A Randomized, Double-Blind, Placebo Controlled Trial to Evaluate the Safety and Efficacy of XG005 Tablets in Subjects Undergoing Bunionectomy
Phase: PHASE2
Conditions: Acute Pain
Sponsor: Xgene Pharmaceutical Group

 
 
 
 
 
 
A RANDOMIZED, DOUBLE-BLIND, PLACEBO- CONTROLLED TRIAL TO 
EVALUATE THE SAFETY AND EFFICACY OF XG005 TABLETS IN SUBJECTS 
UNDERGOING BUNIONECTOMY 
PROTOCOL PR-XG005-02-BUN-01  
Version 5.0 
15 Nov 2022  
 
INVESTIGATIONAL NEW DRUG (IND): 162390 
 
XGENE PHARMACEUTICAL INC. 
 
 
CONFIDENTIALITY STATEMENT 
The information contained in this document or generated during the study are considered 
proprietary and may not be disclosed in whole or in part without the expressed, written consent 
of Xgene Pharmaceutical Inc.  
The study will be conducted according to the International Council for Harmonisation Guideline 
E6(R2): Good Clinical Practice.  
 
 

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TABLE OF CONTENTS  
SPONSOR SIGNATURE PAGE ....................................................................................................2 
TABLE OF CONTENTS .................................................................................................................3 
LIST OF TABLES ...........................................................................................................................6 
1. 
PROTOCOL SUMMARY .....................................................................................................7 
1.1. 
Synopsis ...............................................................................................................................7 
1.2. 
Schedule of Assessments ...................................................................................................16 
2. 
INTRODUCTION ................................................................................................................21 
2.1. 
Background ........................................................................................................................21 
2.2. 
Unmet Medical Need .........................................................................................................21 
2.3. 
XG005 Clinical Experience in Healthy Subjects ...............................................................22 
2.4. 
Study Rationale ..................................................................................................................23 
3. 
OBJECTIVES AND ENDPOINTS .....................................................................................24 
4. 
STUDY DESIGN .................................................................................................................26 
4.1. 
Overall Design ...................................................................................................................26 
4.2. 
Scientific Rationale for Study Design................................................................................27 
4.3. 
Justification for Dose .........................................................................................................27 
4.4. 
End of Study Definition .....................................................................................................28 
5. 
STUDY POPULATION ......................................................................................................29 
5.1. 
Inclusion Criteria ...............................................................................................................29 
5.2. 
Exclusion Criteria ..............................................................................................................29 
5.3. 
Screen Failure ....................................................................................................................32 
5.4. 
Replacement of Subjects ....................................................................................................32 
5.5. 
Number of Subjects and Centers ........................................................................................32 
6. 
STUDY TREATMENT .......................................................................................................33 
6.1. 
Description .........................................................................................................................33 
6.2. 
Dosing and Administration ................................................................................................33 
6.3. 
Preparation/Handling/Storage/Accountability ...................................................................33 
6.3.1. 
Acquisition and Accountability ...................................................................................33 
6.3.2. 
Product Storage and Stability.......................................................................................33 
6.3.3. 
Packaging and Labeling ...............................................................................................34 
6.3.4. 
Randomization .............................................................................................................34 
6.4. 
Blinding..............................................................................................................................34 
6.4.1. 
Blinding Procedures .....................................................................................................34 
6.4.2. 
Breaking the Blind .......................................................................................................34 
6.4.3. 
Study Treatment Compliance ......................................................................................34 

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6.5. 
Prior and Concomitant Medications ..................................................................................35 
6.5.1. 
Prior Medication ..........................................................................................................35 
6.5.2. 
Rescue Medication .......................................................................................................35 
6.5.3. 
Concomitant Medication ..............................................................................................35 
6.5.4. 
Permitted Medications .................................................................................................35 
6.5.5. 
Surgery and Anesthesia................................................................................................35 
7. 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ............................................................................37 
7.1. 
Study Stopping Criteria......................................................................................................37 
7.2. 
Discontinuation of Study Treatment ..................................................................................37 
7.3. 
Participant Discontinuation/Withdrawal ............................................................................38 
7.4. 
Early Termination ..............................................................................................................38 
8. 
STUDY ASSESSMENTS AND PROCEDURES ...............................................................39 
8.1. 
Efficacy Assessments.........................................................................................................39 
8.2. 
Safety Assessments ............................................................................................................39 
8.2.1. 
Reporting Adverse Events and Serious Adverse Events .............................................40 
8.2.1.1. 
Definition of Adverse Events.................................................................................40 
8.2.1.2. 
Definition of Serious Adverse Event .....................................................................41 
8.2.1.3. 
Assessment of Severity ..........................................................................................41 
8.2.1.4. 
Assessment of Relationship to Study Drug ...........................................................41 
8.2.1.5. 
Assessment of Expectedness..................................................................................42 
8.2.1.6. 
Adverse Event Reporting and Follow-up Period ...................................................42 
8.2.1.7. 
Recording of Adverse Events ................................................................................43 
8.2.1.8. 
Serious Adverse Event Reporting ..........................................................................43 
8.2.1.9. 
Reporting of Pregnancy .........................................................................................44 
8.2.2. 
Clinical Laboratory Assessments .................................................................................44 
8.3. 
Pharmacokinetic Assessments ...........................................................................................45 
8.3.1. 
Pharmacokinetic Sampling and Analysis .....................................................................45 
9. 
STATISTICAL METHODS AND DATA ANALYSIS ......................................................46 
9.1. 
Statistical Hypotheses ........................................................................................................46 
9.2. 
Sample Size Determination................................................................................................46 
9.3. 
Multiplicity Adjustment .....................................................................................................46 
9.4. 
Populations .........................................................................................................................46 
9.5. 
Statistical Analyses ............................................................................................................47 
9.5.1. 
General Approach ........................................................................................................47 
9.5.2. 
Efficacy Analyses ........................................................................................................47 

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9.5.3. 
Safety Analyses ............................................................................................................47 
9.5.4. 
Pharmacokinetic Analyses ...........................................................................................48 
9.5.5. 
Handling of Missing Data ............................................................................................48 
9.5.6. 
Interim Analysis ...........................................................................................................48 
9.5.7. 
Protocol Deviations and Violations .............................................................................48 
9.5.8. 
Subgroup Analyses ......................................................................................................48 
10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ...........................................................................................................49 
10.1. Good Clinical Practice .......................................................................................................49 
10.2. Informed Consent Process .................................................................................................49 
10.3. Institutional Review ...........................................................................................................49 
10.4. Confidentiality and Privacy ...............................................................................................49 
10.5. Study Management ............................................................................................................50 
10.5.1. 
Clinical Monitoring ......................................................................................................50 
10.5.2. 
Inspection of Records ..................................................................................................50 
10.5.3. 
Data Quality Insurance ................................................................................................50 
10.5.4. 
Records Retention ........................................................................................................51 
10.5.5. 
Protocol Deviations ......................................................................................................51 
10.5.5.1. 
Unavoidable Protocol Deviations Related to COVID-19 ......................................51 
10.6. Publications ........................................................................................................................52 
11. 
LIST OF ABBREVIATIONS ..............................................................................................53 
12. 
REFERENCES .....................................................................................................................55 
Appendix A: 
Investigator’s Signature ...................................................................................58 
Appendix B: 
Pre-Study Personality Questionnaire ...............................................................59 
Appendix C: 
Numeric Pain Rating Scale ..............................................................................64 
Appendix D: 
Patient Global Assessment ...............................................................................65 
Appendix E: 
Numeric Nausea Rating Scale .........................................................................66 
Appendix F: Sleep Interference Score ........................................................................................67 
Appendix G: 
Ramsay Sedation Scale ....................................................................................68 
Appendix H: 
Patient Health Questionnaire-9 (PHQ-9) .........................................................69 
Appendix I  
General Anxiety Disorder (GAD-7) ......................................................................70 
Appendix J  
Columbia-Suicide Severity Rating Scale (C-SSRS) Baseline/Screening  .............71 
Appendix K  
Columbia-Suicide Severity Rating Scale (C-SSRS) Since Last Visit  ............74 
Appendix L  Toxicity Grading scale tables.................................................................................77 
Appendix M 
Summary of Changes .......................................................................................81 

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LIST OF TABLES 
 
Table 1 Dose and Pill Relationship ................................................................................................33 
 
 
 

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1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
Sponsor: 
Xgene Pharmaceutical Inc. 
Protocol #: 
PR-XG005-02-BUN-01  
Protocol Title: 
A Randomized, Double-Blind, Placebo Controlled Trial to Evaluate the Safety and 
Efficacy of XG005 Tablets in Subjects Undergoing Bunionectomy 
Investigational 
Product: 
XG005 (oral tablets) 
Planned Study Center: 
Three study centers in the United States (US) at minimum 
Phase of Development: 
Phase 2b 
Study Design: 
This is a multi-center, randomized, double-blind, parallel-group, placebo-controlled 
study. 
Subjects scheduled for bunionectomy surgery must meet all of the inclusion criteria 
and none of the exclusion criteria below prior to being enrolled and randomized.   
Eligible subjects will be randomized in a 1:1:1 ratio to receive either 750 mg XG005, 
1250 mg XG005, or placebo. Randomized subjects will receive drug per their 
treatment allocation as follows:  
• 60 minutes prior to surgery and every 12 hours (± 10 minutes) after the first dose 
for 72 hours.  
• Subjects and all study staff performing study assessments will be blinded to 
treatment allocation. To maintain the blind, a total of 5 tablets will be 
administered to each treatment group: 5 identical blue tablets (low or high dose 
XG005 or its placebo) at each time point.   
Subjects will undergo a Screening (Day -28 to Day -1), Pre-Operative Assessment 
(within 24 hours prior to surgery) and Surgery/Treatment Visit (beginning Day 1), 
when the following will occur: 
• 
Study medication administered 60 ± 10 minutes prior to surgery, record 
time.  
• 
Surgery performed, record starting time  
• 
Record time of end of surgery (as time of last suture closed) 
• 
Subjects domiciled in research center for at least 72 hours post-surgery  
• 
Efficacy and safety assessments performed over 72-hour period post-
surgery 
“Time 0” will be defined as the actual start time of the first dose from which 
subsequent 12-hour dosing times will be determined. All study efficacy and safety 
assessments are anchored to time at end of surgery (last suture). Pharmacokinetic 
(PK) sampling timepoints correlate with the collection of the 11-pt Numeric Pain 
Rating Scale (NPRS) efficacy assessments when they overlap.  
Subjects will be advised at Screening that if they terminate the study prior to 
72 hours, it is requested that they remain in the clinic for continued collection of 
scheduled safety data only. Screening will include subjects’ potential placebo 
response by use of a pre-study personality questionnaire (Appendix B).  
Subjects will be discharged at a reasonable hour of the day after the end of the 
72-hour treatment period, which may include the morning after the end of the 
72-hour treatment period.  
There will be a Follow-up Visit on Day 15.   
Early Termination visits will include the following assessments: NPRS, Patient 
Global Assessment (PGA) of pain control, Numeric Nausea Rating Scale (NNRS), 

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Sleep Interference Score (SIS) and safety assessments (vital signs, electrocardiogram 
[ECG], continuous pulse oximetry, laboratory testing, Ramsay Sedation Scale (RSS), 
and concomitant medications). 
Study Assessments 
All assessments are anchored to time at end of surgery (last suture). Details of all 
study assessments are provided in the Schedule of Assessments.  
Efficacy and Safety Assessments  
Study staff will record subject-reported pain assessments via a standard 11-point 
NPRS at the following time points post-end of surgery: 0, 1, 2, 3, 4, 6, 8, 10, 12, 16, 
20, 24, 30, 36, 42, 48, 54, 60, 66, and 72 hours within a ±10-minute window 
(Appendix C). NPRS will be collected prior to PK sampling and administration of 
rescue or study medication.   
Study staff will record subject-reported PGA of pain control using a 5-point scale 
(poor, fair, good, very good, excellent) at the following time points post-end of 
surgery: 24, 48, and 72 hours within a ±10-minute window and just prior to receiving 
a dose of rescue medication if needed (Appendix D).  
Study staff will record the time and the dose of rescue medication administered on 
the rescue medication form. NPRS and PK sampling will be collected immediately 
prior to administering rescue medication.   
Nausea will be self-assessed using an 11-point NNRS at the following time points 
post-end of surgery: 1, 4, 8, 12, 24, 48, 72 hours within a ±10-minute window 
(Appendix E). Additional NNRS assessments will be collected when an AE of 
nausea or vomiting is reported or prior to any rescue antiemetic administration. 
Subject will report Sleep Interference Score (SIS) using an 11-point NRS scale 
(0-10) at 24, 48 and 72 hours post-end of surgery within a ±15-minute window 
(Appendix F).  
Study staff will monitor for adverse events (AEs) and serious AEs (SAEs), ECG 
data, and vital signs (blood pressure [systolic and diastolic], heart rate, respiratory 
rate, oral body temperature, and continuous pulse oximetry), and record relevant 
safety data. 
Trained staff on hand in the research unit will monitor respiratory safety via 
respiration rate, continuous pulse oximetry and oxygen saturation (SpO2) checks 
every 12 hours post-end of surgery within a ±10minute window.  
The Ramsay Sedation Scale (RSS, Appendix G) used to assess somnolence to be 
assessed by study staff within a ±15minute window when NPRS is assessed. 
The Columbia-suicide severity rating scale (C-SSRS, Appendix K) will be 
administered 72 hours after treatment and at the end of study visit to assess suicidal 
ideation.  
Pharmacokinetic 
Blood draws will always be performed after each NPRS, nausea, SIS and/or PGA 
assessment, when applicable, and prior to the first administration of rescue 
medication. The PK sampling plan uses the post-end-of-surgery schedule to be 
consistent with the efficacy assessment schedule. 
Each subject in the PK subgroup (one site only) will have blood samples drawn for 
PK assessments at the following time points: prior to the first dose (pre-dose), and 
post end of surgery at 1, 2, 3, 4, 6, 8, 10, 12, 24, 30, 36, 42, 48, 54, 60, 66, and 72 
hours within a ±15-minute window. The actual clock time when the PK sample is 
collected will be recorded, and the post-dose time for PK analysis will be calculated 
based on the recorded clock time.  
Number of Subjects: 
A total of 450 subjects will be randomized (150 per arm) to achieve 130 evaluable 
subjects per treatment group. An evaluable subject is defined as one who receives 
study drug, completes surgery, and has at least 2 post-operative pain assessments. 

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A PK subgroup of 90 subjects (30 subjects per study arm) will be assessed at 1 site 
only.  
Surgical and 
Anesthetic Protocol: 
Subjects will undergo primary, unilateral, first metatarsal Austin bunionectomy. The 
surgical procedure should be limited to a maximum duration of 90 minutes. End of 
surgery will be defined as completion of the last suture. 
The surgery will be performed under regional anesthesia via a local Mayo block 
using lidocaine (20 mL, 2.0%) without epinephrine, with intravenous (IV) propofol 
for sedation. 
Propofol induction (dose per discretion of anesthesiologist) will be given as an initial 
bolus followed by a continuous infusion of up to 250 μg/kg/min for intraoperative 
sedation. 
A small dose of lidocaine (up to 5 mL of 1% lidocaine without epinephrine) may be 
administered to reduce vein irritation at the infusion site. 
Intraoperatively, all subjects will be given 50 μg of fentanyl IV around the time of 
induction with propofol. 
Once sedated, a Mayo block of the first metatarsal will be induced using lidocaine 
(20 mL, 2.0%) without epinephrine. 
Midazolam 1 mg IV may be administered preoperatively for anxiolysis. 
A pneumatic ankle tourniquet inflated between 150 and 250 mmHg will be applied to 
achieve homeostasis.   
Study Arms: 
1. Placebo [matching tablets Q12 hours] 
2. XG005 [750 mg Q12 hours] 
3. XG005 [1250 mg Q12 hours] 
Rescue Medication: 
First-line rescue pain medication, IV acetaminophen 1 g, will be administered Q 6 
hours, PRN, up to 4 g in 24 hours. If a patient is unable to tolerate acetaminophen or 
if there is insufficient pain relief, 50 mg tramadol will be administered Q 4 hours, 
PRN, up to 300 mg in 24 hours. 
Permitted Medications 
If a subject receives inadequate analgesia from study treatment and allowed rescue 
medication, they may terminate from the efficacy portion of the study and receive 
open-label standard of care analgesia excluding NSAIDs or gabapentinoids as per the 
discretion of the investigator. At the time of receiving standard of care analgesia, the 
following assessments will be performed prior to receiving standard of care 
analgesia:  
• 
NPRS  
• 
PGA 
• 
PK sample 
Because subjects will remain in the unit and continue to have all other assessments 
performed there is no need to do anything else at this time. If a subject is not willing 
to remain in the unit, then they should have all assessments as detailed in the current 
protocol language for early termination. 
Subjects who terminate early due to lack of efficacy will continue to receive their 
allotted study treatment and will continue to undergo all safety and pharmacokinetic 
assessments as scheduled. These subjects will also continue with all scheduled follow 
up visits (unless the subject withdraws consent). Subjects who withdraw because of 
an AE, would not continue to receive study medication.  
Antiemetics 
No pretreatment for potential nausea and vomiting is permitted. Administration of 
antiemetic medications are limited to subjects with active vomiting, subjects with a 
score ≥5 on the NNRS, or by subject request only. 
Study Objectives: 
Primary Efficacy 

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• 
To evaluate the efficacy of high dose XG005 [1250 mgQ12] compared to 
placebo for pain control in subjects undergoing bunionectomy 
Secondary Efficacy 
• 
To evaluate the efficacy of low dose XG005 [750 mg Q12] compared to placebo 
for pain control in subjects undergoing bunionectomy 
• 
To evaluate high and low dose XG005 compared to placebo for total rescue 
consumption and time to first use from end of surgery 
• 
To evaluate high and low dose XG005 compared to placebo for PGA 
• 
To evaluate high and low dose XG005 compared to placebo for postoperative 
nausea  
• 
To evaluate the efficacy of high dose XG005 compared to low dose XG005 for 
pain control in subjects undergoing bunionectomy  
Tertiary Efficacy (All Treatment Arms) 
• 
To evaluate rescue medication consumption at 24, 48, and 72 hours, time to first 
use of rescue medication from end of surgery, and proportion of subjects 
requiring rescue medication. 
• 
To evaluate nausea assessment scores at various timepoints 
• 
To evaluate high and low dose XG005 compared to placebo for SIS 
Exploratory 
• 
To estimate subject’s potential placebo response by use of a pre-study 
personality questionnaire at Screening 
Safety and Tolerability 
• 
To evaluate the safety and tolerability of XG005 in a perioperative population 
Pharmacokinetics 
• 
To investigate the PK of XG005 in a perioperative population 
Primary Efficacy 
Endpoint:  
Summed pain intensity from end of surgery to 48 hours post-surgery (SPI48) for high 
dose XG005 vs placebo 
Secondary Endpoints: 
Key Secondary Endpoints: 
1. SPI48: low dose XG005 vs placebo 
2. Total tramadol rescue medication consumption in morphine equivalents 
(MEQs) over 48 hours: high dose XG005 vs placebo 
3. Total tramadol rescue medication consumption in morphine equivalents 
(MEQs) over 48 hours: low dose XG005 vs placebo  
Additional Endpoints: 
4. Time to first use of rescue medication from end of surgery: high dose XG005 
vs placebo 
5. Time to first use of rescue medication from end of surgery: low dose XG005 
vs placebo 
6. PGA at 48 hours: high dose XG005 vs placebo 
7. PGA at 48 hours: low dose XG005 vs placebo  
8. Cumulative Nausea (NNRS) assessment scores through 24 hours: high dose 
XG005 vs placebo 
9. Cumulative Nausea (NNRS) assessment scores through 24 hours: low dose 
XG005 vs placebo  
10. SPI48: high dose XG005 vs low dose XG005 
Tertiary Endpoints: 
Tertiary Endpoints for All Treatment Arms: 
• 
Total rescue medication consumption at 24, 48, and 72 hours 

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• 
Nausea (NNRS) assessment scores at 1, 4, 8, 12, 24, 48, and 72 hours 
• 
SPI at 0, 1, 2, 3, 4, 6, 8, 10, 12, 16, 20, 24, 30, 36, 42, 48, 54, 60, 66, and 72 
hours 
• 
Pain intensity at various timepoints 
• 
SIS at 24, 48 and 72 hours 
• 
Percentage of subjects requiring rescue at various timepoints 
• 
PGA of pain control at various timepoints  
• 
Ramsay Sedation Scale at various timepoints   
Exploratory:  
• Estimate of subject susceptibility to placebo response at Screening using a pre-
study personality questionnaire 
Safety and PK 
Endpoints 
Safety 
Safety and tolerability of XG005 compared with placebo measured by AE reporting 
(incidence of AEs and SAEs), vital signs, SPO2, ECGs, and laboratory values. 
Sedation will be assessed by study staff by use of the Ramsay Sedation Scale (RSS) 
when NPRS can be assessed. Nausea will be self-assessed using an 11-point NNRS. 
Pharmacokinetics 
Plasma PK parameter endpoints to include the following: 
• Area under the plasma concentration-time curve from time zero to time t of the 
last measured concentration above the limit of quantification (AUClast) 
• Area under the plasma concentration-time curve from zero to infinity (AUCinf) 
• Maximum plasma concentration (Cmax) 
• Trough plasma concentration prior to each dose (Ctrough) 
• Time to reach maximum plasma concentration (Tmax)  
• Terminal elimination rate constant (λz) with the respective half-life (t1/2). 
Inclusion Criteria: 
1. Willing and able to sign the informed consent form (ICF) approved by the 
Institutional Review Board (IRB) 
2. Male or female aged 18–80 years 
3. Scheduled to undergo unilateral first metatarsal bunionectomy 
4. Capable of undergoing a bunionectomy under anesthesia as described in the 
study surgical and anesthetic protocol 
5. Weight > 50 kg and a body mass index (BMI) < 39 kg/m2  
6. No additional planned surgeries other than bunionectomy during the course of 
the study 
7. Have negative urine drug screen for drugs indicative of illicit drug use (unless 
results can be explained by a current prescription or acceptable over-the-counter 
[OTC] medication at Screening as determined by the Investigator) and no 
detectable results on the alcohol test (breath or saliva) indicative of alcohol 
abuse at Screening, and/or prior to surgery (may be repeated if the Investigator 
suspects a false-positive result)  
Note: For those subjects who test positive for tetrahydrocannabinol (THC), if 
they are willing to abstain from use or consumption of THC-containing products 
from Screening through end of the subject’s participation in the study, they may 
be allowed to participate in the study.  
8. Biological female subjects must be non-lactating. They must also be either 
sterile (bilateral tubal ligation, bilateral salpingectomy, or hysterectomy), post-
menopausal for at least 1 year, have a partner who is sterile, be abstinent, have a 
same-sex partner, use a highly effective double-contraception method (hormonal 
protection is insufficient), or use an FDA-approved contraceptive for greater 

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than 2 months prior to Screening visit and commit to an acceptable form of birth 
control for the duration of the study and for 30 days from completion of the 
study. 
9. Willing and able to complete the study procedures and pain scales and to 
communicate meaningfully in English with study personnel. 
10. Negative result of COVID-19 test within 3 days before Day 1 visit. 
Exclusion Criteria: 
1. Medical condition or history that in the investigator’s opinion could adversely 
impact the subject’s participation or safety or the conduct of the study, or 
interfere with the pain assessments, including the following: 
a. 
Serious breathing difficulties or respiratory risk factors (including clinically 
significant use of opioid pain medicines and other drugs that depress the 
central nervous system [CNS]) and conditions such as chronic obstructive 
pulmonary disease (COPD) that reduce lung function) 
b. Clinically unstable hypertension, cardiovascular disease, or history of 
cerebrovascular events. Hypertension must be stable without known end 
organ damage 
c. 
Concurrent painful conditions that may require analgesic treatment during 
the study period 
d. History of significantly reduced hepatic function (alanine aminotransferase 
[ALT], aspartate aminotransferase [AST], or lactase hydrogenase [LDH] 
≥ 1.5 x upper limit of normal [ULN] or renal function (creatinine 
≥1.5 x ULN), angle closure glaucoma, or convulsive disorder 
e. 
Recent history of urinary retention 
f. 
History of gastrointestinal ulcer, bleeding, perforation, or recent surgery of 
gastrointestinal tract  
g. Subject is currently taking or has taken a chronic opioid at a dose greater 
than or equal to 20 mg hydrocodone per day ([≥ 20 MEQs] more than 
30 consecutive days of daily use) for pain in the 2 months prior to surgery. 
h. Active cutaneous disease, or other disease, at the surgical site 
i. 
Peripheral vascular disease, sickle cell disease, vascular grafts, or 
vasospastic disorders 
j. 
Known bleeding disorder or is taking agents affecting coagulation 
preoperatively. Deep venous thrombosis (DVT) prophylaxis of the 
surgeon’s choice is permitted postoperatively 
k. Diabetes mellitus (uncontrolled). Diabetes must be controlled without 
known end organ damage (hemoglobin A1C [HgbA1c] <7%)  
l. 
History of malignancy in the past 5 years with the exception of cured skin 
squamous cell or basal cell carcinoma  
m. Prior bunionectomy on the index foot or other foot surgery on the index foot 
that could impact the surgery or data collection endpoints  
n. Presence of, history of or family history of keloid and/or hypertrophic scar 
2. Use of disallowed medications at the window specified below and planned to 
use throughout the study period, including the following: 
a. 
Pain medication (opioids, NSAIDs, COX-2 inhibitors, tramadol, ketamine, 
clonidine, gabapentin, pregabalin, and/or cannabinoids, etc.) within 2 days 
prior to Day -1. 
b. CNS active drugs such as benzodiazepines, tricyclic antidepressants, 
Serotonin, and norepinephrine reuptake inhibitors (SNRIs), selective 
serotonin reuptake inhibitors (SSRIs), or any other serotonergic medications 
within 7 days prior to Day -1. The use of lorazepam and other sleep 
medications, except those containing analgesic properties, is permitted. 
c. 
Use of parenteral or oral corticosteroid(s) within 14 days prior to Day -1. 
d. Antihypertensive agent or diabetic regimen at a dose that has not been stable 
for at least 30 days, or which is not expected to remain stable throughout the 
study. 

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e. 
Digoxin, warfarin lithium, theophylline preparations, aminoglycosides, and 
all antiarrhythmics except beta-blockers within 7 days prior to Day -1 and 
throughout the study. 
f. 
Current use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs 
within the last 14 days.   
3. Positive results for hepatitis B surface antigen (HbsAg) and/or hepatitis B anti-
core antibody (anti-HBc) but negative results for anti-surface antibody (anti-
HBs) at the Screening Visit.  
4. Positive results for hepatitis C antibody unless patient received curative therapy 
and a negative viral load is documented.  
5. Human immunodeficiency virus (HIV) infection or positive HIV serology at the 
Screening Visit.  
6. Known positive COVID-19 viral test during screening or suspected COVID-19 
infection at the Day 1 Visit 
7. History of illicit drug use, or prescription medicine or alcohol abuse within the 
past 2 years. 
8. History of opioid dependence. 
9. History of NSAID-induced bronchospasm or presence of nasal polyps, history of 
asthma or chronic rhinitis. 
10. Significant history of allergic reactions or known intolerance to naproxen, 
pregabalin or any gabapentinoid, or to any rescue medication used in the study, 
or any medication used in the surgical and anesthetic protocol. 
11. Biological female subjects who are pregnant or lactating, who plan to get 
pregnant, or who have a positive pregnancy test at Screening or at Day 1 (prior 
to surgery). 
12. Participated in another clinical trial within 30 days, or previously participated in 
a clinical study with a similar investigational product. 
13. Presence of severe depression as indicated by Patient Health Questionnaire 
(PHQ-9) total score of ≥20 or item 9 score >0 at the Screening Visit. 
14. Presence of severe anxiety as indicated by General Anxiety Disorder (GAD-7) 
score of ≥15 at the Screening Visit. 
15. Presence of history of suicidal behavior or ideation as indicated by the 
Columbia-Suicide Severity Rating Scale (C-SSRS) Baseline/Screening Version 
at Screening Visit. 

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Statistical 
Considerations: 
 
Statistical Hypotheses 
This primary efficacy endpoint is to test the mean difference of summed pain 
intensity from end of surgery to 48 hours post-surgery (SPI48) between high dose 
XG005 and Placebo groups.  
The study null hypothesis is XG005 high dose and placebo have the same effect. And 
the alternative hypothesis is XG005 high dose and placebo have different effect. These 
will be tested at a two-tailed alpha of 0.05, and the Null hypothesis will be rejected if 
p-value < 0.05.  
Sample Size Determination 
One hundred thirty (130) evaluable subjects per study arm will yield 90% power to 
detect a standardized effect size of 40% (Wang 2010; Wu J, Jiang J, Wei W. 
Confidence intervals of effect size in randomized comparative parallel-group studies. 
Stat Med. 2006;25(4):639-51.; Vevea J, Woods CM. Publication bias in research 
synthesis: sensitivity analysis using A priori weight functions. Psychological 
Methods. 2005;10(4):428–43.; Singla NK, Chelly JE, Lionberger DR, et al. 
Pregabalin for the treatment of postoperative pain: results from three controlled trials 
using different surgical models. J Pain Res. 2015;8:9-20.) at a two-tailed α= 0.05 for 
the familywise type one error. Recruitment goals will be 150 subjects per arm or 
N=450 total. 
Randomization Strata 
• 
Study Site 
Multiplicity Adjustment 
A serial gatekeeping procedure will be used to control the overall type-1 error rate at 
0.05 for primary and secondary endpoints. If the primary endpoint is not significant at 
a two-tailed alpha of 0.05, there is no testing on secondary endpoints. If the primary 
endpoint is significant at a two-tailed alpha of 0.05, the secondary endpoints will be 
tested following the hierarchy testing procedure with a pre-specified order as above. If 
any secondary endpoint is not significant, the successive secondary endpoints will not 
be tested.  
Analysis Populations 
• 
The Intent-to-Treat (ITT) population is defined as all randomized subjects. 
Subjects will be analyzed according to the treatment group to which they 
were randomized.  
• 
The Safety Population is defined as all subjects who receive study 
medication. Subjects will be analyzed according to the actual treatment they 
receive. 
• 
The modified Intent-to-Treat (mITT) Population is defined as all ITT 
subjects who received at least one dose of study medication and have at 
least 2 NPRS assessments post-end of surgery. 
• 
The Per-Protocol Population is defined as all mITT subjects who have no 
major protocol violations which may potentially bias efficacy analysis of the 
study.  
Efficacy 
The primary endpoint of the comparison of summed pain intensity (SPI) from end of 
surgery to 48 hours post-surgery (SPI48) for high dose XG005 vs placebo will be 
analyzed, using analysis of covariance (ANCOVA) model. The model will use 
treatment as main effect, and study site as a covariate. More details for efficacy 
analyses will be specified in SAP. 

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Safety 
The Medical Dictionary for Regulatory Activities (MedDRA® version 23 or higher) 
will be used to classify all AEs with respect to system organ class and preferred term. 
AEs will be summarized by treatment. 
Actual values and changes from baseline for clinical laboratory test results, vital sign 
measurements, and 12-lead ECG results will be summarized by treatment at each 
time point using descriptive statistics (number of subjects, mean, SD, median, 
minimum, and maximum). Shift tables will be generated for clinical laboratory test 
results. Physical examination findings will be presented in a data listing. 
Pharmacokinetics  
Individual plasma concentrations of naproxen, pregabalin and XG005 (as 
appropriate) will be listed by subject and summarized by gender, dose, and nominal 
time point using descriptive statistics (i.e., N, arithmetic mean, SD, percent 
coefficient of variation [CV%], median, minimum, maximum, and geometric mean). 
PK analyses will be addressed in a separate PK Analysis Plan.    
Handling of Missing data 
For the PK analysis, concentrations that are below the limit of quantification (BLQ) 
will be treated as zero for descriptive statistics with the exception that a BLQ value 
between two quantifiable concentrations will be set as missing. Missing 
concentrations will be treated as missing from the PK parameter calculations. If 
consecutive BLQ concentrations are followed by quantifiable concentrations in the 
terminal phase, those concentrations after BLQ concentrations will be treated as 
missing. 
For efficacy analyses, when rescue medication is used, the last pain intensity measure 
prior to the use of rescue medication will be used (imputed) for the subsequent 
protocol-specified time points for measurement of pain intensity after the time of the 
rescue medication. 
Missing data as a result of discontinuation due to adverse event or lack of efficacy 
will be imputed with worst observation carry forward (WOCF) method. 
For safety analyses, missing data will not be imputed in general, otherwise specified. 
More details will be described in the SAP.   
Protocol deviations and violations 
Protocol deviations will be identified on an ongoing basis by the clinical study team.  
Subgroup analyses 
Analyses by subgroup may be further described in the SAP. 
Interim Analysis  
No formal interim analysis will be performed in this study.   

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1.2. 
Schedule of Assessments 
 
Screen 
Day 1: Surgery 
Treatment Period (Hours Post End of Surgery) 
End of 
Study/Early 
Terminationv 
Assessment  
Days -28 
to -1 
Pre-
Surgerya 
Surgery 
0 
1 
2 
4 
8 
12 
24 
36 
48 
60 
72 
Clinic Visit, 
Day 15 (±2) 
Written Informed 
Consentb 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteriac 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical 
Examinationd  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signse 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Electrocardiogramf 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Clinical Laboratory 
Testingg 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Pregnancy Testh 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Urine Drug Screeng 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
COVID-19 testw 
X 
X w 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse Events 
Monitoringi 
 
Prior/Concomitant 
Medications  
 
Pre-study 
personality 
questionnairej 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C-SSRS 
Baseline/Screening 
Version Appendix J 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Screen 
Day 1: Surgery 
Treatment Period (Hours Post End of Surgery) 
End of 
Study/Early 
Terminationv 
Assessment  
Days -28 
to -1 
Pre-
Surgerya 
Surgery 
0 
1 
2 
4 
8 
12 
24 
36 
48 
60 
72 
Clinic Visit, 
Day 15 (±2) 
C-SSRS 
Since Last Visit 
Version Appendix K 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Patient Health 
Questionnaire-9 
(PHQ-9) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
General Anxiety 
Disorder (GAD-7) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Domiciled in Clinic 
 
 
 
Enrollment/ 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Drug Dosing 
(XG005 or 
Placebo)k 
 
X 60 min 
prior to 
surgery 
 
Every 12 hours after the first dose defined as “Time 0” for dosing purposes only 
 
Blood Sample for 
Pharmacokinetic 
Assessmentl 
 
X 
Pre-dose 
 
 
 
 
Drawn at 1, 2, 3, 4, 6, 8, 10, 12, 24, 30, 36, 42, 48, 54, 60, 66, and 72 hours  
(±15 min window) after the end of surgery (last suture) 
 
 
Anesthesia and 
Bunionectomy 
Surgerym  
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Continuous Pulse 
Oximetryn 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
Rescue Medication   
 
 
 
PRN 
 
Numeric Pain 
Rating Scale 
(NPRS)p,q 
 
 
 
 
Measure at 0, 1, 2, 3, 4, 6, 8, 10, 12, 16, 20, 24, 30, 36, 42, 48, 54, 60, 66, and 
72 hours after the end of surgery (±10 min window) 
 
X (ET only) 
Patient Global 
Assessment (PGA) 
of Pain Controlr 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
X (ET only) 

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Screen 
Day 1: Surgery 
Treatment Period (Hours Post End of Surgery) 
End of 
Study/Early 
Terminationv 
Assessment  
Days -28 
to -1 
Pre-
Surgerya 
Surgery 
0 
1 
2 
4 
8 
12 
24 
36 
48 
60 
72 
Clinic Visit, 
Day 15 (±2) 
Numeric Nausea 
Rating Scale 
(NNRS)s 
 
 
 
 
X 
 
X 
X 
X 
X 
 
X 
 
X 
X (ET only) 
Sleep Interference 
Score (SIS)t 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
X (ET only) 
Ramsay Sedation 
Scale 
(Somnolence)u 
 
 
 
 
Measure at 0, 1, 2, 3, 4, 6, 8, 10, 12, 16, 20, 24, 30, 36, 42, 48, 54, 60, 66, and 
72 hours after the end of surgery (±10 min window) 
X (ET only) 
Dischargev 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Abbreviations: PRN = as needed 
a) Signed informed consent must be obtained prior to a subject undergoing any study procedures or assessments.  
b) Subject’s must meet all of the study inclusion criteria as shown in Section 5.1 and none of the exclusion criteria as shown in Section 5.2. All inclusion and 
exclusion criteria must be verified by the Investigator or designee at Screening (Day -28 to Day -1) and Pre-Surgery (Day 1). 
c) All Pre-surgery assessments to be performed within 24 hours prior to surgery. For inclusion/exclusion criteria and medical history only, assess updates since 
Screening and evaluate for continued eligibility. The Investigator or designee may repeat lab tests and vitals/ECGs prior to randomization. 
d) A PE will be obtained at Screening. A complete physical examination will include assessments of the head, eyes, ears, nose, throat, skin, neck (including 
thyroid), lungs, cardiovascular, abdomen, lymph nodes and extremities. The subject’s height and weight will be measured to determine body mass index at 
Screening to determine eligibility. It is not necessary to collect information regarding well-healed surgical scars or tattoos. If abnormalities are noted during 
the Screening, they should be also recorded on the Adverse Event eCRFs or Medical History, as appropriate. Subjects will be advised at Screening that if they 
terminate the study prior to 72 hours, it is requested that they remain in the clinic for continued collection of scheduled safety data only. 
e) Vital signs (blood pressure [systolic/diastolic], heart rate, respiratory rate, oral body temperature) will be collected from all subjects at Screening, before the 
first dose Pre-Surgery (±10 minutes) and Hours 0, 1, 2, 4, 8, 12, 24, 36, 48, 60, and 72, and Day 15/Early Termination (±10 minutes). Monitoring of continuous 
pulse oximetry begins at Hour 0 (start of the domiciling period). Vital signs may be obtained at any other times as deemed necessary by the Investigator. Vital 
signs throughout the study should be obtained supine after resting for approximately 5 minutes. Automated blood pressure machines may be used to standardize 
measurements. Body temperature will be determined by obtaining oral temperature (°C).  
f) 12-lead ECG data will be collected from all subjects at Screening and at the Day 14 clinic visit, and from any subject who is determined to be exhibiting any 
relevant abnormality per the discretion of the investigator. 12-lead ECGs will be obtained at each time point using an ECG machine that automatically calculates 
the heart rate and measures PR, QRS, QT, and QTc intervals. QTcF will also be calculated. 12-lead ECGs will be measured in the supine position, after the 
subject has been supine for at least 10 minutes. 
g) Clinical laboratory parameters include standard chemistry (albumin, total bilirubin, total protein, calcium, alkaline phosphatase, alanine aminotransferase 
[ALT], aspartate aminotransferase [AST], blood urea nitrogen [BUN], creatinine, glucose, sodium, potassium, chloride, bicarbonate, lactate dehydrogenase 

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[LDH], and uric acid; hematology (HbA1c [Screening only], hemoglobin, hematocrit, red blood cell [RBC] count, RBC indices, mean corpuscular hemoglobin 
[MCH], mean corpuscular hemoglobin concentration [MCHC], platelet count, and white blood cell [WBC] count including differential; coagulation panel 
(prothrombin time [PT], partial thromboplastin time [PTT], and fibrinogen); serology (human immunodeficiency virus [HIV] antibody, hepatis B virus surface 
antigen, hepatitis B anti-core antibody (anti-HBc) and anti-surface antibody, and hepatitis C virus antibody); urinalysis (pH, specific gravity, blood and 
leukocyte esterase, glucose, protein, and ketones), and urine drug screen (amphetamines, barbiturates, benzodiazepines, cocaine, opiates, phencyclidine [PCP], 
tetrahydrocannabinol [THC], methamphetamine, methadone, and ecstasy).  
h) For premenopausal women, a serum pregnancy test will be conducted at Screening visit, a urine pregnancy test will be conducted pre-surgery on Day 1 and at 
Exit Visit. Premenopausal women must have a negative serum pregnancy test to be included in study. Results must be available before surgery.  
i) Reporting of treatment-emergent AEs begins at the time of first dose of study drug and ends 30 days after the last dose of study drug. Non-treatment emergent 
AE reporting begins at Screening after signing of ICF until the first dose of study drug is administered.  
j) Subjects will be assessed at Screening on their potential placebo response by use of a pre-study personality questionnaire (Appendix B). This is a exploratory 
analysis for information purposes only. 
k) Study drug will be administered 60 minutes prior to start of surgery and every 12 hours for 72 hours after the time of first dose. The clock time of first dose is 
noted as “Time 0”, and it will be recorded to facilitate the PK analyses.  
l) Blood draws will always be performed after NPRS assessment and prior to the first administration of rescue medication. Considering the surgery time may 
largely vary among subjects, the PK sampling plan used the post-end-of-surgery schedule to be consistent with the efficacy assessment schedule. Each subject 
in the PK group (one site only) will have blood samples collected for PK assessments at predose and at the following intervals post-surgery (last suture) 1, 2, 3, 
4, 6, 8, 10, 12, 24, 30, 36, 42, 48, 54, 60, 66, and 72 hours (±15 min window). XG005, naproxen, and pregabalin concentrations in plasma will be measured. 
The actual clock time when the PK sample is collected will be recorded, and the post-dose time for PK analysis will be calculated based on the recorded clock 
time. All subjects will have blood samples collected for PK assessments at any time in which a subject is determined to be exhibiting any relevant abnormality 
per the discretion of the investigator. 
m) Subjects will undergo primary, unilateral, first metatarsal Austin bunionectomy. The surgical procedure should be limited to a maximum duration of 90 minutes. 
End of surgery will be defined as completion of the last suture. 
n) Subjects will be on continuous pulse oximetry monitoring throughout the confinement period but, absent a respiratory AE, oxygen saturation (Sp02) will be 
recorded every 12 hours post-end of surgery. 
o) Subjects will be permitted rescue medication throughout the 72-hour inpatient domiciling period as follows to manage breakthrough pain only if it occurs while 
domiciled: IV acetaminophen 1 g, will be administered Q 6 hours, PRN, up to 4 g in 24 hours. If a patient is unable to tolerate acetaminophen or if there is 
insufficient pain relief, 50 mg tramadol will be administered Q 4 hours, PRN, up to 300 mg in 24 hours. Study staff will record the time and the dose of rescue 
medication administered on the rescue medication form. NPRS and PK sampling will be collected immediately prior to administering rescue medication. Only 
the protocol-defined rescue medication is permitted in the study.  
p) Study staff will record subject-reported pain assessments via a standard 11-point NPRS at the following time points post-end of surgery: 0, 1, 2, 3, 4, 6, 8, 10, 
12, 16, 20, 24, 30, 36, 42, 48, 54, 60, 66, and 72 hours within a ±10-minute window (Appendix C). NPRS will be collected prior to PK sampling and 
administration of rescue medication.  
q) Pain intensity assessments scheduled between 24:00 and 06:00 may be skipped if the subject is sleeping. However, consecutive pain assessments may not be 
skipped, and the Hour 12, Hour 24, and Hour 48 pain assessments must be completed even when they fall asleep between 24:00 and 06:00.  
r) Study staff will record subject-reported PGA of pain control using a 5-point scale (poor, fair, good, very good, excellent) at the following time points post-end 
of surgery: 24, 48, and 72 hours within a ±10-minute window and just prior to receiving a dose of rescue medication (Appendix D). PGA will also be performed 
and recorded at early termination.  

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s)  Nausea will be measured after the end of surgery by using the 11-point NNRS at the indicated time points with a ± 10-minute window (Appendix E). PK 
sampling blood draws will always be performed after NNRS assessment. Additional NNRS time points will be collected when an AE of nausea or vomiting is 
reported or prior to any rescue antiemetic medication. Administration of antiemetic medications are limited to subjects with active vomiting, subjects with a 
score ≥5 on the NNRS, or by subject request only. No pretreatment for potential nausea and vomiting is permitted. 
t) Sleep Interference Score using the 11-point NRS scale (0=no interference to sleep, 10=worst interference imaginable) to be assessed at 24, 48 and 72 hours 
post-surgery within a ±15-minute window. 
u) Ramsay Sedation Scale to be determined by observation of subject by study staff when NPRS is assessed (Footnote p, above). 
v) Subjects will be discharged at a reasonable hour of the day after the end of the 72-hour treatment period, which may include the morning after the end of the 
72-hour treatment period. Early termination visits will include the following assessments: NPRS, PGA, NNRS, SIS, and safety assessments (vital signs, ECG, 
laboratory testing, and concomitant medications). 
w) All subjects will be tested for COVID-19 during Screening and within 3 days prior to surgery. COVID-19 testing samples will be taken prior to surgery on 
Day 1 from subjects that are in the PK sampling groups. The result of that test is not necessary before surgery.  
 

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2. 
INTRODUCTION  
2.1. 
Background  
Xgene Pharmaceutical has developed XG005, a prodrug conjugating pregabalin, an anti-
hyperalgesic, antiallodynic, and analgesic, with naproxen, an analgesic and anti-inflammatory 
agent. It is the first in a new class of “dual-acting” conjugate analgesics that has been engineered 
to reduce the gastrointestinal (GI) safety risks associated with naproxen and improve clinical 
efficacy in the treatment of acute and chronic pain. XG005 has been evaluated in preclinical and 
Phase 1 clinical studies. In the first Phase 1 study in healthy volunteers, oral XG005-01 (capsule 
formulation) demonstrated an acceptable safety profile with no additional adverse events 
compared with pregabalin or naproxen (parent drugs). Xgene Pharmaceutical has since 
developed an improved tablet formulation (XG005) which showed improved bioavailability for 
pregabalin and naproxen. In two Phase 1 single and multiple ascending dose studies with XG005 
tablet formulation, a clinically relevant dose range was evaluated in healthy volunteers. These 
studies showed a safety profile consistent with pregabalin and naproxen. 
In general, pain symptoms are classiﬁed into two broad mechanism-based pain categories: tissue-
injury pain (nociceptive) or nervous-system-injury pain (neuropathic).  Some of the chronic pain, 
such as the low back pain or moderate to severe arthritis pain, have been shown to be the result 
of neuropathic as well as nociceptive pain mechanisms.  It has been demonstrated that the 
analgesic effects can be enhanced by co-administration of gamma-aminobutyric acid (GABA) 
analogs, such as pregabalin or its predecessor gabapentin together with non-steroidal anti-
inflammatory drugs (NSAIDs) (Yu et al. 2011; Corleto et al. 2014; Banoob et al. 2002; Petroski 
1993; Van Gossumet et al. 1993; D'Haens et al. 1993; Ivey et al. 1980).  They can interact in a 
synergistic or additive manner to control pain in the preclinical animal models as well as in the 
clinical practices.  The synergy of these two classes of drugs can potentially allow a reduction in 
the dose required of each compound, leading to a reduction in the side effects, and the 
enhancement of the clinical utility of these compounds.  Furthermore, combining the prodrug 
strategy and the potential complimentary synergy between the two drugs may lead to an optimal 
clinical outcome in terms of improved clinical efficacy and reduced GI events in patients with 
chronic pain. 
2.2. 
Unmet Medical Need 
Both acute and chronic pain remain as high unmet medical needs with high global burden of 
disease (Enright et al. 2016; Blyth et al. 2019). Acute pain is the most common reason for 
visiting an emergency department, and surgical procedures are associated with acute 
postoperative pain (Sinatra 2010). Chronic pain causes significant suffering as indicated by the 
Global Health Burden of Disease survey demonstrating that headache and low back pain were 
the leading causes of years lived with disability (GBD 2017). 
Multimodal approaches are used for the treatment of pain for both inflammatory and neuropathic 
pain conditions to limit the use of opioid analgesics (Finnerup 2019). There remains a significant 
unmet medical need for treatment of chronic pain with non-opioid drugs that are safe and 
tolerable. In an effort to develop a better analgesic to address these needs, Xgene Pharmaceutical 

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has designed an orally bioavailable “dual-acting” prodrug conjugating two well-established 
analgesics with different mechanisms of action: naproxen and pregabalin conjugated with a 
linker that has been previously approved in a product Horizant® (Horizant [pregabalin] 2013). 
Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used for the management of pain. 
Naproxen, a cyclo-oxygenase inhibitor, is a potent inhibitor of prostaglandin synthesis. It is one 
of the most prescribed NSAIDs in the world, available over the counter, for the treatment of pain 
and inflammation and has the most favorable cardiovascular side effect profile in this class 
(Naprosyn 2017; Trelle et al. 2011; Coxib and traditional NSAID Trialists’ (CNT) Collaboration 
et al. 2013; Inza 2019). 
Pregabalin is structurally related to the naturally occurring amino acids L-leucine and gamma-
aminobutyric acid (GABA). Pregabalin was approved in 2004 to manage peripheral neuropathic 
pain, fibromyalgia in adults (Lyrica 2013) and is now available as a generic drug. The dose range 
in humans is 150 to 600 mg per day. Pregabalin binds to the alpha2-delta protein, an auxiliary 
subunit protein of voltage-gated calcium channels with high affinity (IC50 = 37 nM), which is 
required for its pharmacology. The (R)-enantiomer of pregabalin was 10-fold less potent than its 
(S)-enantiomer (Lyrica 2013). 
XG005 is intended for use in both acute and chronic pain conditions. Due to the unique 
mechanism of action of this prodrug on both neuropathic and inflammatory mechanisms of pain, 
it is expected to have a better benefit in pain management than currently available medications 
and reduce the use of potentially more harmful drugs such as opioids. 
2.3. 
XG005 Clinical Experience in Healthy Subjects 
Xgene Pharmaceutical has completed a Phase 1 single-ascending dose (SAD) study (XG005-01; 
capsule formulation) and a Phase 1 SAD/multiple ascending dose (MAD) study (XG005; tablet 
formulation) in healthy subjects at clinical sites in Australia.  
Study XG005-01  
The completed Phase 1 SAD study in 40 healthy subjects demonstrated that area under the 
plasma concentration-time curve from time 0 to the last quantifiable point (AUC0-t) of naproxen 
and pregabalin increased with dose level of XG005-01 across the dose range 50 mg to 1000 mg, 
with the increase being linear with dose for naproxen but less than dose proportional for 
pregabalin. There was no dose or treatment-related trend in the incidence of treatment-emergent 
adverse events (TEAEs; defined as adverse events reported after treatment was received) for 
subjects who received XG005 compared with subjects who received placebo. Most TEAEs 
reported during this study were mild in intensity, none was severe. The most commonly reported 
adverse event was dizziness in 8 of 30 subjects (27%). No deaths, serious adverse events (SAEs) 
or TEAEs leading to study withdrawal were reported. 
Study XG005-02  
The second Phase 1 study (XG005-02; NCT04067947) evaluated safety, tolerability, and PK 
profile of XG005 (tablet formulation) in 32 healthy volunteers in each SAD and MAD cohorts. 
XG005 was evaluated at the doses of 250, 500, 1000, 1250 mg in the single dose and twice-a-day 

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(BID) dose up to 7 days. Following single and multiple dose administration of XG005, AUCs 
and maximum concentration in plasma (Cmax) of XG005, naproxen, and pregabalin increased in a 
dose proportional manner. There was no dose or treatment-related trend in the incidence of 
TEAEs for subjects who received XG005 compared with subjects who received placebo. Most 
TEAEs reported during this study were mild in intensity, none was severe. The most commonly 
reported adverse event (AE) was dizziness (9 [37.5%] of 24 XG005 subjects) in the SAD cohort, 
and somnolence (7 [29.17%] of 24 XG005 subjects) in the MAD cohort. In comparison, in the 
LYRICA controlled trials in adult patients, dizziness was experienced by 30% of LYRICA-
treated patients and somnolence was experienced by 23% of LYRICA-treated patients (Lyrica 
2013). No deaths or SAEs were reported during this study. None of the subjects in XG005 
groups discontinued study drug due to TEAEs. 
Study XG005-02-PK-02  
This Phase 1 bridging MAD study in Chinese healthy volunteers enrolled 16 subjects. 8 subjects 
were administered 750 mg or 1250 mg XG005 BID for 6.5 days, respectively, following titration 
to target dose levels. All subjects had good tolerance to study drug. No new drug-related TEAEs 
other than those known for naproxen or pregabalin. Notable TEAEs were dizziness, somnolence, 
constipation, and oral ulcer. But all were mild in severity and no subject discontinued from the 
study.  
The Investigator’s Brochure summarizes the nonclinical and clinical experience with XG005, 
naproxen, and pregabalin (XG005 IB 2022). Additional efficacy and safety information for the 
marketed products can be found in the package insert for naproxen (Naprosyn 2017) and 
pregabalin (Lyrica 2013). 
2.4. 
Study Rationale 
XG005 is being developed for the management of pain. Pre-clinical animal models have 
demonstrated improved efficacy for pain and inflammation compared with naproxen alone 
(Hurley et al. 2002), and pilot human studies have shown that both pregabalin and naproxen 
could reduce pain in a bunionectomy model with a possible synergistic effect (Wang et al 2010). 
By targeting both neuropathic and inflammatory aspects of pain in a single prodrug, therapeutic 
advantages are expected. With the use of this conjugate approach, there is a potential for a better 
benefit risk profile compared with available drugs, with lowered use of opiates. 
This study will evaluate the safety, efficacy, and PK of low dose (750 mg) and high-dose 
(1250 mg) XG005 oral tablets compared with placebo in subjects undergoing bunionectomy.   

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3. 
OBJECTIVES AND ENDPOINTS 
 
Objectives 
Endpoints 
Primary Efficacy:  
 
• 
To evaluate the efficacy of high dose XG005 
[1250 mg Q12] compared to placebo for pain 
control in subjects undergoing bunionectomy. 
• 
Summed pain intensity from end of surgery to 
48 hours post-surgery (SPI48) for high dose 
XG005 vs placebo 
Secondary Efficacy: 
 
• 
To evaluate the efficacy of low dose XG005 
[750 mg Q12] compared to placebo for pain 
control in subjects undergoing bunionectomy. 
• 
To evaluate high and low dose XG005 
compared to placebo for total rescue 
consumption and time to first use from end of 
surgery. 
• 
To evaluate high and low dose XG005 
compared to placebo for PGA 
• 
To evaluate high and low dose XG005 
compared to placebo for postoperative nausea. 
• 
To evaluate the efficacy of high dose XG005 
compared to low dose XG005 for pain control 
in subjects undergoing bunionectomy  
 
Key Secondary Endpoints: 
1. SPI48: low dose XG005 vs placebo 
2. Total tramadol rescue medication consumption 
in MEQs over 48 hours: high dose XG005 vs 
placebo 
3. Total tramadol rescue medication consumption 
in MEQs over 48 hours: low dose XG005 vs 
placebo 
Additional Analgesic Endpoints: 
4. Time to first use of rescue medication from end 
of surgery: high dose XG005 vs placebo 
5. Time to first use of rescue medication from end 
of surgery: low dose XG005 vs placebo  
6. PGA at 48 hours: high dose XG005 vs placebo 
7. PGA at 48 hours: low dose XG005 vs placebo  
8. Cumulative nausea (NNRS) assessment scores 
through 24 hours: high dose XG005 vs placebo 
9. Cumulative Nausea (NNRS) assessment scores 
through 24 hours: low dose XG005 vs placebo 
10. SPI48: high dose XG005 vs low dose XG005 
Tertiary Efficacy (All Treatment Arms):  
 
• 
To evaluate rescue medication consumption at 
24, 48, and 72 hours, time to first use of 
rescue medication from end of surgery, and 
proportion of subjects requiring rescue 
medication. 
• 
To evaluate nausea assessment scores at 
various timepoints. 
• 
To evaluate high and low dose XG005 
compared to placebo for SIS 
• 
Total oral opioid rescue medication 
consumption at 24, 48, and 72 hours 
• 
Nausea (NNRS) assessment scores at 1, 4, 8, 12, 
24, 48, 72 hours 
• 
SPI at 0, 1, 2, 3, 4, 6, 8, 10, 12, 16, 20, 24, 30, 
36, 42, 48, 54, 60, 66, and 72 hours 
• 
Pain intensity at various timepoints 
• 
SIS at 24, 48 and 72 hours  
• 
Percentage of subjects requiring rescue at 
various timepoints 
• 
PGA of pain control at various timepoints 
• 
Ramsay Sedation Scale at various timepoints  

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Objectives 
Endpoints 
• 
Exploratory purposes only: To estimate 
subject’s potential placebo response by use 
of a pre-study personality questionnaire at 
Screening. 
• 
Estimated of subject susceptibility to placebo 
response at Screening using a pre-study 
personality questionnaire 
 
Safety:  
 
• 
To evaluate the safety and tolerability of 
XG005 in a perioperative population 
Safety and tolerability of XG005 compared with 
placebo measured:  
• 
The incidence, intensity, relationship, and 
seriousness of TEAEs by treatment group. 
• 
The number and percentage of premature 
withdrawals due to AEs in each treatment 
group. 
• 
Treatment-emergent changes in vital signs 
(blood pressure, heart rate, body temperature, 
respiratory rate, continuous pulse oximetry) and 
Sp02 after each Treatment Period dose and the 
Follow-up Visit compared to Baseline values. 
• 
Treatment-emergent changes in clinical 
laboratory tests and ECGs compared to 
Baseline. 
Pharmacokinetics 
 
• 
To investigate the PK of XG005, naproxen, 
and pregabalin in a perioperative population 
• 
Area under the plasma concentration-time curve 
from time zero to time t of the last measured 
concentration above the limit of quantification 
(AUC0-last) 
• 
Area under the plasma concentration-time curve 
from zero to infinity (AUC0-inf) 
• 
Maximum plasma concentration (Cmax) 
• 
Trough plasma concentration prior to each dose 
(Ctrough) 
• 
Time to reach maximum plasma concentration 
(Tmax)  
• 
Terminal elimination rate constant (λz) with the 
respective half-life (t1/2). 
 

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4. 
STUDY DESIGN 
4.1. 
Overall Design 
This is a multi-center, randomized, double-blind, parallel-group, placebo-controlled study in 
subjects undergoing bunionectomy. 
Subjects scheduled for bunionectomy surgery who meet all of the inclusion criteria and none of 
the exclusion criteria below will be enrolled and randomized.   
Eligible subjects will be randomized in a 1:1:1 ratio to receive either 750 mg XG005 (low dose), 
1250 mg XG005 (high dose), or placebo. Randomized subjects will receive drug per their 
treatment allocation as follows: 
• 60 minutes prior to surgery, then 
• Every 12 hours (± 10 minutes) after the first dose for 72 hours.  
Subjects and all study staff performing study assessments will be blinded to treatment allocation. 
To maintain the blind, a total of 5 tablets will be administered to each treatment group: 
5 identical blue tablets (low or high dose XG005 or its placebo) at each time point.   
Subjects will undergo a Screening Visit (Day -28 to Day -1), Pre-Operative Assessment (within 
24 hours prior to surgery), and a Surgery/Treatment Visit (beginning on Day 1), when the 
following will occur: 
• Study medication administered  
• Surgery performed within 60 minutes of first study drug administration  
• Time of end of surgery recorded (as time of last suture closed) 
• Subjects domiciled in research center for at least 72 hours post-surgery  
• Efficacy, safety, and PK assessments performed over 72-hour period post-surgery 
“Time 0” will be defined as the start time of first dose from which subsequent 12-hour dosing 
times will be determined. All study efficacy, safety, and PK assessments are anchored to time of 
end of surgery (last suture). PK sampling timepoints correlate with the collection of the 11-pt 
NPRS efficacy assessments when they overlap.  
Screening will include subjects’ potential placebo response by use of a pre-study personality 
questionnaire (Appendix B).  
Subjects will be advised at Screening that if they terminate the study prior to 72 hours, it is 
requested that they remain in the clinic for continued collection of scheduled safety data only.  

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Subjects will be confined in the clinic from check-in through 72 hours post last dose to monitor 
subject safety. Subjects will be discharged at a reasonable hour of the day after the end of the 72-
hour treatment period, which may include the morning after the end of the 72-hour treatment 
period.  
There will be a Follow-up Visit on Day 15.   
The Schedule of Assessments is shown in Section 1.2.  
4.2. 
Scientific Rationale for Study Design 
Preemptive administration of analgesic medication is more effective than medication given after 
the onset of the painful stimulus (Error! Reference source not found.; Error! Reference 
source not found.; Ménigaux C, Adam F, Guignard B, Sessler DI, Chauvin M. Preoperative 
gabapentin decreases anxiety and improves early functional recovery from knee surgery. Anesth 
Analg. 2005;100:1394–9.). It has been suggested that the treatment before or during surgery 
prevents or alleviates the formation of peripheral and/or central sensitization which may reduce 
the development of pain for some time after surgery. In the current study, we included both 
preoperative and postoperative dosing to achieve maximal “preventive” analgesia that covers a 
wider window of opportunity to inhibit the formation of peripheral/central sensitization and treat 
postsurgical pain. In addition, by dosing preoperatively, it makes Tmax match the time of 
anticipated onset of pain. Furthermore, the efficacy of pre- and post-operative pain relief using 
the combination of naproxen and pregabalin after bunionectomy surgery has been reported 
(Wang et al 2010). The present study is a double-blind, placebo-controlled randomized trial of 
preemptive analgesia with XG005, a prodrug of naproxen and pregabalin in adult patients. 
The three Phase-I studies showed favorable PK characteristics of naproxen and pregabalin 
following administration of XG005, in particular, the Cmax of both naproxen and pregabalin 
occur simultaneously following oral administration of XG005, with Tmax at approximately 4 
hours. This PK characteristic may result in simultaneous onset of drug effects (additive or 
synergetic) of naproxen and pregabalin that offers a great pharmacological benefit to clinical 
needs for acute pain treatment. Since the pain-relieving efficacy of XG005 is solely associated 
with the systemic exposure of naproxen and pregabalin resulted from the XG005 absorption and 
subsequent hydrolysis, the dose selection for XG005 in the current study is based on the 
considerations to match the systemic exposures of an efficacious naproxen dose and pregabalin 
dose. The steady status Cmax for naproxen and pregabalin resulted from XG005 oral dosing was 
lower than the Cmax from combined dosing of naproxen and pregabalin, which may indicate 
potential advantage on reducing side effects from each drug when dosed combined. 
4.3. 
Justification for Dose 
In this study, the subjects will be randomized in a 1:1:1 ratio to receive one of two doses of 
XG005, or placebo. The two doses of XG005 are selected based on the plasma levels of 
naproxen and pregabalin previously associated with analgesic efficacy (Lyrica® (Pregabalin) 
Prescribing Information. (June 2011) Pfizer Inc., US.; Naprosyn® (naproxen sodium) 
Prescribing Information. (November 2017) Atnahs Pharma Australia Pty Ltd.; Bockbrader HN, 

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Wesche D, Miller R, et al. A comparison of the pharmacokinetics and pharmacodynamics of 
pregabalin and gabapentin. Clin Pharmacokinet. 2010;49(10):661-9.).  
Naproxen is rapidly and completely absorbed from the GI tract with an in vivo bioavailability of 
95%. The elimination half-life of naproxen ranges from 12 to 17 hours. Steady-state levels of 
naproxen are reached in 4 to 5 days. Following oral administration of naproxen 500 mg tablets, 
Cmax of 71,100 ng/mL, Tmax of 2.3 hours, and AUC0-t of 1,218,000 ng.hr/mL were observed. 
Similar AUC and 30% lower Cmax of naproxen were produced by oral administration of 1000 mg 
of XG005 tablet (4 × 250 mg XG005 tablets). In general, the clinical recommended dose ranges 
are 220 mg-1500 mg of naproxen for the various pain symptoms.  
Two dose levels are planned in this study:  
1) XG005 (low dose) with 750 mg XG005 BID which will deliver 375 mg BID of naproxen and 
259 mg BID of pregabalin.   
2) XG005 (high dose) with 1250 mg XG005 BID which will deliver 626 mg BID of naproxen 
and 433 mg BID of pregabalin.   
Based on the PK modeling, 1250 mg XG005 BID will be equivalent to the exposure of naproxen 
at 490 mg BID and the exposure to pregabalin of 225 mg BID; 750 mg XG005 BID will result in 
bioequivalent to naproxen of 300 mg BID and pregabalin of 150 mg BID. So, the planned 
XG005 dose regimen would provide naproxen dose within the commonly prescribed dose for 
treating various pain indications. Pregabalin has been approved for maximum dose of 
600 mg/day, though with 150 mg/day starting dose, in approved pain indications. Phase 1 studies 
in healthy volunteers from XG005 including dose of 1250 mg BID resulted in acceptable safety 
profile, with similar dizziness and somnolence incidences as reported in Lyrica label. Patient’s 
safety will be carefully monitored in the study. 
4.4. 
End of Study Definition 
The end of study (EOS) is defined as the date on which the last subject completes the last visit 
(including the EOS and any additional follow-up). 
The Sponsor reserves the right to discontinue the study at any time for clinical or administrative 
reasons.  

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5. 
STUDY POPULATION 
5.1. 
Inclusion Criteria 
A subject candidate must fulfill all of the following inclusion criteria to be eligible for 
participation in the study:  
1. Willing and able to sign the ICF approved by the IRB. 
2. Male or female aged 18–80 years. 
3. Scheduled to undergo unilateral first metatarsal bunionectomy. 
4. Capable of undergoing a bunionectomy under anesthesia as described in the study 
surgical and anesthetic protocol. 
5. Weight >40 kg and a BMI <39 kg/m2.  
6. No additional planned surgeries other than bunionectomy during the course of the study. 
7. Have negative urine drug screen for drugs indicative of illicit drug use (unless results can 
be explained by a current prescription or acceptable OTC medication at Screening as 
determined by the Investigator) and no detectable results on the alcohol test (breath or 
saliva) indicative of alcohol abuse at Screening, and/or prior to surgery (may be repeated 
if the Investigator suspects a false-positive result).  
Note: For those subjects who test positive for THC, if they are willing to abstain from use 
or consumption of THC-containing products from Screening through end of the subject’s 
participation in the study, they may be allowed to participate in the study.  
8. Biological female subjects must be non-lactating. They must also be either sterile 
(bilateral tubal ligation, bilateral salpingectomy, or hysterectomy), post-menopausal for at 
least 1 year, have a partner who is sterile, be abstinent, have a same-sex partner, use a 
highly effective double-contraception method (hormonal protection is insufficient), or use 
an FDA-approved contraceptive for greater than 2 months prior to Screening visit and 
commit to an acceptable form of birth control for the duration of the study and for 
30 days from completion of the study. 
9. Willing and able to complete the study procedures and pain scales and to communicate 
meaningfully in English with study personnel.  
10. Negative result of COVID-19 test within 3 days before Day 1 visit. 
5.2. 
Exclusion Criteria 
Any of the following criteria will exclude a subject from the study:  

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1. Medical condition or history that in the investigator’s opinion could adversely impact 
the subject’s participation or safety or the conduct of the study, or interfere with the pain 
assessments, including the following: 
a. Serious breathing difficulties or respiratory risk factors (including clinically 
significant use of opioid pain medicines and other drugs that depress the CNS) and 
conditions such as COPD that reduce lung function. 
b. Clinically unstable hypertension, cardiovascular disease, or history of cerebrovascular 
events. Hypertension must be stable without known end organ damage. 
c. Concurrent painful conditions that may require analgesic treatment during the study 
period. 
d. History of significantly reduced hepatic function (ALT, AST, or LDH ≥1.5 x ULN or 
renal function (creatinine ≥1.5 x ULN, angle closure glaucoma, or convulsive 
disorder. 
e. Recent history of urinary retention.  
f. History of gastrointestinal ulcer, bleeding, perforation, or recent surgery of 
gastrointestinal tract  
g. Subject is currently taking or has taken a chronic opioid at a dose greater than or 
equal to 20 mg hydrocodone per day ([≥20 MEQs] more than 30 consecutive days of 
daily use) for pain in the 2 months prior to surgery. 
h. Active cutaneous disease, or other disease, at the surgical site. 
i. Peripheral vascular disease, sickle cell disease, vascular grafts, or vasospastic 
disorders. 
j. Known bleeding disorder or is taking agents affecting coagulation preoperatively. 
DVT prophylaxis of the surgeon’s choice is permitted postoperatively. 
k. Diabetes mellitus (uncontrolled). Diabetes must be controlled without known end 
organ damage (HgbA1c <7%).   
l. History of malignancy in the past 2 years with the exception of squamous cell or 
basal cell carcinoma.  
m. Prior bunionectomy on the index foot or other foot surgery on the index foot that 
could impact the surgery or data collection endpoints.  
n.  Presence of, history of or family history of keloid and/or hypertrophic scar 
2. Use of disallowed medications at the window specified below and planned to use 
throughout the study period, including the following: 

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a. Pain medication (opioids, NSAIDs, COX-2 inhibitors, tramadol, ketamine, clonidine, 
gabapentin, pregabalin, or cannabinoids) within 2 days prior to Day -1. 
b. CNS active drugs such as benzodiazepines, tricyclic antidepressants, Serotonin, and 
norepinephrine reuptake inhibitors (SNRIs), selective serotonin reuptake inhibitors 
(SSRIs), or any other serotonergic medications within 7 days prior to Day -1. The use 
of lorazepam and other sleep medications, except those containing analgesic 
properties, is permitted. 
c. Use of parenteral or oral corticosteroid(s) within 14 days prior to Day -1. 
d. Antihypertensive agent or diabetic regimen at a dose that has not been stable for at 
least 30 days, or which is not expected to remain stable throughout the study. 
e. Digoxin, warfarin lithium, theophylline preparations, aminoglycosides, and all 
antiarrhythmics except beta-blockers within 7 days prior to Day -1 and throughout the 
study. 
f. Current use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the 
last 14 days.   
3. Positive results for hepatitis B surface antigen (HbsAg) and/or hepatitis B anti-core 
antibody (anti-HBc) but negative results for anti-surface antibody (anti-HBs) at the 
Screening Visit.  
4. Positive results for hepatitis C antibody unless patient received curative therapy and a 
negative viral load is documented.  
5. Human immunodeficiency virus (HIV) infection or positive HIV serology at the 
Screening Visit.  
6. Known positive COVID-19 viral test during screening or suspected COVID-19 infection 
at the Day 1 Visit 
7. History of illicit drug use, or prescription medicine or alcohol abuse within the past 
2 years. 
8. History of opioid dependence.  
9. History of NSAID-induced bronchospasm or presence of nasal polyps, history of asthma 
or chronic rhinitis. 
10. Significant history of allergic reactions or known intolerance to naproxen, pregabalin or 
any gabapentinoid, or to any rescue medication used in the study, or any medication used 
in the surgical and anesthetic protocol. 
11. Biological female subjects who are pregnant or lactating, who plan to get pregnant, or 
who have a positive serum pregnancy test at Screening and/or Day 1 (prior to surgery). 

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12. Participated in another clinical trial within 30 days, or previously participated in a clinical 
study with a similar investigational product. 
13. Presence of severe depression as indicated by Patient Health Questionnaire (PHQ-9) total 
score of ≥20 or item 9 score >0 at the Screening Visit (see Appendix H: 
Patient Health 
Questionnaire-9 (PHQ-9)). 
14. Presence of severe anxiety as indicated by General Anxiety Disorder (GAD-7) score of 
≥15 at the Screening Visit (see Appendix I  General Anxiety Disorder (GAD-7)). 
15. Presence of history of suicidal behavior or ideation as indicated by the Columbia-Suicide 
Severity Rating Scale (C-SSRS) Baseline/Screening Version at Screening Visit. (See 
Appendix J  
Columbia-Suicide Severity Rating Scale (C-SSRS) Baseline/Screening 
Version) 
All Inclusion and Exclusion criteria must be verified by the Investigator or designee at Screening 
(Day -28 to Day -1) and Pre-Surgery (Day 1). 
5.3. 
Screen Failure 
A screen failure is defined as any subject who fails Screening assessments or is ineligible based 
on inclusion/exclusion criteria during Screening or on the Day 1 Pre-operative assessment. 
5.4. 
Replacement of Subjects 
Any subject who is withdrawn or discontinued from the study after receiving study drug will not 
be replaced. Subjects who withdraw consent before dosing may be replaced.  
5.5. 
Number of Subjects and Centers 
This study will be conducted at a minimum of 3 study sites in the US. A total of 450 subjects 
will be randomized (150 per arm) to achieve 130 evaluable subjects per treatment group. An 
evaluable subject is defined as one who receives study drug, completes surgery, and has at least 
2 post-operative pain assessments. 
A PK subgroup of 90 subjects (approximately 30 subjects per study arm) will be assessed at 1 
site only. 

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6. 
STUDY TREATMENT 
All subjects will be randomized to receive either low-dose XG005, high-dose XG005, or 
placebo.  
XG005 [750 mg Q12 hours] 
XG005 [1250 mg Q12 hours] 
Placebo [matching tablets Q12 hours] 
6.1. 
Description 
XG005 drug product is formulated as tablets containing 250 mg of XG005. 
Placebo tablets of XG005 are identical in appearance to their respective active drug tablets.  
Each treatment group will be administered a total of 5 tablets to maintain the blind and 
administered as 5 identical blue tablets (low or high XG005 or its placebo) every 12 hours.   
6.2. 
Dosing and Administration 
Study drug (XG005 low or high dose, or placebo) will be administered as an oral dose 60 
minutes prior to surgery on Day 1 then every 12 hours for 72 hours after the time of first dose. 
The number and strength of active drug tablets to be administered at each dose level is shown in 
Table 1. Subjects randomized to placebo will receive the corresponding number of placebo 
tablets.  
Table 1 Dose and Pill Relationship 
Study Arms 
1 
2 
3 
Dose Strength 
Placebo 
XG005 (low dose) 
XG005 (high dose) 
Dose Levels 
No Drug 
750 mg  
1250 mg  
Number of 
Tablets 
5 × XG005 placebo tablets  
3 × 250 mg XG005 tablets  
+ 2 × XG005 placebo tablets  
5 × 250 mg XG005 tablets  
6.3. 
Preparation/Handling/Storage/Accountability 
6.3.1. 
Acquisition and Accountability 
The Sponsor will provide adequate quantities of the study drug kits which will include XG005 
and matching placebo to each study site.  
6.3.2. 
Product Storage and Stability 
All study drugs must be stored at controlled room temperature (20° to 25°C or 68°to 77°F; 
excursions are permitted between 15° and 30°C [59°and 86°F]) in a secure cabinet or room with 

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access restricted to necessary clinic personnel.  The site will be required to keep a temperature 
log to establish a record of compliance with storage conditions.  
6.3.3. 
Packaging and Labeling 
Sufficient quantities of XG005 tablets and matching placebo tablets will be supplied by the 
Sponsor or its designee in high density polyethylene (HDPE) sealed bottles with polypropylene 
child resistant (PPCR) cap with an induction seal liner. In order to maintain the blinding, study 
drug kits will be provided with appropriate labeling to meet regulatory requirements. 
6.3.4. 
Randomization 
The randomization schedule for each treatment group will be generated by Lotus Clinical 
Research, LLC (Lotus). Subjects who meet all entry criteria will be randomized before pre-
surgery dosing on Day 1 by the IXR system.  
Study drug kits will be dispensed by the clinical site pharmacist at each study site according to 
the randomization schedule.  
6.4. 
Blinding 
6.4.1. 
Blinding Procedures 
This is a double-blind study. Neither the subjects nor the investigator will be aware of the 
treatment assignment. Blinding will be maintained throughout the study by using active and 
placebo dosage forms of identical appearance. Access to the randomization code will be strictly 
controlled according to the standard operating procedures of the CRO. 
6.4.2. 
Breaking the Blind 
A subject or subjects may be unblinded in the event of a SAE, or other event, or if there is a 
medical emergency where the identity of the drug must be known to properly treat a subject. If a 
subject becomes seriously ill or pregnant during the study, the blind will be broken only if 
knowledge of the administered study drug will affect that subject’s treatment options. In the 
event of a medical emergency requiring identification of the study drug administered to an 
individual subject, the investigator will make every attempt to contact the independent medical 
monitor to explain the need for opening the code within 24 hours of opening the code. The 
investigator will be responsible for documenting the time, date, reason for the code break, and 
the names of the personnel involved. 
6.4.3. 
Study Treatment Compliance 
All doses of study drug will be administered in the clinical unit under direct observation of clinic 
personnel and will be recorded in the eCRF. Clinic personnel will confirm that the subject has 
received the entire dose of study drug. 
The date and time of study drug dosing will be recorded on the appropriate page of the eCRF. If 
a subject is not administered study drug, the reason for the missed dose will be recorded. 

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6.5. 
Prior and Concomitant Medications 
Restrictions for prior and concomitant medications and therapies are described in Section 5.1.  
6.5.1. 
Prior Medication 
All prior medications received by the subject within 30 days before signing the ICF should be 
recorded in the subject’s eCRF. 
6.5.2. 
Rescue Medication 
During the domiciling period, subjects may be administered IV acetaminophen 1 g, Q 6 hours, 
PRN, up to 4 g in 24 hours. If a patient is unable to tolerate acetaminophen or if there is 
insufficient pain relief, 50 mg tramadol will be administered Q 4 hours, PRN, up to 300 mg in 
24 hours. Intravenous acetaminophen should always be the first rescue medication administered 
with tramadol being used as the second option. 
Prior to receiving any rescue medication, an NPRS assessment must be performed immediately 
before administering any rescue medication.  
6.5.3. 
Concomitant Medication 
Any other concomitant medication deemed necessary for the welfare of the subject (except 
prohibited medications) during the study may be given at the discretion of the investigator. If a 
concomitant medication is taken, except for those specified in the protocol, a joint decision will 
be made by the investigator and the sponsor to continue or discontinue the subject based on the 
time the medication was administered, its pharmacology and PK, and whether the use of the 
medication will compromise the safety of the subject or the interpretation of the data. The 
investigator is responsible for ensuring that details regarding the medication are adequately 
recorded in the eCRF. 
6.5.4. 
Permitted Medications 
Only the protocol-defined rescue medication is permitted in the study. All other analgesics 
administered will result in a subject terminating early from the study. 
No pretreatment for potential nausea and vomiting is permitted. Administration of antiemetic 
medications are limited to subjects with active vomiting, subjects with a score ≥5 on the NNRS, 
or by subject request only. 
6.5.5. 
Surgery and Anesthesia 
Subjects will undergo primary, unilateral, first metatarsal Austin bunionectomy.  The surgical 
procedure should be limited to a maximum duration of 90 minutes.  End of surgery will be 
defined as completion of the last suture. 
The surgery will be performed under regional anesthesia via a local Mayo block using lidocaine 
(20 mL, 2.0%) without epinephrine, with IV propofol for sedation. 

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Propofol induction (dose per discretion of anesthesiologist) will be given as an initial bolus 
followed by a continuous infusion of up to 250 μg/kg/min for intraoperative sedation. 
A small dose of lidocaine (up to 5 mL of 1% lidocaine without epinephrine) may be administered 
to reduce vein irritation at the infusion site. 
Intraoperatively, all subjects will be given 50 μg of fentanyl IV around the time of induction with 
propofol. 
Once sedated, a Mayo block of the first metatarsal will be induced using lidocaine (20 mL, 
2.0%) without epinephrine. 
Midazolam 1 mg IV may be administered preoperatively for anxiolysis. 
A pneumatic ankle tourniquet inflated between 150 and 250 mmHg will be applied to achieve 
homeostasis. 

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7. 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
7.1. 
Study Stopping Criteria 
The following criteria will determine whether to stop study drug dosing. The Investigator and the 
Sponsor may decide to stop drug administration based on other safety signals not described in 
the following criteria: 
• One drug-related SAE without a clear alternative etiology, or 
• Two or more subjects develop a severe adverse event (Grade 3 or above, based on FDA 
Guidance Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled 
in Preventive Vaccine Clinical Trials, see Appendix L) possibly related or related to the 
study drug of the same preferred term or same symptom, or 
• Greater than 25% of subjects develop any severe adverse event (Grade 3 or above, based 
on FDA Guidance Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers 
Enrolled in Preventive Vaccine Clinical Trials, see Appendix L) possibly related or 
related to the study drug.  
If one of the above stopping criteria is met, dosing will be stopped and unblinded assessment 
will be conducted for further decision making. 
So far, there have been no identified adverse events of special interests (AESIs) for XG005 in the 
three completed phase 1 trials, which showed good tolerability and an acceptable safety profile. 
7.2. 
Discontinuation of Study Treatment 
Subjects can withdraw consent and discontinue from the study at any time, for any reason, 
without prejudice to further treatment. 
The investigator may withdraw a subject from the study if the subject meets any of the following 
criteria: 
• Is noncompliant with the protocol 
• Experiences an SAE or intolerable AE(s) that, in the investigator’s opinion, requires 
withdrawal from the study 
• Has laboratory safety assessments that reveal clinically significant hematologic or 
biochemical changes from baseline values 
• Develops symptoms or conditions that are listed in the exclusion criteria during study 
• Requires a medication prohibited by the protocol (including receiving rescue medication 
beyond what is allowed per protocol) 

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• Requests early discontinuation for any reason. 
The investigator can also withdraw a subject upon the request of the sponsor, or if the sponsor 
terminates the study. If withdrawal is considered because of an SAE or intolerable AE, the 
investigator will confer with the sponsor. If a subject is discontinued because of an AE, the event 
will be followed until it is resolved, stable, or judged by the investigator to be not clinically 
significant. 
7.3. 
Participant Discontinuation/Withdrawal 
When a subject withdraws from the study, the reason(s) for withdrawal shall be recorded by the 
investigator on the relevant page of the eCRF. Any subject who fails to return for final 
assessments will be contacted by the site in a reasonable attempt to have them comply with the 
protocol. The status of subjects who fail to complete final assessments will be documented in the 
eCRF. 
7.4. 
Early Termination  
Whenever possible, any subject who prematurely withdraws from the study will undergo all EOS 
assessments per the Schedule of Assessments (Section 1.2) and the Early Termination 
assessments that include NPRS, PGA, SIS, RSS and NNRS. Subjects who terminate early from 
the study will be requested to remain in the clinic for the full 72 hours for continued collection of 
safety assessments only (vital signs, ECGs, laboratory testing, AE monitoring, and concomitant 
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8. 
STUDY ASSESSMENTS AND PROCEDURES  
Before performing any study procedures, all potential subjects will sign an ICF as outlined in 
Section 10.2. 
All assessments and procedural details during Screening (Day -28 to Day -1), Pre-
surgery/Surgery (Day 1), the Treatment Period (hours post end of surgery), and EOS/ET are 
described in the Schedule of Assessments (Section 1.2).  
All efficacy, safety, and PK assessments are anchored to time at end of surgery (last suture). 
Pharmacokinetic (PK) sampling timepoints correlate with the collection of the 11-pt Numeric 
Pain Rating Scale (NPRS) efficacy assessments when they overlap. 
8.1. 
Efficacy Assessments 
Study staff will record subject-reported pain assessments via a standard 11-point NPRS at the 
following time points post-end of surgery: 0, 1, 2, 3, 4, 6, 8, 10, 12, 16, 20, 24, 30, 36, 42, 48, 54, 
60, 66, and 72 hours within a ±10-minute window (Appendix C). NPRS will be collected prior to 
PK sampling and administration of rescue medication.   
Study staff will record subject-reported PGA of pain control using a 5-point scale (poor, fair, 
good, very good, excellent) at the following time points post-end of surgery: 24, 48, and 72 hours 
within a ±10-minute window and just prior to receiving a dose of rescue medication 
(Appendix D).  
Study staff will record the time and the dose of rescue medication administered on the rescue 
medication form. NPRS and PK sampling will be collected immediately prior to administering 
rescue medication.   
Nausea will be self-assessed using an 11-point NNRS at the following time points post-end of 
surgery: 1, 4, 8, 12, 24, 48, 72 hours within a ±10-minute window (Appendix E). Additional 
NNRS assessments will be collected when an AE of nausea or vomiting is reported or prior to 
any rescue antiemetic administration.  Subject will report Sleep Interference Score (SIS) using an 
11-point NRS scale (0-10) at 24, 48 and 72 hours post-end of surgery within a ±15minute 
window (Appendix F) 
8.2. 
Safety Assessments 
The timing and frequency of all safety assessments are provided in the SOA (Section 1.2). Safety 
endpoints include monitoring and recording of AEs and SAEs, clinical laboratory results (serum 
chemistry, hematology, coagulation, and urinalysis), 12-lead ECG results, and vital signs 
measurements (blood pressure [systolic and diastolic], heart rate, respiratory rate, oral body 
temperature, and continuous pulse oximetry), and recording of relevant safety data. 
Trained staff on hand in the research unit will monitor respiratory safety via respiration rate, 
continuous pulse oximetry and oxygen saturation (SpO2) checks every 12 hours post-end of 
surgery within a ±10-minute window, and somnolence if observed by Staff at times other than 

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when a formal assessment of somnolence is scheduled. The Ramsay Sedation Scale (RSS, 
Appendix G) will be used as an assessment of sedation (somnolence) with the same time 
sequence as the NPRS determination, but with a window of ±15 minutes. A Columbia-Suicide 
Severity Rating Scale since last visit (Appendix K) will be administered at 72 hours post 
treatment and at the follow-up visit and at the end of study visit/early termination visit.  
For all safety assessments, the investigator will determine whether results are clinically 
significant, which is defined as any variation in a result that has medical relevance and that may 
result in an alteration in medical care (e.g., active observation, diagnostic measures, or 
therapeutic measures). If clinical significance is noted, the result and reason for significance will 
be documented and an AE reported on the AE page of the subject’s electronic case report form 
(eCRF). The investigator will monitor the subject until the result has reached the reference range 
or the result at Screening, or until the investigator determines that follow-up is no longer 
medically necessary. 
8.2.1. 
Reporting Adverse Events and Serious Adverse Events 
The investigator is responsible for ensuring that all AEs and SAEs are recorded in the eCRF and 
reported to the sponsor, regardless of their relationship to study drug or clinical significance. If 
there is any doubt as to whether a clinical observation is an AE, the event should be reported. 
8.2.1.1. 
Definition of Adverse Events 
An adverse event (AE) is any untoward medical occurrence in a patient or clinical trial subject 
administered a pharmaceutical product, whether or not there is a causal relationship suspected 
between the product and the event. An AE can therefore be any unfavorable and unintended sign, 
symptom or disease that is temporally associated with the use of the pharmaceutical product.  
An AE includes any untoward medical occurrence in a subject or clinical trial participant 
administered a pharmaceutical product, whether or not there is a causal relationship suspected 
between the product and the event.  An AE can therefore be any unfavorable and unintended 
sign, symptom, or disease that is temporally associated with the use of the pharmaceutical 
product. 
A treatment emergent adverse event (TEAE) is defined as any event that was not present before 
exposure to study drug or any event already present that worsens in intensity or frequency after 
exposure. 
A suspected adverse reaction is any AE for which there is a reasonable possibility that the study 
drug caused the AE. For the purposes of investigational new drug safety reporting, “reasonable 
possibility” means that there is evidence to suggest a causal relationship between the study drug 
and the AE. A suspected adverse reaction implies a lesser degree of certainty about causality 
than an adverse reaction. 
An adverse reaction is any AE caused by a study drug. Adverse reactions belong to a subset of 
all suspected adverse reactions and indicate that there are reasons to conclude that the study drug 
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8.2.1.2. 
Definition of Serious Adverse Event 
An AE or suspected adverse reaction is considered “serious” if, in the view of either the 
investigator or sponsor, it results in any of the following outcomes: 
• Death 
• Life-threatening AE (i.e., immediate risk of death from the event as it occurred; this does 
not include an AE that, had it occurred in a more serious form, might have caused death). 
• Inpatient hospitalization or prolongation of existing hospitalization 
• Persistent or significant disability/incapacitation 
• Congenital anomaly 
Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, they 
may jeopardize the subject and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias 
or convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse. 
8.2.1.3. 
Assessment of Severity 
The severity (or intensity) of an AE will be assessed based on FDA Guidance Toxicity Grading 
Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical 
Trials (Appendix L). The investigator will assess the intensity of each AE/SAE based on his/her 
clinical judgment.  
An AE that is assessed as severe should not be confused with an SAE. Severity is a category 
utilized for rating the intensity of an event; both AEs and SAEs can be assessed as severe. 
Changes in the severity of an AE should be documented to allow the duration of the event at 
each level of intensity to be assessed. An AE characterized as intermittent does not require 
documentation of the onset and duration of each episode. 
8.2.1.4. 
Assessment of Relationship to Study Drug 
The investigator’s assessment of an AE’s relationship to study drug is part of the documentation 
process but is not a factor in determining what is or is not reported in the study. 
The investigator will assess causality (i.e., whether there is a reasonable possibility that the study 
drug caused the event) for all AEs and SAEs. The relationship will be classified as follows: 
• Not related: There is not a reasonable possibility of relationship to study drug. The AE 
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reasonably explained by the subject’s clinical state or other factors (e.g., disease under 
study, concurrent diseases, and concomitant medications). 
• Unlikely Related: when the temporal association between the AE and the drug is such 
that the drug is not likely to have any reasonable association with the AE 
• Possibly Related: when the AE follows a reasonable temporal sequence from the time of 
drug administration but could have been produced by the subject’s clinical state or the 
study procedures/conditions 
• Related: There is a reasonable possibility of relationship to study drug. The AE follows a 
reasonable temporal sequence from study drug administration and cannot be reasonably 
explained by the subject’s clinical state or other factors (e.g., disease under study, 
concurrent diseases, or concomitant medications), represents a known reaction to the 
study drug or other drugs in its class, is consistent with the known pharmacologic 
properties of the study drug, and/or resolves with discontinuation of the study drug 
(and/or recurs with re-challenge, if applicable). 
8.2.1.5. 
Assessment of Expectedness 
An AE or suspected adverse reaction is considered “unexpected” if it is not listed in the 
Investigator Brochure or package inserts of the individual components of the IMP, or if it occurs 
with specificity or severity that has not been previously observed with the study drug being 
tested; or, if an investigator brochure is not required or available, the AE or suspected adverse 
reaction is not consistent with the risk information described in the general investigational plan 
or elsewhere in the current application. For example, under this definition, hepatic necrosis 
would be unexpected (by virtue of greater severity) if the investigator brochure referred only to 
elevated hepatic enzymes or hepatitis. Similarly, cerebral thromboembolism and cerebral 
vasculitis would be unexpected (by virtue of greater specificity) if the investigator brochure 
listed only cerebral vascular accidents. “Unexpected,” as used in this definition, also refers to 
AEs or suspected adverse reactions that are mentioned in the investigator brochure as occurring 
with a class of drugs or as anticipated from the pharmacologic properties of the drug but are not 
specifically mentioned as occurring with the particular drug under investigation. 
8.2.1.6. 
Adverse Event Reporting and Follow-up Period 
The AE reporting period begins at the time of first dose of study drug and ends 30 days after the 
last dose of study drug.  
During the treatment period of the study, participants will be asked about AEs. All AEs that 
occur during the course of the study must be collected, documented, and reported to the principal 
investigator. The occurrence of AEs will be assessed at baseline and daily while in the clinical 
research unit and at each follow-up clinic visit. 
Subjects will be asked a standard question to elicit any medically related changes in their well-
being. They will also be asked if they have used any new medications or changed concomitant 
medication regimens (both prescription and over-the-counter medications). 

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In addition to subject observations, AEs will be documented from any data collected on the AE 
page of the eCRF (eg, laboratory values, physical examination findings, and ECG changes) or 
other documents that are relevant to subject safety. 
All AEs and SAEs observed while a subject is receiving study drug should be followed until they 
are resolved, stable, or judged by the investigator to be not clinically significant. 
8.2.1.7. 
Recording of Adverse Events 
All AEs reported or observed during the study will be recorded on the AE page of the eCRF. 
Information to be collected includes dose level, type and frequency of event, date and time of 
onset, investigator-specified assessment of severity and relationship to study drug, date, and time 
of resolution of the event, seriousness, any required treatment or evaluations, and outcome. Any 
AEs resulting from concurrent illnesses, reactions to concurrent illnesses, reactions to concurrent 
medications, or progression of disease states must also be reported. All AEs will be followed 
until they are resolved, stable, or judged by the investigator to be not clinically significant. 
MedDRA (version 23.0 or higher) will be used to code all AEs. 
8.2.1.8. 
Serious Adverse Event Reporting 
Any AE that is considered serious by the investigator or which meets SAE criteria (Section 
8.1.1.2) must be reported to the sponsor immediately (after the investigator has confirmed the 
occurrence of the SAE). The investigator and the study medical monitors will assess whether 
there is a reasonable possibility that the study drug caused the SAE. The sponsor will be 
responsible for notifying the relevant regulatory authorities of any SAE as outlined in US Title 
21 Code of Federal Regulations (CFR) Parts 312 and 320. The investigator is responsible for 
notifying the IRB directly. 
For this study, the following contact information is to be used for SAE reporting: 
Lotus Medical Monitor: 
 
24/7 SAE and medical question hotline: 
 
SAE email: 
 
Sponsor Medical Monitor: 
 
Xgene Pharmaceutical Inc.  
Email: 
 
Telephone: 
 

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8.2.1.9. 
Reporting of Pregnancy 
Pregnancy diagnosed during the study, or that occurs within 30 days after stopping study 
medication, must be reported immediately to the Investigator.  Pregnancy, in and of itself, is not 
regarded as an adverse event, unless there is suspicion that study medication may have interfered 
with the effectiveness of a contraceptive medication.  If the subject becomes pregnant while on-
study, the study drug must be immediately discontinued.  Pregnancy information about a female 
subject or a female partner of a male subject should be reported immediately from the time the 
Investigator first becomes aware of a pregnancy or its outcome. This will be performed by the 
Investigator completing a Pregnancy Form. 
Any pregnancy complication, spontaneous abortion, elective termination of a pregnancy for 
medical reasons, outcome of stillbirth, congenital anomaly/birth defect, or serious adverse event 
in the mother will be recorded as an SAE and will be reported as described in Section 8.2.1.8. 
8.2.2. 
Clinical Laboratory Assessments 
Clinical laboratory samples will be analyzed at the central laboratory.   
Blood and urinalysis samples will be collected. The following standard clinical laboratory 
assessments will be performed at the time points indicated in the SOA (Section 1.2).  
Hematology: 
Complete blood count including hemoglobin, hematocrit, RBC count, RBC 
indices, MCH, MCHC, platelet count, and WBC count including 
differential. HbA1c will be assessed at Screening only.  
Coagulation: 
PT, PTT, and fibrinogen 
Serum Chemistry: Albumin, total bilirubin, total protein, calcium, ALP, ALT, AST, BUN, 
creatinine, glucose, sodium, potassium, chloride, bicarbonate, LDH, and uric 
acid. Creatinine clearance will be calculated by the Cockcroft/Gault formula 
(Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum 
creatinine. Nephron 1976;16: 31-41.)  
Urinalysis: 
pH, specific gravity, blood and leukocyte esterase, glucose, protein, and 
 
ketones 
Serology: 
Hepatitis B virus surface antigen, hepatitis B anti-core antibody (anti-HBc) 
and anti-surface antibody, hepatitis C virus antibody, and HIV antibody 
types 1 and 2 (Screening only) 
All subjects will undergo a urine drug screen (amphetamines, barbiturates, benzodiazepines, 
cocaine, opiates [including heroin, codeine, and oxycodone], phencyclidine [PCP], THC, 
methamphetamines, methadone, and ecstasy), and alcohol screen at Screening only. 
A serum pregnancy test will be performed at Screening and a urine pregnancy test on Day 1 prior 
to dosing only in premenopausal women of childbearing potential or women who are not 
surgically sterile. Results must be available before surgery.  

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Clinical laboratory tests may be repeated at the discretion of the investigator, if necessary, for 
assessment of inclusion and exclusion criteria or evaluation of clinical laboratory abnormalities. 
8.3. 
Pharmacokinetic Assessments 
8.3.1. 
Pharmacokinetic Sampling and Analysis 
Blood draws will always be performed after each NPRS, nausea, SIS and/or PGA assessment, 
when applicable, and prior to the first administration of rescue medication. The PK sampling 
plan uses the post-end-of-surgery schedule to be consistent with the efficacy assessment 
schedule. 
Each subject in the PK subgroup (one site only) will have blood samples drawn for PK 
assessments at the following time points: prior to the first dose (pre-dose), and post end of 
surgery at 1, 2, 3, 4, 6, 8, 10, 12, 24, 30, 36, 42, 48, 54, 60, 66, and 72 hours within a ±15-minute 
window. The actual clock time when the PK sample is collected will be recorded, and the post-
dose time for PK analysis will be calculated based on the recorded clock time. 
The timing and frequency of PK sample collection is listed in the SOA (Section 1.2). 
Details for the collection, processing, storage, and shipping of PK samples will be provided to 
the clinical unit separately. 
Pharmacokinetic samples will be analyzed using a validated liquid chromatography coupled with 
tandem mass spectrometry assay for XG005 in human plasma. Assay details, results, and 
validation will be provided in a separate bioanalytical report. 

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9. 
STATISTICAL METHODS AND DATA ANALYSIS 
Full details of the statistical analysis methodology will be provided in a separate Statistical 
Analysis Plan (SAP). A separate PK analysis plan will also be prepared.  
A change to the data analysis methods described in the protocol will require a protocol 
amendment only if it alters a principal feature of the protocol. The SAP will be finalized prior to 
database lock. Any changes to the methods described in the final SAP will be described and 
justified in the clinical study report. 
9.1. 
Statistical Hypotheses 
This primary efficacy endpoint is to test the mean difference of summed pain intensity from end 
of surgery to 48 hours post-surgery (SPI48) between high dose XG005 and Placebo groups.  
The study null hypothesis is XG005 high dose and placebo have the same effect. And the 
alternative hypothesis is XG005 high dose and placebo have different effect. These will be tested 
at a two-tailed alpha of 0.05, and the Null hypothesis will be rejected if p-value < 0.05.  
9.2. 
Sample Size Determination 
One hundred thirty (130) evaluable subjects per study arm will yield 90% power to detect a 
standardized effect size of 40% (Wang 2010; Wu J, Jiang J, Wei W. Confidence intervals of 
effect size in randomized comparative parallel-group studies. Stat Med. 2006;25(4):639-51.; 
Vevea J, Woods CM. Publication bias in research synthesis: sensitivity analysis using A priori 
weight functions. Psychological Methods. 2005;10(4):428–43.; Singla NK, Chelly JE, 
Lionberger DR, et al. Pregabalin for the treatment of postoperative pain: results from three 
controlled trials using different surgical models. J Pain Res. 2015;8:9-20.) at a two-tailed a= 0.05 
for the familywise type one error. Recruitment goals will be 150 subjects per arm or N=450 total. 
Randomization Strata: Study Site 
9.3. 
Multiplicity Adjustment 
A serial gatekeeping procedure will be used to control the overall type-1 error rate at 0.05 for 
primary and secondary endpoints. If the primary endpoint is not significant at a two-tailed alpha 
of 0.05, there is no testing on secondary endpoints. If the primary endpoint is significant at a 
two-tailed alpha of 0.05, the secondary endpoints will be tested following the hierarchy testing 
procedure with a pre-specified order as Section 3. If any secondary endpoint is not significant, 
the successive secondary endpoints will not be tested.  
9.4. 
Populations 
• The Intent-to-Treat (ITT) population is defined as all randomized subjects. Subjects will 
be analyzed according to the treatment group to which they were randomized.  
• The Safety Population is defined as all subjects who receive study medication. Subjects 
will be analyzed according to the actual treatment they receive. 

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• The modified Intent-to-Treat (mITT) Population is defined as all ITT subjects who 
received at least one dose of study medication and have at least 2 NPRS assessments 
post-end of surgery. 
• The Per-Protocol Population is defined as all mITT subjects who have no major protocol 
violations which may potentially bias efficacy analysis of the study.  
9.5. 
Statistical Analyses  
9.5.1. 
General Approach 
All data collected will be presented in data listings.  Data from subjects excluded from an 
analysis population will be presented in the data listings, but not included in the calculation of 
summary statistics.  
For categorical variables, frequencies and percentages will be presented. Continuous variables 
will be summarized using descriptive statistics (number of subjects, mean, median, standard 
deviation (SD), minimum and maximum).  
Baseline demographic and background variables will be summarized overall for all subjects. The 
number of subjects who enroll in the study and the number and percentage of subjects who 
complete the study will be presented. Frequency and percentage of subjects who withdraw or 
discontinue from the study, and the reason for withdrawal or discontinuation, will also be 
summarized. 
9.5.2. 
Efficacy Analyses  
The primary endpoint of the comparison of summed pain intensity (SPI) from end of surgery to 
48 hours post-surgery (SPI48) for high dose XG005 vs placebo will analyzed, using analysis of 
covariance (ANCOVA) model. The model will use treatment as main effect, and study site as a 
covariate. More details for efficacy analyses will be specified in SAP. 
9.5.3. 
Safety Analyses 
Adverse events will be coded by preferred term and system organ class (SOC) using the latest 
version of MedDRA (version 23 or higher). All AE data will be presented in a data listing. 
Treatment-emergent AEs will be summarized by treatment and overall, as well as by severity 
and relationship to study drug. Serious AEs and AEs leading to discontinuation of study drug 
will also be presented in the data listings and summarized by treatment and overall. 
Actual values and changes from baseline for clinical laboratory test results, vital sign 
measurements, and 12-lead ECG results will be summarized by treatment at each time point 
using descriptive statistics (number of subjects, mean, SD, median, minimum, and maximum). 
Shift tables will be generated for clinical laboratory test results. Physical examination findings 
will be presented in a data listing. 
 
 

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9.5.4. 
Pharmacokinetic Analyses 
PK analyses will be addressed in a separate PK Analysis Plan. 
Individual plasma concentrations of naproxen, pregabalin and XG005 (and/or other metabolites 
as appropriate) will be listed by subject and summarized by gender, dose, and nominal time point 
using descriptive statistics (i.e., N, arithmetic mean, SD, percent coefficient of variation [CV%], 
median, minimum, maximum, and geometric mean). 
The PK parameters of XG005 will be analyzed based on the actual sampling times. All 
parameters will be calculated using the latest version of Phoenix® WinNonlin® (Certara USA 
Inc., Princeton, New Jersey) or SAS® (SAS Institute Inc., Cary, North Carolina). 
Pharmacokinetic parameters will be summarized by time point for each dose level using 
descriptive statistics (number of subjects, mean, SD, CV, median, minimum, and maximum). 
Geometric means will be reported for AUC0-t, AUC0-inf, AUC0-48, and Cmax. 
9.5.5. 
Handling of Missing Data 
For the PK analysis, concentrations that are below the limit of quantification (BLQ) will be 
treated as zero for descriptive statistics with the exception that a BLQ value between two 
quantifiable concentrations will be set as missing. Missing concentrations will be treated as 
missing from the PK parameter calculations. If consecutive BLQ concentrations are followed by 
quantifiable concentrations in the terminal phase, those concentrations after BLQ concentrations 
will be treated as missing. 
For efficacy analyses, when rescue medication is used, the last pain intensity measure prior to the 
use of rescue medication will be used (imputed) for the subsequent protocol-specified time 
points for measurement of pain intensity after the time of the rescue medication. 
Missing data as a result of discontinuation due to adverse event or due to lack of efficacy will be 
imputed with worst observation carry forward (WOCF) method. 
For safety analyses, missing data will not be imputed in general, otherwise specified. 
More detail will be described in the SAP.   
9.5.6. 
Interim Analysis 
No formal interim analysis will be performed in this study. 
9.5.7. 
Protocol Deviations and Violations 
Protocol deviations will be identified on an ongoing basis by the clinical study team.  
9.5.8. 
Subgroup Analyses  
Analyses by subgroup may be further described in the SAP.  

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10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
10.1. Good Clinical Practice 
The investigator agrees to conduct the study as outlined in this protocol, and in accordance with 
the ethical principles that have their origin in the Declaration of Helsinki; ICH E6(R2): Good 
Clinical Practice; the protocol; and all national, state, and local laws or regulations. 
10.2. Informed Consent Process 
Written informed consent in compliance with US Title 21 CFR Part 50 shall be obtained from 
each subject before he or she enters the study or before performing any unusual or nonroutine 
procedure that involves risk to the subject. If any institution-specific modifications to 
study-related procedures are proposed or made by the site, the consent should be reviewed by the 
sponsor or its designee or both before IRB submission. Once reviewed, the investigator will 
submit the ICF to the IRB for review and approval before the start of the study. 
Before recruitment and randomization, each prospective subject or his/her legal guardian will be 
given a full explanation of the study and will be allowed to read the approved ICF. Once the 
investigator is assured that the subject/legal guardian understands the implications of 
participating in the study, the subject/legal guardian will be asked to give his or her consent to 
participate in the study by signing the ICF. A copy of the ICF will be provided to the 
subject/legal guardian. 
10.3. Institutional Review 
Federal regulations and ICH guidelines require that approval be obtained from an IRB before 
participation of human subjects in research studies. Before study onset, the protocol, ICF, 
advertisements to be used for the recruitment of study subjects, and any other written 
information regarding this study that is to be provided to the subject or the subject’s legal 
guardian must be approved by the IRB. Documentation of all IRB approvals and of the IRB 
compliance with the ICH E6(R2): Good Clinical Practice will be maintained by the site and will 
be available for review by the sponsor or its designee. 
All IRB approvals should be signed by the IRB chairman or designee and must identify the IRB 
name and address, the clinical protocol by title or protocol number or both, and the date approval 
or a favorable opinion was granted. 
10.4. Confidentiality and Privacy 
All laboratory specimens, evaluation forms, reports, and other records will be identified in a 
manner designed to maintain subject confidentiality. All records will be kept in a secure storage 
area with limited access. Clinical information will not be released without the written permission 
of the subject (or the subject’s legal guardian), except as necessary for monitoring and auditing 
by the sponsor, its designee, the FDA, or the IRB. 
The investigator and all employees and coworkers involved with this study may not disclose or 
use for any purpose other than performance of the study, any data, record, or other unpublished, 

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confidential information disclosed to those individuals for the purpose of the study. Prior written 
agreement from the sponsor or its designee must be obtained for the disclosure of any said 
confidential information to other parties. 
10.5. Study Management 
10.5.1. 
Clinical Monitoring 
All aspects of the study will be carefully monitored by the sponsor or its designee for compliance 
with applicable government regulation with respect to current ICH E6(R2) guidelines and 
standard operating procedures. 
Monitoring for this study will be performed by Lotus. The clinical monitor, as a representative of 
the sponsor will visit the investigator and study site at periodic intervals in addition to 
maintaining necessary telephone and email contact. The monitor will maintain current personal 
knowledge of the study through observation, review of study records and source documentation, 
and discussion of the conduct of the study with the investigator and staff. 
Details of clinical site monitoring are documented in the Clinical Monitoring Plan (CMP). 
10.5.2. 
Inspection of Records 
The investigator and institution involved in the study will permit study-related monitoring, 
audits, IRB review, and regulatory inspections by providing direct access to all study records. In 
the event of an audit, the investigator agrees to allow the sponsor, their representatives, the FDA, 
or other regulatory agencies access to all study records. 
The investigator should promptly notify the sponsor and study site(s) of any audits scheduled by 
any regulatory authorities and promptly forward copies of any audit reports received to the 
sponsor. 
10.5.3. 
Data Quality Insurance 
This study will be conducted using the quality processes described in applicable procedural 
documents. The quality management approach to be implemented will be documented and will 
comply with current International Council for Harmonization (ICH) guidance on quality and risk 
management. All aspects of the study will be monitored for compliance with applicable 
government regulatory requirements, current Good Clinical Practice, the protocol, and standard 
operating procedures.  
Electronic CRFs and electronic data capture will be utilized. The electronic data capture system 
is validated and compliant with US Title 21 CFR Part 11. Each person involved with the study 
will have an individual identification code and password that allows for record traceability. Thus, 
the system, and any subsequent investigative reviews, can identify coordinators, investigators, 
and individuals who have entered or modified records, as well as the time and date of any 
modifications. There may be an internal quality review audit of the data and additional reviews 
by the clinical monitor. 

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Each eCRF is presented as an electronic copy, allowing data entry by site personnel, who can 
add and edit data, add new subjects, identify and resolve discrepancies, and view records. This 
system provides immediate direct data transfer to the database, as well as immediate detection of 
discrepancies, enabling site coordinators to resolve and manage discrepancies in a timely 
manner. 
Site personnel will maintain source documentation, enter subject data into the eCRF as 
accurately as possible, and will rapidly respond to any reported discrepancies. 
Paper copies of the eCRFs and other database reports may be printed and signed by the 
investigator. This system provides site personnel, monitors, and reviewers with access to 
hardcopy audits, discrepancy reviews, and investigator comment information. 
10.5.4. 
Records Retention  
Essential documents should be retained until at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or until at least 2 years have elapsed since the formal 
discontinuation of clinical development of the study drug. These documents should be retained 
for a longer period, however, if required by applicable regulatory requirements or by an 
agreement with the sponsor. The sponsor is responsible for informing the investigator/institution 
when these documents no longer need to be retained. 
10.5.5. 
Protocol Deviations 
A protocol deviation is any change, divergence, or departure from the study design or procedures 
defined in the protocol. An important deviation (sometimes referred to as a major or significant 
deviation) is a subset of protocol deviations that leads to a subject being discontinued from the 
study, or significantly affects the subject’s rights, safety, or well-being and/or the completeness, 
accuracy, and reliability of the study data. An important deviation can include nonadherence to 
inclusion or exclusion criteria or nonadherence to FDA regulations or ICH E6(R2) guidelines. 
The investigator or designee must document and explain in the subject’s source documentation 
any deviation from the approved protocol. The investigator may implement a deviation from, or 
a change to, the protocol to eliminate an immediate hazard to study subjects without prior IRB 
approval. As soon as possible after such an occurrence, the implemented deviation or change, the 
reasons for it, and any proposed protocol amendments should be submitted to the IRB for review 
and approval, to the sponsor for agreement, and to the regulatory authorities, if required. 
Protocol deviations will be documented by the clinical monitor throughout the course of 
monitoring visits. The investigator will be notified in writing by the monitor of deviations. The 
IRB should be notified of all protocol deviations, if appropriate, in a timely manner. 
10.5.5.1. 
Unavoidable Protocol Deviations Related to COVID-19  
Unavoidable protocol deviations involving study procedure scheduling delays, early or missed 
visits, and missing information might occur due to the COVID-19 situation. In general, if a study 
procedure is completed, it might not be considered a protocol deviation, even if it is completed 

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remotely, out-of-window, or using alternative methods. If a procedure cannot be completed and 
results in missing data, it might be considered a protocol deviation. COVID-19 related Protocol 
deviations are to be documented, and specific information that explains the basis of missing data 
including relationship to COVID-19 must be captured in the CSR. Missing data related to 
COVID-19 will be treated as non-COVID-19 related missing data. Any causal relationship 
between the study drug and an SAE in a trial participant diagnosed with CoVID-19 must be 
submitted to the FDA. The sponsors and investigators are required to document how restrictions 
related to CoVID-19 led to changes in study conduct, duration of those changes, which trial 
participants were impacted and how they were impacted. 
10.6. Publications 
The clinical study plan and the results of the study will be published on www.ClinicalTrials.gov 
in accordance with 21 CFR § 50.25I. After completion of the study, the data may be considered 
for reporting at a scientific meeting or for publication in a scientific journal. In these cases, the 
sponsor will be responsible for determining how the manuscript is written and edited, the number 
and order of authors, the publication to which it will be submitted, and any other related issues. 
The sponsor has final approval authority over all such matters. 
Data are the property of the sponsor and cannot be published without their prior authorization, 
but data and any permission for publication thereof will not be unduly withheld. 

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11. 
LIST OF ABBREVIATIONS 
 
AE 
adverse event 
ALT 
alanine aminotransferase  
ANCOVA 
analysis of covariance 
AST 
aspartate aminotransferase  
AUC 
area under the concentration-time curve 
AUC0-∞ 
area under the concentration-time curve, extrapolated to infinity 
AUC0-t 
area under the concentration-time curve from time 0 to the last measurable 
concentration timepoint 
BID 
twice daily 
BMI 
body mass index 
bpm 
beats per minute 
BUN 
blood urea nitrogen 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CK 
creatine kinase 
Cmax 
maximum concentration  
Cmax, ss 
maximum concentration at steady state 
Cmin 
minimum concentration 
CrCL 
creatinine clearance 
CRF 
case report form 
CRO 
Clinical research organization 
ECG 
Electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
FDA 
Food and Drug Administration 
GABA  
gamma-aminobutyric acid 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 
h 
Hour 
HBsAg 
surface antigen of Hepatitis-B-Virus 
HCV 
hepatitis C virus 
HDPE 
high density polyethylene 
HIV 
human immunodeficiency virus 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation  
IRB 
Institutional Review Board 
LDH 
lactic dehydrogenase 
MAD 
multiple ascending dose 
MAOI 
monoamine oxidase inhibitor 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCV 
mean corpuscular volume 

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MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
min 
Minute 
mL 
Milliliter 
mmHg 
millimeters of mercury 
NSAIDs 
non-steroidal anti-inflammatory drugs 
PE 
physical examination 
PK 
Pharmacokinetic 
PPI 
proton pump inhibitor 
PT 
preferred term; prothrombin time 
PTT 
partial thromboplastin time 
RBC 
red blood cell (count) 
SAD 
single ascending dose 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
standard deviation 
SOA 
Schedule of Assessments 
SOC 
system organ class 
SOP 
standard operating procedure 
TEAEs 
treatment-emergent adverse events 
Tmax 
time to maximum concentration 
US 
United States 
WBC 
white blood cell (count) 
WOCBP 
women of childbearing potential 
 

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12. 
REFERENCES 
1. Banoob DW, McCloskey WW, Webster W. Risk of gastric injury with enteric- versus 
nonenteric-coated aspirin. Ann Pharmacother. 2002;36(1): 163-6. 
2. Blyth FM, Briggs AM, Schneider CH, et al. The global burden of musculoskeletal pain- 
where to from here? Am J Public Health. 2019;109(1):35-40. 
3. Bockbrader HN, Wesche D, Miller R, et al. A comparison of the pharmacokinetics and 
pharmacodynamics of pregabalin and gabapentin. Clin Pharmacokinet. 
2010;49(10):661-9. 
4. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. 
Nephron 1976;16: 31-41.  
5. Corleto VD, Festa S, Di Giulio E, Annibale B. Proton pump inhibitor therapy and 
potential long-term harm. Curr Opin Endocrinol Diabetes Obes. 2014;21(1): 3-8. 
6. Coxib and traditional NSAID Trialists’ (CNT) Collaboration, Bhala N, Emberson J, et 
al. Lancet. 2013;382(9894):769–79. 
7. Dahl JB, Mathiesen O, Møiniche S. Protective premedication: an option with 
gabapentin and related drugs? Acta Anaesthesiologica Scandinavica. 2004;48: 1130-36.  
8. D'Haens G, Breysem Y, Rutgeerts P, van Besien B, Geboes K, Ponette E, Vantrappen 
G. Proctitis and rectal stenosis induced by nonsteroidal antiinflammatory suppositories. 
J Clin Gastroenterol. 1993;17(3): 207-12. 
9. Enright A, Goucke R. The global burden of pain: the tip of the iceberg? Anesth Analg. 
2016;123(3):529-30. 
10. Fassoulaki A, Triga A, Melemeni A, Sarantopoulos C. Multimodal analgesia with 
gabapentin and local anesthetics prevents acute and chronic pain after breast surgery for 
cancer. Anesth Analg. 2005;101(5):1427-32.  
11. Finnerup NB. Nonnarcotic methods of pain management. N Engl J Med. 
2019;380(25):2440-48. 
12. GBD 2017 Disease and Injury Incidence and Prevalence Collaborators. Global, 
regional, and national incidence, prevalence, and years lived with disability for 354 
diseases and injuries for 195 countries and territories, 1990-2017: a systematic analysis 
for the Global Burden of Disease Study 2017. Lancet. 2018;392(10159):1789-858. 
13. FDA 2007 Guidance For Industry- Toxicity Grading Scale for Healthy Adult and 
Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials. 
14. Horizant. 2013. Horizant® (Pregabalin) Product Information. (April 2013) Arbor 
Pharmaceuticals, LLC. 

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15. Hurley RW, Chatterjea D, Rose Feng M, et al. Gabapentin and pregabalin can interact 
synergistically with naproxen to produce antihyperalgesia. Anesthesiology. 
2002;97(5):1263-73. 
16. Inza. 2019. Inza® (Naproxen) Product Information. (July 2019) Alphapharm Pty 
Limited. 
17. Ivey KJ, Paone DB, Krause WJ. Acute effect of systemic aspirin on gastric mucosa in 
man. Dig Dis Sci. 1980;25(2): 97-9. 
18. Lyrica® (Pregabalin) Prescribing Information. (June 2011) Pfizer Inc., US. 
19. Lyrica® (pregabalin) Product Information. (January 2013) Pfizer Australia Pty Ltd. 
20. Ménigaux C, Adam F, Guignard B, Sessler DI, Chauvin M. Preoperative gabapentin 
decreases anxiety and improves early functional recovery from knee surgery. Anesth 
Analg. 2005;100:1394–9. 
21. Naprosyn® (naproxen sodium) Prescribing Information. (November 2017) Atnahs 
Pharma Australia Pty Ltd. 
22. Petroski D. Endoscopic comparison of three aspirin preparations and placebo. Clin 
Ther. 1993;15(2): 314-20. 
23. Sinatra R. Causes and consequences of inadequate management of acute pain. Pain 
Med. 2010;11(12):1859-71. 
24. Singla NK, Chelly JE, Lionberger DR, et al. Pregabalin for the treatment of 
postoperative pain: results from three controlled trials using different surgical models. J 
Pain Res. 2015;8:9-20. 
25. Trelle S, Reichenbach S, Wandel S, Hildebrand P, Tschannen B, Villiger PM, Egger M, 
Juni P. Cardiovascular safety of non-steroidal anti-inflammatory drugs: network meta-
analysis. BMJ. 2011;342: c7086. 
26. Van Gossum A, Zalcman M, Adler M, Peny MO, Houben JJ, Cremer M. Anorectal 
stenosis in patients with prolonged use of suppositories containing paracetamol and 
acetylsalicylic acid. Dig Dis Sci. 1993;38(11): 1970-7. 
27. Vevea J, Woods CM. Publication bias in research synthesis: sensitivity analysis using 
A priori weight functions. Psychological Methods. 2005;10(4):428–43. 
28. Wang H, Gargano C, Lukac S, et al. An enhanced bunionectomy model as a potential 
tool for early decision-making in the development of new analgesics. Adv Ther.2010; 
27(12):963-80. 
29. Wu J, Jiang J, Wei W. Confidence intervals of effect size in randomized comparative 
parallel-group studies. Stat Med. 2006;25(4):639-51. 

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30. XG005 IB (2022). Investigator's Brochure, XG005, Edition 2.0. 
31. Yu EW, Bauer SR, Bain PA, Bauer DC. Proton pump inhibitors and risk of fractures: a 
meta-analysis of 11 international studies. Am J Med. 2011;124(6): 519-26. 
 
 
 
 
 
 
 
 
 
 

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APPENDIX A: 
INVESTIGATOR’S SIGNATURE 
Study Title: 
A Randomized, Double-Blind, Placebo -Controlled Trial to Evaluate 
the Safety and efficacy of XG005 Tablets in Subjects Undergoing 
Bunionectomy 
Study Number: 
Study Version: 
PR-XG005-02-BUN-01  
Version 5.0 
Protocol Date: 
15 Nov 2022 
I have read the attached protocol entitled “A Randomized, Double-Blind, Placebo Controlled 
Trial to Evaluate the Safety and efficacy of XG005 Tablets in Subjects Undergoing 
Bunionectomy” and agree to abide by all provisions set forth therein. 
I agree to comply with the International Conference on Harmonisation Tripartite Guideline on 
Good Clinical Practice, The Declaration of Helsinki (2004), and applicable FDA regulations/ 
guidelines set forth in 21 CFR Parts 11, 50, 54, 56, and 312. 
I agree to ensure that the confidential information contained in this document will not be used for 
any purpose other than the evaluation or conduct of the clinical investigation without the prior 
written consent of Xgene Pharmaceuticals, Inc. 
Clinical Site:  
Principal Investigator or Investigator: 
 
Name 
 
Role 
 
Affiliation 
 
City, State 
 
 
 
 
Investigator’s Signature 
 
Date 

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APPENDIX B: 
PRE-STUDY PERSONALITY QUESTIONNAIRE 
 
 
 
 
 
 
 
Pre-Study Personality Questionnaire 
 
A. Please answer the following questions about yourself by indicating the extent of your agreement 
using the following scale: 
 
Strongly 
Disagree 
Neutral 
Agree 
Strongly Agree 
1 
2 
3 
4 
5 
 
1. In uncertain times, I usually expect the best   
 
 
2. It's easy for me to relax.   
 
 
3. If something can go wrong for me, it will. _____ 
4. I'm always optimistic about my future.   
 
5. I enjoy my friends a lot.   
 
6. It's important for me to keep busy.   
 
7. I hardly ever expect things to go my way.   
 
8. I don't get upset too easily.   
 
9. I rarely count on good things happening to me.  
 
 
10. Overall, I expect more good things to happen to me than bad.  
 
 
 
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Pre-Study Personality Questionnaire 
B. Here are a number of characteristics that may or may not apply to you. For example, do you agree 
that you are someone who likes to spend time with others? Please write a number next to each 
statement to indicate the extent to which you agree or disagree with that statement. 
 
Disagree 
strongly 
Disagree a 
little 
Neither agree 
nor disagree 
Agree a little 
Agree Strongly 
1 
2 
3 
4 
5 
 
 
I see Myself as Someone Who 
1. Is original, comes up with new ideas   
 
2. Is curious about many different things   
 
3. Is ingenious, a deep thinker   
 
4. Has an active imagination   
 
5. Is inventive   
 
6. Values artistic, aesthetic experiences   
 
7. Prefers work that is routine   
 
8. Likes to reflect, play with ideas   
 
9. Has few artistic interests   
 
10.  Is sophisticated in art, music, or literature ________  
 
C. Please indicate how often each statement applies to you generally in daily life. 
Never 
Always 
0 
1 
2 
3 
4 
5 
 
1. I do not notice (I ignore) physical tension or discomfort until they become more severe. _____ 
2.  I distract myself from sensations of discomfort.  ______ 
3.  When I feel pain or discomfort, I try to power through it.  _____ 
 
 
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Pre-Study Personality Questionnaire 
D. Please indicate how often each statement applies to you generally in daily life. 
Never 
Always 
0 
1 
2 
3 
4 
5 
 
1. I can pay attention to my breath without being distracted by things happening around me. 
_______ 
2. I can maintain awareness of my inner bodily sensations even when there is a lot going on around 
me. ______ 
 
3. When I am in conversation with someone, I can pay attention to my posture.  
_ 
4. I can return awareness to my body if I am distracted.   
 
5. I can refocus my attention from thinking to sensing my body.   
 
6. I can maintain awareness of my whole body even when a part of me is in pain or discomfort.  
 
 
7. I am able to consciously focus on my body as a whole.   
 
 
E. Please indicate how often each statement applies to you generally in daily life. 
Never 
Always 
0 
1 
2 
3 
4 
5 
 
1. I notice how my body changes when I am angry.  _________ 
2. When something is wrong in my life, I can feel it in my body.   
 
3. I notice that my body feels different after a peaceful experience.   
 
4. I notice that my breathing becomes free and easy when I feel comfortable.   
 
5. I notice how my body changes when I feel happy / joyful.   
 
 
F. Please indicate how often each statement applies to you generally in daily life. 
Never 
Always 
0 
1 
2 
3 
4 
5 
 
1. When I feel overwhelmed, I can find a calm place inside.  ________ 
2. When I bring awareness to my body, I feel a sense of calm.   
 
3. I can use my breath to reduce tension.   
 
4. When I am caught up in thoughts, I can calm my mind by focusing on my body/breathing. 
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Pre-Study Personality Questionnaire 
STUDY STAFF USE ONLY 
 
For all items, higher score predicts greater placebo response 
 
A. OPTIMISM 
Source: Revised Life Orientation Test (LOT-R). Reverse score items 3, 7 and 9. Items 2, 5, 6, and 
8 are filler items, do not score. 
(Geers, 2005: “Dispositional optimism was related to less cold pressor pain in the placebo condition as 
compared with the control condition.”) 
 
B. OPENNESS 
Source: The Big Five Inventory (BFI). Reverse score items 7 and 9. 
 
C. NOT DISTRACTING 
Source: Multidimensional Assessment of Interoceptive Awareness (MAIA) 
Not-Distracting: Tendency not to ignore or distract oneself from sensations of pain or discomfort 
(Note: original instructions are to reverse score all 3 items, resulting in a “not distracting” 
score 
negatively correlated with placebo response. For our purposes we will not reverse score; higher 
score predicts higher placebo response). 
 
D. ATTENTION REGULATION 
Source: Multidimensional Assessment of Interoceptive Awareness (MAIA) 
Attention Regulation: Ability to sustain and control attention to body sensations 
 
E. EMOTIONAL AWARENESS 
Source: Multidimensional Assessment of Interoceptive Awareness (MAIA) 
Emotional Awareness: Awareness of the connection between body sensations and emotional states 
 
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STUDY STAFF USE ONLY 
 
 
 
 
 
 
 
Pre-Study Personality Questionnaire 
F. SELF-REGULATION 
Source: Multidimensional Assessment of Interoceptive Awareness (MAIA) 
Self-Regulation: Ability to regulate distress by attention to body sensations 
 
(Vachon-Presseau, 2018: “… openness (from the big 5 personality dimensions) and 4 out of 8 
subscales from the Multidimensional Assessment of Interoceptive Awareness (MAIA)- Not Distracting 
(maia/nd), Attention Regulation (maia/a), Emotional Awareness (maia/e), and Self-Regulation 
(maia/sr)- correlated with the magnitude of response after correcting for multiple comparisons (p < 
 0.0013) ... 
Patients with increased emotional awareness experience greater placebo analgesia… whereas 
patients who tend not to ignore or distract themselves from discomfort experience less placebo 
analgesia (Mais/nd displayed in e) … In our patients, placebo pill response was driven primarily by a 
combination of a greater openness to experience, increased emotional awareness, decreased 
distraction about pain and discomfort, augmented capabilities in describing inner experiences, and 
higher sensitivity to non-painful situations.”) 
 
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APPENDIX C: 
NUMERIC PAIN RATING SCALE 
On a scale of 0-10, please rate your pain by marking an “X” in the appropriate box that 
best describes your pain level NOW. 
 
 0 
 1 
 2 
 3 
 4 
 5 
 6 
 7 
 8 
 9 
 10 
No 
Pain 
 
 
 
 
 
 
 
 
Worst pain 
imaginable 
The NPRS should also be administered prior to administration of any per protocol rescue 
medication.  
 
 

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APPENDIX D: 
PATIENT GLOBAL ASSESSMENT 
5-Point PGA of Pain Control 
“Overall, please rate how well your pain has been controlled during the last 24 (48, 72) 
hours since you received study medication?” 
 
   Poor (0) 
   Fair (1) 
   Good (2) 
   Very Good (3) 
   Excellent (4) 
 
 

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APPENDIX E: 
NUMERIC NAUSEA RATING SCALE 
On a scale of 0-10, please rate your nausea by marking an “X” in the appropriate box that 
best describes your nausea level NOW. 
 
 0 
 1 
 2 
 3 
 4 
 5 
 6 
 7 
 8 
 9 
 10 
No 
nausea 
 
 
 
 
 
 
 
 
Worst nausea 
imaginable 
 
 
 

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APPENDIX F: 
SLEEP INTERFERENCE SCORE 
On a scale of 0-10, please rate how the pain at the operation site has interfered with your 
sleep during the last 24 hours (0=no interference, 10=worst interference imaginable).  
 
 0 
 1 
 2 
 3 
 4 
 5 
 6 
 7 
 8 
 9 
 10 
No 
interference 
 
 
 
 
 
 
 
 
Worst 
interference 
imaginable 
 
 
 

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APPENDIX G: 
RAMSAY SEDATION SCALE 
Performed using a series of steps: observation of behavior (score 1 or 2), followed (if necessary) 
by assessment of response to voice (score 3), followed (if necessary) by assessment of response 
to loud auditory stimulus or light glabellar tap (score 4 to 6) 
 
 
 
 
 

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APPENDIX H: 
PATIENT HEALTH QUESTIONNAIRE-9 (PHQ-9) 
 

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APPENDIX I  
GENERAL ANXIETY DISORDER (GAD-7) 
 
 
 

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APPENDIX J  
COLUMBIA-SUICIDE SEVERITY RATING SCALE (C-SSRS) 
BASELINE/SCREENING VERSION 
 

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APPENDIX K  
COLUMBIA-SUICIDE SEVERITY RATING SCALE (C-SSRS) 
SINCE LAST VISIT VERSION 
 
 

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APPENDIX L  
TOXICITY GRADING SCALE TABLES 
 
 

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APPENDIX M 
SUMMARY OF CHANGES 
Version 4.0 to Version 5.0 
Additions to text are noted by underlining and deletions are noted by cross-out. 
Section and/or 
page number 
Changes from previous version   
Justification 
Section 7.1 
Revision of Stopping Criteria 
Per FDA’s 
recommendation  
Section 8.2.1.3 
Revision of assessment of severity 
 
Per FDA’s 
recommendation 
Appendix L 
Inserted Toxicity Grading Scale Tables for Healthy Adult and 
Adolescent Volunteers Enrolled in Preventive Vaccine 
Clinical Trials 
Per FDA’s 
recommendation 
Section 12 
Addition of Guidance (toxicity Grading Scale for Healthy 
Adult and Adolescent Volunteers Enrolled in Preventive 
Vaccine Clinical Trials) in Reference list.  
Per FDA’s 
recommendation