Clinical trial NCT05764525
Conditions: Pain, Postoperative Acute Pain
Sponsor: Vivozon Pharmaceutical Inc.
Start date: 2021-07-19; Completion date: 2022-11-22
Enrollment: 285 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this phase 3 study is to evaluate the efficacy and safety of VVZ-149 Injections for the treatment of postoperative pain following laparoscopic colectomy.

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: VVZ-149 Injections intervention 2: Placebo
Intervention descriptions: intervention 1: IV infusion of 1000 mg of VVZ-149 intervention 2: IV infusion of 0 mg of VVZ-149

Protocol documents:
Prot_SAP_000.pdf: 
Vivozon Pharmaceutical Inc.  
 
CONFIDENTIAL 
Protocol No: VVZ149-POP-P3-K301 
 
PRT/SAP Version: 2.5/1.0 
 
1 
Version Date: Jan. 27, 2023             
 
Protocol and 
Statistical Analysis Plan Summary 
 
 
 
 
A Phase 3, Multicenter, Randomized, Double-Blind, Parallel Group, 
Placebo-Controlled Study to Evaluate the Efficacy and Safety of  
VVZ-149 Injections for the Treatment of Postoperative Pain  
following Laparoscopic Colectomy  
 
 
 
 
Investigational Product 
VVZ-149 Injections 
Protocol Number 
VVZ149-POP-P3-K301 
NCT Number 
NCT05764525 
Protocol/SAP Version 
Version 2.5/1.0 
Version Date 
January 27th, 2023 
Phase 
3  
Confidentiality Statement 
The information in this document is confidential and is not to be disclosed without the written consent of 
Vivozon, Inc., the first developer of VVZ-149, which granted a domestic license to Vivozon Pharmaceutical 
Inc. except to the extent that disclosure would be required by law and for the purpose of evaluating and/or 
conducting a clinical study for Vivozon Pharmaceutical Inc. You are allowed to disclose the contents of this 
document only to your Institutional Review Board and study personnel directly involved with conducting this 
protocol including the study director, study manager, pharmacist, and administrative agency. If you want to 
use it for any other purpose, you must acquire the written consent of Vivozon, Inc., and the confidentiality of 
this document must be maintained.  


Vivozon Pharmaceutical Inc.  
 
CONFIDENTIAL 
Protocol No: VVZ149-POP-P3-K301 
 
PRT/SAP Version: 2.5/1.0 
 
2 
Version Date: Jan. 27, 2023             
 
Title:   
A Phase 3, Multicenter, Randomized, Double-Blind, Parallel Group, Placebo-Controlled Study to 
Evaluate the Efficacy and Safety of VVZ-149 injections for the Treatment of Postoperative Pain 
following Laparoscopic Colectomy  
Protocol Number: VVZ149-POP-P3-K301 
Inverstigational Product: VVZ-149 Injections 
Phase: 3 
Indication: Postoperative pain 
Study Rationale:  
VVZ-149 (Opiranserin, INN) is a dual antagonist of GlyT2 and 5HT2A, which plays an important role 
in modulating the induction and transmission of pain signals via the central and peripheral nervous 
systems. GlyT2 antagonists reduce the reuptake of glycine that inhibits pain signals at spinal synapses, 
which depresses the transmission of pain signals toward the brain. 5-HT2A is expressed in the termini 
of descending facilitatory projection neurons in the midbrain and involved in the amplification of pain 
signals in the spinal dorsal horn. 5HT2A is also expressed in the termini of peripheral nociceptive 
neurons (a start point of postoperative pain) and generates pain signals. Thus, 5-HT2A antagonists inhibit 
facilitatory pain signals and activation of nociceptive receptors, which reduces the sensation of pain. 
VVZ-149 has demonstrated comparable efficacy to morphine in well-controlled (blind, complete 
randomization with a positive control) animal studies using rat models of postoperative pain and 
formalin-induced pain. 
Two Phase 1 studies (PT-VVZ149-01/02), five Phase 2 studies (PT-VVZ149-04/05, VVZ149-POP-P2-
US001/US002/US004), and one Phase 3 study (VVZ149-POP-P3-US003) have been completed in 
Korea and the US to evaluate the efficacy, pharmacokinetics (PK) and safety of VVZ-149 Injections 
(Unafra, Brand name) for treating postoperative pain. Clinical trials with a continuous 8 to10-hours IV 
infusion of VVZ-149 Injections administered pre-, during-, and postoperatively demonstrated effective 
analgesia using VVZ-149 Injections with substantially reduced opioid consumption compared to the 
placebo. The most frequent adverse events (AEs) reported were nausea, vomiting, headache, dizziness, 
and somnolence, and to date, there have been no other clinically significant AEs, which indicates the 
excellence in safety and drug tolerance of VVZ-149 Injections. 
OBJECTIVES: 
Primary Objectives: 
To make a pivotal assessment of the analgesic effects of VVZ-149 Injections (1000 mg VVZ-149 for 10 
hours, administered as a loading dose of 160 mg for 30 minutes followed by a maintenance dose of 840 
mg for 9.5 hours) for treating postoperative pain following laparoscopic colectomy. 
Secondary Objectives : 
To evaluate (1) the extended analgesic effects and reduced postoperative opioid requirements by VVZ-
149 Injections, and (2) the safety and tolerability of VVZ-149 Injections up to 48 hours postdose 


Vivozon Pharmaceutical Inc.  
 
CONFIDENTIAL 
Protocol No: VVZ149-POP-P3-K301 
 
PRT/SAP Version: 2.5/1.0 
 
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Version Date: Jan. 27, 2023             
Inclusion and Exclusion Criteria: 
Inclusion Criteria 
Subjects who meet all of the following criteria will be eligible to participate in the study. 
1. Men and women must be at least 18 years of age.  
2. Female subjects who are not pregnant or breastfeeding. 
3. Subjects must be undergoing a planned first laparoscopic colectomy. 
4. Subjects classified in American Society Anesthesiologist (ASA) risk class of I or II. 
5. Subjects who report the pain intensity ≥ 5 on the NRS (NRS: Numeric Rating Scale, 0~10) 
assessed after surgery. 
6. Subjects must have the ability to understand study procedures and communicate clearly with the 
investigator and staff. 
7. Subjects must have the ability to provide written informed consent. 
Exclusion Criteria 
A subject will be excluded from participation in the study if he/she met any of the following criteria:  
Surgical Factors 
8. Subjects undergoing emergency or unplanned surgery. 
9. Subjects who had a previous laparoscopic colectomy or resection procedure. 
10. Subjects with pre-existing conditions causing preoperative pain around the site of surgery 
Subject Characteristics 
Subjects:  
Adult men and women at least 18 years of age undergoing a planned laparoscopic colectomy  
300 subjects who meet all of the inclusion and exclusion criteria 
1:1 randomization to VVZ-149 Injections or placebo 
Study Design:  
This is a multicenter, randomized, double-blind, parallel group, placebo-controlled Phase 3 study in 
adults undergoing a planned laparoscopic colectomy to evaluate the efficacy and safety of VVZ-149 
Injections on postoperative pain. The subjects who provide informed consent, meet all the 
inclusion/exclusion criteria from screening to post-surgery, and report the initial Numerical Rating Scale 
(NRS) of ≥ 5 measured immediately after regaining consciousness from anesthesia will be eligible for 
randomly assigned to the VVZ-149 treatment group or the placebo treatment group. 
The VVZ-149 treatment group will receive a dosing regimen of a continuous IV infusion (1,000 mg of 
VVZ-149 mixed into a 500 mL saline bag; 160 mg as a loading dose will be administered for 30 minutes 
at the beginning of infusion followed by a maintenance dose of 840 mg for 9.5 hours) over 10 hours. 
The placebo group will be administered a placebo in the same way as the VVZ-149 treatment group over 
10 hours. All subjects will be provided with a patient-controlled analgesia (PCA) pump upon emergence 
from anesthesia. After the start of the study drug infusion, subjects are allowed to self-administer IV 
PCA of fentanyl (5 µg IV bolus, 10 min lock-out) as needed to facilitate adequate pain relief. If the 
subject has been dosing with IV PCA of fentanyl but still reports the NRS score of ≥ 5 upon and requests 
additional pain medication, the subject will be given rescue medications. The efficacy, safety, and 
pharmacokinetics of the VVZ-149 Injections will be evaluated at scheduled time points for 48 hours 
from the start of the study drug infusion. 


Vivozon Pharmaceutical Inc.  
 
CONFIDENTIAL 
Protocol No: VVZ149-POP-P3-K301 
 
PRT/SAP Version: 2.5/1.0 
 
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11. Female subjects who are pregnant or breastfeeding. 
12. Diagnosis of chronic pain (e.g., persistent pain with the intensity of NRS ≥ 5 at baseline)  
13. Unstable or poorly controlled psychiatric conditions (e.g., post-traumatic stress disorder, anxiety, 
or depression). Antidepressant and antianxiety medication are allowed as long as the subject has 
been on a stable dose for at least 60 days prior to screening. Intraoperative antianxiety drugs are 
allowed. 
14. Unstable, acute medical condition (e.g., unstable angina, congestive heart failure, renal failure, 
hepatic failure, or acquired immunodeficiency syndrome). 
15. Clinically significant ECG findings as determined by the investigator at the screening visit: 
Prolonged QRS duration (> 200 msec), QTcF > 450 msec (male) or > 470 msec (female). 
16. Body weight < 50 kg. 
Drug, Alcohol, and Pharmacological Considerations 
17. History of alcohol, opiate, or other drug abuse or dependence within 12 months prior to the 
Screening Visit. 
18. Ongoing or recent (within 30 days prior to surgery) use of opioids. 
19. History of opioid tolerance based on the patient report or investigator’s judgment. 
20. Alcohol consumption within 24 hours of surgery. 
21. Use of nonsteroidal anti-inflammatory drugs (NSAIDs) or non-opioid analgesics (including COX-
2 inhibitors) within 24 hours of surgery. 
22. Use of herbal medicine or dietary supplements (e.g., chaparral, comfrey, germander, jin bu huan, 
kava, pennyroyal, skullcap, St. John’s wort, or valerian) within 7 days prior to surgery 
23. Use of drugs that are known to increase the PR and QRS interval (Appendix 16.1) within 24 hours 
prior to surgery. 
24. Use of weak/moderate/strong CYP3A inhibitors and inducers or the drugs that are known clinical 
substrates of renal transporters OCT2 and MATE1/2K (Appendix 16.1) within 24 hours prior to 
surgery. 
Anesthetic and Other Exclusion Considerations 
25. Use of any CNS drugs or local anesthetic wound infiltration. 
26. Use of parenteral ketamine (any doses of), gabapentin, pregabalin, or lidocaine (> 1 mg/kg) intra- 
or peri-operatively, or within 24 hours of surgery. 
27. Subjects with hypersensitivity to opioids. 
28. Subjects who received another investigational drug within 30 days of the scheduled surgery.. 
Study Procedures:  
Screening 
Subjects will give informed consent and complete Screening Visit assessments to determine eligibility 
for the study.  
Anesthesia 
Laparoscopic colectomy will be performed under general anesthesia induced with propofol 2 mg/kg, 
rocuronium 0.6 mg/kg, and remifentanil 0.05-0.1 µg/kg, while blood pressure, ECG, saturation levels 
(SpO2) will be monitored. Using a 50% oxygen-containing anesthetic ventilator, the following 
conditions will be maintained: The respiratory rate of 10-15 times per minute, the tidal volume of 8 
mL/kg, the positive end-expiratory pressure of 5 cm H2O, the end-tidal CO2 (ETCO2) of 35-42 mmHg, 
and an I (inhalation): E (exhalation) ratio of 1:2. After the induction of anesthesia, an inhalational 


Vivozon Pharmaceutical Inc.  
 
CONFIDENTIAL 
Protocol No: VVZ149-POP-P3-K301 
 
PRT/SAP Version: 2.5/1.0 
 
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Version Date: Jan. 27, 2023             
anesthetic agent at a minimum alveolar concentration (MAC) of 0.6-1.0 will be used depending on age, 
and remifentanil of 0.03-0.1 µg/kg/min will be infused continuously to maintain anesthesia condition. 
In case of suturing the incision area, 30 µg of IV fentanyl and antiemetics will be provided. The 
mode/setting of ventilation and the types, or amounts of anesthetics/anti-emetics will be determined 
according to the condition of patients and clinical sites.  
Randomization 
Subjects who report the NRS score of ≥ 5 after emergence from anesthesia will be randomized in an 
1:1 ratio. Subjects with the initial NRS of < 5 will be eligible for randomization if they report the NRS 
score of ≥ 5 when reassessed within 30 minutes after emergence from anesthesia.  
Study Drug Administration 
The VVZ-149 treatment group will receive a continuous IV infusion of VVZ-149 Injections as loading 
dose of 160 mg for 30 minutes followed by maintenance dose of 840 mg for 9.5 hours via an IV 
infusion pump. 100 mL of VVZ-149 (1,000 mg) will be mixed into 400-mL saline in a total 500-mL 
infusion bag. The placebo group will be administered with a placebo as in the VVZ-149 treatment 
group for 10 hours. The start of study drug infusion will be designated as Time 0 hour. Subjects will 
receive a full clinical supportive care for at least 2 hours until vital signs become stable after emergence 
from anesthesia according to the standard operating procedures at the post anesthesia care unit (PACU). 
Subjects will be encouraged to wait for at least 30 minutes after the start of the study drug infusion 
until they requests opiod analgesics by PCA or rescue medication. If the subject reports severe 
postoperative pain or requests additional pain medication, allowed rescue medications or 
administration of PCA will be provided.  
PCA Opioid 
After the emergence from anesthesia, subjects will report their pain intensity and will be provided with 
a PCA pump (Accumate 1200; WooYoung Medical, Seoul, Korea, etc.). After the start of the study 
drug infusion, subjects are allowed to self-administer PCA (fentanyl 5 µg IV bolus, 10-minute lock-
out). For PCA administration, 2,000 µg of fentanyl and 0.3 mg of ramosetron (Nasea®, Astellas 
Pharma Korea, Seoul, Korea) mixed into 400-mL saline will be used (fentanyl 5 µg/mL).   
Rescue medication 
Allowed rescue medications will be provided if subjects report a pain intensity score of ≥ 5 on the NRS 
and require additional analgesia in addition to PCA. For the first 2 hours after the start of the study 
drug infusion, subjects will be allowed to receive IV fentanyl up to 2 doses in 1 hour with the first dose 
of 30 µg and the second dose of 20 µg at a 10-minute lockout interval. If subjects request additional 
rescue medications exceeding allowed fentanyl administrations for 1 hour, IV Oxycodone (Oxynorm, 
2 mg, 2-hour lock-out) or Morphine (Morphine Sulfate Injection, 2 mg, 2-hour lock-out) will be given. 
After 2 hours from the start of the study drug infusion, IV pethidine (25 mg, 4-hour lock-out) in addition 
to PCA will be administered upon request in the ward. If subjects experience inadequate pain relief 
despite the use of PCA opioids and protocol-specified rescue medications, they will be provided 
appropriate pain medications at the investigator’s discretion. 
Pain Intensity Assessment 
Pain intensity will be assessed using the NRS (0-10) at scheduled time points for 48 hours from the 
start of the study drug infusion. When a subject requests rescue medications, the corresponding pain 


Vivozon Pharmaceutical Inc.  
 
CONFIDENTIAL 
Protocol No: VVZ149-POP-P3-K301 
 
PRT/SAP Version: 2.5/1.0 
 
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Version Date: Jan. 27, 2023             
intensity score at the time of request will be recorded using the NRS, and the rescue medication will 
be administered. 
Dropouts 
Subjects are free to discontinue from the study at any time, without prejudice to future treatment. 
Reasons for withdrawal or discontinuation from the study may include the following and must be 
documented in the eCRF: a lack of efficacy, safety criteria (e.g., adverse events, unexpected drug 
reaction), pregnancy, protocol deviations, and sponsor/investigator decision. Once a subject is 
discontinued from the study, no data will be collected except for the safety data. 
Safety Follow-Up 
After discharge, subjects will be contacted for a follow-up phone interview. Subjects may visit the site 
at any time during the study for the postoperative care depending on the judgment of the investigator 
or the condition of a subject, but this follow-up visit is not included as part of this study. A total duration 
of the study is approximately 21 to 30 days including a safety follow-up. 
Efficacy Endpoints:  
The primary efficacy endpoint 
Time-weighted Sum of Pain Intensity Difference (SPID) from baseline over 12 hours after the start of 
the study drug infusion (i.e., post-dose). 
The secondary efficacy endpoints 
• 
Total number of PCA requests for 12 hours post-dose  
• 
Total amount of PCA and rescue medication consumption for 12 hours post-dose  
• 
Proportion of subjects with ≥ 40% decrease in pain area at 6 hours post-dose compared to the 
maximum pain area with the pre-dose pain intensity 
• 
Time-weighted SPID for 24 hours post-dose (SPID 24) 
Exploratory endpoints 
• 
Time-weighted SPID for 6 hours post-dose (SPID 6) 
• 
Total number of PCA requests for 24 and 48 hours post-dose 
• 
Total amount of PCA and rescue medication consumption for 24 and 48 hours post-dose  
• 
Population of subjects with ≥40%, ≥60%, and ≥80% decrease in pain area at 12, 24, and 48 
hours post-dose compared to the maximum pain area with the pre-dose pain intensity 
• 
Proportion of subjects who have not requested any rescue medication between 0-2, 2-6, 6-12, 
12-24, and 24-48 hours post-dose 
• 
Time to the first and the second rescue medication requested by subject 
• 
Pharmacokinetic (PK) profile of VVZ-149 Injections 
Safety Endpoints: 
Postoperative nausea and vomiting, 12-lead electrocardiograms (ECGs), vital signs, clinical laboratory 
evaluation (blood chemistry, hematology, blood coagulation, and thyroid testing), oxygen saturation, 
physical examination, and adverse events reported during the study. 
Statistical Analysis: 


Vivozon Pharmaceutical Inc.  
 
CONFIDENTIAL 
Protocol No: VVZ149-POP-P3-K301 
 
PRT/SAP Version: 2.5/1.0 
 
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Version Date: Jan. 27, 2023             
The primary objective is to evaluate a pivotal assessment of the analgesic effects of VVZ-149 Injections 
in subjects with moderate to severe postoperative pain following laparoscopic colectomy. The secondary 
objectives include the extended analgesic efficacy, safety and PK of VVZ-149 Injections.  
General Statistical Considerations 
Statistical analyses will be performed using SAS® Enterprise Guide (version 9.4) 64 bit (SAS Institute 
Inc., Cary, NC, USA) or higher. 
Continuous variables will be summarized using descriptive statistics, including number of subjects (n), 
mean, median, standard deviation (STD), minimum and maximum. The mean and median will be 
reported to an additional level of precision than the original observation in its rawest form (i.e., 
electronic case report form, eCRF), and the STD and other measures of variability (e.g., standard error) 
will be reported to two additional levels of precision than the original observations. The minimum and 
maximum will be the same precision as the original data.  
Categorical variables will be summarized using counts of subjects (n) and percentages (%) and will be 
presented in the form “n (xx.x)”. Percentages will be rounded to one decimal place. If counts of subjects 
is zero (0), then percentage will not be displayed. To ensure completeness, summaries for categorical 
variables will include all categories, even if no subjects had a response in a particular category. Unless 
otherwise specified, the denominator for each percentage will be based on the number of subjects with 
available data in the population being summarized.  
Unless otherwise specified, all statistical tests will be 2-sided using α=0.05. Estimates and confidence 
intervals will be reported to 1 more decimal than the original data. P-values will be reported to 4 decimal 
places. Pvalues less than 0.0001 will be displayed as “< 0.0001”; p-values greater than 0.9999 will be 
displayed “> 0.9999”. Summary tables will be summarized by treatment and overall, as appropriate. All 
data, including those derived, will be presented in individual subject data listings. 
Demographic Data Analysis 
The Modified Intent-to-Treat (mITT) population will be used for the analysis of demographic variables.  
Age, height, body weight and body mass index (BMI) will be summarized using descriptive statistics. 
Age group, sex, race and American Society of Anesthesiologists (ASA) risk classification will be 
summarized with the number and percentage of subjects in each parameter category.  
Subjects who have not initiated the study drug infusion, or who do not have a baseline pain intensity 
score nor any post-dose pain intensity score will be excluded from the mITT population.  
Descriptive statistics will be performed in all subjects and by treatment group. Continuous variables 
will be summarized using descriptive statistics (sample size, mean, standard deviation, minimum, 
median, and maximum values). Categorical variables will be summarized using the number and 
percentage of subjects. 
Safety Analyses 
- 
The Safety Population who have initiated study drug infusion will be used for all safety analyses. 
The occurrence, the number of subjects, severity, and relatedness will be summarized for adverse 
events (AEs) and serious adverse events (SAEs) using descriptive statistics. 
- 
Vital signs, 12-lead ECGs, and clinical laboratory evaluations per group will be summarized 
using descriptive statistics, and further statistical analyses will be performed regarding indices 
considered clinically significant as necessary. 
Efficacy Analyses 
- 
The Modified Intent-to-Treat (mITT) population will be used for the efficacy analyses. 


Vivozon Pharmaceutical Inc.  
 
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Protocol No: VVZ149-POP-P3-K301 
 
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Participants who have not initiated the study drug infusion, or who do not have a baseline pain 
intensity score nor any post-dose pain intensity score will be excluded from the mITT population. 
- 
To assess the robustness of the efficacy analyses, additional sensitivity analyses will be performed 
for the Per-Protocol (PP) population who completed at least 6 hours of study drug infusion, who 
have safety and efficacy data at least until Time 6 hours, and do not have any significant protocol 
deviations and for the Full Analysis Set (FAS) population who meet major inclusion/exclusion 
criteria, who have initiated study drug infusion, and who have any efficacy data after 
randomization. 
- 
The primary efficacy endpoint is the time-weighted Sum of Pain Intensity Difference (SPID) for 
the first 12 hours postdose. The SPID for 12 hours postdose (SPID 12) will be estimated using 
the lineartrapezoidal rule (L x Hour) with the PI scores assigned from Time 0 to Time 12 hours 
postdose. SPID 12 will be summarized using descriptive statistics by treatment group, and 
analyzed using an analysis of variance (ANOVA) model with treatment as a main effect. The 
treatment effect will be tested at a two-sided alpha=0.05 level of significance. The means, 
standard error (SE), two-sided 95% confidence interval, and two-sided p-value from the ANOVA 
model will be presented. If the normality assumption is not met using Shapiro-Wilk test, a ranked 
ANOVA will be used to analyze the primary efficacy endpoint. The rank of the SPID 12 ranked 
across both treatment arms will be analyzed using a ranked ANOVA model with treatment as the 
main effect. 
- 
All secondary efficacy analyses will be carried out using two-sided tests at the alpha = 0.05 level 
of significance. The total number of PCA requests and the total amount of opioid consumption 
by PCA and/or rescue medication at pre-defined time intervals until 12 hours postdose will be 
summarized and analyzed using a repeated-measures ANOVA. The main effects of treatment and 
time and their interaction (treatment x time) will be evaluated. The proportion of subjects with ≥ 
40% decrease in pain area at 6 hours post-dose compared to the maximum decrease in pain area 
with the pre-dose pain intensity will be summarized and analyzed by treatment group using Chi-
square test (or Fisher’s test if the expected cell counts with less than 5 is greater than 20%). The 
same method described for the primary efficacy endpoint (ANOVA) will be used to analyze the 
time-weighted SPID for 24 hours postdose (SPID 24). 
- 
All exploratory efficacy analyses will be carried out using two-sided tests at the alpha = 0.05 
level of significance. SPID 6 will be analyzed using an ANOVA model with treatment as the main 
effect. The total number of PCA requests and the total amount of opioid consumption by PCA 
and rescue medication for 24 (at a 6-h interval) and 48 hours (at a 12-h interval) post-dose will 
be analyzed using a separate repeated measures ANOVA with the main effects of treatment and 
time and their interaction (treatment x time). 
Proportion endpoints measured per time interval will be analyzed by treatment group using Chi-
square test (or Fisher’s test). Additional analysis will performed using a generalized linear model 
with repeated measures using a logit link. 
The time-to-event exploratory endpoints (time to first and second rescue medications requested 
by subject) will be analyzed based on the Kaplan-Meier (KM) estimate of median time (in 
minutes) with log-rank test and Cox proportional hazard model with treatment as a factor. 
 


Vivozon Pharmaceutical Inc.  
 
CONFIDENTIAL 
Protocol No: VVZ149-POP-P3-K301 
 
PRT/SAP Version: 2.5/1.0 
 
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Version Date: Jan. 27, 2023             
Schedule of Assessments 
ET = Early Termination 
a. 
The start time of the study drug (VVZ-149 Injections or placebo) infusion will be designated as Time 0 hour. 
b. 
Randomization will be performed only for the subjects who met all inclusion/exclusion criteria. 
c. 
A full physical examination (General condition, nutritional status, Skin/Mucosa, eyes (except impaired vision), ear, nose, throat, 
thyroid, lungs, cardiovascular system, abdomen, kidney/urogenital system, neuropsychiatric system, spinal/limbs/tumor, 
peripheral circulation, endocrine system, others) will be performed. Any abnormal symptoms or signs will be recorded.  
d. 
Pregnancy test will be performed for all female subjects at the screening visit and prior to surgery, except for those who are in 
menopause. The serum β-HCG and urine tests will be performed at screening and pre-op, respectively. 
e. 
Clinical laboratory evaluations will be performed on empty stomach (fasting for 8 hours) at screening, including blood chemistry, 
hematology, blood coagulation, and thyroid testing. If the same clinical laboratory evaluation is performed within 30 days of 
screening, the test result can be used alternatively. A serology test will be performed only at screening, and the results performed 
within 60 days of screening can be used. 
Period 
Screen
Baseline 
Treatment Dosing and Assessment 
F/Uq 
Visit 
1 
2 
3 
Study Day 
-30to-1 
1 
2 
2 to 3 
21 
Time Point 
 
Pre 
op 
Pre 
dose 0ha 0.5h 1h 
2h 
4h 
6h 
8h 10h 12h 18h 24h 30h 36h 42h 48h /
ET 
 
Time Point 
Window 
 
 
 
 
±5 m 
±10 m 
±15 m 
-30 m±15m
±1 h 
+7 d 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion 
exclusion criteria 
X 
Xb 
Xb 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HADS/PCSr 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight and 
height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/ 
medication 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical 
Examinationc 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Pregnancy testd 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical 
laboratory 
evaluationse,g 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
Vital signsf,g 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
12-lead ECGg 
X 
 
X 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
Pain intensity 
(NRS)h,g 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
PK sampling,i,g 
 
 
 
 
Xj X 
 
 
 
 
Xk 
 
 
 
 
 
 
 
 
Randomizationl 
 
 
Xl 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study drug 
infusionm 
 
 
 
X 
 
 
 
 
 
 
 
 
PCA Infusionn 
 
 
 
X 
 
Rescue 
medicationo 
 
 
 
X 
 
Nausea/vomiting 
assessment 
 
 
X 
 
Pulse oximetryg 
 
 
 
X 
 
AEp and 
ConMeds 
 
X 
X 


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Protocol No: VVZ149-POP-P3-K301 
 
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* It is allowed to confirm results of partial laboratory tests performed at screening (e.g., thyroid, serum, and blood chemistry) 
before randomization, depending on study site circumstances. 
f. 
Vital signs (pulse rate, respiration rate, blood pressure, and temperature measured from tympanum) will be collected after the 
subject had been in the supine or semi-fowler position for at least 5 minutes. 
g. 
When scheduled for the same time point, assessments will be recommended to be performed in the following order: NRS – Vital 
signs – Oxygen saturation via pulse oximetry – 12-lead ECG – PK sampling – Blood sampling for clinical laboratory evaluations. 
The order of study assessments is allowed to make changes depending on study site circumstances.  
* It is allowed to use 12-lead electrocardiogram results within 30 days in the absence of medical history. 
* It is allowed to perform the electrocardiogram and oxygen saturation at Time 10 hours within ± 2 hours of the scheduled time 
point. 
h. 
Pain intensity (NRS, 0-10) will be assessed for 48 hours postdose. Additional pain intensity will be assessed immediately before 
administration of any rescue medication, and both the NRS and corresponding time will be recorded.  
i. 
Pharmacokinetic (PK) samples will be collected from the opposite arm to the study drug infusion. If the blood sampling is not 
available from the opposite arm, the venipuncture is performed from other body parts except for the infusion arm.  
j. 
A PK sample at Time 0.5 h will be collected before the completion of the loading dose infusion (-5 minutes).  
k. 
A PK sample at Time 10 h will be collected before the completion of the maintenance dose infusion (-15 minutes). If the total 
duration of the study drug infusion is less or more than 10 hours, PK sampling at Time 10 h will be performed within 15 minutes 
before the completion of the infusion. Additional PK samples will be collected 30 minutes after termination of the study drug 
infusion (±5 minutes). 
l. 
Subjects with pain intensity scores of ≥5 on the NRS upon emergence from anesthesia will be randomly assigned to either the 
VVZ-149 or placebo group (1:1 ratio). Subjects with the initial NRS of <5 will be eligible for randomization once they report the 
NRS score of ≥5 within 30 minutes after emergence from anesthesia. 
m. 
Randomized subject will be assigned with a study drug number and and the corresponding study drug will be administered. A 
continuous IV infusion of VVZ-149 (1,000 mg) or a placebo over 10 hours will be administered as a loading dose of 160 mg for 
30 minutes followed by a maintenance dose of 840 mg for 9.5 hours.  
n. 
Subjects will be provided with a PCA pump for fentanyl IV infusion upon emergence from anesthesia. Once the study drug 
infusion has been initiated, subjects may self-administer fentanyl (5 µg IV bolus, 10-min lock-out) by pushing a button of the 
PCA pump for pain control. 
o. 
If subjects request additional rescue medications in addition to the PCA opioid, the pain intensity and corresponding time will be 
recorded. Upon confirming the criteria for rescue medication administration, subjects will be provided with rescue opioid within 
15 minutes of the pain intensity assessment using the NRS. 
p. 
Adverse events identified before the study drug infusion will be documented as medical history. 
q. 
Safety follow-up will be conducted over the phone. If clinically significant adverse events are reported at the safety follow-up, 
subjects will be allowed to return to the site for the postoperative standard of care follow-up as necessary and will receive clinical 
laboratory evaluations, physical examination, and/or vital signs examination. 
r. 
The HADS and PCS questionnaires can be performed on the day before surgery (Day-1) depending on study site.