................................................................... 21 
9.4. 
Multiple Comparisons/ Multiplicity ............................................................................................................. 22 
9.5. 
Examination of Subgroups ............................................................................................................................ 22 
10. OUTPUT PRESENTATIONS ...................................................................................... 22 
11. DISPOSITION AND PROTOCOL DEVIATIONS ................................................... 23 
12. DEMOGRAPHICS AND BASELINE CHARACTERISTICS ................................. 23 
12.1.  Derivations ..................................................................................................................................................... 24 
13. MEDICAL HISTORY .................................................................................................. 24 
14. CONCOMITANT MEDICAL CONDITIONS ........................................................... 25 
15. MEDICATIONS ............................................................................................................ 25 
16. STUDY TREATMENT EXPOSURE .......................................................................... 25 
16.1.  Derivations ..................................................................................................................................................... 26 
17. STUDY TREATMENT COMPLIANCE .................................................................... 26 
17.1.  Derivations ..................................................................................................................................................... 26 
18. EFFICACY OUTCOMES ............................................................................................ 28 
18.1.  Primary Efficacy ............................................................................................................................................ 28 
18.1.1. 
Primary Efficacy Variable & Derivation ................................................................................................. 28 
18.1.2. 
Missing Data Methods for Primary Efficacy Variable ............................................................................ 28 
18.1.3. 
Primary Analysis of Primary Efficacy Variable ...................................................................................... 28 
18.1.4. 
Sensitivity Analysis of Primary Efficacy Variable .................................................................................. 30 


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18.1.5. 
Supplementary Analysis of Primary Efficacy Variable ........................................................................... 31 
18.2.  Secondary Efficacy ........................................................................................................................................ 31 
18.2.1. 
Secondary Efficacy Variables & Derivations .......................................................................................... 31 
18.2.2. 
Missing Data Methods for Secondary Efficacy Variables ....................................................................... 32 
18.2.3. 
Analysis of Secondary Efficacy Variables ............................................................................................... 33 
18.2.4. 
Sensitivity Analysis of Secondary and Key Exploratory Efficacy Variables .......................................... 34 
18.3.  Exploratory Efficacy ..................................................................................................................................... 35 
19.  SAFETY OUTCOMES ................................................................................................. 49 
19.1.  Adverse Events ............................................................................................................................................... 49 
19.1.1. 
All TEAEs ............................................................................................................................................... 49 
19.1.2. 
Severity .................................................................................................................................................... 50 
19.1.3. 
Relationship to Study Treatment ............................................................................................................. 50 
19.1.4. 
TEAEs Leading to Discontinuation of Study Treatment ......................................................................... 50 
19.1.5. 
Teaes Leading to Study Discontinuation ................................................................................................. 51 
19.1.6. 
Serious and Non-Serious Teaes ............................................................................................................... 51 
19.1.7. 
Teaes Leading to Death ........................................................................................................................... 51 
19.1.8. 
Teaes Of Special Interest ......................................................................................................................... 51 
19.1.9. 
Overall Summary of Adverse Events ...................................................................................................... 51 
19.2.  Deaths ............................................................................................................................................................. 52 
19.3.  Laboratory Evaluations ................................................................................................................................ 52 
19.3.1. 
Laboratory Reference Ranges and Markedly Abnormal Criteria ............................................................ 53 
19.4.  12-lead ECG ................................................................................................................................................... 53 


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19.4.1. 
12-Lead ECG: Outlier and Morphology Analyses ................................................................................... 54 
19.5.  Vital Signs ....................................................................................................................................................... 55 
19.5.1. 
Vital Signs Specific Derivations .............................................................................................................. 57 
19.6.  Physical Examination .................................................................................................................................... 57 
20.  PHARMACOKINETICS ANALYSIS ........................................................................ 57 
20.1.  Plasma Concentration Data .......................................................................................................................... 58 
20.2.  Plasma Pharmacokinetic Parameters .......................................................................................................... 59 
21.  IMPACT OF COVID-19 ............................................................................................... 62 
22.  GENETIC AND BIOMARKERANALYSES ............................................................. 62 
23.  DATA NOT SUMMARIZED OR PRESENTED ....................................................... 62 
24.  REFERENCES .............................................................................................................. 64 
26.  APPENDIX 2. PARTIAL DATE CONVENTIONS ................................................... 67 
Algorithm for Treatment Emergence of Adverse Events: ..................................................................................... 67 
Algorithm for Prior / Concomitant Medications: ................................................................................................... 68 
27. 
 
28.  APPENDIX 4. EXAMPLE SAS CODE ....................................................................... 77 
 
 


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Analysis Plan – Main Study 
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1. LIST OF ABBREVIATIONS 
Abbreviation 
Meaning 
AABS 
average abdominal bloating score 
AADS 
average abdominal discomfort score 
AAPS 
average abdominal pain score 
AE 
adverse event 
ANCOVA 
analysis of covariance 
APS 
abdominal pain score 
ATC 
Anatomical Therapeutic Chemical 
ATC3 
Anatomical Therapeutic Chemical: Therapeutic (Level 3) 
AUC 
area under the curve 
BLQ 
below the lower limit of quantification 
BM 
bowel movement 
BMI 
body mass index 
BP 
blood pressure 
CC 
complete cases 
CI 
confidence interval 
CM 
concomitant medication 
CMH 
Cochran-Mantel-Haenszel 
CS 
clinically significant 
CSBM 
complete spontaneous bowel movement 
CSR 
clinical study report 
CV 
coefficient of variation 
DSMB 
Data Safety Monitoring Board 
ECG 
electrocardiograms 
eCRF 
electronic case report form 
EDC 
electronic data capture 


PROTOCOL APD371-202 
Analysis Plan – Main Study 
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Abbreviation 
Meaning 
EQ-5D 
European Quality of Life-5 
ET 
early termination 
FAS 
Full Analysis Set 
HADS 
Hospital Anxiety and Depression Scale 
HR 
heart rate 
IBS 
irritable bowel syndrome 
IBS-C 
irritable bowel syndrome with predominant constipation 
IBS-D 
irritable bowel syndrome with predominant diarrhea 
IBS-QoL 
Irritable Bowel Syndrome-Quality of Life 
IBS-SSS 
Irritable Bowel Syndrome-Severity Scoring System 
ICF 
informed consent form 
LS 
least-squares 
LTE 
long-term extension 
MAR 
missing at random 
MCMC 
Markov Chain Monte Carlo 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
multiple imputation 
MMRM 
mixed-effects model repeated measures 
NCS 
not clinically significant 
NRI 
non-responder imputation 
OC 
observed cases 
PCS 
Potentially Clinically Significant 
PGIC 
Patient Global Impression of Change 
PK 
pharmacokinetic 
PROMIS 
Patient-Reported Outcomes Measurement Information System 
PT 
preferred term 


PROTOCOL APD371-202 
Analysis Plan – Main Study 
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Abbreviation 
Meaning 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SBM 
spontaneous bowel movement 
SD 
standard deviation 
SI 
International System of Units 
SOC 
System Organ Class 
TEAE 
treatment-emergent adverse event 
TFL 
table, figure, and listing 
TID 
3 times per day 
ULQ 
upper limit of quantification 
VAS 
Visual Analog Scale 
VS 
vital signs 
WHODD 
World Health Organization Drug Dictionary  
WK 
week 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


PROTOCOL APD371-202 
Analysis Plan – Main Study 
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2. INTRODUCTION 
This document describes the rules and conventions to be used in the presentation and analysis 
of efficacy, safety, and pharmacokinetic (PK) data for the Main Study described in Protocol 
APD371-202. It describes the data to be summarized and analyzed, including specifics of the 
statistical methods to be implemented. This statistical analysis plan (SAP) is based on 
protocol version APD371-202 (Amendment 3, dated 03FEB2020) and focuses on analyses 
for the Main Study. There will be a separate SAP or an amendment to this SAP for the long-
term extension (LTE) part of the study. A separate analysis plan will describe the genetic and 
biomarker analyses. 
 
The table, figure and listing (TFL) shells are prepared in a separate file based on this analysis 
plan. Upon approval of the SAP, some updates (including but not limited to titles, footnotes, 
headings and re-numbering of tables, etc.) on TFL shells are allowed without a SAP 
amendment as long as the updates within TFL shells do not conflict with the contents of the 
SAP.  
3. STUDY OBJECTIVES 
3.1. PRIMARY OBJECTIVES 
The primary objectives are: 
 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 
3.2. SECONDARY OBJECTIVES 
The secondary objectives are: 
 
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 of olorinab and its predominant 
metabolites, 
, and 
, in subjects with IBS 
 


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Analysis Plan – Main Study 
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4. STUDY DESIGN 
4.1. GENERAL DESCRIPTION 
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 
predominant diarrhea (IBS-D) who are not on concomitant treatment for IBS. The 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 (at least 2 weeks; 14-19 days), 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 (male, female) and IBS 
subtype (IBS-C, IBS-D). The number of subjects enrolled with IBS-C will be approximately 
equal to the number of subjects enrolled with IBS-D. Subjects will be screened until 
approximately 60 subjects have been randomized per treatment group for a total of 
approximately 240 subjects. For subjects randomized under protocol amendment 1, there was 
an overnight observation period following randomization on Day 1, with orthostatic vital 
sign (VS) and 12-lead electrocardiogram (ECG) measured at multiple timepoints. Blood 
samples will be collected for measurement of plasma concentrations of olorinab and its 
metabolites.  Samples will be used to evaluate the PK of olorinab and its predominant 
metabolites 
.  
 
The PK sampling schemes specified in protocol amendment 1 include the following 
timepoints: 
 Blood samples for the analysis of olorinab and metabolite plasma concentrations will 
be collected at study visits at Weeks 2 (Visit 4) through 10 (Visit 7) prior to the first 
daily dose. Blood samples will also be collected at Weeks 12 and 14 during the 
scheduled study visit. At Week 4 (Visit 5), in addition to samples collected prior to 
the first daily dose of study treatment, blood samples will be drawn 0.5, 1, and 2 
hours after the first daily dose of study treatment. If a subject discontinues the study, 
a final PK sample will be collected at the Early Termination visit. 
 Pharmacokinetic blood samples will be collected on Day 1 prior to and 0.5, 1, 2, 4, 
and 8 hours after the first dose of study treatment and 10 hours after the first dose of 
study treatment (2 hours after second dose). Additional samples will be collected on 
Day 2, prior to the first daily dose of study treatment and 2 and 4 hours after the first 
daily dose. 


PROTOCOL APD371-202 
Analysis Plan – Main Study 
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The PK sampling schemes specified in protocol amendment 2 and protocol amendment 3 
(Main Study) include the following timepoints: 
 Pharmacokinetic blood samples will be collected at study visits at Weeks 2 (Visit 4) 
through 10 (Visit 7) prior to the first daily dose. Blood samples will also be collected 
at Weeks 12 and 14 during the scheduled study visit. At Week 4 (Visit 5), in addition 
to samples collected prior to the first daily dose of study treatment, blood samples 
will be drawn 0.5, 1, and 2 hours after the first daily dose of study treatment 
administered at the clinic during the study visit. If a subject discontinues the study, a 
final PK sample will be collected at the Early Termination visit. 
 
Pharmacokinetic blood samples will be collected on Day 1 prior to the administration of 
study treatment and 0.5, 1, and 2 hours after the administration of study treatment. 
 
 
Figure 1: Schematic Diagram of Main Study Design 
 
Abbreviations: 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 Main Study Treatment Period is Day 1. There is not a designated Day 0 in this study. For subjects 
randomized under protocol amendment 1, there was an overnight observation period following randomization on Day 1, with orthostatic vital 
sign (VS) and 12-lead electrocardiogram (ECG) measured at multiple timepoints. See orthostatic VS and ECG analyses under Safety Section for 
details. 
4.2. SCHEDULE OF EVENTS 
Schedule of events can be found in 
 of the protocol. 


PROTOCOL APD371-202 
Analysis Plan – Main Study 
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4.3. CHANGES TO ANALYSIS FROM PROTOCOL 
There are no changes in analysis or definitions from those planned in the final protocol and 
no changes required due to COVID-19. 
5. PLANNED ANALYSES 
The following analyses will be performed for this study: 
 
Regular and ad hoc review of aggregate safety data by DSMB 
 
Final Analysis of the Main Study  
 
No formal interim analyses are planned.  
5.1. DATA SAFETY MONITORING BOARD (DSMB)  
A DSMB SAP, describing the methodology and presentation of results and access to results 
will be provided by the Sponsor as a separate document. 
5.2. FINAL ANALYSIS  
All final, planned analyses identified in this SAP will be performed following Sponsor 
Authorization of this SAP, Database Lock, Sponsor Authorization of Analysis Sets and 
Unblinding of Treatment. PK analysis will be performed and is described in this analysis 
plan. 
 
After all subjects have completed the Main Study, outstanding data queries have been 
resolved/closed, and the data have been cleaned and finalized, the Sponsor will authorize 
breaking of the study blind and the final analysis of the data will be performed. The SAP 
must be approved and signed by the Sponsor before the database is locked and treatment 
assignment unblinded. 
 
Any post-hoc, exploratory analyses completed to support planned study analyses, which were 
not identified in the SAP, will be documented and reported in the clinical study report. Any 
results from these unplanned analyses will also be clearly identified in the text of the clinical 
study report. 


PROTOCOL APD371-202 
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6. ANALYSIS SETS 
Agreement and authorization of subjects included/excluded from each analysis set will be 
conducted prior to the unblinding of the study. A summary of analysis sets will be presented. 
6.1. SCREENED SET  
The screened set will include all subjects who provide informed consent for this study. 
6.2. ALL SUBJECTS ENROLLED SET  
The enrolled set will include all subjects who are enrolled in the Run-in Period of this study. 
6.3. FULL ANALYSIS SET [FAS] 
The full analysis set (FAS) will include all randomized subjects, irrespective of whether they 
received study treatment. Subjects will be classified according to randomized treatment. 
6.4. PER PROTOCOL SET  
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 protocol violations may include not meeting key inclusion/exclusion criteria, gross 
treatment non-compliance, receiving incorrect treatment, treatment unblinding by the 
investigator, or concomitant use of protocol-prohibited medications. The final determination 
on protocol violations, and thereby the composition of the Per Protocol set will be made prior 
to database lock of the Main Study and will be separately documented. Subjects will be 
summarized by treatment to which they were randomized, regardless of treatment actually 
received. If subjects are randomized but not treated, they will be excluded from Per Protocol 
set. 
6.5. SAFETY SET  
The safety set will include all subjects who are randomized and receive at least one dose of 
study treatment. Subjects will be classified according to actual treatment received. If there is 
any doubt whether a subject was treated or not, they will be assumed treated by the 
randomized treatment for the purposes of analysis.  


PROTOCOL APD371-202 
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6.6. PHARMACOKINETIC ANALYSIS SET 
The pharmacokinetic analysis set will include all subjects in the FAS with at least 1 post-
dose PK measurement who receive the active study drug, and who have at least 1 PK 
measurement at a scheduled post-dose or Ctrough PK timepoint after treatment started on Day 
1 for at least 1 PK analyte 
, and who 
have no protocol violations or events with potential to affect the PK concentrations. Subjects 
will be classified according to the treatment received. 
 
Only those in the PK analysis set who receive the active treatments will have PK 
(noncompartmental) or analyses (tabular or graphical summaries). In the case of a protocol 
violation/deviation or event that impacts PK, the affected PK sample data will be excluded 
from the summaries (i.e., the PK analysis set), but will still be reported in the study result 
listings. Protocol deviations impacting PK samples will be discussed in trial and adjudicated 
between IQVIA and Arena PK scientists and clinical pharmacologists, and the Protocol 
Deviation and its adjudication will be listed in listings. 
7. GENERAL CONSIDERATIONS 
7.1. REFERENCE START DATE AND STUDY DAY 
Study Day will be calculated from the reference start date and will be used to show start/stop 
day of assessments and events. Reference start date is defined as Day 1, the date of 
randomization (Day 1 is the day of the first dose of study treatment) and will appear in every 
listing where an assessment date or event date appears.  
 
If the date of the event is on or after the reference date then:  
 
Study day = (date of event – reference date) + 1.  
 
If the date of the event is prior to the reference date then:  
 
Study day = (date of event – reference date) .  
In the situation where the event date is partial or missing, Study Day, and any corresponding 
durations will appear as missing in the listings. In the situation where the subject is 
randomized but not treated, the reference date is defined as the baseline visit date. 
7.2. BASELINE/POST-BASELINE 
Unless otherwise specified, baseline is defined as the last non-missing measurement taken 


PROTOCOL APD371-202 
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prior to the reference start date. If measurements include time, the date/time will be used to 
define baseline; where time is not fully populated in the reference start date and fully 
populated in the measurement date, missing time values will be imputed to the earliest 
possible time measurement. Otherwise, only dates will be compared. In the case where the 
last non-missing measurement and the reference start date coincide and time is not collected, 
the measurement will be considered a baseline record, but adverse events (AEs) and 
medications commencing on the reference start date will be considered post-baseline records. 
For subjects randomized but not treated, baseline is defined as the last non-missing 
measurement taken on or before the baseline visit date.  
 
Baseline AAPS is defined as the average abdominal pain score (APS) over the Run-in Period 
preceding the reference start date. The inclusion criteria to progress to randomization 
includes the requirement of “adequate compliance with entry of daily eDiary completed for ≥ 
80% of days of the Run-in Period (Visit 2 to Visit 3 [Day 1])”. Baseline AAPS will be 
calculated in the EDC system if at least 80% of the eDiary entries for APS are available and 
will be calculated as the average APS over all non-missing entries. If a subject has APS 
values recorded for less than 80% of the eDiary entries for the Run-in Period but is 
randomized, baseline AAPS will still be calculated based on the available APS.  
 
Post-baseline AAPS at each week during the treatment period (Week 1 to Week 12) is 
calculated by taking the average value over each 7-day increment, beginning with the 7 days 
including and succeeding the Day 1 Visit, and continuing with 7-day increments for 12 
weeks, regardless of the timing of the actual visits. AAPS during the follow-up period 
(Weeks 13 and 14) is calculated by taking the average value over the 7-day increment, 
beginning with the day after the last dose date, and continuing with 7-day increments for 2 
weeks. If APS values are missing for more than 3 days in the 7-day window for the average 
weekly value, it will be reported as missing.  
 
Post-baseline weekly AAPS by scheduled visit is calculated by taking the average value over 
the window of 7 days prior to and including the scheduled visit day if the endpoint is 
recorded for at least 4 of the 7 days in the window.  If APS values are missing for more than 
3 days in the 7-day window, the average value for the AAPS by scheduled visit will be 
reported as missing. 
 
For other continuous endpoints collected in the Daily Diary form (e.g., bloating, discomfort, 
and number of bowel movements), baseline and post-baseline will be derived in the same 
manner. 


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7.3. RETESTS, UNSCHEDULED VISITS AND EARLY TERMINATION 
DATA 
For by-visit analyses and summaries of efficacy and safety, data (including scheduled, 
retests, unscheduled, and early termination) will be assigned to visits after the application of 
the windowing conventions described in Section 7.4. All measurements will be considered in 
summaries of abnormalities or worst-case values post-baseline. 
 
In the case of a retest (same visit number assigned), the measurement nearest to the visit date 
will be used for by-visit summaries. In the case of several measurements equally close to the 
visit date, the earliest non-missing measurement will be taken. If multiple assessments are 
available on the same day, then the average of the assessment will be used in the analysis 
except for laboratory and ECG data, where the assessment at the earliest time of the same 
day will be used. If both central and local assessments of the same laboratory test are 
available on the same day, the central assessment will take precedence over the local 
assessment. Listings will include scheduled, unscheduled, retest and early discontinuation 
data. 
7.4. WINDOWING CONVENTIONS  
All scheduled study visits are defined relative to Study Day 1, the date of randomization and 
first dose of study treatment. Scheduled visit windows are defined in Appendix 1 of the 
protocol. A windowing convention will be used to determine the analysis visit value for a 
given measurement and will be applicable for all by-visit summaries and analyses for 
efficacy and safety data. The early discontinuation visits and unscheduled visits will be 
eligible for allocation to an analysis visit.  The 2-week follow-up visit will be summarized 
separately. 
 displays the specific visit windows used for the FAS, SAF and Per 
Protocol Set populations for efficacy and safety analysis. See 
 Additional Visit 
Windows for additional visit windows. 
 
Windowing will be applied to the data prior to any missing data calculations. If one or more 
results for a variable are assigned to the same analysis visit, the result with the date closest to 
the protocol scheduled day will be used in the analysis. If two measurements in the same 
analysis visit window are equally close to the protocol scheduled study day, the earliest 
measurement will be used in the analysis. For ePRO measurements (PROMIS, EQ-5D, etc.), 
the stamp date in the device will be used to calculate the study day, and Day 1 will include 
those ePROs collected on Randomization Date or the date after randomization day (Day 1 


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and Day 2). 
 
7.5. STATISTICAL TESTS 
The default significance level will be 5%; confidence intervals (CIs) will be 95% and all tests 
will be two-sided, unless otherwise specified in the description of the analyses. 
7.6. COMMON CALCULATIONS 
For quantitative measurements: 
 Change from baseline = (Test Value at Visit X – Baseline Value) 


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 Percent change from baseline = ((Test Value at Visit X – Baseline Value) / Baseline 
Value) x 100 
 Proportion at Visit X = (Number of subjects satisfying criteria at Visit X / Total number 
of subjects at Visit X)  
 Proportion achieving an improvement from Visit X to Visit Y = (Number of subjects 
achieving an improvement from Visit X to Visit Y / Total number of subjects with non-
missing data for that parameter at both Visit X and Visit Y)  
7.7. GENERAL STUDY INFORMATION 
All analyses, except for PK, will be conducted using SAS® (version 9.4 or later, SAS 
Institute Inc., Cary, NC).  
 
For PK, non-compartmental parameter calculations will be performed using Phoenix® 
WinNonlin® 8.0 or higher (Certara, L.P., Princeton, New Jersey). Graphics may be prepared 
using the same versions of SAS®. A general table with summary of study information will be 
generated, including date first subject signed ICF, last subject last visit date, database lock 
date and versions of the MedDRA, World Health Organization Drug Dictionary Global 
(Enhanced w/WHO Herbal Dictionary) (WHODD), and software used for analyses (SAS, 
WinNonlin) etc. 
  
8. SAMPLE SIZE JUSTIFICATION 
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). 
  
 


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9. STATISTICAL CONSIDERATIONS 
9.1. ADJUSTMENTS FOR COVARIATES AND FACTORS TO BE 
INCLUDED IN ANALYSES 
The following covariates and factors are used in the analyses. For details of their inclusion in 
the models, see the specific analysis section. 
 
Baseline AAPS value 
 
Treatment: (Placebo, Olorinab 10 mg, Olorinab 25 mg, Olorinab 50 mg) and, 
additionally for primary and secondary efficacy endpoints, (Placebo and 
Olorinab pooled; Placebo, Olorinab 10 mg, Olorinab 25 and 50 mg pooled)  
 
Stratification factors:  
 
Sex: Male, Female 
 
IBS subtype: IBS-C, IBS-D 
 
Week: Week 1 - Week 14 
 
Scheduled Visit: Day 1, Week 2, Week 4, Week 8, Week 10, Week 12, Week 14 
 
Treatment-by-week interaction 
 
Treatment-by-visit interaction 
9.2. MULTICENTER STUDIES 
This study will be conducted by multiple investigators at multiple investigational sites within 
the United States. Randomization to treatment arms is not stratified by center. Randomization 
to treatment arms is stratified by sex (male, female) and IBS subtype (IBS-C, IBS-D). Data 
from all sites will be pooled and statistical analyses will not be adjusted for investigational 
site or geographic region. Ad-hoc analyses may be conducted by site or by pooling sites. 
9.3. MISSING DATA 
Missing safety data will generally not be imputed, with the exceptions of AE relationship to 
study treatment (as described in Section 19.1.3), partial or missing AE start dates, and 
Concomitant Medication (CM) start dates. Details about date imputations are described in 
Appendix 2. Partial Date Conventions. No other missing safety data will be imputed. 
 
Missing efficacy data will be handled as described in Sections 18.1.2, 18.2.2, and 18.3.21 of 
this analysis plan. Sensitivity analyses will be conducted to assess the robustness of the 


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primary and secondary endpoint results, as described in Sections 18.1.4 and 18.2.4, 
respectively. Missing PK data will be handled as described in Section 20.2 of this analysis 
plan. 
9.4. MULTIPLE COMPARISONS/ 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. 
9.5. EXAMINATION OF SUBGROUPS 
The following subgroups will be assessed for the primary endpoint: 
 
Sex (Female, Male) 
 
IBS subtype (IBS-C, IBS-D) 
 
Stratification factor (Female IBS-C, Female IBS-D, Male IBS-C, Male IBS-D) 
 
Baseline AAPS (< Median, ≥ Median) 
 
Age (< Median, ≥ Median) 
 
Race (Caucasian, Non-Caucasian) 
 
Ethnicity (Hispanic, Non-Hispanic) 
 
Baseline BMI (< Median, ≥ Median) 
 
Baseline Duration of IBS (< Median, ≥ Median) 
 
Baseline IBS-SSS (<75 (remission), ≥ 75 and < 175 (mild), ≥ 175 and < 300 
(moderate), ≥ 300 (severe)) 
 
Baseline IBS-QoL (>40 (non-severe), ≤40 (severe))  
 
Baseline HADS anxiety scores (≥ 8 or < 8) 
 
Baseline HADS depression scores (≥ 8 or < 8) 
Additional subgroups may be assessed, if deemed necessary. It should be noted that the study 
was not designed to detect treatment differences with statistical power within any of the 
above subgroups. 
10. OUTPUT PRESENTATIONS 
Appendix 1. Programming Conventions for Outputs shows conventions for presentation of 
data in outputs. The templates provided with this SAP describe the presentations for this 
study and therefore the format and content of the summary tables, figures, and listings to be 


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provided for the clinical study report. 
11. DISPOSITION AND PROTOCOL DEVIATIONS 
All subjects who provide informed consent will be accounted for in this study.  
 
Subject disposition and withdrawals will be provided for the FAS. This summary will note 
subjects who complete the Week 12 visit as well as subjects who complete the Week 14 visit. 
An analysis set listing will also be provided. Inclusion and exclusion criteria will be 
presented for the screened set. 
 
Protocol deviations will be displayed for the FAS. Deviations will be categorized as 
Critical/Major or Minor. Critical/major deviations will be summarized by treatment (placebo, 
olorinab 10 mg, olorinab 25 mg, olorinab 50 mg), olorinab 25 and 50 mg pooled, and 
olorinab pooled for the following categories as described in the Protocol Deviation and 
Classification Guidance document. All critical/major deviations will also be listed. 
 Informed Consent Criteria 
 Eligibility and Entry Criteria 
 Concomitant Medication Criteria 
 Laboratory Assessment Criteria 
 Study Procedures Criteria 
 SAE Criteria 
 Randomization Criteria 
 Visit Schedule Criteria 
 Investigational Product Compliance 
 Efficacy Criteria 
 Administrative Criteria 
 Source Document Criteria 
 Regulatory or Ethics Approvals Criteria 
 Other Criteria 
 
A summary of protocol deviations related to COVID-19 will also be presented, as well as a 
listing of subjects with study conduct impacted by COVID-19. 
12. DEMOGRAPHICS AND BASELINE CHARACTERISTICS 
Demographics and baseline characteristics data will be presented for the FAS and Safety Set. 


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The data will be summarized by treatment, olorinab 25 and 50 mg pooled, and olorinab 10, 
25, and 50 mg pooled without statistical testing. The following demographic and baseline 
characteristics will be reported for this study: 
 
Age on consent (years)   
 
Sex at birth: Female and Male 
 
Child-bearing potential for women: Yes, No 
 
Race: American Indian or Alaska Native, Asian, Black or African American, 
Native Hawaiian or Other Pacific Islanders, Multiple, White, Not Reported 
 
Race group: White, Non-White, Not Reported  
 
Ethnicity: Hispanic or Latino, Non-Hispanic or Latino, Not Reported, Unknown 
 
Weight (kg) 
 
Height (cm) 
 
BMI (kg/m2) 
 
 
 
 
Time since IBS diagnosis (years) – calculated relative to date of randomization 
 
IBS subtype: IBS-C, IBS-D 
 
eDiary Compliance Rate (%) 
 
Baseline AAPS 
 
Baseline AAPS Category: (≤ 7, ˃7) 
 
12.1. DERIVATIONS 
 
BMI (kg/ m2) = weight (kg)/ height (m)2 
 
Time since IBS diagnosis (years) = (date of randomization – date of IBS 
diagnosis + 1) / 365.25 
o 
Partial dates are imputed to the earliest possible date  
 
Weight (kg) = Weight (lb) * 0.4536  
 
Height (cm) = Height (in) * 2.54 
 
Height (m) = Height (in) * 0.0254 = Height (cm) * 0.01 
13. MEDICAL HISTORY 
Medical History conditions are defined as those conditions which stop prior to Screening. 
Medical History will be collected on the Medical History eCRF and coded using Medical 


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Dictionary for Regulatory Activities (MedDRA, version 23.0 or higher). Medical History 
will be summarized for the Safety Set by system organ class (SOC) and preferred term (PT).  
14. CONCOMITANT MEDICAL CONDITIONS 
Concomitant medical conditions are conditions (other than the indication being studied) 
which started prior to or at Screening and are ongoing at the date of Screening. Concomitant 
medical conditions will be captured on the Medical History eCRF page and coded using 
MedDRA version 23.0 or higher. Concomitant medical conditions will be summarized for 
the Safety Set by SOC and PT. 
15. MEDICATIONS 
Medications will be collected on the Prior or Concomitant Medications eCRF and coded 
using WHODD version 01Mar2020 or higher.  
 
The prior and concomitant medications are defined below. See Appendix 2. Partial Date 
Conventions for handling of partial dates for medications. In the case where it is not possible 
to define a medication as prior or concomitant, the medication will be classified by the worst 
case; i.e., concomitant.  
 
‘Prior’ medications are medications which started and stopped prior to the first 
dose of study treatment.  
 
‘Concomitant’ medications are medications which started prior to, on or after 
the first dose of study treatment and continued into the main study period. 
Prior and concomitant medications will be summarized separately by ATC Level 3 and 
Preferred Drug name for the Safety set. In addition, prior and concomitant medications 
related to IBS will be summarized.  
16. STUDY TREATMENT EXPOSURE 
The date of first and last study treatment administration will be taken from the eCRF “On 
Site Dosing Administration” form. Interruptions, compliance, and dose changes are not taken 
into account for duration of exposure. Study duration and treatment duration will be 
summarized as continuous variables for each treatment, olorinab 25/50 mg pooled, and 
pooled olorinab using descriptive statistics. The duration of treatment will also be 
summarized categorically: ≤ 4 weeks, > 4 to ≤ 8 weeks, > 8 weeks. Additionally, the total 


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subject-years of exposure and subject-years on study will be included in the summary. 
 
Treatment formulation (capsules or tablets), number of capsules/tablets taken, missed, and 
frequency and percentage of subjects who missed at least one dose or who had at least one 
dose interruptions recorded on the Dosing Administration eCRF will also be summarized. 
Treatment compliance will also be summarized using both descriptive statistics and 
summarized categorically: < 85%, ≥ 85 to ≤ 115%, and > 115%. 
16.1. DERIVATIONS 
 Study Duration (days) = date of last study visit – date of screening visit + 1 
 Treatment duration (days) = date of last study treatment administration – date of first 
study treatment administration + 1 
 Treatment duration (weeks) = (date of last study treatment administration – date of first 
study treatment administration + 1)/7. 
 Total subject-years on study = sum of duration of time on study across all subjects 
divided by 365.25 
 Total subject-years of exposure = sum of duration of treatment exposure across all 
subjects divided by 365.25 
17. STUDY TREATMENT COMPLIANCE  
Compliance to study treatment will be summarized for the Safety Set. Total number of 
tablets expected, total number of tablets taken, total number of tablets missed, overall 
compliance to study treatment, frequency and percentage with overall compliance with the 
following categories: <85%, ≥85% to ≤115%, and ˃115%. By-visit compliance will also be 
summarized. 
 
Subjects with administration compliance greater than 115% and subjects who do not return 
any study treatment or study packaging will be asked for the reason for the overcompliance 
or missing study treatment. Their responses will be recorded on the Drug Accountability 
eCRF and will be listed. 
17.1. DERIVATIONS 
Compliance to study treatment is based on the Drug Accountability eCRF and will be 
calculated as the number of capsules/tablets taken (total dispensed – total returned) divided 


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by the prescribed number of capsules/tablets, expressed as a percentage (see calculations 
below).  
 
The study treatment is given three times daily (tid), and it is assumed that the subject should 
take study treatment from the morning of the visit day at which their treatment is initially 
dispensed to the evening before their last treatment return date, as subjects are advised to 
wait to take their dose at the study site until all assessments and procedures have been 
completed on study days. For example, if the initial dispensation date is Day 1 and the last 
return date is Day 85, then the subject should have taken 3 capsules/tablets each day on Days 
1 to 84; hence, the total number of prescribed capsules would be 84×3 = 252. Multiple 
bottles may be dispensed at one visit; in these cases, “Per Visit” compliance will be non-
missing if at least one bottle is returned. 
 
 
 “Per Visit” Compliance to study treatment at Visit X will be calculated as follows: 
 
 ሺሾ୒ ୭୤ େୟ୮ୱ୳୪ୣୱ ୢ୧ୱ୮ୣ୬ୱୣୢ ୟ୲ ୚୧ୱ୧୲ ሺଡ଼ሻሿ ି ሾ୒ ୭୤ େୟ୮ୱ୳୪ୣୱ ୰ୣ୲୳୰୬ୣୢ ୟ୲ ୚୧ୱ୧୲ ଡ଼ାଵሿሻ
ሼ ሾୈୟ୲ୣ ୭୤ ୚୧ୱ୧୲ ଡ଼ାଵሿ ି ሾୈୟ୲ୣ ୭୤ ୈ୧ୱ୮ୣ୬ୱ୧୬୥ ୟ୲ ୚୧ୱ୧୲ ሺଡ଼ሻሿ  ሽ ୶ ଷ
  x 100 
 
 
Overall Compliance to study treatment will be calculated as follows: 
 
ሼሺሾ୒ ୭୤ େୟ୮ୱ୳୪ୣୱ ୢ୧ୱ୮ୣ୬ୱୣୢ ୟ୲ ୚୧ୱ୧୲ ଵሿ – ሾ୒ ୭୤ େୟ୮ୱ୳୪ୣୱ ୰ୣ୲୳୰୬ୣୢ ୟ୲ ୚୧ୱ୧୲ ଶሿሻ
ା⋯ା
ሺሾ୒ ୭୤ େୟ୮ୱ୳୪ୣୱ ୢ୧ୱ୮ୣ୬ୱୣୢ ୟ୲ ୚୧ୱ୧୲ ሺଡ଼ିଵሻሿ – ሾ୒ ୭୤ େୟ୮ୱ୳୪ୣୱ ୰ୣ୲୳୰୬ୣୢ ୟ୲ ୚୧ୱ୧୲ ଡ଼ሿሻሽ 
ሾୈୟ୲ୣ ୭୤ ୚୧ୱ୧୲ ଡ଼ሿ ି ሾୈୟ୲ୣ ୭୤ ୈ୧ୱ୮ୣ୬ୱ୧୬୥ ୟ୲ ୚୧ୱ୧୲ ଵሿ ൈଷ
  x 100 
 
For subjects who permanently stop the study treatment before Week 12, the “Date of Visit 
X” in Overall Compliance calculations will be replaced by the date of study withdrawal.  
 


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18. EFFICACY OUTCOMES  
18.1. PRIMARY EFFICACY 
18.1.1. 
PRIMARY EFFICACY VARIABLE & DERIVATION 
The primary efficacy variable is the change in the AAPS from baseline to Week 12, where 
baseline is based on the randomization date (Day 1). Baseline AAPS and AAPS by week 
during the treatment period is derived as described in Section 7.2. Baseline AAPS is a 
required datapoint for eligibility; therefore, no missing data for baseline AAPS is expected. 
For the treatment period, if any AAPS value is completely missing, the primary efficacy 
analysis will be conducted on the non-missing data.  
18.1.2. 
MISSING DATA METHODS FOR PRIMARY EFFICACY VARIABLE 
Missing AAPS will not be imputed for the primary analysis. The primary analysis method, 
MMRM, will utilize all data available during the Main Study treatment period from subjects 
included in the FAS. Analysis of sensitivity to missing data for the primary endpoint will be 
performed as described in Section 18.1.4. 
18.1.3. 
PRIMARY ANALYSIS OF PRIMARY EFFICACY VARIABLE 
The primary efficacy analysis will be performed using the FAS population. The primary 
efficacy endpoint will be analyzed using a MMRM analysis with treatment group (placebo, 
olorinab 10 mg, olorinab 25 mg, olorinab 50 mg), stratification factors (sex and IBS 
subtype), week, and treatment-by-week interaction as factors and baseline AAPS as a 
covariate. Week will include each week from Week 1 to Week 12 based on eDiary data 
beginning from Day 1 (Randomization). In addition, two additional MMRMs will be 
completed with the following treatment groupings: 1) placebo, olorinab 10 mg, and olorinab 
25 and 50 mg pooled and 2) placebo and pooled olorinab. 
 
The primary objective of this study is to test the hypothesis that the change in AAPS from 
baseline to Week 12 is the same across treatment group (placebo, olorinab 10 mg, 25 mg, and 
50 mg). The alternative hypothesis is that the change in AAPS from baseline to Week 12 
differs between placebo and one of the olorinab treatments (10 mg, 25 mg, or 50 mg) or 
olorinab 25 mg/50 mg pooled.  
 
Four hypothesis tests for the primary endpoint using the primary analysis methodology 


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described above are specified below. 
o MMRM model with treatment groups (placebo, 10 mg, 25 mg, and 50 mg), and with 
3 pre-specified comparisons of placebo vs. the individual treatment groups of 
olorinab (10 mg, 25 mg, and 50 mg) 
o MMRM with treatment “groups” placebo, 10 mg, and pooled olorinab [25 mg + 50 
mg], and with 1 pre-specified comparison of placebo vs. the pooled olorinab group 
[25 mg + 50 mg] 
 
No multiplicity control is planned for this Phase 2 study. If any of the four pre-specified 
hypothesis test analyses demonstrates statistical significance at the 0.05 (2-sided) 
significance level at Week 12, then the study successfully demonstrated that the primary 
endpoint was met. 
 
Change from baseline to Week 12 by scheduled visit is considered the supporting primary 
efficacy endpoint. It will be analyzed using a model of MMRM with treatment (placebo, 
olorinab 10 mg, olorinab 25 mg, olorinab 50 mg), stratification factors (sex and IBS 
subtype), visit, and treatment-by-visit interaction as factors and baseline AAPS as a 
covariate. Visits will include all scheduled visits except Visit 9 (Week 14).  The analysis will 
also be repeated using the treatment groupings described in the preceding paragraph. If one 
of the MMRM models demonstrates statistically significant difference between placebo and 
one of the active doses of olorinab at Week 12, olorinab may be declared to achieve a 
statistically better reduction in AAPS than placebo.  
 
All models will be run under the assumption of an unstructured covariance matrix. If the 
unstructured covariance matrix results in a lack of convergence, the heterogeneous Toeplitz 
covariance structure, followed by the heterogeneous autoregressive covariance structure, 
followed by compound symmetry will be used. The Newton-Raphson with ridging 
optimization technique will be used to aid with convergence. The Kenward-Rogers method 
will be used to estimate the denominator degrees of freedom. An example of the SAS PROC 
MIXED code used for the repeated measures models is provided in Appendix 4. Example 
SAS Code.  
 
Descriptive statistics, including the number of observations, mean, SD, median, minimum, 
and maximum will be provided by treatment at each scheduled visit or each week. 
Additionally, p-values for within-treatment group change (for the primary efficacy variable, 
change in AAPS from baseline to Week 12) resulting from a one sample t-test using least 
squares mean estimates and associated standard errors will be presented by treatment. Least 
square mean differences between treatment groups ([i.e., olorinab 10 mg vs. placebo, 


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olorinab 25 mg vs. placebo, and olorinab 50 mg vs. placebo], [olorinab pooled vs. placebo] 
or [olorinab 10 mg vs. placebo, olorinab 25 and 50 mg pooled vs. placebo]), the 
corresponding standard errors, 95% CIs, and p-values will also be presented. 
18.1.4. 
SENSITIVITY ANALYSIS OF PRIMARY EFFICACY VARIABLE 
The robustness of the primary endpoint result will be assessed for the FAS using various 
sensitivity analyses. The following analyses will be used: 
 ANCOVA with observed cases (OC): Treatment comparisons of the change in the 
AAPS from baseline to Week 12 will be made using an ANCOVA model with 
treatment and stratifications (sex and IBS subtype) as factors and baseline AAPS as a 
covariate. Type III sums of squares for least-squares (LS) will be used for the 
statistical comparison; the least squares mean differences, 95% CI, and p-value for 
each least squares mean difference value will be reported.  
 ANCOVA with multiple imputation (MI): MI under the missing at random (MAR) 
assumption will be performed. Any missing AAPS data from Week 1 to Week 12 at 
the planned assessments will be imputed using MI under MAR. MAR assumes the 
missing value is independent of unobserved outcomes given observed data (i.e., 
subjects with missing AAPS can be modeled based on subjects with observed AAPS). 
Unscheduled visits are not included in the analysis for this approach. The following 
steps will be implemented: 
 Step 1: Non-monotone missing data will first be imputed to a monotone missing 
pattern using the multivariate joint Gaussian imputation model that utilizes the 
Markov Chain Monte Carlo (MCMC) method in the SAS PROC MI procedure. 
The number of imputations will be 100 and SEED = 4161. Each imputed dataset 
will only have missing data at the end of subjects’ records (monotone missing 
data pattern). A separate imputation model will be used for each treatment group 
and only subjects with non-missing baseline AAPS will be included. If 
convergence cannot be met using a separate imputation model for each treatment 
group, data for all treatments will be imputed using the same model. The 
stratification variables at each planned visit will be included in the imputation 
models.  
 Step 2: The remaining monotone missing data will be imputed using sequential 
regression MI, where a separate regression model is estimated for the imputation 
of each variable (i.e. measurement at each time point). Each regression model will 
include explanatory variables for treatment, baseline AAPS, and the stratification 
factors. The number of imputations will be 1 and SEED = 4161. 
 Step 3: An ANCOVA model with treatment, randomization stratification (sex and 


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IBS subtype) as factors and baseline AAPS as a covariate will be run for each of 
the 100 datasets to obtain 100 estimators of interest. 
 Step 4: SAS PROC MIANALYZE will be used to produce overall pooled 
estimates (mean of 100 estimates) of least squares mean differences between 
placebo and each treatment with associated standard errors, CIs, and pooled p-
values presented. Additionally, SAS PROC MIANALYZE will be used to 
produce p-values for within-treatment group change based on a one sample t-test 
using pooled least squares mean estimates and associated standard errors. 
Summary statistics presented for Week 12 records will be based on the mean of 
the imputed records per subject per time point.  
 
The missing AAPS values will be imputed first and change from baseline values will 
be calculated based on imputed AAPS scores. 
 
There could be certain adjustments to the MI model specified in Step 2 above due to 
unexpected data issues after unblinding treatment. All post-unblinding modifications 
to the MI model or approaches to address missing data will be described in the 
Clinical Study Report (CSR). 
 
Nonparametric Wilcoxon Rank-Sum Test: The Wilcoxon Rank-Sum Test will be 
used to compare change in AAPS at Week 12 between treatment (each dose of 
olorinab vs placebo, olorinab 25 and 50 mg pooled versus placebo, and pooled 
olorinab vs placebo).  
18.1.5. 
SUPPLEMENTARY ANALYSIS OF PRIMARY EFFICACY VARIABLE 
All analyses described in Sections 18.1.3 and 18.1.4 will be repeated using the Per Protocol 
Set. 
18.2. SECONDARY EFFICACY 
18.2.1. 
SECONDARY EFFICACY VARIABLES & DERIVATIONS 
The secondary efficacy analyses will be performed for the FAS. The secondary efficacy 
endpoints are: 
 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 


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least 6 of the 12 weeks during the Treatment Period 
 The proportion of subjects achieving a ≥ 40% improvement in AAPS from baseline to 
Week 12 
 The proportion of subjects achieving a ≥ 40% improvement in AAPS from baseline for at 
least 6 of the 12 weeks during the Treatment Period 
 The proportion of subjects achieving a ≥ 50% improvement in AAPS from baseline to 
Week 12 
 The proportion of subjects achieving a ≥ 50% improvement in AAPS from baseline for at 
least 6 of the 12 weeks during the 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 
 
The secondary variables will be derived from the information recorded on the Daily Diary.  
 
Baseline and post-baseline AAPS are calculated as described in Section 7.2.  
18.2.2. 
MISSING DATA METHODS FOR SECONDARY EFFICACY VARIABLES 
For the continuous endpoint of percent change in AAPS from baseline to Week 12, the 
MMRM models described in Section 18.1.3 will be used. For the continuous endpoint of 
change in number of pain free days per week from baseline to Week 12, the by-week 
MMRM model described in Section 18.1.3 will be used. For the change in number of pain 
free days per week endpoint, a subject with a missing value for a given day when there are 
non-missing values during the week will be assumed to not be pain free for that day.  
 
For the binary endpoints of proportion of subjects achieving a ≥ 30% improvement in AAPS 
from baseline to Week 12 and 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, 
all missing post-baseline AAPS values will be imputed using MI under the MAR assumption 
as described in Steps 1 and 2 of Section 18.1.4. The following steps will then follow: 
 
 Step 3: Subjects will be classified as responders or non-responders per imputed data 
based on the endpoint criteria specified in Section 18.2.1 for the endpoint of interest. 
For each dataset, the proportion of responders and non-responders will be calculated.  
 Step 4: The Cochran-Mantel-Haenszel (CMH) test, stratified by sex and IBS subtype, 
will be run for each of the 100 datasets to obtain 100 odds ratio estimates of interest 
(active treatment over placebo). Common risk difference estimates, CIs, and two-
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Mantel-Haenszel weights. For the 100 odds ratio estimates and difference estimates in 
each treatment, the estimates will be passed directly to PROC MIANALYZE, along 
with their associated standard errors. In some cases, an odds ratio estimate may be 
calculated as missing due to a value of zero in the denominator for certain treatment 
comparisons; the missing value for that imputation cannot be passed to PROC 
MIANALYZE. As a result there may be fewer than 100 odds ratio estimates used to 
calculate the pooled estimate in these instances.  
 Step 5: SAS PROC MIANALYZE will be used to produce an overall pooled estimate 
(mean of 100 estimates) of the odds ratio with associated CI, and of the percentage 
difference estimate with associated standard error, CI, and two-sided pooled p-values. 
Counts and percentages of responders will also be summarized using SAS PROC 
MIANALYZE. 
 
The MI model will be pre-defined before database lock. However, there could be certain 
adjustments due to unexpected data issues after unblinding treatment. All post-unblinding  
modifications to the MI model or approaches to address missing data will be described in  
the CSR. 
 
The robustness of the secondary endpoint results will be assessed using various sensitivity 
analyses, described in Section 18.2.4. 
18.2.3. 
ANALYSIS OF SECONDARY EFFICACY VARIABLES 
For the continuous secondary efficacy endpoints, percent change in AAPS from baseline to 
Week 12 and change in number of pain free days per week from baseline to Week 12, the 
same methodology used for the primary efficacy endpoint will be used for the analysis. The 
analyses for percent change in AAPS from baseline at Week 12 will include both evaluation 
at the scheduled visit for Week 12 (Visit 8) and Week 12 based on baseline day as described 
in Section 18.1.3. The analyses for change in number of pain free days per week from 
baseline at Week 12 above will include the evaluation at Week 12 based on baseline day as 
described in Section 18.1.3. 
 
For the binary secondary efficacy endpoints (proportion of subjects with a ≥ 30%,  ≥ 40%, 
and  ≥  50% improvement in AAPS from baseline to Week 12 and proportion of subjects 
achieving a ≥ 30%,  ≥ 40%, and  ≥ 50% improvement in AAPS from baseline for at least 6 of 
the 12 weeks during the Main Study Treatment Period), a CMH test will be conducted to 
compare placebo against each of the olorinab treatments (10 mg, 25 mg, 50 mg, pooled 25 
and 50 mg, and olorinab pooled), stratified by the randomization factor (sex and IBS 


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subtype). The responder rate and the odds ratio relative to placebo will be presented with 
corresponding CIs, and the percentage of difference from placebo will be presented together 
with corresponding 95% CIs and the p-values. The 95% CI for the responder rate of each 
treatment group will be generated using the normal approximation method. Missing data will 
be imputed using MI, as described in Section 18.2.2.  
18.2.4. 
SENSITIVITY ANALYSIS OF SECONDARY AND KEY EXPLORATORY EFFICACY 
VARIABLES 
The robustness of the secondary endpoints’ results will be assessed using various sensitivity 
analyses. The following analyses will be used: 
 For continuous endpoints, the ANCOVA with OC, ANCOVA with MI, and Non-
parametric Wilcoxon Rank-Sum Test will be implemented as described in Section 
18.1.4. 
 For binary endpoints based on AAPS and bowel motility endpoints (including the 
three composite responder endpoints for IBS-C and IBS-D), the sensitivity to missing 
data assumptions will be evaluated with the following models: 
o CMH with OC: The CMH test described in the analysis of secondary efficacy 
variables Section will be repeated on the population of subjects with observed 
data for the given analysis.  
o CMH with NRI (non-responder imputation): The CMH test described in the 
analysis of secondary efficacy analysis Section will be completed on all 
subjects in the FAS. Subjects will be considered a non-responder if they do 
not meet the endpoint criteria (e.g. a ≥ 30% improvement in AAPS) or are 
missing data at the time point of interest. All non-responders at the time point 
of interest, as well as subjects who discontinue study treatment at any time 
prior to that time point for any reason, will be defined as non-responders for 
the analysis. Randomized subjects without at least 1 post-baseline observation 
will also be defined as non-responders in NRI analyses.   
o Logistic regression (OC): A logistic regression model using observed cases 
will be used to analyze treatment comparisons between the proportion of 
subjects achieving a ≥ 30% improvement in AAPS from baseline to the given 
time point, with the explanatory variable of treatment (placebo, olorinab 10 
mg, olorinab 25 mg, olorinab 50 mg), randomization stratification factor (sex 
and IBS subtype) and baseline AAPS as a covariate. In addition, two 
additional logistic regression models will be completed with the following 
treatment groupings: 1) placebo, olorinab 10 mg, and olorinab 25 and 50 mg 
pooled and 2) placebo and pooled olorinab. The endpoint of subjects 


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achieving a ≥ 30% improvement in AAPS from baseline for at least 6 of the 
12 weeks during the Treatment Period will also be analyzed using the same 
logistic regression models. 
 Sensitivity to analysis set: The secondary analysis will be repeated for the Per 
Protocol Set. 
 
The sensitivity analyses for the composite responder endpoint based on AAPS reduction and 
no worsening in bowel motility as defined in Section 18.3.8, will be performed using CMH 
with OC and CMH with NRI in FAS only. 
 


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19. SAFETY OUTCOMES 
All analyses for safety outcomes will be based on the safety analysis set. All safety data will 
be listed and summarized by actual treatment group. There will be no statistical comparisons 
between the treatments for safety data, unless otherwise specified. Unless otherwise stated, 
treatments displayed will include placebo, olorinab 10 mg, olorinab 25 mg, olorinab 50 mg, 
olorinab 25 and 50 mg pooled, and pooled olorinab. 
19.1. ADVERSE EVENTS 
AEs will be coded using Medical Dictionary for Regulatory Activities (MedDRA) central 
coding dictionary, Version 23.0 or higher. Treatment-emergent adverse events (TEAEs) are 
defined as: 
 An AE that occurs after the first dose of study treatment (olorinab or placebo) that 
was not present before the first dose of treatment, OR 
 An AE that increases in severity after the first dose of study treatment (olorinab or 
placebo), if the event was present before the first dose of treatment. 
All TEAEs will be coded and summarized by system organ class (SOC) and preferred term 
(PT) and will be presented by descending order of frequency. AEs occurring before the first 
dose of study treatment will be summarized separately. Listings will include all AEs (TEAEs 
and Non-TEAEs).  
 
See Appendix 2. Partial Date Conventions for handling of partial dates for AEs for the 
purpose of assigning treatment-emergent flags. In the case where it is not possible to define 
an AE as treatment-emergent or not, the AE will be classified by the worst case; i.e. 
treatment emergent.  
19.1.1. 
ALL TEAES  
All TEAEs will be summarized by SOC and PT in each treatment and with olorinab 25 and 
50 mg pooled and olorinab active treatments pooled and presented by descending order of 


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frequency in any treatment. TEAEs will also be summarized by maximum severity and 
relationship to study treatment. A separate summary of related TEAEs and related TEAEs by 
maximum severity will also be provided. 
19.1.2. 
SEVERITY 
Severity is classified by grade using the Common Terminology Criteria for Adverse Events 
version 5.0 (CTCAE v5.0) system as defined below. The CTCAE grade will be assessed by a 
nurse and/or physician and will be recorded in the AE severity Section on the Adverse 
Events eCRF.  
 
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 (e.g., 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. 
 
TEAEs with a missing severity but identified as a life-threatening serious adverse event 
(SAE) or one requiring initial or prolonged hospitalization will be classified as Grade 4 
(Potentially Life-threatening), otherwise missing severity will be classified as Grade 3 
(severe). If a subject reports a TEAE more than once within that SOC/ PT, the AE with the 
greatest severity will be used in the corresponding severity summaries.  
19.1.3. 
RELATIONSHIP TO STUDY TREATMENT 
Relationship is classed as “not related”, “unlikely related”, “probably related”, or “related” 
(increasing severity of relationship) by the Investigator. A “related” TEAE for the purpose of 
TEAE summaries is defined as a TEAE with a relationship to study treatment as “related” or 
“probably related” to study treatment. TEAEs with a missing relationship to study treatment 
will be regarded as “related” to study treatment. “Unlikely related” will be counted as non-
related TEAE.  If a subject reports the same AE more than once within the same SOC/ PT, 
the AE with the strictest causality will be used in the corresponding relationship summaries. 
All TEAEs will be summarized by SOC, PT, and relationship to study treatment. 


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19.1.4. 
TEAES LEADING TO DISCONTINUATION OF STUDY TREATMENT 
TEAEs leading to permanent discontinuation of study treatment will be identified by action 
taken being recorded as “Drug withdrawal” on the AE page of the eCRF. All TEAEs leading 
to discontinuation of study treatment will be summarized by SOC and PT. A listing of all 
TEAEs leading to discontinuation of study treatment will also be presented.  
19.1.5. 
TEAES LEADING TO STUDY DISCONTINUATION 
TEAEs leading to study discontinuation will be noted on the End of Study eCRF. All TEAEs 
leading to study discontinuation will be summarized by SOC and PT. 
19.1.6. 
SERIOUS AND NON-SERIOUS TEAES 
Serious adverse events (SAEs) are those events recorded as “Serious” on the Adverse Events 
page of the eCRF. All serious TEAEs will be summarized by SOC and PT. All non-serious 
TEAEs will also be summarized by SOC and PT. A serious AE listing will also be presented. 
19.1.7. 
TEAES LEADING TO DEATH 
TEAEs leading to Death are those events which are recorded as “Fatal” on the Adverse 
Events page of the eCRF. A summary of TEAEs leading to death by SOC and PT will be 
prepared by treatment. 
19.1.8. 
TEAES OF SPECIAL INTEREST  
To date, no AEs of special interest have been identified related to olorinab. Potential AEs of 
special interest may be identified by clinical or medical reviewers. In addition to appropriate 
reporting of these events as an AE or SAE, supplementary detailed information may be 
collected. Any identified AEs of special interest will be summarized by SOC and PT 
separately. A listing will also be provided.  
19.1.9. 
OVERALL SUMMARY OF ADVERSE EVENTS 
In addition to the summaries by SOC and PT as described in Sections 19.1.1 to 19.1.5, an 
overview of TEAEs will be summarized (not broken down by SOC or PT) by number and 
frequency of subjects and by number of AEs by treatment: 
 
Any AE (including non-TEAEs) 


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 
Any TEAE 
 
Any related TEAE 
 
TEAEs by maximum severity 
 
Related TEAEs by maximum severity 
 
TEAEs by relationship to study treatment 
 
TEAEs leading to death 
 
Serious TEAEs 
 
Non-serious TEAEs 
 
Related Serious TEAEs 
 
TEAEs leading to study treatment discontinuation 
 
TEAEs leading to study treatment interruption 
 
TEAEs leading to study discontinuation 
 
Related TEAEs leading to study treatment discontinuation 
 
Related TEAEs leading to study treatment interruption 
 
Related TEAEs leading to study discontinuation 
 
TEAE leading to death 
19.2. DEATHS 
For any reports of death during the study as recorded on the End of Study page of the eCRF, 
the information will be presented in a listing. 
19.3. LABORATORY EVALUATIONS 
Results from the central laboratory will be included in the reporting of this study for 
chemistry, hematology, coagulation, urinalysis, thyroid chemistry, celiac, basal metabolic 
panel, virology, and serum pregnancy. A list of laboratory assessments to be included in the 
outputs is included in Table 3 in the protocol. If local and central laboratory assessments are 
available from the same day, central laboratory assessments will be used in the analysis. 
 
Presentations will use SI Units. Quantitative laboratory measurements reported as “< X”, i.e. 
below the lower limit of quantification (BLQ), or “> X”, i.e. above the upper limit of 
quantification (ULQ), will be converted to X for the purpose of quantitative summaries, but 
will be presented as recorded, i.e. as “< X” or “> X” in the listings. 
 
Laboratory parameters such as hepatic enzymes, renal function and hematology values will 
be grouped and presented together. The following summaries will be provided for laboratory 
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 
Value and change from baseline by visit (for quantitative measurements) 
 
Incidence of abnormal values according to laboratory reference ranges by visit 
 
Shift from baseline to end of treatment according to laboratory reference range 
(for quantitative measurements and categorical measurements) 
 
Summary of subjects with treatment-emergent abnormal lab results  
 
Listing of subject’s laboratory assessments at all timepoints. Values outside of 
the central laboratory reference range will be flagged. Values obtained from 
local laboratory will be flagged. 
19.3.1. 
LABORATORY REFERENCE RANGES AND MARKEDLY ABNORMAL CRITERIA 
Quantitative laboratory measurements will be compared with the relevant laboratory 
reference ranges in SI units and categorized as: 
 
Low: Below the lower limit of the laboratory reference range.  
 
Normal: Within the laboratory reference range (upper and lower limit included). 
 
High: Above the upper limit of the laboratory reference range. 
 
Treatment-emergent high result: a change from a value less than or equal to the 
high limit at all baseline visits to  a value greater than the high limit at any time 
during the treatment period. 
 
Treatment-emergent low result: a change from a value greater than or equal to 
the low limit at all baseline visits to a value less than the low limit at any time 
during the treament period. 
 
19.4. 12-LEAD ECG  
Results from the central 12-lead ECG Reading Centre will be included in the reporting of this 
study. The ECGs will be read and interpreted by the central ECG laboratory. For subjects 
enrolled before protocol amendment 2, there was an over-night observation period following 
randomization, and ECGs were collected at multiple timepoints on Day 1 and Day 2 (see 
below). 
 Day 1:  Prior to the first dose of study treatment and 2, 4, and 8 hours after the 
first dose (prior to the second dose), and 10 hours after the first dose (2 hours 
after the second dose). 
 Day 2:  Prior to the first dose of study treatment, and 2 and 4 hours after the 
first dose. 
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administration of the first daily dose of study treatment. 
 
For subjects enrolled after protocol amendment 2, on Day 1, ECG was collected prior to the 
first dose of study treatment and 2 hours after administration of study treatment. At all other 
indicated visits after baseline, ECGs were collected once per visit, prior to administration of 
the first daily dose of study treatment. 
 
The following ECG parameters will be reported for this study on the central read for each 
safety ECG: 
 
PR Interval (msec) 
 
QRS Interval (msec) 
 
QT Interval (msec) 
 
QTcF Interval (msec) [derived] 
 
QTcB Interval (msec) [derived, optional] 
 
Heart Rate (HR) (bpm) 
 
Overall interpretation of ECG (Investigator’s judgment): 
 Normal 
 Abnormal, Not Clinically Significant (Abnormal NCS) 
 Abnormal, Clinically Significant (Abnormal CS) 
The following summaries will be provided by treatment group for ECG data: 
 
Value and change from baseline by visit (for quantitative measurements) 
 
Shift in normal/abnormal NCS/abnormal CS from baseline to worst investigator 
overall interpretation of clinical significance post-baseline 
 
Shift in markedly abnormal categories from baseline to post-baseline by visit 
 
19.4.1. 
12-LEAD ECG: OUTLIER AND MORPHOLOGY ANALYSES 
The following Outlier and Morphology findings will be summarized with frequency count and 
percentage by treatment:  
 HR, tachycardic  
 HR, bradycardic 
 Short PR <120 ms  
 Prolonged PR >220ms 
 QRS >120 ms 
 QT new >500 ms 


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 QT new > 450 ms (male) 
 QT new > 470 ms (female) 
 QTcF new >500 ms 
 QTcF new >480 ms 
 QTcF >30 ms increase from baseline 
 QTcF >60 ms increase from baseline 
 New atrial fibrillation 
 New atrial flutter 
 New abnormal U waves 
 New ST segment depression changes 
 New ST segment elevation changes 
 New T wave inverted 
 New 2nd degree heart block 
 New 3rd degree heart block 
 New complete RBBB 
 New complete LBBB 
 New MI 
19.5. VITAL SIGNS 
Orthostatic vital signs (VS) include the collection of blood pressure (BP) and HR after the 
subject has been resting in the supine position for at least 5 minutes and then again after 1 and 3 
minutes of standing. For subjects enrolled before protocol amendment 2, there was an over-night 
observation period following randomization, and the orthostatic VS were collected at multiple 
timepoints on Day 1 and Day 2 (see below). 
 
• Day 1: 
Prior to the first dose of study treatment and 2, 4, 8 hours after the first dose 
(prior to the second dose), and 10 hours after the first dose (2 hours after the 
second dose). 
• Day 2: 
Prior to the first dose of study treatment and 2 and 4 hours after the first dose. 
 
At all other visits after baseline, orthostatic vital signs were collected once per visit, prior to 
administration of the first daily dose of study treatment. For Day 1 and Day 2, the assessment at 
the earliest time of the same day will be used for analysis. 
 
For subjects enrolled after protocol amendment 2, orthostatic BP and HR assessments were 
collected once per visit, prior to administration of the first daily dose of study treatment for the 
post-baseline visits. 


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The following VS data will be summarized using descriptive statistics by treatment group as well 
as for active treatment groups pooled. 
 
 The actual measurement values of vital signs (BP and HR at Supine, Standing 1 
and 3 minutes) at each visit/timepoint 
 Change from baseline for orthostatic VS (BP and HR at Supine, Standing 1 and 3 
minutes):  calculated as post-baseline values minus the value prior to the first dose 
on Day 1.  
 Change from supine to standing in orthostatic vital signs (BP and HR): calculated 
as the standing measurement minus the supine measurement by visit/timepoint. It 
will be calculated for 1-minute standing and 3-minute standing separately. 
 
Body temperature and respiratory rate were collected once per visit, prior to the administration of 
the first daily dose of study treatment (for visits occurring during the Treatment Period). Change 
from baseline will be summarized in a similar manner. Baseline is defined as the last 
measurement collected before the first dose on Day 1. 
Vital sign values meeting the criteria as defined in  
Table 2 below will be categorized as potentially clinically significant (PCS) findings. These 
findings will be summarized with frequency count and percentage for each treatment as well as 
for the active treatments pooled, both overall and by visit for the pre-dose period (including 
Screening, Run-in and Day 1/Pre-dose) and for the post-dose period  The summaries and counts 
will be presented at both the subject level (counting subjects with PCS findings) and event level 
(counting all PCS events).  
Table 2: Vital Sign PCS Criteria 
 
 
 
 
PCS Criteria 
 
Parameter 
PCS 
Category 
Systolic BP (mm Hg) 
High 
(> 155 Standing or ≥ 140 Supine) and Supine increase from 
baseline ≥ 20
Low 
(≤ 80 Standing or ≤ 90 Supine) and Supine decrease from 
baseline ≥ 20
Diastolic BP (mm Hg) 
High 
(> 105 Standing or ≥ 90 Supine) and Supine increase from 
baseline ≥ 15
Low 
(< 35 Standing or < 40 Supine) and Supine decrease from 
baseline ≥ 15
  Pulse Rate (bpm) 
High 
≥ 120 Standing or ≥ 100 Supine 
Low 
< 40 Standing or Supine 
  Orthostatic Systolic BP (mm Hg) 
Low
Supine to Standing decrease ≥ 20 


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PCS Criteria 
 
Parameter 
PCS 
Category 
  Orthostatic Diastolic BP (mm Hg) 
 
Low
Supine to Standing decrease ≥ 10 
Orthostatic Pulse Rate (bpm) 
High
Supine to Standing increase ≥ 30 
Respiratory Rate (brpm) 
High
≥ 28
Low
≤ 8
Temperature (°C) 
High
> 38
Low
< 35
 
Abbreviation: bpm = beats per minute; BP = blood pressure; brpm = breaths per minute; PCS = potentially clinically  
                       significant.  
Note: Standing is from Standing 1 or Standing 3 measurement.  
 
19.5.1. 
VITAL SIGNS SPECIFIC DERIVATIONS  
 
Temperature (⁰C) = (5/9) (Temperature (⁰F) – 32) 
19.6. PHYSICAL EXAMINATION 
All physical examination assessments will be listed.  
20. PHARMACOKINETICS ANALYSIS 
The PK analyses for the Main Study are described in the subsequent paragraphs. 
All PK concentrations will be reported and analyzed with the same precision as the source 
data provided by the bio-analytical laboratory regardless of how many significant figures or 
decimals the data carry. The unrounded derived PK parameters will be considered the source 
data for the calculation of descriptive statistics and rounded for reporting purposes in by-
subject listings. Pharmacokinetic parameters will be listed with the following 
rounding/precision conventions: 
 
Parameters directly obtained from source data (e.g., Cmax, dose-normalized Cmax, and 
Ctrough) will be reported and analyzed with the same precision as the source 
concentration data. 
 
Parameters obtained from actual elapsed sample collection times (e.g., tmax) will be 
reported with the same precision as the actual elapsed sampling time value (2 
decimal places) of the source data. 
 
All other pharmacokinetic parameters will be listed to one significant figure greater 
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Summary statistics for PK concentrations will include: number of observations (n), mean, 
SD, coefficient of variation (CV%), geometric mean, geometric CV%, minimum, median, 
and maximum.  
 
Summary statistics for PK parameters, except tmax, will include: n, arithmetic mean, 
arithmetic SD, CV%, minimum, median, maximum, geometric mean, and geometric CV%; 
geometric mean and geometric CV% will be calculated from available individual values that 
are greater than 0. For geometric mean calculation, the mean of log transformed values will 
be calculated, and then transformed back to the original scale by exponentiation. 
 
The PK parameter tmax will be summarized using n, median, minimum, and maximum. 
 
An n ≥3 will be required for calculations of descriptive statistics. If n <3, no descriptive 
statistics will be calculated; only n, minimum, and maximum, will be presented. 
 
For the reporting of descriptive statistics, the mean, SD, geometric mean, and geometric 
CV% will be presented to one digit more precision than rounding of the source data. The 
minimum, median, and maximum will be presented to the same precision as rounding of the 
source data.  Coefficient of variation will always be reported to 1 decimal place. 
20.1. PLASMA CONCENTRATION DATA 
Individual PK blood sample collection times, derived sampling time deviations where 
scheduled times are specified, and plasma concentrations of olorinab and the metabolites 
 and 
 will be listed.   
 
Plasma concentrations of each analyte will be summarized at the scheduled visit by 
scheduled time (where applicable) and stratified by formulation and treatment. Summaries 
for overall treatment group will also be presented.   
 
Concentrations that are BLQ will be treated as missing for the computation of geometric 
descriptive statistics, and zero for the computation of the remaining descriptive statistics. 
Concentrations that are missing will be omitted from the calculation of descriptive statistics. 
Concentrations associated with sampling time deviations will be included in the summaries, 
providing: 
 
For pre-dose timepoint, the samples are collected before the next dose,  
 
For post-dose timepoints, the samples are collected after the previous scheduled time 


PROTOCOL APD371-202 
Analysis Plan – Main Study 
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and before the next scheduled time, and the time deviation is not significant, as 
adjudicated by PK scientist and clinical pharmacologist (in which case their time 
deviance and its adjudication will be noted in protocol deviations). 
Only samples collected on Day 1 will be included in the Day 1 summaries (i.e., 0 day for the 
time window). For the summaries of visits after Day 1, under assumption for steady-state, 
samples collected on a day outside of the time window of ±3 days allowed in the protocol 
will still be included in the summaries for the corresponding scheduled visit.   
 
For each PK analyte, figures of arithmetic mean (SD) concentration-time serial profiles 
overlaid by treatment group, by dosage form and overall will be presented for Day 1, Day 2, 
and Week 4. By-subject plots of concentration-time serial profiles, overlaying parent and all 
metabolites will also be presented for Day 1, Day 2, and Week 4, with the 3 assessment days 
represented as panels in a single plot. All concentration-time profiles will be depicted on 
linear and semi-logarithmic scales. 
       Additional data presentation of pre-dose (Ctrough) concentrations is described in Section 20.2.  
20.2. PLASMA PHARMACOKINETIC PARAMETERS 
Plasma PK parameters for olorinab and the metabolites 
 and 
 after the first dose of the corresponding day on Day 1, Day 2, and at Week 4 will 
be calculated by noncompartmental methods. Actual elapsed time from dosing will be used.   
The following data handling conventions apply to the PK analyses for all analytes on Day 1, 
Day 2, and at Week 4, unless otherwise indicated: 
 
Pre-dose samples that are BLQ will be assigned a numerical value of zero. 
 
Any pre-dose concentration values that are quantifiable on Day 1 will be included in the 
PK analysis and identified in the CSR and the subject will be considered for potential 
exclusion from the pharmacokinetic analysis set. Although quantifiable concentration 
values at pre-dose on Day 1 are considered as anomalous, the PK parameters shall be 
listed and included in the parameter summaries for all such cases as a conservative 
approach to retain data for the study in patient population. 
 
Missing pre-dose samples: 
 
On Day 1, will be assigned a numerical value of zero and the subject will be 
considered for potential exclusion from the pharmacokinetic analysis set, 
 
On Day 2 and at Week 4, will be kept as missing and Ctrough will not be calculated.  
 
Post-dose BLQ concentrations will be assigned a value of zero if they precede 
quantifiable data points in the initial portion of the profile. 


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 
A BLQ value that occurs between quantifiable data points prior to Cmax, will be assigned 
concentration of zero.  
 
Following Cmax, BLQ values embedded between 2 quantifiable data points will be treated 
as missing. 
 
Trailing BLQ values after the last quantifiable concentration will be set to zero. 
In addition, for calculating Day 1 AUC(0-8): 
 
Actual time of sample collection, regardless of time deviations, rather than scheduled 
time shall be used to derive AUC0-8. 
 
If concentration at t=8 h is available but collection time is missing, AUC(0-8) will be 
calculated using scheduled time. 
 
If concentration at t=8 h is missing, AUC(0-8) will not be calculated 
 
AUCall shall be used as an estimate of AUC(0-8) if concentrations fall to BLQ at or before 
reaching t=8 h. 
The same nominal dose administered will be used for both the powder in capsule (PIC) and 
tablet formulations (as the dose input for the olorinab analysis and for calculating dose-
normalized exposures for the different analytes). 
   
The following PK parameters will be calculated for olorinab and the metabolites 
 
 unless otherwise indicated: 


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Ctrough  
Observed plasma concentration at the end of the dosing interval, obtained from the value 
measured prior to the next dose. 
(Unit: ng/mL). 
Cmax 
Maximum concentration in plasma 
 (Unit: ng/mL). 
Cmax /D 
Dose-normalized Cmax. 
(Unit: ng/mL/mg). 
tmax 
Time of maximum concentration 
(Unit: h). 
MRCmax 
Molar-corrected metabolite to parent (olorinab) Cmax ratio ,calculated as follows: 
metabolite Cmax
olorinab Cmax  ൈ
olorinab MW
metabolite MW 
MRCmax will be calculated for 
 and 
. 
AUC(0-8) 
Area under the concentration-time curve of the analyte in plasma during the dosing 
interval. 
(Unit: ng*h/mL) 
AUC(0-8) /D 
Dose-normalized AUC(0-8) 
(Unit: ng*h/mL/mg). 
MRAUC(0-8) 
Molar-corrected metabolite to parent (olorinab) AUC(0-8) ratio, calculated as follows: 
metabolite AUCሺ0 െ8ሻ
olorinab AUCሺ0 െ8ሻ ൈ
olorinab MW
metabolite MW 
MRAUC(0-8) will be calculated for 
 and 
. 
The areas under the curve will be calculated by linear up/log down trapezoidal summation, 
where at least 3 quantifiable post-dose concentrations are available. 
 
 
 
 
The parameter Ctrough will be obtained from concentrations measured pre-dose at Weeks 2, 4, 8, 
10, and 12. Other parameters (Cmax, Cmax/D, tmax and MRCmax) will be calculated for Day 1, Day 
2 (protocol Amendment 1 only), and Week 4.  In addition, for subjects who are randomized 
under protocol Amendment 1 with more timepoints in the PK sampling schemes, Ctrough obtained 
from concentrations measured at 8-hour timepoint on Day 1 and pre-dose on Day 2, and AUC(0-8) 
and MRAUC(0-8) on Day 1 will also be calculated. 
 


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Individual plasma PK parameters will be listed and summarized for each analyte at the scheduled 
visit and by treatment, formulation, and IBS subtype. Day 1 PK parameters will be summarized 
separately for subjects who are randomized under protocol Amendment 1 and after protocol 
Amendment 1. In the event that subject numbers are too low to summarize Day 1 PK parameters 
by treatment, formulation, and IBS subtype (less than 3 subjects in each subgroup), parameters 
may be summarized by treatment and formulation, and additionally by treatment and IBS 
subtype.  
 
Ctrough of each analyte will be summarized per day, treatment, formulation, and IBS subtype, for 
all pre-dose trough concentrations sampled within the following time brackets: 12 hours of the 
previous day’s dose (immediate prior dose was not more than 12 hours before trough sample) 
and within one hour of dosing (trough sample taken at or not more than one hour before) on the 
trough assessment day. Summaries for overall treatment group will also be presented. For each 
analyte, figures of geometric mean (geometric CV%) Ctrough profiles overlaid by treatment group 
will be presented on linear scales. Individual values and geometric means of Cmax will be plotted 
versus dose for Day 1, Day 2, and at Week 4. In addition, plots of individual values and 
geometric means of AUC(0-8) versus dose on Day 1 will be presented for the overall treatment 
group of subjects who are randomized under protocol amendment 1.  
21. IMPACT OF COVID-19 
The study has been closely monitored during the period of COVID-19 and the impact of 
COVID-19 to data analyses is minimal. The below analyses related to COVID-19 are 
planned to document any impacts of the pandemic. Post hoc explanatory data analyses may 
be planned after database lock if the data warrants the request. 
 Summary of major protocol deviations caused by COVID-19 
 A listing of any adverse events related to COVID-19  
 A listing of any subjects with phone or remote visits due to COVID-19. 
22. GENETIC AND BIOMARKERANALYSES 
Genetic and biomarker analyses will be completed by Sponsor and will be described in a 
separate analysis plan if needed. 
23. DATA NOT SUMMARIZED OR PRESENTED 
The other variables and/or domains not summarized or presented are: 


PROTOCOL APD371-202 
Analysis Plan – Main Study 
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 
Comments 
 
Meals (Day 1)  
These domains and/or variables will not be summarized or presented but will be available in 
the clinical study database, SDTM and/or ADaM datasets. 


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Analysis Plan – Main Study 
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24. REFERENCES  
Dobson, A. J. (2002). An introduction to generalized linear models, 2nd ed. Chapman & 
Hall/CRC. 
EMA. (n.d.). Guideline on Missing Data in Confirmatory Clinical Trials. Retrieved 
December 15, 2011, from European Medicines Agency: 
http://www.ema.europa.eu/docs/en GB/document library/Scientific guideline/2010/09/WC
500096793.pdf 
Liang, K., Zeger, S., Longitudinal Data Analysis for Continuous and Discrete Responses for 
Pre-Post Designs. Sankhyta: The Indian Journal of Statistics. 2000. 62(B): 134-148. 
Little, R., & Yau, L. (1996). Intent-to-Treat Analysis for Longitudinal Studies with Drop-
Outs. Biometrics , vol 52, 1324-1333. 
 
 
 
 
 
 
 
 
 


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START 
DATE 
STOP 
DATE 
ACTION 
Partial 
Impute stop date as latest possible date (i.e. last day of 
month if day unknown or 31st December if day and month 
are unknown), then: 
If medication stop date < study treatment first dose date, 
assign as prior 
If medication stop date ≥ study treatment first dose date, 
assign as concomitant 
Missing 
Assign as concomitant 


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Statistical Analysis Plan - Main Study - 21-Jan-2021
Electronic Signature Manifestation
This page is a manifestation of the electronic signature(s) used in compliance with the organization's
electronic signature policies and procedures.
Page 79 - Object 1000551A0000000033CEBDD8
Signer Full Name
Meaning of Signature
Date and Time
Document Approval (I certify that I have the
education, training and experience to perform
this task)
15 Jan 2021 23:37:46 UTC
Document Approval (I certify that I have the
education, training and experience to perform
this task)
21 Jan 2021 14:58:11 UTC




PROTOCOL APD371-202 
Analysis Plan – Long-Term Extension Study 
Page 1 of 50
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
APD371-202 
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 
 
 
 
 
 
AUTHOR: 
  
VERSION NUMBER AND DATE: 1.0 17MAY2021 
 
 
 


PROTOCOL APD371-202 
Analysis Plan – Long-Term Extension Study 
Page 2 of 50
 
 
STATISTICAL ANALYSIS PLAN SIGNATURE PAGE 
Statistical Analysis Plan V1.0 (Dated 17MAY2021) for Protocol APD371-202 
Amendment 3. 
 
 
Name 
Signature 
Date 
Author: 
 
 
 
 
Position: 
Associate Director 
 
Company: 
IQVIA 
 
 
Upon review of this document, the undersigned approves this version of the Statistical 
Analysis Plan, authorizing that the content is acceptable for the reporting of this study. 
 
Name 
Signature 
Date 
Approved By: 
 
 
 
 
Position: 
Sr. Director 
 
Company: 
Arena Pharmaceuticals 
 
Approved By: 
 
 
 
 
Position: 
VP, Biostatistics & Data Management 
 
Company: 
Arena Pharmaceuticals 


PROTOCOL APD371-202 
Analysis Plan – Long-Term Extension Study 
Page 3 of 50
 
 
MODIFICATION HISTORY 
 
Unique 
Identifier 
for this 
Version 
Date of the 
Document 
Version 
Author 
Significant Changes from  
Previous Authorized Version 
1.0 
17MAY2021 
 
Not Applicable – First Version 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Copyright © 2009, 2010, 2012, 2016, 2018 IQVIA. All rights reserved. The contents of this document are confidential and proprietary 
to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly proh bited. 
Document: 
\\quintiles.net\enterprise\Apps\sasdata\SASb\SAS\Arena\APD371\FZA87549\Biostatistics\Documentati
on\SAP\APD371-202_LTE_Study_SAP_FINAL.docx 
 
 
Author: 
  
Version 
Number: 
1.0 
 
Version Date:  
17MAY2021
Template No.:  CS_TP_BS016 Revision 5 
Reference:  CS_WI_BS005 
Effective Date: 01Apr2018 
 


PROTOCOL APD371-202 
Analysis Plan – Long-Term Extension Study 
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TABLE OF CONTENTS 
1. 
LIST OF ABBREVIATIONS ......................................................................................... 8 
2. 
INTRODUCTION ......................................................................................................... 11 
3. 
STUDY OBJECTIVES ................................................................................................. 11 
3.1. 
Primary Objectives ........................................................................................................................................ 11 
3.2. 
Exploratory Objectives ................................................................................................................................. 11 
4. 
STUDY DESIGN ........................................................................................................... 12 
4.1. 
General Description ....................................................................................................................................... 12 
4.2. 
Schedule of Events ......................................................................................................................................... 13 
4.3. 
Changes to Analysis from Protocol .............................................................................................................. 13 
5. 
PLANNED ANALYSES ............................................................................................... 13 
5.1. 
Final Analysis ................................................................................................................................................. 13 
6. 
ANALYSIS SETS .......................................................................................................... 14 
6.1. 
Enrolled Set .................................................................................................................................................... 14 
6.2. 
Full Analysis Set [FAS] ................................................................................................................................. 14 
6.3. 
Safety Set ........................................................................................................................................................ 14 
7. 
GENERAL CONSIDERATIONS ................................................................................ 15 
7.1. 
Reference Start Date and Study Day ........................................................................................................... 15 
7.2. 
Baseline/Post-Baseline ................................................................................................................................... 15 
7.3. 
Retests, Unscheduled Visits and Early Termination Data ......................................................................... 16 
7.4. 
Windowing Conventions ............................................................................................................................... 16 
7.5. 
Common Calculations ................................................................................................................................... 18 
7.6. 
General Study Information ........................................................................................................................... 18 
8. 
STATISTICAL CONSIDERATIONS ......................................................................... 18 


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8.1. 
Adjustments for Covariates and Factors to be Included in Analyses ....................................................... 18 
8.2. 
Multicenter Studies ........................................................................................................................................ 18 
8.3. 
Missing Data ................................................................................................................................................... 19 
8.4. 
Multiple Comparisons/ Multiplicity ............................................................................................................. 19 
8.5. 
Examination of Subgroups ............................................................................................................................ 19 
9. 
OUTPUT PRESENTATIONS ...................................................................................... 19 
10.  DISPOSITION AND PROTOCOL DEVIATIONS ................................................... 19 
11.  DEMOGRAPHICS AND BASELINE CHARACTERISTICS ................................. 20 
11.1.  Derivations ..................................................................................................................................................... 21 
12.  MEDICAL HISTORY .................................................................................................. 21 
13.  CONCOMITANT MEDICAL CONDITIONS ........................................................... 21 
14.  MEDICATIONS ............................................................................................................ 22 
15.  STUDY TREATMENT EXPOSURE .......................................................................... 22 
15.1.  Derivations ..................................................................................................................................................... 23 
16.  STUDY TREATMENT COMPLIANCE .................................................................... 23 
16.1.  Derivations ..................................................................................................................................................... 23 
17.  EFFICACY OUTCOMES ............................................................................................ 24 
17.1.  Primary Efficacy ............................................................................................................................................ 24 
17.2.  Secondary Efficacy ........................................................................................................................................ 24 
17.3.  Exploratory Efficacy ..................................................................................................................................... 24 


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18.  SAFETY OUTCOMES ................................................................................................. 31 
18.1.  Adverse Events ............................................................................................................................................... 32 
18.1.1. 
All TEAEs ............................................................................................................................................... 32 
18.1.2. 
Severity .................................................................................................................................................... 32 
18.1.3. 
Relationship to Study Treatment ............................................................................................................. 33 
18.1.4. 
TEAEs Leading to Discontinuation of Study Treatment ......................................................................... 33 
18.1.5. 
Teaes Leading to Study Discontinuation ................................................................................................. 33 
18.1.6. 
Serious and Non-Serious Teaes ............................................................................................................... 34 
18.1.7. 
Teaes Leading to Death ........................................................................................................................... 34 
18.1.8. 
Teaes Of Special Interest ......................................................................................................................... 34 
18.1.9. 
Overall Summary of Adverse Events ...................................................................................................... 34 
18.2.  Deaths ............................................................................................................................................................. 35 
18.3.  Laboratory Evaluations ................................................................................................................................ 35 
18.3.1. 
Laboratory Reference Ranges and Markedly Abnormal Criteria ............................................................ 35 
18.4.  12-lead ECG ................................................................................................................................................... 36 
18.4.1. 
12-Lead ECG: Outlier and Morphology Analyses ................................................................................... 36 
18.5.  Vital Signs ....................................................................................................................................................... 37 
18.5.1. 
Vital Signs Specific Derivations .............................................................................................................. 38 
18.6.  Physical Examination .................................................................................................................................... 39 
19.  PHARMACOKINETICS ANALYSIS ........................................................................ 39 
20.  IMPACT OF COVID-19 ............................................................................................... 39 
21.  GENETIC AND BIOMARKER ANALYSES ............................................................ 39 
22.  DATA NOT SUMMARIZED OR PRESENTED ....................................................... 39 
23.  REFERENCES .............................................................................................................. 40 
24.  APPENDIX 1. PROGRAMMING CONVENTIONS FOR OUTPUTS ................... 41 
Output Conventions .................................................................................................................................................. 41 
Decimals, Percentages, and P-values ........................................................................................................................ 41 
Dates & Times ............................................................................................................................................................ 41 
Spelling Format ......................................................................................................................................................... 41 
Presentation of Treatment Groups .......................................................................................................................... 41 
Presentation of Visits ................................................................................................................................................. 43 


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Analysis Plan – Long-Term Extension Study 
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Listings ....................................................................................................................................................................... 43 
25.  APPENDIX 2. PARTIAL DATE CONVENTIONS ................................................... 44 
Algorithm for Treatment Emergence of Adverse Events: ..................................................................................... 44 
Algorithm for Prior / Concomitant Medications: ................................................................................................... 45 
26. 
 
 
 


PROTOCOL APD371-202 
Analysis Plan – Long-Term Extension Study 
Page 8 of 50
 
 
1. LIST OF ABBREVIATIONS 
Abbreviation 
Meaning 
AABS 
average abdominal bloating score 
AADS 
average abdominal discomfort score 
AAPS 
average abdominal pain score 
AE 
adverse event 
APS 
abdominal pain score 
ATC 
Anatomical Therapeutic Chemical 
ATC3 
Anatomical Therapeutic Chemical: Therapeutic (Level 3) 
BM 
bowel movement 
BMI 
body mass index 
BP 
blood pressure 
CI 
confidence interval 
CM 
concomitant medication 
CS 
clinically significant 
CSBM 
complete spontaneous bowel movement 
CSR 
clinical study report 
DSMB 
Data Safety Monitoring Board 
ECG 
electrocardiograms 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EQ-5D 
European Quality of Life-5 
ET 
early termination 
FAS 
Full Analysis Set 
HADS 
Hospital Anxiety and Depression Scale 
HR 
heart rate 
IBS 
irritable bowel syndrome 


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Analysis Plan – Long-Term Extension Study 
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Abbreviation 
Meaning 
IBS-C 
irritable bowel syndrome with predominant constipation 
IBS-D 
irritable bowel syndrome with predominant diarrhea 
IBS-QoL 
Irritable Bowel Syndrome-Quality of Life 
IBS-SSS 
Irritable Bowel Syndrome-Severity Scoring System 
ICF 
informed consent form 
LTE 
long-term extension 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCS 
not clinically significant 
OC 
observed cases 
PCS 
Potentially Clinically Significant 
PGIC 
Patient Global Impression of Change 
PK 
pharmacokinetic 
PROMIS 
Patient-Reported Outcomes Measurement Information System 
PT 
preferred term 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SBM 
spontaneous bowel movement 
SD 
standard deviation 
SI 
International System of Units 
SOC 
System Organ Class 
TEAE 
treatment-emergent adverse event 
TFL 
table, figure, and listing 
TID 
3 times per day 
VAS 
Visual Analog Scale 
VS 
vital signs 
WHODD 
World Health Organization Drug Dictionary  


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Abbreviation 
Meaning 
WK 
week 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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2. INTRODUCTION 
This document describes the rules and conventions to be used in the presentation and 
analyses of efficacy, safety, and pharmacokinetic (PK) data for the Long-Term Extension 
(LTE) Period described in Protocol APD371-202. It describes the data to be summarized and 
analyzed, including specifics of the statistical methods to be implemented. This statistical 
analysis plan (SAP) is based on protocol version APD371-202 (Amendment 3, dated 
03FEB2020). A separate analysis plan will describe the genetic and biomarker analyses. 
 
The table, figure and listing (TFL) shells are prepared in a separate file based on this analysis 
plan. Upon approval of the SAP, some updates (including but not limited to titles, footnotes, 
headings and re-numbering of tables, etc.) on TFL shells are allowed without a SAP 
amendment as long as the updates within TFL shells do not conflict with the contents of the 
SAP.  
3. STUDY OBJECTIVES 
3.1. PRIMARY OBJECTIVES 
The primary objective is: 
 To evaluate the safety and tolerability of long-term administration of olorinab in 
 
subjects with irritable bowel syndrome (IBS) 
3.2. EXPLORATORY OBJECTIVES 
The exploratory objectives are: 
 
To measure the population PK (Ctrough) of olorinab and its predominant 
metabolites 
 and 
 in subjects with IBS during 
long-term administration of olorinab 
 
To evaluate the efficacy of long-term administration of olorinab in subjects with 
IBS 
 


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4. STUDY DESIGN 
4.1. GENERAL DESCRIPTION 
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. 
 
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. 


PROTOCOL APD371-202 
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Figure 1: Schematic Diagram of Long-Term Extension Design 
 
Abbreviations: 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. 
4.2. SCHEDULE OF EVENTS 
Schedule of events can be found in Appendix 1 of the protocol. 
4.3. CHANGES TO ANALYSIS FROM PROTOCOL 
After completing the analysis for the Main Study Period, the decision was made to terminate 
the study early and end the LTE for all subjects. Analyses for the LTE will reflect all data 
collected until the study is terminated.  Population PK endpoints, Ctrough of olorinab and its 
primary metabolites, will not be included in this SAP. Removal of PK exhibits (TFLs) was 
agreed upon on 01APR2021.  
5. PLANNED ANALYSES 
The following analyses will be performed for this study: 
 
Final Analysis of the LTE Study  
5.1. FINAL ANALYSIS  
All final, planned analyses identified in this SAP will be performed following Sponsor 
Authorization of this SAP, Database Lock, Sponsor Authorization of Analysis Sets and 


PROTOCOL APD371-202 
Analysis Plan – Long-Term Extension Study 
Page 14 of 50
 
 
Unblinding of Treatment. PK analysis datasets will be created but no formal PK tables, 
figures or listings will be produced.  
 
After all subjects have completed or terminated the LTE, outstanding data queries have been 
resolved/closed, the data have been cleaned and finalized, and the database is locked, the 
Sponsor will authorize breaking of the study blind and the final analysis of the data will be 
performed. The SAP must be approved and signed by the Sponsor before the database is 
locked and treatment assignment unblinded. 
 
Any post-hoc, exploratory analyses completed to support planned study analyses, which were 
not identified in the SAP, will be documented and reported in the clinical study report. Any 
results from these unplanned analyses will also be clearly identified in the text of the clinical 
study report. 
6. ANALYSIS SETS 
Agreement and authorization of subjects included/excluded from each analysis set will be 
conducted prior to the unblinding of the study. A summary of analysis sets will be presented. 
6.1. ENROLLED SET  
The enrolled set will include all subjects who signed the ICF for LTE.   
6.2. FULL ANALYSIS SET [FAS] 
The full analysis set (FAS) will include all randomized subjects in LTE, irrespective of 
whether they received study treatment. Subjects will be classified according to randomized 
treatment. 
6.3. SAFETY SET  
The safety set will include all subjects who received at least one dose of study treatment. 
Subjects will be classified according to actual treatment received. If there is any doubt 
whether a subject was treated or not, they will be assumed treated by the randomized 
treatment for the purposes of analysis.  


PROTOCOL APD371-202 
Analysis Plan – Long-Term Extension Study 
Page 15 of 50
 
 
7. GENERAL CONSIDERATIONS 
7.1. REFERENCE START DATE AND STUDY DAY 
Study Day will be calculated from the reference start date and will be used to show start/stop 
day of assessments and events. Reference start date is defined as Day 1, the date of LTE 
randomization (Day 1 is the day of the first dose of LTE study treatment) and will appear in 
every listing where an assessment date or event date appears.  
 
If the date of the event is on or after the reference date then:  
Study day = (date of event – reference date) + 1 
 
If the date of the event is prior to the reference date then:  
Study day = (date of event – reference date) 
In the situation where the event date is partial or missing, Study Day, and any corresponding 
durations will appear as missing in the listings. In the situation where the subject is 
randomized but not treated, the reference date is defined as the LTE baseline visit date. 
7.2. BASELINE/POST-BASELINE 
Unless otherwise specified, baseline is defined as the last non-missing measurement taken 
prior to the reference start date. If measurements include time, the date/time will be used to 
define baseline; where time is not fully populated in the reference start date and fully 
populated in the measurement date, missing time values will be imputed to the earliest 
possible time measurement. Otherwise, only dates will be compared. In the case where the 
last non-missing measurement and the reference start date coincide and time is not collected, 
the measurement will be considered a baseline record, but adverse events (AEs) and 
medications commencing on the reference start date will be considered post-baseline records. 
For subjects randomized but not treated, baseline is defined as the last non-missing 
measurement taken on or before the baseline visit date.  
 
Main study baseline AAPS is defined as the average abdominal pain score (APS) over the 
main study Run-in Period preceding Visit 3. The detailed derivation can be found in the 
approved SAP for the Main Study.  
 
LTE baseline AAPS is defined separately for continuing subjects and gap subjects. LTE 
baseline AAPS for continuing subjects is calculated using the Week 14 visit from the Main 
Study. Gap subject LTE baseline AAPS is calculated by taking the average value over the 


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window of 7 days prior to Day 1 in LTE.  
 
Post-baseline weekly AAPS by scheduled visit is calculated by taking the average value over 
the window of 7 days prior to and including the scheduled visit day if the endpoint is 
recorded for at least 4 of the 7 days in the window.  If APS values are missing for more than 
3 days in the 7-day window, the average value for the AAPS by scheduled visit will be 
reported as missing. 
 
For other continuous endpoints collected in the Daily Diary form (e.g., bloating, discomfort, 
and number of bowel movements), baseline and post-baseline will be derived in the same 
manner. 
7.3. RETESTS, UNSCHEDULED VISITS AND EARLY TERMINATION 
DATA 
For by-visit analyses and summaries of efficacy and safety, data (including scheduled, 
retests, unscheduled, and early termination) will be assigned to visits after the application of 
the windowing conventions described in Section 7.4. All measurements will be considered in 
summaries of abnormalities or worst-case values post-baseline. 
 
In the case of a retest (same visit number assigned), the measurement nearest to the visit date 
will be used for by-visit summaries. In the case of several measurements equally close to the 
visit date, the earliest non-missing measurement will be taken. If multiple assessments are 
available on the same day, then the average of the assessment will be used in the analysis 
except for laboratory and ECG data, where the assessment at the earliest time of the same 
day will be used. If both central and local assessments of the same laboratory test are 
available on the same day, the central assessment will take precedence over the local 
assessment. Listings will include scheduled, unscheduled, retest and early discontinuation 
data. 
7.4. WINDOWING CONVENTIONS  
All scheduled study visits are defined relative to Study Day 1, the date of randomization and 
first dose of study treatment. Scheduled visit windows are defined in Appendix 1 of the 
protocol. A windowing convention will be used to determine the analysis visit value for a 
given measurement and will be applicable for all by-visit summaries and analyses for 
efficacy and safety data. The early discontinuation visits and unscheduled visits will be 


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eligible for allocation to an analysis visit.  The 2-week follow-up visit will be summarized 
separately. 
 displays the specific visit windows used for the FAS and Safety Set 
populations for efficacy and safety analysis. See 
. Additional Visit Windows for 
additional visit windows. 
 
Windowing will be applied to the data prior to any missing data calculations. If one or more 
results for a variable are assigned to the same analysis visit, the result with the date closest to 
the protocol scheduled day will be used in the analysis. If two measurements in the same 
analysis visit window are equally close to the protocol scheduled study day, the earliest 
measurement will be used in the analysis. For ePRO measurements (PROMIS, EQ-5D, etc.), 
the stamp date in the device will be used to calculate the study day, and Day 1 will include 
those ePROs collected on the date of Randomization. 
 


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7.5. COMMON CALCULATIONS 
For quantitative measurements: 
 Change from main study baseline = (Test Value at Visit X – Main Study Baseline Value) 
 Percent change from main study baseline = ((Test Value at Visit X – Main Study 
Baseline Value) / Main Study Baseline Value) x 100 
 Change from LTE baseline = (Test Value at Visit X – LTE Baseline Value) 
 Percent change from LTE baseline = ((Test Value at Visit X – LTE Baseline Value) / 
LTE Baseline Value) x 100 
 Proportion at Visit X = (Number of subjects satisfying criteria at Visit X / Total number 
of subjects at Visit X)  
 Proportion achieving an improvement from Visit X to Visit Y = (Number of subjects 
achieving an improvement from Visit X to Visit Y / Total number of subjects with non-
missing data for that parameter at both Visit X and Visit Y)  
7.6. GENERAL STUDY INFORMATION 
All analyses will be conducted using SAS® (version 9.4 or later, SAS Institute Inc., Cary, 
NC).  
 
A general table with summary of study information will be generated, including date first 
subject signed ICF, last subject last visit date, database lock date and versions of the Medical 
Dictionary for Regulatory Activities (MedDRA), World Health Organization Drug 
Dictionary Global (Enhanced w/WHO Herbal Dictionary) (WHODD), and SAS etc. 
8. STATISTICAL CONSIDERATIONS 
8.1. ADJUSTMENTS FOR COVARIATES AND FACTORS TO BE 
INCLUDED IN ANALYSES 
No formal analyses with statistical tests between treatments will be conducted. Summary 
statistics will be presented for all analyses. 
8.2. MULTICENTER STUDIES 
This study will be conducted by multiple investigators at multiple investigational sites within 
the United States. Subjects who received placebo or Olorinab 10 mg in the Main Study will 


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be re-randomized (1:1) to receive either Olorinab 25 mg or Olorinab 50 mg. Subjects who 
received Olorinab 25 mg or Olorinab 50 mg in the Main Study will continue to receive the 
same dose. Data from all sites will be pooled and summary analyses will not be adjusted for 
investigational site or geographic region. Ad-hoc analyses may be conducted by site or by 
pooling sites. 
8.3. MISSING DATA 
Missing safety data will generally not be imputed, with the exceptions of AE relationship to 
study treatment (as described in Section 18.1.3), partial or missing AE start dates, and 
Concomitant Medication (CM) start dates. Details about date imputations are described in 
Appendix 2. Partial Date Conventions. No other missing safety data will be imputed. 
8.4. MULTIPLE COMPARISONS/ MULTIPLICITY 
Not applicable as no formal statistical comparisons between treatments are planned. 
8.5. EXAMINATION OF SUBGROUPS 
No subgroup analysis is planned for this study. 
9. OUTPUT PRESENTATIONS 
Appendix 1. Programming Conventions for Outputs shows conventions for presentation of 
data in outputs. The templates provided with this SAP describe the presentations for this 
study and therefore the format and content of the summary tables, figures, and listings to be 
provided for the clinical study report. 
10. DISPOSITION AND PROTOCOL DEVIATIONS 
All subjects who provide informed consent will be accounted for in this study.  
 
Subject disposition and withdrawals will be provided for the FAS. This summary will note 
subjects who complete the Week 52 visit (end of treatment) as well as subjects who complete 
the Week 54 visit (end of study). An analysis set listing will also be provided. Inclusion and 
exclusion criteria will be presented for the screened set. A summary and listing of screen 
failures and reason for screen failure will be presented for the screened set. 


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Protocol deviations will be displayed for the FAS. Deviations will be categorized as 
Critical/Major or Minor. Critical/major deviations will be summarized by treatment as 
denoted in the Presentation of Treatment Groups in Appendix 1 for the following categories 
as described in the Protocol Deviation and Classification Guidance document. All 
critical/major deviations will also be listed. 
 Informed Consent Criteria 
 Eligibility and Entry Criteria 
 Concomitant Medication Criteria 
 Laboratory Assessment Criteria 
 Study Procedures Criteria 
 SAE Criteria 
 Randomization Criteria 
 Visit Schedule Criteria 
 Investigational Product Compliance 
 Efficacy Criteria 
 Administrative Criteria 
 Source Document Criteria 
 Regulatory or Ethics Approvals Criteria 
 Other Criteria 
 
A summary of protocol deviations related to COVID-19 will also be presented, as well as a 
listing of subjects with study conduct impacted by COVID-19. 
11. DEMOGRAPHICS AND BASELINE CHARACTERISTICS 
Demographics and baseline characteristics data will be presented for the FAS and Safety Set. 
The data will be summarized by treatment as denoted in the Presentation of Treatment 
Groups in Appendix 1 without statistical testing. The following demographic and baseline 
characteristics will be reported for this study: 
 
Age on consent (years)   
 
Sex at birth: Female and Male 
 
Child-bearing potential for women: Yes, No 
 
Race: American Indian or Alaska Native, Asian, Black or African American, 
Native Hawaiian or Other Pacific Islanders, Multiple, White, Not Reported 
 
Race group: White, Non-White, Not Reported  
 
Ethnicity: Hispanic or Latino, Non-Hispanic or Latino, Not Reported, Unknown 


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 
Weight (kg) 
 
Height (cm) 
 
BMI (kg/m2) 
 
 
 
 
Time since IBS diagnosis (years) – calculated relative to date of randomization 
in Main Study 
 
IBS subtype: IBS-C, IBS-D 
 
Main Study eDiary Compliance Rate (%) 
 
Main Study Baseline AAPS 
 
Main Study Baseline AAPS Category: (< 7, ≥7) 
 
LTE Baseline AAPS 
 
LTE Baseline AAPS Category: (< 7, ≥7) 
 
11.1. DERIVATIONS 
 
BMI (kg/ m2) = weight (kg)/ height (m)2 
 
Time since IBS diagnosis (years) = (date of randomization in the Main Study – 
date of IBS diagnosis + 1) / 365.25 
o 
Partial dates are imputed to the earliest possible date  
 
Weight (kg) = Weight (lb) * 0.4536  
 
Height (cm) = Height (in) * 2.54 
 
Height (m) = Height (in) * 0.0254 = Height (cm) * 0.01 
12. MEDICAL HISTORY 
Medical History conditions are defined as those conditions which stop prior to the first dose 
of study treatment in the LTE. Medical History will be collected on the Medical History 
eCRF and coded using MedDRA (version 23.0 or higher). Medical History will be 
summarized for the Safety Set by system organ class (SOC) and preferred term (PT).  
13. CONCOMITANT MEDICAL CONDITIONS 
Concomitant medical conditions are conditions (other than the indication being studied) 
which started prior to or on the date of the first dose of LTE study treatment and are ongoing 


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at the date of the first dose of LTE study treatment. Concomitant medical conditions will be 
captured on the Medical History eCRF page and coded using MedDRA version 23.0 or 
higher. Concomitant medical conditions will be summarized for the Safety Set by SOC and 
PT. 
14. MEDICATIONS 
Medications will be collected on the Prior or Concomitant Medications eCRF and coded 
using WHODD version 01Mar2020 or higher.  
 
The prior and concomitant medications are defined below. See Appendix 2. Partial Date 
Conventions for handling of partial dates for medications. In the case where it is not possible 
to define a medication as prior or concomitant, the medication will be classified by the worst 
case, i.e., concomitant.  
 
‘Prior’ medications are medications which started after or were ongoing during 
the last dose of main study treatment and stopped prior to the first dose of LTE 
study treatment.  
 
‘Concomitant’ medications are medications which started prior to, on or after 
the first dose of LTE study treatment and continued into the LTE period. 
Prior and concomitant medications will be summarized separately by ATC Level 3 and 
Preferred Drug name for the Safety set. In addition, prior and concomitant medications 
related to IBS will be summarized.  
15. STUDY TREATMENT EXPOSURE 
The date of first dose will be taken from the LTE Day 1 “On Site Dosing Administration” form, 
and the date of last dose will be taken from the LTE “End of Study” form.  Interruptions, 
compliance, and dose changes are not taken into account for duration of exposure. Study 
duration and treatment duration will be summarized as continuous variables for each treatment as 
denoted in the Presentation of Treatment Groups in Appendix 1 using descriptive statistics. The 
duration of treatment will also be summarized categorically: ≤ 4, > 4 – 8, > 8 – 12, > 12 – 20, > 
20 – 28, > 28 – 36, > 36 – 44, and > 44 weeks. Additionally, the total subject-years of exposure 
and subject-years on study will be included in the summary. 
 
Number of tablets taken, missed, and frequency and percentage of subjects who missed at least 
one dose or who had at least one dose interruptions recorded on the Dosing Administration eCRF 
will also be summarized. Treatment compliance will also be summarized using both descriptive 
statistics and summarized categorically: < 85%, ≥ 85 to ≤ 115%, and > 115%. 


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15.1. DERIVATIONS 
 Study Duration (days) = date of last study visit – date of LTE Day 1 visit + 1 
 Treatment duration (days) = date of last LTE study treatment administration – date of 
first LTE study treatment administration + 1 
 Treatment duration (weeks) = (date of last LTE study treatment administration – date of 
first LTE study treatment administration + 1)/7. 
 Total subject-years on study = sum of duration of time on study across all subjects 
divided by 365.25 
 Total subject-years of exposure = sum of duration of treatment exposure across all 
subjects divided by 365.25 
16. STUDY TREATMENT COMPLIANCE  
Compliance with study treatment will be summarized for the Safety Set. Total number of 
tablets expected, total number of tablets taken, total number of tablets missed, overall 
compliance with study treatment, frequency and percentage with overall compliance with the 
following categories: <85%, ≥85% to ≤115%, and ˃115%. By-visit compliance will also be 
summarized. 
 
Subjects with administration compliance greater than 115% and subjects who do not return 
any study treatment or study packaging will be asked for the reason for the overcompliance 
or missing study treatment. Their responses will be recorded on the Drug Accountability 
eCRF and will be listed. 
16.1. DERIVATIONS 
Compliance to study treatment is based on the Drug Accountability eCRF and will be 
calculated as the number of capsules/tablets taken (total dispensed – total returned) divided 
by the prescribed number of capsules/tablets, expressed as a percentage (see calculations 
below).  
 
The study treatment is given three times daily (tid), and it is assumed that the subject should 
take study treatment from the morning of the visit day at which their treatment is initially 
dispensed to the evening before their last treatment return date, as subjects are advised to 
wait to take their dose at the study site until all assessments and procedures have been 
completed on study days. For example, if the initial dispensation date is Day 1 and the last 
return date is Day 387, then the subject should have taken 3 capsules/tablets each day on 


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Days 1 to 386; hence, the total number of prescribed capsules would be 386×3 = 1,158. 
Multiple bottles may be dispensed at one visit; in these cases, “Per Visit” compliance will be 
non-missing if at least one bottle is returned. 
 
 
 “Per Visit” Compliance to study treatment at Visit X will be calculated as follows: 
 
 ሺሾ୒ ୭୤ ୘ୟୠ୪ୣ୲ୱ ୢ୧ୱ୮ୣ୬ୱୣୢ ୟ୲ ୚୧ୱ୧୲ ሺଡ଼ሻሿ ି ሾ୒ ୭୤ ୘ୟୠ୪ୣ୲ୱ ୰ୣ୲୳୰୬ୣୢ ୟ୲ ୚୧ୱ୧୲ ሺଡ଼ାଵሻሿሻ
ሼ ሾୈୟ୲ୣ ୭୤ ୚୧ୱ୧୲ ሺଡ଼ାଵሻሿ ି ሾୈୟ୲ୣ ୭୤ ୈ୧ୱ୮ୣ୬ୱ୧୬୥ ୟ୲ ୚୧ୱ୧୲ ሺଡ଼ሻሿ  ሽ ୶ ଷ
 
x 100 
 
 
Overall Compliance to study treatment will be calculated as follows: 
 
ሼሺሾ୒ ୭୤ ୘ୟୠ୪ୣ୲ୱ ୢ୧ୱ୮ୣ୬ୱୣୢ ୟ୲ ୚୧ୱ୧୲ ଵሿ – ሾ୒ ୭୤ ୘ୟୠ୪ୣ୲ୱ ୰ୣ୲୳୰୬ୣୢ ୟ୲ ୚୧ୱ୧୲ ଶሿሻ
ା⋯ା
ሺሾ୒ ୭୤ ୘ୟୠ୪ୣ୲ୱ ୢ୧ୱ୮ୣ୬ୱୣୢ ୟ୲ ୚୧ୱ୧୲ ሺଡ଼ିଵሻሿ – ሾ୒ ୭୤ ୘ୟୠ୪ୣ୲ୱ ୰ୣ୲୳୰୬ୣୢ ୟ୲ ୚୧ୱ୧୲ ଡ଼ሿሻሽ 
ሾୈୟ୲ୣ ୭୤ ୚୧ୱ୧୲ ଡ଼ሿ ି ሾୈୟ୲ୣ ୭୤ ୈ୧ୱ୮ୣ୬ୱ୧୬୥ ୟ୲ ୚୧ୱ୧୲ ଵሿ ൈଷ
 
x 100 
 
For subjects who permanently stop the study treatment before Week 52, the “Date of Visit 
X” in Overall Compliance calculations will be replaced by the date of study withdrawal.  
17. EFFICACY OUTCOMES  
17.1. PRIMARY EFFICACY 
Not applicable. No primary efficacy analysis was conducted for the LTE.  
17.2. SECONDARY EFFICACY 
Not applicable. No secondary efficacy analysis was conducted for the LTE. 
17.3. EXPLORATORY EFFICACY  


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18. SAFETY OUTCOMES 
All analyses for safety outcomes will be based on the safety analysis set. All safety data will 
be listed and summarized by actual treatment group. There will be no statistical comparisons 


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between the treatments for safety data, unless otherwise specified. Unless otherwise stated, 
exhibits will be displayed by treatment as denoted in the Presentation of Treatment Groups in 
Appendix 1. 
18.1. ADVERSE EVENTS 
AEs will be coded using MedDRA central coding dictionary, Version 23.0 or higher. New 
treatment-emergent adverse events (TEAEs) in LTE are defined as: 
 An AE that occurs after the first dose of LTE study treatment that was not present 
before the dosing, OR 
 An AE that increases in severity after the first dose of LTE study treatment if the 
event was present before the dosing treatment. 
All TEAEs will be coded and summarized by system organ class (SOC) and preferred term 
(PT) and will be presented by descending order of frequency. AEs occurring before the first 
dose of study treatment will be summarized separately from new TEAEs occurring in the 
LTE. Listings will include all AEs (TEAEs and Non-TEAEs).  
 
See Appendix 2. Partial Date Conventions for handling of partial dates for AEs for the 
purpose of assigning treatment-emergent flags. In the case where it is not possible to define 
an AE as treatment-emergent or not, the AE will be classified by the worst case, i.e. 
treatment emergent.  
18.1.1. 
ALL TEAES  
All TEAEs will be summarized by SOC and PT and by treatment as denoted in the 
Presentation of Treatment Groups in Appendix 1 and presented by descending order of 
frequency in any treatment. TEAEs will also be summarized by maximum severity and 
relationship to study treatment. A separate summary of related TEAEs and related TEAEs by 
maximum severity will also be provided. 
18.1.2. 
SEVERITY 
Severity is classified by grade using the Common Terminology Criteria for Adverse Events 
version 5.0 (CTCAE v5.0) system as defined below. The CTCAE grade will be assessed by a 
nurse and/or physician and will be recorded in the AE severity Section on the Adverse 
Events eCRF.  
 


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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 (e.g., 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. 
 
TEAEs with a missing severity but identified as a life-threatening serious adverse event 
(SAE) or one requiring initial or prolonged hospitalization will be classified as Grade 4 
(Potentially Life-threatening), otherwise missing severity will be classified as Grade 3 
(severe). If a subject reports a TEAE more than once within that SOC/ PT, the AE with the 
greatest severity will be used in the corresponding severity summaries.  
18.1.3. 
RELATIONSHIP TO STUDY TREATMENT 
Relationship is classed as “not related”, “unlikely related”, “probably related”, or “related” 
(increasing severity of relationship) by the Investigator. A “related” TEAE for the purpose of 
TEAE summaries is defined as a TEAE with a relationship to study treatment as “related” or 
“probably related” to study treatment. TEAEs with a missing relationship to study treatment 
will be regarded as “related” to study treatment. “Unlikely related” will be counted as non-
related TEAE.  If a subject reports the same AE more than once within the same SOC/ PT, 
the AE with the strictest causality will be used in the corresponding relationship summaries. 
All TEAEs will be summarized by SOC, PT, and relationship to study treatment. 
18.1.4. 
TEAES LEADING TO DISCONTINUATION OF STUDY TREATMENT 
TEAEs leading to permanent discontinuation of study treatment will be identified by action 
taken being recorded as “Drug withdrawal” on the AE page of the eCRF. All TEAEs leading 
to discontinuation of study treatment will be summarized by SOC and PT. A listing of all 
TEAEs leading to discontinuation of study treatment will also be presented.  
18.1.5. 
TEAES LEADING TO STUDY DISCONTINUATION 
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leading to study discontinuation will be summarized by SOC and PT. 
18.1.6. 
SERIOUS AND NON-SERIOUS TEAES 
Serious adverse events (SAEs) are those events recorded as “Serious” on the Adverse Events 
page of the eCRF. All serious TEAEs will be summarized by SOC and PT. All non-serious 
TEAEs will also be summarized by SOC and PT. A serious AE listing will also be presented. 
18.1.7. 
TEAES LEADING TO DEATH 
TEAEs leading to Death are those events which are recorded as “Fatal” on the Adverse 
Events page of the eCRF. A summary of TEAEs leading to death by SOC and PT will be 
prepared by treatment. 
18.1.8. 
TEAES OF SPECIAL INTEREST  
To date, no AEs of special interest have been identified related to olorinab. Potential AEs of 
special interest may be identified by clinical or medical reviewers. In addition to appropriate 
reporting of these events as an AE or SAE, supplementary detailed information may be 
collected. Any identified AEs of special interest will be summarized by SOC and PT 
separately. A listing will also be provided.  
18.1.9. 
OVERALL SUMMARY OF ADVERSE EVENTS 
In addition to the summaries by SOC and PT as described in Sections 18.1.1 to 18.1.5, an 
overview of TEAEs will be summarized (not broken down by SOC or PT) by number and 
frequency of subjects and by number of AEs by treatment: 
 
Any AE (including non-TEAEs) 
 
Any TEAE 
 
Any related TEAE 
 
TEAEs by maximum severity 
 
Related TEAEs by maximum severity 
 
TEAEs by relationship to study treatment 
 
TEAEs leading to study treatment discontinuation 
 
TEAEs leading to study treatment interruption 
 
TEAEs leading to study discontinuation 
 
Related TEAEs leading to study treatment discontinuation 
 
Related TEAEs leading to study treatment interruption 


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 
Related TEAEs leading to study discontinuation 
18.2. DEATHS 
For any reports of death during the study as recorded on the End of Study page of the eCRF, 
the information will be presented in a listing. 
18.3. LABORATORY EVALUATIONS 
Results from the central laboratory will be included in the reporting of this study for 
chemistry, hematology, coagulation, urinalysis, thyroid chemistry, celiac, and virology. 
pregnancy. A list of laboratory assessments to be included in the outputs is included in Table 
3 in the protocol. If local and central laboratory assessments are available from the same day, 
central laboratory assessments will be used in the analysis. 
 
Presentations will use SI Units. Quantitative laboratory measurements reported as “< X”, i.e. 
below the lower limit of quantification (BLQ), or “> X”, i.e. above the upper limit of 
quantification (ULQ), will be converted to X for the purpose of quantitative summaries, but 
will be presented as recorded, i.e. as “< X” or “> X” in the listings. 
 
Laboratory parameters such as hepatic enzymes, renal function and hematology values will 
be grouped and presented together. The following summaries will be provided for laboratory 
data: 
 
Value and change from LTE baseline by visit (for quantitative measurements) 
 
Incidence of abnormal values according to laboratory reference ranges by visit 
 
Shift from LTE baseline to end of treatment according to laboratory reference 
range (for quantitative measurements and categorical measurements) 
 
Summary of subjects with treatment-emergent abnormal lab results  
 
Listing of subject’s laboratory assessments at all timepoints. Values outside of 
the central laboratory reference range will be flagged. Values obtained from 
local laboratory will be flagged. 
18.3.1. 
LABORATORY REFERENCE RANGES AND MARKEDLY ABNORMAL CRITERIA 
Quantitative laboratory measurements will be compared with the relevant laboratory 
reference ranges in SI units and categorized as: 
 
Low: Below the lower limit of the laboratory reference range.  


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 
Normal: Within the laboratory reference range (upper and lower limit included). 
 
High: Above the upper limit of the laboratory reference range. 
 
Treatment-emergent high result: a change from a value less than or equal to the 
high limit at all baseline visits to  a value greater than the high limit at any time 
during the treatment period. 
 
Treatment-emergent low result: a change from a value greater than or equal to 
the low limit at all baseline visits to a value less than the low limit at any time 
during the treament period. 
18.4. 12-LEAD ECG  
Results from the central 12-lead ECG Reading Centre will be included in the reporting of this 
study. The ECGs will be read and interpreted by the central ECG laboratory. At all scheduled 
visits, ECGs were collected once per visit, prior to administration of the first daily dose of 
study treatment. 
 
The following ECG parameters will be reported for this study on the central read for each 
safety ECG: 
 
PR Interval (msec) 
 
QRS Interval (msec) 
 
QT Interval (msec) 
 
QTcF Interval (msec) [derived] 
 
QTcB Interval (msec) [derived, optional] 
 
Heart Rate (HR) (bpm) 
 
Overall interpretation of ECG (Investigator’s judgment): 
 Normal 
 Abnormal, Not Clinically Significant (Abnormal NCS) 
 Abnormal, Clinically Significant (Abnormal CS) 
The following summaries will be provided by treatment group for ECG data: 
 
Value by visit (for quantitative measurements) 


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18.5. VITAL SIGNS 
Orthostatic vital signs (VS) include the collection of blood pressure (BP) and HR after the 
subject has been resting in the supine position for at least 5 minutes and then again after 1 and 3 
minutes of standing. For gap subjects, orthostatic VS were collected at the screening and for 
continuing subjects, orthostatic VS were collected at the main study Week 14 visit. Screening 
orthostatic vital signs will be included in data listings of vital signs.  
 
For all other visits, supine vital signs were collected once per visit, prior to administration of the 
first daily dose of study treatment. 
 
Baseline VS is defined as the supine VS collected prior to or on the date of the administration of 
the first daily dose of LTE study treatment on Day 1. 
 


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The following VS data will be summarized using descriptive statistics by treatment group as 
denoted in the Presentation of Treatment Groups in Appendix 1. 
 
 The actual measurement values of vital signs at each visit/timepoint 
 Change from LTE baseline: calculated as post-baseline values minus the VS 
baseline value.  
 
Body temperature and respiratory rate were collected once per visit, prior to the administration of 
the first daily dose of study treatment (for visits occurring during the Treatment Period). 
Vital sign values meeting the criteria as defined in  
 
Table 2 below will be categorized as potentially clinically significant (PCS) findings. These 
findings will be summarized with frequency count and percentage for each treatment as well as 
for the active treatments pooled, both overall and by scheduled visit.  The summaries and counts 
will be presented at both the subject level (counting subjects with PCS findings) and event level 
(counting all PCS events).  
 
Table 2: Vital Sign PCS Criteria 
 
 
 
 
PCS Criteria 
 
Parameter 
PCS 
Category 
Systolic BP (mm Hg) 
High
≥140 Supine and Supine increase from baseline ≥ 20
Low
≤ 90 Supine and Supine decrease from baseline ≥ 20
Diastolic BP (mm Hg) 
High
≥90 Supine and Supine increase from baseline ≥ 15
Low
< 40 Supine and Supine decrease from baseline ≥ 15
  Pulse Rate (bpm) 
High 
≥ 100 Supine 
Low 
< 40 Supine 
Respiratory Rate (brpm) 
High
≥ 28
Low
≤ 8
Temperature (°C) 
High
> 38
Low
< 35
 
Abbreviation: bpm = beats per minute; BP = blood pressure; brpm = breaths per minute; PCS = potentially clinically  
                       significant 
18.5.1. 
VITAL SIGNS SPECIFIC DERIVATIONS  
 
Temperature (⁰C) = (5/9) (Temperature (⁰F) – 32) 


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18.6. PHYSICAL EXAMINATION 
All physical examination assessments will be listed.  
19. PHARMACOKINETICS ANALYSIS 
Pharmacokinetic analyses may be completed by Sponsor and will be described in a separate 
analysis plan if needed. 
20. IMPACT OF COVID-19 
The study has been closely monitored during the period of COVID-19 and the impact of 
COVID-19 on data analyses is minimal. The below analyses related to COVID-19 are 
planned to document any impacts of the pandemic. Post hoc exploratory data analyses may 
be planned after database lock if the data warrants the request. 
 Summary of major protocol deviations caused by COVID-19 
 A listing of any adverse events related to COVID-19  
 A listing of any subjects with phone or remote visits due to COVID-19. 
21. GENETIC AND BIOMARKER ANALYSES 
Genetic and biomarker analyses will be completed by Sponsor and will be described in a 
separate analysis plan if needed. 
22. DATA NOT SUMMARIZED OR PRESENTED 
The other variables and/or domains not summarized or presented are: 
 
Comments 
 
Meals (Day 1)  
These domains and/or variables will not be summarized or presented but will be available in 
the clinical study database, SDTM and/or ADaM datasets. 


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23. REFERENCES  
Dobson, A. J. (2002). An introduction to generalized linear models, 2nd ed. Chapman & 
Hall/CRC. 
EMA. (n.d.). Guideline on Missing Data in Confirmatory Clinical Trials. Retrieved 
December 15, 2011, from European Medicines Agency: 
http://www.ema.europa.eu/docs/en GB/document library/Scientific guideline/2010/09/WC
500096793.pdf 
Liang, K., Zeger, S., Longitudinal Data Analysis for Continuous and Discrete Responses for 
Pre-Post Designs. Sankhyta: The Indian Journal of Statistics. 2000. 62(B): 134-148. 
Little, R., & Yau, L. (1996). Intent-to-Treat Analysis for Longitudinal Studies with Drop-
Outs. Biometrics , vol 52, 1324-1333. 
. 
 
 
 
 
 
 
 
 


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START 
DATE 
STOP 
DATE 
ACTION 
 
Partial 
Impute stop date as latest possible date (i.e. last day of 
month if day unknown or 31st December if day and month 
are unknown), then: 
If medication stop date < study treatment first LTE dose 
date, assign as prior 
If medication stop date ≥ study treatment first LTE dose 
date, assign as concomitant 
 
Missing 
Assign as concomitant 
 
 
 


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Statistical Analysis Plan - Long-Term Extension - 17-May-2021
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