Clinical trial NCT04182880
Conditions: Abdominoplasty
Sponsor: Cali Pharmaceuticals LLC
Start date: 2020-01-06; Completion date: 2020-02-28
Enrollment: 20 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Evaluate the Safety and Pharmacokinetic Profile of CPL-01 in patients after mini-abdominoplasty

Detailed description:
This is a randomized, double-blind, study to evaluate the safety, PK profile of CPL-01 for the management of postoperative pain after mini-abdominoplasty surgery.

Arms: arm 1: Placebo arm 2: CPL-01
Interventions: intervention 1: CPL-01 intervention 2: Placebo
Intervention descriptions: intervention 1: CPL-01 will be administered intervention 2: Placebo will be administered

Protocol documents:
Prot_000.pdf: 
CALI Pharmaceuticals LLC 
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PROTOCOL 
 
PRODUCT NAME/NUMBER: 
CPL-01 
PROTOCOL NUMBER: 
CPL-01_AB_001 
IND NUMBER: 
136759 
DEVELOPMENT PHASE: 
Phase 2a 
PROTOCOL TITLE: 
Phase 2a, Randomized, Double-blind, Placebo-controlled 
Study to Evaluate the Safety and Pharmacokinetic Profile 
of CPL-01 in the Management of Acute Postoperative Pain 
After Mini-abdominoplasty Surgery 
PROTOCOL DATE: 
25-Nov-2019, Final Version 3.0  
COORDINATING/PRINCIPAL 
INVESTIGATOR: 
Ira J. Gottlieb, DPM 
8030B Governor Ritchie Hwy Suite 100 
Pasadena, MD 21122, United States 
+1 410-761-0118 
SPONSORED BY: 
CALI Pharmaceuticals 
9675 Businesspark Ave 
San Diego, CA 92131, United States 
+1 858-546-0924 
CONTRACT RESEARCH 
ORGANIZATION: 
Rho  
2635 E NC Hwy 54 
Durham, NC 27713, United States 
 
This study will be performed in compliance with International Council for Harmonisation of 
Technical Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practices (GCP) 
and applicable regulatory requirements, including the archiving of essential documents. 
Information contained in this protocol is confidential in nature, and may not be used, divulged, 
published, or otherwise disclosed to others except to the extent necessary to obtain approval of the 
institutional review board (IRB), or as required by law. Persons to whom this information is 
disclosed should be informed that it is confidential and may not be further disclosed without the 
express permission of CALI Pharmaceuticals. 
 




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2 
PROTOCOL SUMMARY 
2.1 
Synopsis 
PRODUCT 
NAME/NUMBER 
CPL-01 
PROTOCOL 
NUMBER 
CPL-01_AB_001 
DEVELOPMENT 
PHASE 
Phase 2a 
PROTOCOL TITLE 
Phase 2a, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Safety 
and Pharmacokinetic Profile of CPL-01 in the Management of Acute Postoperative Pain 
After Mini-abdominoplasty Surgery 
INDICATION 
Postoperative pain management 
OBJECTIVES 
• 
To assess the safety and tolerability of CPL-01 in the management of acute 
postoperative pain after mini-abdominoplasty as compared with placebo. 
• 
To characterize the pharmacokinetic (PK) profile of CPL-01 during 
mini-abdominoplasty. 
• 
To explore the efficacy and analgesic duration of action of CPL-01 for 
postoperative pain during mini-abdominoplasty. 
• 
To assess the analgesic duration of action of CPL-01 as compared with placebo. 
• 
To inform the design of an ascending dose phase 2 trial of CPL-01. 
• 
To evaluate the opioid-sparing effect of CPL-01. 
• 
To evaluate the effect of CPL-01 on postoperative wound healing. 
RATIONALE  
NAROPIN® Injection (ropivacaine hydrochloride; Fresenius Kabi, Lake Zurich, 
Illinois) is approved for local or regional anesthesia for surgery and for acute pain 
management. The maximum approved daily dose is 300 mg when administered as a 
major nerve block for surgical anesthesia, and up to 200 mg as the infiltration dose for 
postoperative pain management. Pain relief is observed within 1 to 5 minutes but only 
for a duration of 2 to 6 hours when delivered by infiltration. Therefore, because of its 
short duration of effect, frequent injections or infusion by catheter are required if 
protracted local analgesia is required for postoperative pain management.  
A long-acting formulation could potentially prolong the duration of local analgesia for 
several days after a single local administration by infiltration. CALI Pharmaceuticals 
LLC (CALI) is developing an extended-release injectable gel formulation of 
ropivacaine hydrochloride (CPL-01) to prolong its duration at the local site, leading to 
an extended local analgesic effect as observed in several nonclinical animal models.  
CALI proposes opening the investigational new drug program with healthy elective 
surgery subjects (phase 2) rather than with healthy volunteers (phase 1) because healthy 
elective surgery subjects will be the clinically relevant model with an appropriate 
administration route (i.e., wound infiltration and instillation as opposed to subcutaneous 
injections) for this product. The maximum approved dose of NAROPIN (200 mg) has 
been selected because ropivacaine is known to be safe for postsurgical infiltration at this 
dose level. 
STUDY DESIGN 
 
 
This is a randomized, double-blind, single-site study to evaluate the safety, PK profile, 
and analgesic duration of action of CPL-01 in men and women ≥18 and ≤70 years of 
age for the management of postoperative pain after mini-abdominoplasty surgery.  


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The study will evaluate approximately 20 subjects who will be enrolled and randomly 
assigned in a 3:1 ratio to either 2% CPL-01 (200 mg ropivacaine [10 mL]) or placebo 
(0.9% NaCl).  
Study Periods: 
The study will include 4 periods: Screening Period, Surgical/Anesthesia Period 
(Confinement), Post-anesthesia Period (Confinement); and Post-treatment Follow-up 
Period. 
Screening Period (Day -42 up to Day -1): Subjects will be screened within 42 days 
before the planned surgery; however, Screening can be performed as late as on the 
morning of the surgery if all inclusion/exclusion criteria can be verified. Subjects who 
give written informed consent will be assessed for eligibility. Screening evaluations will 
include collection of demographic information, medical history, full neurological 
examination, complete physical examination, vital signs (resting blood pressure, heart 
rate, respiratory rate, and oral body temperature), height, weight, body mass index 
(BMI), 12-lead electrocardiogram (ECG), clinical laboratory tests (hematology, 
chemistry, and urinalysis), serology tests, serum pregnancy test (women of childbearing 
potential only), urine drug screen, and recording of concomitant medications. 
Additionally, subjects will be trained on the use of the numeric rating scale (NRS) for 
pain assessment at Screening. 
Surgical/Anesthesia Period (Day 1 through Hour 1, Confinement): On Day 1, at 
check-in, inclusion/exclusion criteria will be confirmed and medical history, full 
neurological examination, vital signs, 12-lead ECG, urine pregnancy test, urine drug 
screen, and concomitant medications will be updated. Before surgery, subjects will be 
trained again on the NRS and assigned a randomization number.  
Subjects will be administered general anesthesia according to a standard regimen 
(Appendix D), during which they will undergo a mini-abdominoplasty. At the end of 
the surgical procedure but before the wound is closed, the investigational product (IP) 
will be administered by wound infiltration and instillation (Time 0). Blood samples will 
be collected for PK analysis at baseline (before IP administration) and 15, 30, and 
45 minutes after administration of IP. Continuous pulse oximetry will be monitored 
immediately following surgery, throughout transport, and in the post-anesthesia care 
unit, until subjects switch from intravenous morphine to oral rescue analgesia 
medication. If O2 saturation drops below 93% or if subjects have clinical signs or 
symptoms that suggest respiratory depression while on the oral medication, or subjects 
switch back to intravenous morphine, they will be kept on continuous pulse oximetry as 
required. Following surgery, subjects will be admitted and confined to the study site 
through Day 4(72 hours). 
Post-anesthesia Period (Day 1, Hour 1 [1 hour after administration of IP] through 
Day 4, Confinement): Assessments during the Post-anesthesia Period will include local 
anesthetic systemic toxicity (LAST) assessment (including vital signs, Richmond 
Agitation and Sedation Scale [RASS] assessment (Appendix A), and focused 
neurological examination), 12-lead ECG, pain intensity assessments, surgical wound 
site assessment (including photograph), concomitant medications, and adverse events 
(AEs). Continuous pulse oximetry will be conducted in the post-anesthesia care unit 
until subjects switch from intravenous morphine to oral rescue analgesia medication. If 
O2 saturation drops below 93% or subjects have clinical signs or symptoms that suggest 
respiratory depression while on the oral medication, or subjects switch back to 
intravenous morphine, they will be kept on continuous pulse oximetry as required. 
Subjects will also receive a diary to record their pain intensity (using NRS) and rescue 
medication usage when they are discharged from the study site on Day 4. On non-visit 
days prior to the Day 7-10 Follow-up Visit, a brief daily telephone call will be conducted 
to remind subjects to record their pain intensity (using NRS), and rescue medication 
usage in the diary. Subjects will be instructed to return their completed diary at the Day 
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Rescue analgesia: Subjects with inadequately controlled pain symptoms may request 
rescue analgesia. Pain intensity using an NRS will be recorded just prior to receiving 
rescue analgesia. After administration of the IP, rescue analgesia will be restricted to 2 
to 4 mg intravenous morphine every hour as needed until the subject is able to tolerate 
oral medication. Once oral medication can be tolerated, oxycodone 5 to 10 mg every 
3 to 4 hours will be used as needed for analgesia. After the subject’s pain intensity is 
≤4, oral acetaminophen 1000 mg should be used every 6 to 8 hours as needed for 
analgesia (not to exceed 4000 mg within 24 hours). For breakthrough pain intensity >4 
that is not relieved by the oral acetaminophen, oral oxycodone 5 to 10 mg every 3 to 4 
hours as need for pain may continue to be used. For breakthrough severe pain intensity 
>8, intravenous morphine 2 to 4 mg every hour as needed may be allowed. 
Post-treatment Follow-up Period (Days 5 and 6, 7 to 10 days, and 30 days after 
administration of IP): Subjects will return to the study site for collection of PK blood 
samples and for pain intensity assessment using an NRS at 96 and 120 hours after 
administration of IP (Days 5 and 6). Assessments at the Day 7-10 Follow-up Visit (7 to 
10 days after administration of IP) include a full neurological examination, abbreviated 
physical examination, vital signs, 12-lead ECG, surgical wound site assessment 
(including photograph), clinical laboratory evaluations, concomitant medications, and 
AEs. Subjects will return their completed diary at the Day 7-10 Follow-up Visit (7 to 
10 days after administration of IP or upon early termination). 
At the Day 30 Follow-up Visit (30 days after administration of IP), AEs and concomitant 
medications will be recorded and a surgical wound site assessment (including 
photograph) will be performed. 
Study Assessments 
Pharmacokinetic measurement: Blood samples will be collected for PK analysis at 
baseline (before IP administration), 15, 30, and 45 minutes (Surgical/Anesthesia 
Period), and at 1, 2, 4, 6, 8, 10, 12, 18, 24, 30, 36, 48, 60, and 72 hours (Post-anesthesia 
Period) after administration of IP. Subjects will return to the study site for collection of 
PK blood samples at 96 and 120 hours after administration of IP (Days 5 and 6). 
Efficacy assessment: Subjects will evaluate pain intensity using an NRS at 1, 2, 3, 4, 5, 
6, 7, 8, 10, 12, 16, 24, 32, 40, 48, 56, 64, and 72 hours after administration of IP. 
Additionally, pain intensity using an NRS will be recorded just prior to receiving rescue 
analgesia. The pain intensity will also be recorded when subjects return to the study site 
at 96 and 120 hours after administration of IP to collect PK blood samples (Days 5 and 
6). 
Safety assessments: Safety will be assessed based on AEs, vital signs, clinical 
laboratory evaluations, 12-lead ECGs, physical examination, full neurological 
examination, LAST assessment, and wound evaluation. Safety assessments will be 
performed during the study at the time points shown in the Schedule of Events table. 
PLANNED 
NUMBER OF 
SUBJECTS 
Approximately 20 subjects will be enrolled and randomly assigned in a 3:1 ratio to either 
2% CPL-01 (200 mg ropivacaine [10 mL]) or placebo (0.9% NaCl). 
STUDY ENTRY 
CRITERIA 
Inclusion criteria:  
1. Subject provides signed, written informed consent before participation in the study. 
2. Subject is aged ≥18 and ≤70 years at the time of informed consent and is male or 
female.  
3. Subject is scheduled to undergo elective mini-abdominoplasty surgery under 
general anesthesia without collateral procedures. 
4. Subject has a BMI >19 and <30 kg/m2. 
5. Subject has an American Society of Anesthesiology subject (physical) 
classification status of I or II (as assessed at Screening). 


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6. Female subjects are eligible only if all the following apply: 
a. 
Not pregnant (female subjects of childbearing potential must have a 
negative serum pregnancy test within 42 days before surgery [Screening] 
and a negative urine pregnancy test prior to surgery [check-in]) 
b. Not breastfeeding 
c. 
Not planning to become pregnant during participation in the study 
d. Committed to the use of an acceptable form of birth control (i.e., hormonal 
contraception, intrauterine device, condoms in combination with a 
spermicidal cream or total sexual abstinence, includes surgical 
sterilization and confirmed postmenopausal state) for the duration of the 
study until at least 30 days after administration of IP. 
7. Male subjects must commit to the use of a reliable method of birth control for the 
duration of the study until at least 30 days after administration of IP or be surgically 
sterile (biologically or surgically). 
8. Subject has the ability to read and understand the study procedures, use the pain 
scale, and to communicate meaningfully with the investigator and staff, in the 
opinion of the investigator. 
9. Subject is free of any physical, mental, or medical conditions which, in the opinion 
of the investigator, make mini-abdominoplasty or study participation inadvisable. 
Exclusion criteria:  
1. Subject has been receiving or has received chronic opioid therapy defined as any 
opioid for greater than 3 out of 7 days per week over a 1-month period 
(consecutively and/or accumulatively) within 12 months of IP initiation. 
2. Subject has taken chaparral, comfrey, germander, jin bu huan, kava, pennyroyal, 
skullcap, St. John’s wort, or valerian within 14 days before surgery. 
3. Subject has a chronic pain condition or any significant medical disease, laboratory 
abnormality (including ECG abnormality), or condition that, in the investigator’s 
judgment, could compromise his or her welfare, ability to communicate with the 
study staff, complete study activities, may confound the assessments of 
postoperative pain, or otherwise contraindicate study participation. 
4. Subject has known hypersensitivity or known allergy, as determined by the 
investigator, to ropivacaine, sesame oil, soy beans, oxycodone, other opioids, 
acetaminophen, or the inactive ingredients (i.e., excipients) of the IP or any peri- 
or postoperative medications used in this study. 
5. Subject has known, suspected, or reported history of alcohol or drug abuse or 
dependence within the previous 2 years as assessed by the investigator. 
6. Subject has impaired liver function (e.g., aspartate aminotransferase/alanine 
aminotransferase greater than 3 times the upper limit of the reference range, 
bilirubin greater than 1.5 times the upper limit of the reference range unless due to 
Gilbert’s syndrome, active hepatic disease, evidence of clinically significant liver 
disease, or other condition such as alcoholism, cirrhosis, or hepatitis, etc.) that 
suggests the potential for an increased susceptibility to hepatic toxicity with IP 
exposure. 
7. Subject has clinically significant renal abnormalities (creatinine ≥1.5 × upper limit 
of normal). 
8. Subject has hemoglobin A1c ≥7.0%. 
9. Subject has been treated with monoamine oxidase inhibitors within 14 days before 
surgery. 
10. Subject has participated in another clinical study and/or received an IP (marketed 
or premarket) within 30 days before surgery. 


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11. Subject has a history of, or positive test results for, human immunodeficiency virus, 
hepatitis B surface antigen, or hepatitis C virus antibody at Screening. 
12. Subject has a history of a migraine headache (within past 6 months or 2 within the 
past 12 months) or frequent headaches (≥2 events per week requiring analgesics) 
as determined by the investigator, seizures, or is currently taking anticonvulsants. 
13. Subject has a history of malignant hyperthermia. 
14. Subject has glucose-6-phosphate dehydrogenase deficiency. 
15. Subject has a positive urine drug screen test result at Screening or at check-in on 
the day of surgery for amphetamines, barbiturates, benzodiazepines, cocaine, 
opiates, phencyclidine, or tetrahydrocannabinol; indicating drug use. 
16. Subject has used a concurrent therapy that could interfere with the evaluation of 
efficacy or safety, such as any drugs that in the investigator’s opinion may exert 
significant analgesic properties or act synergistically with the IP. 
17. Subject has used corticosteroids, either systemically or by intra-articular injection, 
within 6 weeks prior to the study surgical procedure; inhaled, nasal, and topical 
steroids are allowed. 
18. Subject concurrently uses potent CYP1A2 inhibitors, including cimetidine, 
enoxacin, 
fluvoxamine, 
ciprofloxacin 
(Cipro), 
gemifloxacin 
(Factive), 
levofloxacin (Levaquin), moxifloxacin (Avelox), norfloxacin (Noroxin), or 
ofloxacin (Floxin). 
19. Subject has persistent or recurrent nausea and/or vomiting because of other 
etiologies, including, but not limited to, gastric outlet obstruction, hypercalcemia, 
active peptic ulcer, increased intracranial pressure, chemotherapy, or brain 
metastases. 
20. Subject experiences a clinically significant event during surgery prior to the 
administration of the IP (e.g., excessive bleeding, hemodynamic instability) that 
would render him or her medically unstable, complicate their postsurgical course, 
or significantly increase the risk of IP administration as per the judgment of the 
investigator. 
21. Subjects who have a difficult airway on preoperative screening or history of airway 
difficulties in the past. 
22. Subject with an upper respiratory infection/cough in the 14 days before surgery.  
23. Subjects with a history of significant postoperative nausea and vomiting. 
TEST PRODUCT 
Name: CPL-01 is an extended-release injectable gel formulation of ropivacaine 
hydrochloride  
Dose, route, frequency:  
2% CPL-01 200 mg ropivacaine (10 mL) 
To be administered into soft tissue before closure by wound infiltration and instillation. 
CONTROL 
PRODUCTS 
Name: Placebo (0.9% NaCl) 
Dose, route, frequency:  
0.9% NaCl (10 mL) 
To be administered into soft tissue before closure by wound infiltration and instillation.  
TREATMENT 
REGIMENS 
Each subject will receive 2% CPL-01 (200 mg ropivacaine [10 mL]) or placebo (0.9% 
NaCl) administered into soft tissue before closure after mini-abdominoplasty by wound 
infiltration and instillation. Subjects will be randomly assigned (3:1 ratio) to receive 
either 2% CPL-01 (200 mg ropivacaine) or placebo (0.9% NaCl). 
The following dosing method of the IP will be performed. 
Materials 
• 
Two 1 cc Luer-lock syringes 
• 
Two 5 cc Luer-lock syringes 


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• 
Four 21 gauge needles, length 1.5 inches 
• 
10 mL study drug (2% CPL-01 [200 mg ropivacaine] or placebo [0.9% NaCl]) 
Draw Technique 
Based on the randomization schedule, draw up a total of 10 mL of the study drug into 
the 4 syringes as follows: 
• 
Fill TWO – 1 cc Luer-lock syringes with exactly 1 mL of study drug. 
• 
Fill TWO – 5 cc Luer-lock syringes with exactly 4 mL of study drug. 
Dosing Technique 
1. Plication – After plication of the diastasis recti is complete and prior to skin 
closure infiltrate (inject) 1 mL of the study drug using one 1 cc syringe in 5 
separate, equally spaced, injections of 0.2 mL each, along the entire length of 
the plication of the rectus abdominus. The injections should be precisely placed 
along the posterior (deep) rectus sheath. 
2. External Fascial Layer – Infiltrate (inject) in 2 parallel tracks using the two 5 cc 
syringes (total of 8 mL), lateral to the plication line along the linea semilunaris 
into the deep external facial layer beneath the external oblique muscle. A total 
of 10 injections (5 on each side) of 0.8 mL each, at equally spaced sites along 
the 2 semilunaris lateral tracks (4 mL each side). Carefully orient the syringe 
and needle at a 45 degree angle when injecting. Visualize the entire length of 
the needle via the translucency of the fascia to avoid deep abdominal and 
intramuscular injection. 
3. Prior to skin closure – Instill (surface application) 1 mL of the study drug using 
one 1 cc syringe onto the upper third of the subcutaneous tissue along the 
length of the upper and lower abdominal incisions where the subcutaneous 
fascia emerges from the deeper tissue. Again, apply (do not inject) the study 
drug through the end of the needle for controlled slow application. 
ANESTHESIA 
REGIMEN AND 
RESCUE 
ANALGESICS: 
Anesthesia: 
Subjects will undergo mini-abdominoplasty under general anesthesia administered 
according to a standard regimen (Appendix D). 
Rescue Analgesics: 
Subjects with inadequately controlled pain symptoms may request rescue analgesia. 
Pain intensity using an NRS will be recorded just prior to receiving rescue analgesia. 
After administration of the IP, rescue analgesia will be restricted to 2 to 4 mg of 
intravenous morphine every hour as needed until the subject is able to tolerate oral 
medication. Once oral medication can be tolerated, oxycodone 5 to 10 mg every 
3 to 4 hours as needed for analgesia will be used. After the subject’s pain intensity is 
≤4, oral acetaminophen 1000 mg should be used every 6 to 8 hours as needed for 
analgesia (not to exceed 4000 mg within 24 hours). For breakthrough pain intensity >4 
that is not relieved by the oral acetaminophen, oral oxycodone 5 to 10 mg every 3 to 4 
hours as needed for pain may continue to be used. For breakthrough severe pain intensity 
>8, intravenous morphine 2 to 4 mg every hour as needed may be allowed. 
COORDINATING/ 
PRINCIPAL 
INVESTIGATOR 
Ira J. Gottlieb, DPM 
8030B Governor Ritchie Hwy Suite 100 
Pasadena, MD 21122, United States 
+1 410-761-0118 
PLANNED STUDY 
SITES 
One study site in the United States 
CRITERIA FOR 
EVALUATION 
Safety endpoints:   
• 
Adverse events 
• 
Vital signs 


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• 
Clinical laboratory evaluations (hematology, chemistry, and urinalysis) 
• 
12-lead ECGs 
• 
Physical examination 
• 
Full neurological examination 
• 
LAST assessment 
• 
Surgical wound site assessment (including incidence of wound infection 
and wound-related AEs) 
Pharmacokinetic endpoints: 
• 
Maximum (peak) plasma concentration (Cmax) 
• 
Time to reach highest observed (peak) concentration in plasma following 
IP administration (tmax) 
• 
Elimination half-life (t1/2) 
• 
Terminal elimination rate constant (λz) with the respective t1/2 
• 
Area under the plasma concentration-time curve (AUC) from Time 0 to 
time of last quantifiable plasma concentration (AUC0-last) (Time 0 is defined 
as the moment that IP is administered) 
• 
AUC from Time 0 to infinity (AUC0-∞) 
Exploratory endpoints: 
• 
Time-weighted summed pain intensity over 1 to 24 hours (SPI1-24) for 
CPL-01 subjects compared with placebo subjects 
• 
SPI at other time points: SPI1-6, SPI6-12, SPI1-12, SPI12-24, SPI24-48, SPI1-48, 
SPI48-72, and SPI1-72 for CPL-01 subjects compared with placebo subjects 
• 
Total dose of opioid rescue analgesia (morphine equivalents) over 24, 48, 
and 72 hours after administration of IP 
• 
Time to administration of first dose of opioid rescue analgesia 
• 
The percentage of subjects who used no opioid rescue analgesia over 24, 
48, and 72 hours after administration of IP 
• 
The percentage of subjects who remain pain free over 24, 48, and 72 hours 
after administration of IP (pain intensity ≤1). 
STATISTICAL 
METHODS 
 
 
 
 
 
 
 
 
 
 
Analysis Populations 
• Intent-to-treat (ITT) Population: all subjects who are successfully screened and 
randomized. The ITT population will be used for the efficacy analysis. 
• Safety Population: all subjects who are treated with IP. The Safety population is 
the population for all safety analyses. 
• PK Population: all subjects who received IP during surgery and who have at least 
1 measurable plasma concentration. All PK analyses will be based on the 
PK population. 
In the event that a subject is administered the incorrect IP, analyses of the 
ITT population will be based on the randomized treatment, whereas analyses of the 
Safety population will be based on the actual treatment received. 


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Subject characteristics 
Demographic and baseline characteristics (including age, gender, race, weight, height, 
BMI, and prior medication) will be summarized for each treatment group and for the 
overall population using descriptive statistics. Medical history will be displayed in a 
listing. 
Pharmacokinetic analysis 
The PK parameters will be estimated using non-compartmental PK analysis for each 
subject with sufficient data to characterize the administered dose. These parameters will 
be summarized and a mean concentration figure with plots will be produced both with 
a linear y-axis and with a log y-axis. Individual concentrations will be listed, graphed, 
and summarized by scheduled sampling time. 
Efficacy Analyses  
Descriptive summaries will be provided using number of subjects, arithmetic mean, 
standard deviation (SD), median, minimum, and maximum. 
Individual NRS pain intensity scores will be tabulated for each time point and 
summarized descriptively by treatment group.  
The analysis of continuous efficacy endpoints will be performed using an analysis of 
variance (ANOVA) model. The ANOVA model will include the specific endpoint as 
the response variable (e.g., NRS SPI-t, where t=1-6, 6-12, 1-12, 1-24, 12-24, 24-48, 1-
48, 48-72, 1-72, respectively) and will have Treatment as the main effect. Contrast tests 
will be carried out to compare CPL-01 against placebo. Since all exploratory analyses 
in this study are intended for hypothesis generation, there will be no adjustment for 
multiplicity and each analysis will be based on a 2-sided test at the significance level of 
0.05. This approach will be used to analyze all continuous exploratory efficacy 
variables, including total dose of opioid (morphine equivalents) used over 24, 48, and 
72 hours, respectively. 
Time to first use of opioid rescue analgesia for postoperative surgical pain will be 
analyzed using the Kaplan-Meier method. The log-rank test will be used to test the 
hypothesis of overall treatment differences. In addition, a Cox proportional hazards 
model will be used to allow individual contrasts tests comparing CPL-01 against 
placebo. Hazard ratios as well as 95% confidence intervals will be generated for each 
contrast.  
The percentage of subjects who used no opioid rescue analgesia and the percentage of 
subjects who remain pain free over 24, 28, and 72 hours after IP administration will be 
analyzed using Fisher’s exact test. 
Additional exploratory efficacy analyses may be conducted as required. 
Imputation Methods for Missing Efficacy Data 
To assess the impact of missing data, multiple imputation will be used as a sensitivity 
analysis for the primary endpoint. 
Safety Analyses 
Summaries of safety results will be presented by treatment group for the safety analysis 
population. 
The latest version of the Medical Dictionary for Regulatory Activities will be used to 
classify all AEs by system organ class (SOC) and preferred term (PT). The number and 
percentage of subjects with treatment-emergent AEs will be summarized by SOC, PT, 
and treatment group. Serious AEs will be summarized in a similar fashion. 
Treatment-emergent AEs and SAEs will also be presented by severity and by 
relationship. All AEs will be presented in full in a comprehensive listing. Details of 
SAEs and AEs leading to withdrawal will be listed separately. 


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Descriptive summaries of actual values and changes from baseline for vital signs 
measurements, clinical laboratory values, and ECGs will be presented by study visit and 
by treatment group. A descriptive summary of the RASS assessment will be presented 
by study visit and by treatment group. A descriptive summary of surgical wound site 
assessment findings (including wound infection and wound related AEs) at the Day 7-10 
Follow-up Visit (7 to 10 days after administration of IP) and the Day 30 Follow-up Visit 
(30 days after administration of IP) will be presented by treatment group. Surgical 
wound site assessment findings at 24, 48, 72, 96, and 120 hours after IP administration 
will be displayed in a listing. Physical and neurological examination results will be 
displayed in a listing. 
RANDOMIZATION 
AND BLINDING 
Subjects will be randomized in a 3:1 ratio to 2% CPL-01 (200 mg ropivacaine) or 
placebo (0.9% NaCl). Subjects and all study personnel involved in postoperative pain 
assessments will be blinded to the treatment assignment. 
SAMPLE SIZE 
DETERMINATION 
This is a proof-of-concept study with a primary goal of estimation rather than hypothesis 
testing. The sample sizes are consistent with similar studies of this type, but are not 
based on power considerations for specific treatment-effect sizes. 
STUDY AND 
TREATMENT 
DURATION 
The overall study duration is expected to be approximately 3 months. 
The study includes a Screening Period, Surgical/Anesthesia Period, Post-anesthesia 
Period; and Post-treatment Follow-up Period: 
The sequence and maximum duration of the study periods for each subject will be as 
follows: 
1. Screening Period: 42 days 
2. Surgical/Anesthesia Period: 1 day 
3. 
Post-anesthesia Period: 4 days 
4. Post-treatment Follow-up Period: 
Days 5 and 6 Assessments: 2 days 
Day 7-10 Follow-up Visit: 7 to 10 days after administration of IP 
Day 30 Follow-up Visit: 30 days after administration of IP 
The maximum study duration for each subject is approximately 73 days. 
 
 


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2.2 
Schedule of Events 
 
Screenin
g Period 
(-42 days 
to -1 day 
before 
surgery)a 
Surgical/ 
Anesthesia 
Period 
(Confinemen
t)b 
Post-anesthesia Period 
(Confinement) 
Post-treatment Follow-up Period 
Day 1 
through 
Hour 1  
Day 1, Hour 1 
(1 hour after 
administration 
of IP) 
to Hour 24 
Day 2 
Day 3 
Day 4 
Days 5 
and 6 
Day 7-10  
Follow-up Visit 
(7 to 10 days after 
administration of 
IP or upon early 
termination)c 
Day 30 
Follow-up 
Visit 
(30 days after 
administration 
of IP) 
Written informed consent 
X 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X (at check-
in) 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Medical history 
X 
X (at check-
in) 
 
 
 
 
 
 
 
Full neurological examinationd 
X 
X 
 
 
 
 
 
X 
 
LAST assessmente 
 
 
X 
X 
X 
 
 
 
 
Physical examinationf 
X 
 
 
 
 
 
 
X 
 
Vital signsg 
X 
X (at check-
in) 
 
 
 
 
 
X 
 
Height, weight, and BMI 
X 
 
 
 
 
 
 
 
 
12-lead electrocardiogram 
X 
Xh 
Xh 
Xh 
Xh 
Xh 
Xh (Day 5 
only) 
X 
 
Clinical laboratory evaluationsi 
X 
 
 
 
 
 
 
X 
 
Serology testsj 
X 
 
 
 
 
 
 
 
 
Pregnancy testk 
X 
X (at check-
in) 
 
 
 
 
 
 
 
Urine drug screenl 
X 
X (at check-
in) 
 
 
 
 
 
 
 
Train subjects how to use NRS 
X 
X (before 
surgery) 
 
 
 
 
 
 
 
Dispense diary and dischargem 
 
 
 
 
 
X 
 
 
 
Assign randomization number 
 
 
X (before 
surgery) 
 
 
 
 
 
 
 


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Screenin
g Period 
(-42 days 
to -1 day 
before 
surgery)a 
Surgical/ 
Anesthesia 
Period 
(Confinemen
t)b 
Post-anesthesia Period 
(Confinement) 
Post-treatment Follow-up Period 
Day 1 
through 
Hour 1  
Day 1, Hour 1 
(1 hour after 
administration 
of IP) 
to Hour 24 
Day 2 
Day 3 
Day 4 
Days 5 
and 6 
Day 7-10  
Follow-up Visit 
(7 to 10 days after 
administration of 
IP or upon early 
termination)c 
Day 30 
Follow-up 
Visit 
(30 days after 
administration 
of IP) 
 
 
 
 
 
 
Mini-abdominoplasty and IP 
administrationn 
 
X 
 
 
 
 
 
 
 
Rescue analgesiao 
 
X 
X 
X 
X 
X 
 
 
 
Continuous pulse oximetryp 
 
X 
X 
X 
X 
X 
 
 
 
Pain intensity assessmentsq 
 
 
X 
X 
X 
X 
X 
 
 
Wound evaluation, including 
photographr 
 
 
 
X 
X 
X 
X 
X 
X 
PK blood sample collections 
 
X 
X  
X 
X 
X 
X 
 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse eventst 
 
X 
X 
X 
X 
X 
X 
X 
X 
Subject returns completed diary 
 
 
 
 
 
 
 
X 
 
Abbreviations: AE = adverse event; BMI = body mass index; ECG = electrocardiogram; HIV = human immunodeficiency virus; IP = investigational product; LAST = local anesthetic 
systemic toxicity; NRS = numeric rating scale; PK = pharmacokinetic; RASS: Richmond Agitation and Sedation Scale  
a 
Screening can be performed as late as on the morning of the surgery if all inclusion/exclusion criteria can be verified. Subjects must be at rest for a minimum of 15 minutes in 
the resting position before any assessments are performed during each study visit, unless otherwise specified. 
b 
Subjects will be admitted to the study site on the morning of the scheduled surgery and confined at the study site through Day 4. 
c 
On non-visit days prior to the Day 7-10 Follow-up Visit, a brief daily telephone call will be conducted to remind subjects to record their pain intensity (using NRS), and rescue 
medication usage in the diary. 


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d 
A full neurological examination will be performed at Screening, on Day 1 any time prior to anesthesia induction, and at the Day 7-10 Follow-up Visit or upon early termination. 
The full neurological examination will include a mental status examination and evaluation of cranial nerve, motor, sensory, and cerebellar function. In addition, the findings 
will be summarized in a neurologic assessment. The examiner will be asked to record whether the subject’s overall neurologic status is normal or abnormal. 
e 
Signs and symptoms of LAST will be monitored every 4 hours on Day 1 and at least once daily on Days 2 and 3 using the following: vital signs (resting blood pressure, heart 
rate, respiratory rate, and oral body temperature), RASS assessment (Appendix A), and a focused neurological examination. The focused neurological examination will include 
a basic mental status examination and an evaluation to see if the subject is tremulous or complaining of any unusual symptoms (e.g., perioral paresthesias, metallic taste, or 
dizziness). If abnormal neurological findings are observed during the LAST assessment, a full neurological examination will be performed. If any signs or symptoms of LAST 
are observed, including a change in the ECG, the following will be performed: unscheduled PK sample collection, 12- lead ECG, and vital sign measurements. 
f 
A complete physical examination will be performed at Screening (including height and weight), and an abbreviated physical examination (changes since Screening), will be 
performed at the Day 7-10 Follow-up Visit (7 to 10 days after administration of IP or upon early termination). 
g 
Vital signs (resting blood pressure, heart rate, respiratory rate, and oral body temperature) will be measured after the subject has been in a resting position for 5 minutes. Vital 
signs will be measured and recorded at Screening, at check-in on Day 1, and at the Day 7-10 Follow-up Visit. 
h 
A 12-lead ECG will be performed immediately prior to induction of anesthesia and at 1, 2, 4, 8, 10, 12, 24, 48, 72, and 96 hours after IP administration. 
i 
The clinical laboratory evaluations will be hematology, chemistry, and urinalysis. 
j 
The serology tests will be HIV, hepatitis B surface antigen, and hepatitis C virus antibody. 
k 
For women of childbearing potential only, a serum pregnancy test will be done at Screening and a urine pregnancy test will be done at check-in on Day 1. 
l 
The urine drug screen will test for amphetamines, barbiturates, benzodiazepines, cocaine, opiates, phencyclidine, and tetrahydrocannabinol. 
m 
Subjects will receive a diary to record their pain intensity (using NRS) and rescue medication usage when they are discharged from the study site on Day 4. They will be 
instructed to complete the diary daily until they return to the study site for the Day 7-10 Follow-up Visit (7 to 10 days after administration of IP or upon early termination). 
n 
Subjects will be administered general anesthesia according to a standard regimen (Appendix D), during which they will undergo a mini-abdominoplasty. At the end of the 
surgical procedure but before the wound is closed, the IP will be administered by wound infiltration and instillation (see Section 9.2.1). 
o 
Subjects with inadequately controlled pain symptoms may request rescue analgesia. Pain intensity using an NRS will be recorded just prior to receiving rescue analgesia. After 
administration of the IP, rescue analgesia will be restricted to 2 to 4 mg of intravenous morphine every hour as needed until the subject is able to tolerate oral medication. Once 
oral medication can be tolerated, oxycodone 5 to 10 mg every 3 to 4 hours will be used as needed for analgesia. After the subject’s pain intensity is ≤4, oral acetaminophen 
1000 mg will be used every 6 to 8 hours as needed for analgesia (not to exceed 4 g within 24 hours). For breakthrough pain intensity >4 that is not relieved by the oral 
acetaminophen, oral oxycodone 5 to 10 mg every 3 to 4 hours as needed for pain may continue to be used. For breakthrough severe pain intensity >8, intravenous morphine 2 to 
4 mg every hour as needed may be allowed. Subjects should receive a prescription for rescue analgesia for use after they are discharged from the study site. 
p 
Continuous pulse oximetry will be monitored immediately following surgery, throughout transport, and in the post-anesthesia care unit until subjects switch from intravenous 
morphine to oral rescue analgesia medication. If O2 saturation drops below 93% or if subjects have clinical signs or symptoms that suggest respiratory depression while on the 
oral medication, or subjects switch back to intravenous morphine, they will be kept on continuous pulse oximetry as required.  
q 
Pain intensity will be assessed using an NRS at 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16, 24, 32, 40, 48, 56, 64, and 72 hours after administration of IP. Additionally, pain intensity using 
an NRS will be recorded just prior to receiving rescue analgesia. The pain intensity will also be recorded when subjects return to the study site at 96 and 120 hours after 
administration of IP. 
r 
Study site staff will evaluate the wound by direct visualization and record the numerical rating score on the eCRF (see Appendix B) at 24, 48, 72, 96 (Day 5), and 120 hours 
(Day 6) after administration of IP, and also at the Day 7-10 and Day 30 Follow-up Visits. Additionally, study site staff will photograph the wound area following the standardized 
instructions (Appendix C). Subjects will be instructed to call with any concerns about the appearance of the wound after being discharged from the study site. If subjects call 
with concerns, they will be asked to return to the study site for an unscheduled visit. 
s 
Blood samples will be collected for PK analysis at baseline (before IP administration), 15, 30, and 45 minutes, and at 1, 2, 4, 6, 8, 10, 12, 18, 24, 30, 36, 48, 60, and 72 hours 
after administration of IP (± 5 minutes for samples taken during the first hour and ± 10 minutes for the remainder of the samples). Subjects will return to the study site for 
collection of PK blood samples at 96 and 120 hours after administration of IP (± 1 hour) (Days 5 and 6). 
t 
Adverse events will be monitored throughout the study. If a subject has an AE after being discharged from the study site, he or she will return to the study site for safety 
assessments, including a photograph of the wound. 
 


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3 
TABLE OF CONTENTS 
1 
APPROVAL SIGNATURES ...................................................................................................2 
2 
PROTOCOL SUMMARY ........................................................................................................3 
2.1 
Synopsis ..........................................................................................................................3 
2.2 
Schedule of Events ........................................................................................................12 
3 
TABLE OF CONTENTS .......................................................................................................15 
3.1 
List of In-Text Figures ..................................................................................................19 
4 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ...........................................20 
5 
INTRODUCTION ..................................................................................................................22 
5.1 
Background and Rationale ............................................................................................22 
5.2 
Nonclinical Experience .................................................................................................23 
5.3 
Clinical Experience .......................................................................................................24 
5.4 
Summary of Potential Risks and Benefits .....................................................................24 
6 
OBJECTIVES AND ENDPOINTS ........................................................................................26 
6.1 
Objectives ......................................................................................................................26 
6.2 
Endpoints ......................................................................................................................26 
6.2.1 Safety Endpoints ................................................................................................26 
6.2.2 Pharmacokinetic Endpoints ...............................................................................26 
6.2.3 Exploratory Endpoints .......................................................................................27 
7 
STUDY DESIGN ...................................................................................................................28 
7.1 
Overall Study Design and Plan .....................................................................................28 
7.2 
Screening Period (Day -42 up to Day -1)......................................................................28 
7.3 
Surgical/Anesthesia Period (Day 1 through Hour 1, Confinement). ............................28 
7.4 
Post-anesthesia Period (Day 1, Hour 1 [1 Hour After Administration of IP] through 
Day 4, Confinement) ..............................................................................................................28 
7.5 
Post-treatment Follow-up Period (Days 5 and 6, 7 to 10 days, and 30 days after 
administration of IP) ...............................................................................................................29 
7.6 
Study Assessments ........................................................................................................29 
7.7 
Rationale and Discussion of Study Design ...................................................................30 
7.8 
Selection of Doses in the Study ....................................................................................30 
7.9 
Study Sites .....................................................................................................................31 
7.10 End of Study Definition ................................................................................................31 
8 
SUBJECT POPULATION .....................................................................................................32 
8.1 
Selection of Study Population .......................................................................................32 
8.2 
Study Entry Criteria ......................................................................................................32 
8.2.1 Inclusion Criteria ...............................................................................................32 
8.2.2 Exclusion Criteria ..............................................................................................33 
8.3 
Premature Subject Withdrawal .....................................................................................34 
8.4 
Participant Discontinuation/Withdrawal from the Study ..............................................34 


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9 
TREATMENTS ......................................................................................................................36 
9.1 
Identification of Investigational Products .....................................................................36 
9.2 
Treatments Administered ..............................................................................................36 
9.2.1 Investigational Product Administration .............................................................36 
9.2.2 Rescue Medication ............................................................................................37 
9.3 
Selection of Timing of Dose for Each Subject..............................................................37 
9.4 
Treatment Compliance ..................................................................................................37 
9.5 
Method of Assigning Subjects to Treatment Groups ....................................................37 
9.6 
Blinding and Unblinding Treatment Assignment .........................................................38 
9.7 
Permitted and Prohibited Therapies ..............................................................................38 
9.7.1 Permitted Therapies ...........................................................................................38 
9.7.2 Prohibited Therapies ..........................................................................................39 
9.7.3 Restrictions ........................................................................................................39 
9.8 
Treatment After End of Study .......................................................................................39 
9.9 
Dispensing and Storage .................................................................................................39 
9.10 Drug Accountability ......................................................................................................40 
9.11 Labeling and Packaging ................................................................................................40 
10 STUDY PROCEDURES ........................................................................................................41 
10.1 Study Duration ..............................................................................................................41 
10.2 Study Periods and Visits ...............................................................................................41 
10.2.1 Screening Period (-42 Days to -1 Day Before Surgery) ....................................41 
10.2.2 Surgical/Anesthesia Period (Day 1 through Hour 1, Confinement) ..................42 
10.2.3 Post-anesthesia Period (Day 1, Hour 1 through Day 4, Confinement) .............44 
10.2.4 Post-treatment Follow-up Period .......................................................................46 
10.2.4.1 Days 5 and 6 ..........................................................................................46 
10.2.4.2 Day 7-10 Follow-up Visit (7 to 10 days after Administration of 
Investigational Product or Upon Early Termination) ............................................46 
10.2.4.3 Day 30 Follow-up Visit (30 days After Administration of IP) .............47 
10.3 Assessments ..................................................................................................................47 
10.3.1 Safety .................................................................................................................47 
10.3.1.1 Clinical Laboratory Safety Assessments ...............................................47 
10.3.1.2 Clinical Examinations ...........................................................................48 
10.3.1.3 Adverse Events......................................................................................50 
10.3.2 Pharmacokinetic Evaluation ..............................................................................50 
10.3.2.1 Pharmacokinetic Sampling Assessments ..............................................50 
10.3.3 Efficacy .............................................................................................................51 
10.3.3.1 Numeric Rating Scale ...........................................................................51 
10.3.3.2 Opioid Rescue Analgesia Use ...............................................................51 


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11 ADVERSE EVENTS..............................................................................................................52 
11.1 Definitions .....................................................................................................................52 
11.1.1 Adverse Events (AEs) .......................................................................................52 
11.1.2 Serious Adverse Events (SAEs) ........................................................................52 
11.1.3 Treatment-Emergent Adverse Events ...............................................................53 
11.2 Event Assessment and Follow-up of Adverse Events ..................................................53 
11.2.1 Assessment ........................................................................................................53 
11.2.2 Evaluation ..........................................................................................................54 
11.2.2.1 Severity of Adverse Events ...................................................................54 
11.2.2.2 Seriousness ............................................................................................54 
11.2.2.3 Action(s) Taken with Investigational Product ......................................54 
11.2.2.4 Outcome at the Time of Last Observation ............................................54 
11.2.2.5 Adverse Event Relationship to the Investigational Product ..................55 
11.2.3 Documentation ..................................................................................................55 
11.2.4 Treatment of Adverse Events ............................................................................55 
11.2.5 Follow-up ..........................................................................................................56 
11.2.6 Reporting ...........................................................................................................56 
11.2.6.1 Serious Adverse Events.........................................................................56 
11.2.6.2 Nonserious Adverse Events ..................................................................57 
11.3 Special Considerations ..................................................................................................57 
11.3.1 Adverse Events of Special Interest ....................................................................57 
11.3.2 Pregnancy ..........................................................................................................57 
12 DATA SAFETY MONITORING BOARD ...........................................................................59 
13 STATISTICS ..........................................................................................................................60 
13.1 Statistical Analysis ........................................................................................................60 
13.1.1 Analysis Populations .........................................................................................60 
13.1.2 Study Subjects and Demographics ....................................................................60 
13.1.2.1 Disposition and Withdrawals ................................................................60 
13.1.2.2 Protocol Deviations ...............................................................................60 
13.1.2.3 Demographics and Other Baseline Characteristics ...............................61 
13.1.3 Exposure and Compliance .................................................................................61 
13.1.4 Pharmacokinetics ...............................................................................................61 
13.1.5 Safety and Tolerability Analyses ......................................................................61 
13.1.5.1 Adverse Events......................................................................................61 
13.1.5.2 Clinical Laboratory Evaluations ...........................................................62 
13.1.5.3 Vital Signs .............................................................................................62 
13.1.5.4 Twelve-lead Electrocardiograms ..........................................................62 
13.1.5.5 Wound Evaluation .................................................................................62 


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13.1.5.6 Physical and Neurological Examination Findings ................................63 
13.1.5.7 Richmond Agitation and Sedation Scale Assessment ...........................63 
13.1.6 Efficacy Analysis ..............................................................................................63 
13.1.6.1 Efficacy Exploratory Endpoints ............................................................63 
13.1.6.2 Analysis .................................................................................................63 
13.1.7 Interim Analysis ................................................................................................64 
13.2 Sample Size Determination ...........................................................................................64 
14 STUDY CONDUCT ...............................................................................................................65 
14.1 Sponsor and Investigator Responsibilities ....................................................................65 
14.1.1 Sponsor Responsibilities ...................................................................................65 
14.1.2 Investigator Responsibilities .............................................................................65 
14.1.3 Confidentiality and Privacy ...............................................................................65 
14.2 Site Initiation .................................................................................................................66 
14.3 Screen Failures ..............................................................................................................66 
14.4 Study Documents ..........................................................................................................66 
14.4.1 Informed Consent ..............................................................................................66 
14.4.2 Investigator’s Regulatory Documents ...............................................................67 
14.4.3 Case Report Forms ............................................................................................67 
14.4.4 Source Documents .............................................................................................67 
14.5 Data Quality Control .....................................................................................................68 
14.5.1 Monitoring Procedures ......................................................................................68 
14.5.2 Data Management ..............................................................................................68 
14.5.3 Quality Assurance/Audit ...................................................................................69 
14.6 Study Termination .........................................................................................................69 
14.6.1 Premature Study Termination ...........................................................................69 
14.7 Study Site Closure .........................................................................................................70 
14.7.1 Record Retention ...............................................................................................70 
14.7.2 Sample Retention ..............................................................................................70 
14.8 Changes to the Protocol ................................................................................................71 
14.9 Use of Information and Publication ..............................................................................71 
15 FINAL CLINICAL STUDY REPORT ..................................................................................72 
16 ETHICAL AND LEGAL CONSIDERATIONS ....................................................................73 
16.1 Good Clinical Practice ..................................................................................................73 
16.2 Subject Information and Informed Consent ..................................................................73 
16.3 Approval by Institutional Review Board ......................................................................73 
16.4 Finance and Insurance ...................................................................................................73 
17 REFERENCES .......................................................................................................................74 
18 ATTACHMENTS ...................................................................................................................75 


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18.1 Investigator’s Agreement ..............................................................................................75 
19 APPENDICES ........................................................................................................................76 
A. 
Richmond Agitation and Sedation Scale ......................................................................77 
B. 
Surgical Wound Site Assessment..................................................................................78 
C. 
Wound Photography Instructions ..................................................................................80 
D. 
Standardized General Anesthesia Regimen ..................................................................81 
E. 
Regulations and Good Clinical Practice .......................................................................82 
 
 
3.1 
List of In-Text Figures 
Figure 7-1: 
Study Design .....................................................................................................30 
 
 


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4 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
ABBREVIATION 
EXPLANATION 
AE 
adverse event 
ANOVA 
analysis of variance 
AUC 
area under the plasma concentration-time curve 
BMI 
body mass index 
CALI 
CALI Pharmaceuticals LLC 
CFR 
Code of Federal Regulations 
Cmax 
maximum peak plasma concentration 
CRA 
clinical research associate 
CSR 
clinical study report 
ECG 
electrocardiogram 
EDC 
electronic data capture 
eCRF 
electronic case report form 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HED 
human equivalent dose 
ICF 
informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
IND 
Investigational New Drug 
IP 
investigational product 
IRB 
institutional review board 
ITT 
intent-to-treat 
IV  
intravenous 
IVP 
intravenous push 
LAST 
local anesthetic systemic toxicity 
MAC 
minimum alveolar concentration 
MOE 
margins of exposure 
MOS 
margins of safety 
MTD 
maximum tolerated dose 
NRS 
numeric rating scale 
PK 
pharmacokinetic(s) 
PT 
preferred term 
RASS 
Richmond Agitation and Sedation Scale 
RBC 
red blood cell 
SAE 
serious adverse event 


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ABBREVIATION 
EXPLANATION 
SAP 
statistical analysis plan 
SD 
standard deviation 
SOC 
system organ class 
SPI1-24 
summed pain intensity over 1 to 24 hours 
t1/2 
elimination half-life 
tmax 
time to reach highest observed (peak) concentration in plasma following 
drug administration 
US 
United States 
 


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5 
INTRODUCTION 
5.1 
Background and Rationale 
The use of local anesthetics within a surgical wound (i.e., wound infiltration) has been used 
extensively in a vast number of patients1 as a relatively simple and safe means to reduce 
postoperative pain.2 Local anesthetics block the generation and the conduction of nerve impulses, 
presumably by increasing the threshold for electrical excitation in the nerve, by slowing the 
propagation of the nerve impulse, and by reducing the rate of rise of the action potential. In general, 
the progression of anesthesia is related to the diameter, myelination, and conduction velocity of 
affected nerve fibers. Clinically, the order of loss of nerve function is as follows: (1) pain, 
(2) temperature, (3) touch, (4) proprioception, and (5) skeletal muscle tone.  
Current local anesthetics used for infiltration are limited by their duration of effect (6-12 hours) 
after surgery.3 For day-case surgery, it is estimated that 30 to 40% of patients experience moderate 
to severe pain during the first 24 to 48 hours. Therefore, the development of a long-acting local 
anesthetic formulation for this patient population is needed.4 
NAROPIN® (ropivacaine HCl) Injection, a member of the amino amide class of local anesthetics, 
is approved for local or regional surgical anesthesia and for acute pain management.5 The 
maximum daily dose of NAROPIN is 300 mg when administered as a major nerve block for 
surgical anesthesia and up to 200 mg when administered as an infiltration dose for postoperative 
pain management. Pain relief is observed within 1 to 5 minutes but only for a duration of 2 to 
6 hours when delivered by infiltration. Therefore, frequent injections would be required if 
protracted local analgesia by infiltration is desired for postoperative pain management.  
A long-acting formulation could potentially prolong the duration of local analgesia for several 
days after a single local administration by infiltration. CALI Pharmaceuticals, LLC (CALI) is 
developing an extended-release injectable gel formulation of ropivacaine hydrochloride (CPL-01) 
to prolong its duration at the local site, leading to an extended local analgesic effect. This 
extended-release, single-phase, slightly viscous (mineral oil like) liquid formulation has been 
tested in several nonclinical animal models. CPL-01 has been tested by several surgeons and 
demonstrated to be injectable manually through combinations of needles and syringes. The 
extended release is achieved by a local in-situ depot mechanism, which is generated by a novel 
proprietary phospholipid gel-based formulation technology (PG Depot). A long-acting formulation 
could potentially prolong the duration of local analgesia for several days after a single local 
administration. 
CALI Pharmaceuticals LLC (CALI) proposes opening the Investigational New Drug application 
with healthy elective surgery subjects (phase 2) rather than with healthy volunteers (phase 1) 
because healthy elective surgery subjects will be the clinically relevant model with an appropriate 
administration route (i.e., wound infiltration and instillation as opposed to subcutaneous (SC) 
injections) for this product. 
The present study is designed to evaluate the safety and pharmacokinetic (PK) profile of CPL-01 
in men and women ≥18 and ≤70 years of age for the management of postoperative pain after 
mini-abdominoplasty surgery.  


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5.2 
Nonclinical Experience 
The efficacy of CPL-01 was evaluated in the guinea pig pin-prick pain model 
(Study ZJPC20170413). CPL-01 (1% or 2% ropivacaine) exhibited prolonged local anesthetic 
efficacy compared with 1% ropivacaine HCl aqueous solution (same as NAROPIN). The clinical 
strength of CPL-01 (2% ropivacaine) exhibited an analgesic effect within 15 minutes with 
significant efficacy (≥50%) sustained for 12 to 13 hours after administration, 4-fold longer than 
the 1% ropivacaine HCl aqueous solution. 
Pharmacokinetic (PK) evaluation of CPL-01 (2% or 4% ropivacaine) by single subcutaneous (SC) 
administration has been performed in rats (Study 03051-17003, Study 03051-17005, and Study 
03051-17008), 
and 
in 
minipigs 
(Study 
03051-17004, 
Study 
03051-17006, 
and 
Study 03051-17009). These studies indicated that ropivacaine tmax ranged from 0.5 to 4 hours 
postdose in rats and 5 to 11 hours postdose in minipigs, with a t1/2 of 13 to 35 hours in rats and 
17 to 46 hours in minipigs. Following wound infiltration and instillation of CPL-01 in minipigs 
(Study S10065), the tmax ranged from 1 to 5 hours postdose, with a t1/2 ranging from 18 to 31 hours. 
In contrast, the tmax for NAROPIN (1% ropivacaine HCl) was generally between 0.25 and 1 hour 
in both species, with a t1/2 of ≤1 hour in rats and 6 to 7 hours in minipigs. Overall, the tmax and t1/2 
of ropivacaine following CPL-01 were later and longer than NAROPIN, and the dose normalized 
Cmax of CPL-01 were 70% to 95% lower than that of NAROPIN in both species. 
In an SC toxicity study in rats (Study 03051-17008), single SC administration of CPL-01 at 50, 
200, or 400 mg/kg in Sprague-Dawley rats was well tolerated, and test article-related toxicity was 
limited to reversible, non-adverse injection site reactions observed mainly in the higher 
dose/injection volume groups (200 and 400 mg/kg). There were no abnormalities in clinical 
observations or gross observation of local injection sites at 50 mg/kg. The local effects of the 
injection site at higher doses were the result of the formulation depot, which was designed for a 
slow release of ropivacaine over time prior to resorption of the formulation matrix. Compared with 
the NAROPIN formulation, which resulted in death after a single administration at a dose of 
44 mg/kg, CPL-01 at 50 mg/kg exhibited a significantly lower systemic Cmax (approximately 84% 
lower) and no systemic toxicity. Overall, the maximum tolerated dose (MTD) for single 
subcutaneous injection of CPL-01 in Sprague-Dawley rats was determined to be 400 mg/kg, which 
corresponds to a Human Equivalent Dose (HED) of 3,871 mg based on body surface area 
(assuming a 60 kg human). 
In an SC toxicity study in minipigs (Study 03051-17009), CPL-01 15, 30 or 60 mg/kg was well 
tolerated. Test article-related toxicity was limited to reversible, non-adverse, minimal to mild 
injection site reactions, which were observed in all dosing groups, including the CPL-01 vehicle 
group. All injection sites had returned to normal by Day 30. No systemic clinical signs or systemic 
toxicity by histopathological evaluation of selected organs were noted at any CPL-01 dose. 
Compared with the NAROPIN formulation, CPL-01 at higher doses (2- to 8-fold) showed a similar 
safety profile, which likely benefits from a significantly lower Cmax and prolonged t1/2 of 
ropivacaine. Overall, the MTD for a single subcutaneous injection of CPL-01 in Ba-Ma Minipig 
was determined to be 60 mg/kg, which corresponds to an HED of 3,273 mg based on body surface 
area (assuming 60 kg human). 
In a wound infiltration and instillation toxicity/wound healing study in minipigs (Study S16005), 
CPL-01 was administered into a 6 to 10 cm abdominal incision at midline down to the peritoneum 
at doses of 0 (vehicle), 10, 20, and 40 mg/kg. Each group had a 3-day and 28-day cohort (N=3 
animals/group/sex/cohort). All doses of CPL-01 were well tolerated. There were no adverse 


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clinical observations or CPL-01-related effects on food consumption, body weight, 
ophthalmology, electrocardiographic assessment (heart rate, RR interval, PR interval, QRS 
duration, QT interval, or QTc interval), or systemic gross observations or microscopic findings in 
any of the non-wound site organs/tissues at any dose level. CPL-01 at 0 (vehicle control), 10, 20, 
or 40 mg/kg caused transient, mild to moderate local tissue reactions including local response to 
the vehicle (macrophage infiltrates) within the subcutis that was considered non-adverse, 
biocompatible, and tolerable. The majority of wounds treated with CPL-01 were completely 
re-epithelialized by Day 29, and tensile strength testing of the incisional site skin tissues indicated 
nearly completed recovery relative to normal intact skin at Day 29 for all treatment groups. In 
conclusion, there was no evidence of significant local or systemic toxicity due to administration, 
indicating that the NOAEL of CPL 01 is above 40 mg/kg for a single wound infiltration and 
instillation administration.  
Margin of Safety (MOS) based on dose: The NOAEL dose of CPL-01 at 40 mg/kg ropivacaine 
(HED = 2182 mg, assumes 60 kg human) by wound infiltration and instillation in minipigs 
provides a 10-fold MOS for a clinical dose of 200 mg ropivacaine. 
Margin of Exposure (MOE) was calculated relative to a human AUC0-t of approximately 
11,600 ng*h/mL ropivacaine following a dose of 300 mg ropivacaine HCl (NAROPIN) by 
infiltration following hernia surgery.6 At the NOAEL dose of CPL-01 at 40 mg/kg ropivacaine by 
wound infiltration and instillation in minipigs, a combined male and female AUC0-t of 
approximately 42,700 ng*h/mL was obtained, providing an approximately 4-fold safety MOE 
compared with the human exposure following infiltration of a surgical wound after hernia surgery.   
5.3 
Clinical Experience 
This is a first-in-human study. 
5.4 
Summary of Potential Risks and Benefits 
Like other amino amide local anesthetics, the adverse effects that may be associated with CPL-01 
when administered by wound infiltration include the classic symptoms of local anesthetic systemic 
toxicity (LAST). These symptoms, though unlikely to occur, might include early neurological 
symptoms such as circumoral and/or tongue numbness, metallic taste, lightheadedness and/or 
dizziness; and cardiovascular symptoms such as hypotension and arrhythmia. Later symptoms, 
which are very unlikely in this study, include visual and visual and auditory disturbances (difficulty 
focusing and tinnitus), disorientation, drowsiness, agitation, and seizures. Given the single 
moderate local anesthetic dose being used in this study, respiratory and cardiovascular symptoms 
observed in more severe local anesthetic toxicity are a theoretical concern only and are not 
expected to occur. 
The potential benefit of study participation is that subjects with postsurgical pain from elective 
abdominoplasty may experience a reduction in their pain over a longer period of time compared 
with NAROPIN as a result of treatment with CPL-01. With this longer duration of anesthetic 
effect, there is an expectation that less opioid rescue medication will be needed. No other benefits 
of participation are anticipated. 
CPL-01 is contraindicated in subjects with known hypersensitivity to ropivacaine or to any local 
anesthetic agent of the amide type. A major cause of adverse reactions to this group of drugs may 
be associated with excessive plasma levels, which may be due to overdose, unintentional 
intravascular injection, or slow metabolic degradation. 


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A population with healthy elective surgery subjects rather than healthy volunteers was selected 
because they will be the clinically relevant model for wound infiltration administration of this 
product. 
The potential risks of study participation include those associated with exposure to CPL-01 and 
the risks of surgery and medical evaluation, including venipuncture.  
A summary of the pharmaceutical properties and known potential risks of ropivacaine HCl is 
provided in the prescribing information for NAROPIN.5  


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6 
OBJECTIVES AND ENDPOINTS 
6.1 
Objectives 
The objectives of the study are as follows: 
• To assess the safety and tolerability of CPL-01 in the management of acute postoperative 
pain after mini-abdominoplasty compared with placebo. 
• To characterize the pharmacokinetic (PK) profile of CPL-01 during mini-abdominoplasty. 
• To explore the efficacy and analgesic duration of action of CPL-01 for postoperative pain 
during mini-abdominoplasty compared with placebo. 
• To inform the design of an ascending dose phase 2 trial of CPL-01. 
• To evaluate the opioid-sparing effect of CPL-01. 
• To evaluate the effect of CPL-01 on postoperative wound healing. 
6.2 
Endpoints 
6.2.1 Safety Endpoints 
The safety endpoints are as follows: 
• Adverse events (AEs) 
• Vital signs 
• Clinical laboratory evaluations (hematology, chemistry, and urinalysis) 
• 12-lead electrocardiograms (ECGs) 
• Physical examination 
• Full neurological examination 
• LAST assessment 
• Surgical wound site assessment (including incidence of wound infection and 
wound-related AEs) 
6.2.2 Pharmacokinetic Endpoints 
The PK and bioavailability endpoints are as follows: 
• Maximum (peak) plasma concentration (Cmax) 
• Time to reach highest observed (peak) concentration in plasma following IP administration 
(tmax) 
• Elimination half-life (t1/2) 
• Terminal elimination rate constant (λz) with the respective t1/2 
• Area under the plasma concentration-time curve (AUC) from Time 0 to time of last 
quantifiable plasma concentration (AUC0-last) (Time 0 is defined as the moment that IP is 
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• AUC from Time 0 to infinity (AUC0-∞) 
6.2.3 Exploratory Endpoints 
The exploratory endpoints are as follows: 
• Time-weighted summed pain intensity over 1 to 24 hours (SPI1-24) for CPL-01 subjects 
compared with placebo subjects 
• SPI at other time points: SPI1-6, SPI6-12, SPI1-12, SPI12-24, SPI24-48, SPI1-48, SPI48-72, and 
SPI1-72 for CPL-01 subjects compared with placebo subjects 
• Total dose of opioid rescue analgesia (morphine equivalents) over 24, 48, and 72 hours 
after administration of IP 
• Time to administration of first dose of opioid rescue analgesia 
• The percentage of subjects who used no opioid rescue analgesia over 24, 48, and 72 hours 
after administration of IP 
• The percentage of subjects who remain pain free over 24, 48, and 72 hours after 
administration of IP (pain intensity ≤1). 


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7 
STUDY DESIGN 
7.1 
Overall Study Design and Plan 
This is a randomized, double-blind, single-site study to evaluate the safety, PK profile, and 
analgesic duration of action of CPL-01 in men and women ≥18 and ≤70 years of age for the 
management of postoperative pain after mini-abdominoplasty surgery.  
The study will evaluate approximately 20 subjects who will be enrolled and randomly assigned in 
a 3:1 ratio to either 2% CPL-01 (200 mg ropivacaine [10 mL]) or placebo (0.9% NaCl). 
The study will include 4 periods: Screening Period, Surgical/Anesthesia Period (Confinement), 
Post-anesthesia Period (Confinement); and Post-treatment Follow-up Period. The details of the 
procedures for each period are included in the schedule of events (Section 2.2) and Section 10. 
7.2 
Screening Period (Day -42 up to Day -1) 
Subjects will be screened within 42 days before the planned surgery; however, Screening can be 
performed as late as on the morning of the surgery if all inclusion/exclusion criteria can be verified. 
Subjects who give written informed consent will be assessed for eligibility. Screening evaluations 
will include collection of demographic information, medical history, full neurological 
examination, complete physical examination, vital signs (resting blood pressure, heart rate, 
respiratory rate, and oral body temperature), height, weight, body mass index (BMI), 12-lead ECG, 
clinical laboratory tests (hematology, chemistry, and urinalysis), serology tests, serum pregnancy 
test (women of childbearing potential only), urine drug screen, and recording of concomitant 
medications. Additionally, subjects will be trained on the use of the numeric rating scale (NRS) 
for pain assessment at Screening. 
7.3 
Surgical/Anesthesia Period (Day 1 through Hour 1, Confinement).  
On Day 1, at check-in, inclusion/exclusion criteria will be confirmed and medical history, full 
neurological examination, vital signs, 12-lead ECG, urine pregnancy test, urine drug screen, and 
concomitant medications will be updated. Before surgery, subjects will be trained again on the 
NRS and assigned a randomization number.  
Subjects will be administered general anesthesia according to a standard regimen (Appendix D), 
during which they will undergo a mini-abdominoplasty. At the end of the surgical procedure but 
before the wound is closed, the investigational product (IP) will be administered by wound 
infiltration and instillation (Time 0). Blood samples will be collected for PK analysis at baseline 
(before IP administration) and 15, 30, and 45 minutes after administration of IP. Continuous pulse 
oximetry will be monitored immediately following surgery, throughout transport, and in the 
post-anesthesia care unit, until subjects switch from intravenous morphine to oral rescue analgesia 
medication. If O2 saturation drops below 93% or if subjects have clinical signs or symptoms that 
suggest respiratory depression while on the oral medication, or subjects switch back to intravenous 
morphine, they will be kept on continuous pulse oximetry as required. Following surgery, subjects 
will be admitted and confined to the study site through Day 4. 
7.4 
Post-anesthesia Period (Day 1, Hour 1 [1 Hour After Administration of IP] through 
Day 4, Confinement) 
Assessments during the Post-anesthesia Period will include LAST assessment (including vital 
signs, Richmond Agitation and Sedation Scale [RASS] assessment [Appendix A], and focused 


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neurological examination), 12-lead ECG, pain intensity assessments, surgical wound site 
assessment (including photograph), concomitant medications, and AEs. Continuous pulse 
oximetry will be conducted in the post-anesthesia care unit, until subjects switch from intravenous 
morphine to oral rescue analgesia medication. If O2 saturation drops below 93% or if subjects have 
clinical signs or symptoms that suggest respiratory depression while on the oral medication, or 
subjects switch back to intravenous morphine, they will be kept on continuous pulse oximetry as 
required. Subjects will also receive a diary to record their pain intensity (using NRS) and rescue 
medication usage when they are discharged from the study site on Day 4. On non-visit days prior 
to the Day 7-10 Follow-up Visit, a brief daily telephone call will be conducted to remind subjects 
to record their pain intensity (using NRS), and rescue medication usage in the diary. Subjects will 
be instructed to return their completed diary at the Day 7-10 Follow-up Visit (7 to 10 days after 
administration of IP or upon early termination).  
Rescue analgesia: Subjects with inadequately controlled pain symptoms may request rescue 
analgesia. Pain intensity using an NRS will be recorded just prior to receiving rescue analgesia. 
After administration of the IP, rescue analgesia will be restricted to 2 to 4 mg intravenous morphine 
every hour as needed until the subject is able to tolerate oral medication. Once oral medication can 
be tolerated, oxycodone 5 to 10 mg every 3 to 4 hours will be used as needed for analgesia. After 
the subject’s pain intensity is ≤4, oral acetaminophen 1000 mg should be used every 6 to 8 hours 
as needed for analgesia (not to exceed 4000 mg within 24 hours). For breakthrough pain intensity 
>4 that is not relieved by the oral acetaminophen, oral oxycodone 5 to 10 mg every 3 to 4 hours as 
needed for pain may continue to be used. For breakthrough severe pain intensity >8, intravenous 
morphine 2 to 4 mg every hour as needed may be allowed. 
7.5 
Post-treatment Follow-up Period (Days 5 and 6, 7 to 10 days, and 30 days after 
administration of IP) 
Subjects will return to the study site for collection of PK blood samples and for pain intensity 
assessment using an NRS at 96 and 120 hours after administration of IP (Days 5 and 6). 
Assessments at the Day 7-10 Follow-up Visit (7 to 10 days after administration of IP) include full 
neurological examination, abbreviated physical examination, vital signs, 12-lead ECG, surgical 
wound site assessment (including photograph), clinical laboratory evaluations, concomitant 
medications, and AEs. Subjects will return their completed diary at the Day 7-10 Follow-up Visit 
(7 to 10 days after administration of IP or upon early termination). 
At the Day 30 Follow-up Visit (30 days after administration of IP), AEs and concomitant 
medications will be recorded and a surgical wound site assessment (including photograph) will be 
performed. 
7.6 
Study Assessments 
Blood samples will be collected for PK analysis at baseline (before IP administration), 15, 30, and 
45 minutes (Surgical/Anesthesia Period), and at 1, 2, 4, 6, 8, 10, 12, 18, 24, 30, 36, 48, 60, and 
72 hours (Post-anesthesia Period) after administration of IP. Subjects will return to the study site 
for collection of PK blood samples at 96 and 120 hours after administration of IP (Days 5 and 6). 
Subjects will evaluate pain intensity using an NRS at 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16, 24, 32, 40, 
48, 56, 64, and 72 hours after administration of IP. Additionally, pain intensity using an NRS will 
be recorded just prior to receiving rescue analgesia. The pain intensity will also be recorded when 
subjects return to the study site at 96 and 120 hours after administration of IP to collect PK blood 
samples (Days 5 and 6). 


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Safety will be assessed based on AEs, vital signs, clinical laboratory evaluations, 12-lead ECGs, 
physical examination, full neurological examination, LAST assessment, and wound evaluation. 
Safety assessments will be performed during the study at the time points shown in the Schedule of 
Events table. 
 
Figure 7-1: 
Study Design 
 
 
IP = investigational product 
a 
One hour after administration of IP. 
 
7.7 
Rationale and Discussion of Study Design 
Subjects will be randomly assigned to CPL-01 or placebo and both the subject and any individuals 
directly involved in pain assessment are blinded to prevent bias. It is difficult for the surgeon to 
remain blinded since the appearance and consistency of CPL-01 differs significantly from placebo. 
However randomization of the subject will prevent bias on the part of the surgeon.  
This study will explore the analgesic effects of administration of CPL-01 in an accepted model of 
postoperative pain. Mini-abdominoplasty surgery produces generally reliable and persistent pain 
symptoms for a period typically lasting over 72 hours from the surgical insult, which will allow 
for analysis of acute analgesic effect of CPL-01 over an extended period of time.  
Healthy elective surgery subjects rather than healthy volunteers were selected because they will 
be the clinically relevant model for wound infiltration administration of this product.  
Efficacy measures will be collected to gain a better knowledge of the analgesic effect time curve 
of CPL-01 compared with placebo (0.9% NaCl) following a surgical procedure. In addition, the 
study will further characterize the safety and PK profile of CPL-01 and inform the design of future 
safety and efficacy trials. 
The timing and frequency of the PK blood draws are designed to determine the Cmax as well as the 
overall systemic exposure. 
7.8 
Selection of Doses in the Study 
The proposed starting human clinical dose of 200 mg ropivacaine in CPL-01 is well supported by 
the current nonclinical results in rats and minipigs (see Section 5.2). Ropivacaine is known to be 
safe for postsurgical infiltration at this dose level. In rats (Study 3051-17008), the CPL-01 
maximally tolerated dose (HED of 3871 mg ropivacaine) provided an approximately 19-fold MOS 
based on dose relative to the proposed clinical dose of 200 mg/subject. In minipigs following 
Screening Period 
Day -42 to Day -1
Surgical/Anesthesia Period
Day 1 through Hour 1
(Confinement)
Post-anesthesia Period
Day 1, Hour 1a through Day 3
(Confinement) 
Post-treatment 
Follow-up Period
• Days 4 and 5
• Day 7-10 Follow-up Visit 
(7 to 10 days after IP 
administration)
• Day 30 Follow-up Visit
(30 days after IP 
administration)
Mini-abdominoplasty under general anesthesia
and study drug administration before wound closure
2% CPL-01 (200 mg ropivacaine [10 mL]) or placebo (0.9% NaCl)
Study assessments
Study assessments


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wound infiltration and instillation of CPL-01 (Study S16005), the CPL-01 NOAEL dose (HED of 
2182 mg ropivacaine) provided an approximately 10-fold MOS relative to the proposed clinical 
dose of 200 mg/subject and an approximately 4-fold safety MOE relative to the human exposure 
(AUC0-t) at an infiltration dose of 300 mg ropivacaine HCl (NAROPIN) following hernia surgery.6 
7.9 
Study Sites 
The study will take place at 1 study site in the United States (US). 
7.10 End of Study Definition 
The clinical trial will be considered completed when the last subject’s last Day 30 Follow-up Visit 
(30 days after administration of IP) has occurred. 


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8 
SUBJECT POPULATION 
8.1 
Selection of Study Population 
Approximately 20 subjects between 18 and 70 years who are scheduled to undergo elective 
mini-abdominoplasty surgery will be enrolled in the study. A screening log of potential study 
candidates and an enrollment log of enrolled subjects must be maintained at the study site. 
Subjects who do not meet all of the eligibility criteria will not be enrolled. 
8.2 
Study Entry Criteria 
To adequately assess the PK and safety of CPL-01, only subjects who are undergoing elective 
mini-abdominoplasty surgery should be enrolled. 
8.2.1 Inclusion Criteria 
A subject will be eligible for study participation if he or she meets all of the following criteria: 
1. Subject provides signed, written informed consent before participation in the study. 
2. Subject is aged ≥18 and ≤70 years at the time of informed consent and is male or female.  
3. Subject is scheduled to undergo elective mini-abdominoplasty surgery under general 
anesthesia without collateral procedures. 
4. Subject has a BMI >19 and <30 kg/m2. 
5. Subject has an American Society of Anesthesiology subject (physical) classification status 
of I or II (as assessed at Screening). 
6. Female subjects are eligible only if all the following apply: 
a. Not pregnant (female subjects of childbearing potential must have a negative serum 
pregnancy test within 42 days before surgery [Screening] and a negative urine 
pregnancy test prior to surgery [check-in]) 
b. Not breastfeeding 
c. Not planning to become pregnant during participation in the study 
d. Committed to the use of an acceptable form of birth control (i.e., hormonal 
contraception, intrauterine device, condoms in combination with a spermicidal cream 
or total sexual abstinence, includes surgical sterilization and confirmed 
postmenopausal state) for the duration of the study until at least 30 days after 
administration of IP. 
7. Male subjects must commit to the use of a reliable method of birth control for the duration 
of the study until at least 30 days after administration of IP or be surgically sterile 
(biologically or surgically). 
8. Subject has the ability to read and understand the study procedures, use the pain scale, and 
to communicate meaningfully with the investigator and staff, in the opinion of the 
investigator. 
9. Subject is free of any physical, mental, or medical conditions which, in the opinion of the 
investigator, make mini-abdominoplasty or study participation inadvisable. 


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8.2.2 Exclusion Criteria 
A subject will be excluded from the study if he or she meets any of the following criteria: 
1. Subject has been receiving or has received chronic opioid therapy defined as any opioid 
for greater than 3 out of 7 days per week over a 1-month period within 12 months of IP 
initiation. 
2. Subject has taken chaparral, comfrey, germander, jin bu huan, kava, pennyroyal, skullcap, 
St. John’s wort, or valerian within 14 days before surgery. 
3. Subject has a chronic pain condition or any significant medical disease, laboratory 
abnormality (including ECG abnormality), or condition that, in the investigator’s 
judgment, could compromise his or her welfare, ability to communicate with the study 
staff, complete study activities, may confound the assessments of postoperative pain, or 
otherwise contraindicate study participation. 
4. Subject has known hypersensitivity or known allergy, as determined by the investigator, to 
ropivacaine, sesame oil, soy beans, oxycodone, other opioids, acetaminophen, or the 
inactive ingredients (i.e., excipients) of the IP or any peri- or postoperative medications 
used in this study. 
5. Subject has known, suspected or reported history of alcohol or drug abuse or dependence 
within the previous 2 years as assessed by the investigator. 
6. Subject 
has 
impaired liver function (e.g., aspartate aminotransferase/alanine 
aminotransferase greater than 3 times the upper limit of the reference range, bilirubin 
greater than 1.5 times the upper limit of the reference range unless due to Gilbert’s 
syndrome, active hepatic disease, evidence of clinically significant liver disease, or other 
condition such as alcoholism, cirrhosis, or hepatitis, etc.) that suggests the potential for an 
increased susceptibility to hepatic toxicity with IP exposure. 
7. Subject has clinically significant renal abnormalities (creatinine ≥1.5 × upper limit of 
normal). 
8. Subject has hemoglobin A1c ≥7.0%. 
9. Subject has been treated with monoamine oxidase inhibitors within 14 days before surgery. 
10. Subject has participated in another clinical study and/or received an IP (marketed or 
premarket) within 30 days before surgery. 
11. Subject has a history of, or positive test results for, human immunodeficiency virus, 
hepatitis B surface antigen, or hepatitis C virus antibody at Screening. 
12. Subject has a history of a migraine headache (within past 6 months or 2 within the past 
12 months) or frequent headaches (≥2 events per week requiring analgesics) as determined 
by the investigator, seizures, or is currently taking anticonvulsants. 
13. Subject has a history of malignant hyperthermia. 
14. Subject has glucose-6-phosphate dehydrogenase deficiency. 
15. Subject has a positive urine drug screen test result at Screening or at check-in on the day 
of surgery for amphetamines, barbiturates, benzodiazepines, cocaine, opiates, 
phencyclidine, or tetrahydrocannabinol; indicating drug use. 


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16. Subject has used a concurrent therapy that could interfere with the evaluation of efficacy 
or safety, such as any drugs that in the investigator’s opinion may exert significant 
analgesic properties or act synergistically with the IP. 
17. Subject has used corticosteroids, either systemically or by intra-articular injection, within 
6 weeks prior to the study surgical procedure; inhaled, nasal, and topical steroids are 
allowed. 
18. Subject concurrently uses potent CYP1A2 inhibitors, including cimetidine, enoxacin, 
fluvoxamine, ciprofloxacin (Cipro), gemifloxacin (Factive), levofloxacin (Levaquin), 
moxifloxacin (Avelox), norfloxacin (Noroxin), or ofloxacin (Floxin). 
19. Subject has persistent or recurrent nausea and/or vomiting because of other etiologies, 
including, but not limited to, gastric outlet obstruction, hypercalcemia, active peptic ulcer, 
increased intracranial pressure, chemotherapy, or brain metastases. 
20. Subject experiences a clinically significant event during surgery prior to the administration 
of the IP (e.g., excessive bleeding, hemodynamic instability) that would render him or her 
medically unstable, complicate their postsurgical course, or significantly increase the risk 
of IP administration as per the judgment of the investigator. 
21. Subjects who have a difficult airway on preoperative screening or history of airway 
difficulties in the past. 
22. Subject with an upper respiratory infection/cough in the 14 days before surgery.  
23. Subjects with a history of significant postoperative nausea and vomiting. 
8.3 
Premature Subject Withdrawal 
All subjects will be advised that they are free to withdraw from participation in this study at any 
time, for any reason, and without prejudice. The investigator should make every reasonable 
attempt to keep subjects in the study; however, subjects must be withdrawn from the study if they 
withdraw consent to participate. Investigators must attempt to contact subjects who fail to attend 
scheduled visits by telephone or other means to exclude the possibility of an AE being the cause 
of withdrawal. Should this be the cause, the AE must be documented, reported, and followed as 
described in Section 11.2. 
The sponsor reserves the right to request the withdrawal of a subject due to protocol deviations or 
other reasons. 
The investigator also has the right to withdraw subjects from the study at any time for lack of 
therapeutic effect that is intolerable or otherwise unacceptable to the subject, for intolerable or 
unacceptable AEs, intercurrent illness, noncompliance with study procedures, administrative 
reasons, or in the investigator’s opinion, to protect the subject’s best interest. 
If a subject is withdrawn before completing the study, the reason for withdrawal and the date of 
discontinuation will be recorded on the appropriate page of the electronic case report form (eCRF). 
Whenever possible and reasonable, the evaluations that were to be conducted at the completion of 
the study should be performed at the time of premature discontinuation. 
8.4 
Participant Discontinuation/Withdrawal from the Study 
Participants are free to withdraw from participation in the study at any time upon request. 


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An investigator may discontinue or withdraw a participant from the study for the following 
reasons: 
• Pregnancy 
• Significant study noncompliance  
• If any clinical AE, laboratory abnormality, or other medical condition or situation occurs 
such that continued participation in the study would not be in the participant’s best interest 
• If the participant meets an exclusion criterion (either newly developed or not previously 
recognized) that precludes further study participation 
The reason for participant discontinuation or withdrawal from the study will be recorded on the 
eCRF. Subjects who sign the informed consent form (ICF) and are randomized but do not receive 
the study intervention may be replaced. Subjects who sign the ICF, are randomized, and receive 
the study intervention, and subsequently withdraw, or are withdrawn or discontinued from the 
study will not be replaced. For subjects not completing the 24 hours of PK sampling, additional 
subjects may be added at the sponsor’s discretion. 
A participant will be considered lost to follow-up if he or she fails to return for the Day 7-10 
Follow-up Visit (7 to 10 days after administration of IP) and is unable to be contacted by the study 
site staff.  
The following actions must be taken if a participant fails to return to the clinic for a required study 
visit: 
• The site will attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain if the participant wishes to and/or should continue in the study. 
• Before a participant is deemed lost to follow-up, the investigator or designee will make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, if 
necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the participant’s 
medical record or study file.  
• Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 


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9 
TREATMENTS 
9.1 
Identification of Investigational Products 
CPL-01 is an extended-release injectable gel formulation of ropivacaine hydrochloride.  
CPL-01 will be provided in the form of 2% ropivacaine in 10 mL glass vials (200 mg dose/vial) at 
the strength of 20 mg/mL (manufactured by Bioserv; San Diego, CA). 
Placebo (0.9% NaCl) will be supplied by the study site. 
9.2 
Treatments Administered 
Each subject will be randomly assigned (3:1 ratio) to receive 2% CPL-01 (200 mg ropivacaine 
[10 mL]) or placebo (0.9% NaCl) administered into soft tissue before closure after 
mini-abdominoplasty by wound infiltration and instillation. 
The mini-abdominoplasty soft-tissue model is best suited for wound infiltration into 2 anatomic 
areas, the plication area of the rectus sheath and along the length of the incision. 
9.2.1 Investigational Product Administration 
The following dosing method of the IP will be performed. 
Materials 
• Two 1 cc Luer-lock syringes 
• Two 5 cc Luer-lock syringes 
• Four 21 gauge needles, length 1.5 inches 
• 10 mL study drug (2% CPL-01 [200 mg ropivacaine] or placebo [0.9% NaCl]) 
Draw Technique 
Based on the randomization schedule, draw up a total of 10 mL of the study drug into the 4 syringes 
as follows: 
• Fill TWO – 1 cc Luer-lock syringes with exactly 1 mL of study drug. 
• Fill TWO – 5 cc Luer-lock syringes with exactly 4 mL of study drug. 
Dosing Technique 
1. Plication – After plication of the diastasis recti is complete and prior to skin closure 
infiltrate (inject) 1 mL of the study drug using one 1 cc syringe in 5 separate, equally 
spaced, injections of 0.2 mL each, along the entire length of the plication of the rectus 
abdominus. The injections should be precisely placed along the posterior (deep) rectus 
sheath. 
2. External Fascial Layer – Infiltrate (inject) in 2 parallel tracks using the two 5 cc syringes 
(total of 8 mL), lateral to the plication line along the linea semilunaris into the deep external 
facial layer beneath the external oblique muscle. A total of 10 injections (5 on each side) 
of 0.8 mL each, at equally spaced sites along the 2 semilunaris lateral tracks (4 mL each 
side). Carefully orient the syringe and needle at a 45 degree angle when injecting. Visualize 


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the entire length of the needle via the translucency of the fascia to avoid deep abdominal 
and intramuscular injection. 
3. Prior to skin closure – Instill (surface application) 1 mL of the study drug using one 1 cc 
syringe onto the upper third of the subcutaneous tissue along the length of the upper and 
lower abdominal incisions where the subcutaneous fascia emerges from the deeper tissue. 
Again, apply (do not inject) the study drug through the end of the needle for controlled 
slow application. 
9.2.2 Rescue Medication 
The study site will supply rescue analgesia that will be obtained locally. 
Subjects with inadequately controlled pain symptoms may request rescue analgesia. After 
administration of the IP, rescue analgesia will be restricted to 2 to 4 mg of intravenous morphine 
every hour as needed until the subject is able to tolerate oral medication. Once oral medication can 
be tolerated, oxycodone 5 to 10 mg every 3 to 4 hours as needed for analgesia will be used. After 
the subject’s pain intensity is ≤4, oral acetaminophen 1000 mg should be used every 6 to 8 hours 
as needed for analgesia (not to exceed 4000 mg within 24 hours). For breakthrough pain intensity 
>4 that is not relieved by the oral acetaminophen, oral oxycodone 5 to 10 mg every 3 to 4 hours as 
needed for pain may continue to be used. For breakthrough severe pain intensity >8, intravenous 
morphine 2 to 4 mg every hour as needed may be allowed. Subjects should receive a prescription 
for rescue analgesia for use after they are discharged from the study site. 
The date and time of rescue analgesia, as well as the name and dosage regimen, must be recorded. 
9.3 
Selection of Timing of Dose for Each Subject 
Subjects will be administered general anesthesia according to a standard regimen (Appendix D), 
during which they will undergo a mini-abdominoplasty at the study site. At the end of the surgical 
procedure but before the wound is closed, the IP will be administered by wound infiltration and 
instillation (Time 0). Continuous pulse oximetry will be monitored immediately following surgery, 
throughout transport, and in the post-anesthesia care unit, until subjects switch from intravenous 
morphine to oral rescue analgesia medication. If O2 saturation drops below 93% or if subjects have 
clinical signs or symptoms that suggest respiratory depression while on the oral medication, or 
subjects switch back to intravenous morphine, they will be kept on continuous pulse oximetry as 
required. 
Following surgery, subjects will be confined to the study site through Day 4 for study assessments 
and return to the study site at 96 and 120 hours and 7 to 10 days after administration of IP for PK 
and safety assessments. The study procedure details are provided in Section 2.2 and Section 10. 
9.4 
Treatment Compliance 
All subjects will receive the IP at the study site under the surveillance of appropriate study 
personnel.  
9.5 
Method of Assigning Subjects to Treatment Groups 
Subjects who meet study entry criteria will be randomly assigned in a 3:1 ratio to CPL-01 or 
placebo.  


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The randomization schedule will be computer generated using a permuted block algorithm and 
will randomly allocate IP to randomization numbers.  
The randomization schedule will be prepared by a specified unblinded statistician before the start 
of the study. No subject will be randomized into this study more than once. 
9.6 
Blinding and Unblinding Treatment Assignment 
All personnel involved with evaluating the safety and efficacy of the treatment will remain blinded 
to the treatment that the subjects receive. The following individuals will be unblinded: the 
pharmacist (or qualified designee), anesthesia provider, the surgeon at the study site, the clinical 
research associate (CRA) performing drug accountability, a specified statistician (who will prepare 
the randomization schedule), and other operating room personnel. The unblinded study personnel 
will not participate in postoperative evaluations or data analysis prior to unblinding of the study 
data to all study-related personnel. 
Study site personnel will make every effort to safeguard the integrity of the study blind to minimize 
bias in the conduct of the study. Treatment unblinding is discouraged if knowledge of the treatment 
assignment will not materially change the planned management of a medical emergency. 
Unblinding will be permitted in a medical emergency that requires immediate knowledge of the 
subject’s treatment assignment. 
Unblinding should be discussed in advance with the medical monitor, if possible. For emergency 
unblinding, study site personnel should contact the medical monitor to discuss the need to 
determine the IP received by the subject. 
Overall unblinding will take place at the end of the study only after database lock has been 
achieved. 
9.7 
Permitted and Prohibited Therapies 
All concomitant medications used (including over-the-counter medications and herbal 
supplements) will be recorded in the source document and on the appropriate eCRF. 
9.7.1 Permitted Therapies 
Subjects with inadequately controlled pain symptoms may request rescue analgesia. After 
administration of the IP, rescue analgesia will be restricted to 2 to 4 mg intravenous morphine 
every hour as needed until the subject is able to tolerate oral medication. Once oral medication can 
be tolerated, oxycodone 5 to 10 mg every 3 to 4 hours will be used as needed for analgesia. After 
the subject’s pain intensity is ≤4, oral acetaminophen 1000 mg should be used every 6 to 8 hours 
as needed for analgesia (not to exceed 4000 mg within 24 hours). For breakthrough pain intensity 
>4 that is not relieved by the oral acetaminophen, oral oxycodone 5 to 10 mg every 3 to 4 hours as 
needed for pain may continue to be used. For breakthrough severe pain intensity >8, intravenous 
morphine 2 to 4 mg every hour as needed may be allowed. 
The package inserts for the rescue medications to be used during the study will be provided to each 
investigator. 
Other non-analgesic concomitant medications are allowed, but should be limited to those 
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9.7.2 Prohibited Therapies 
All concomitant medications used (including over-the-counter medications and herbal 
supplements) will be recorded in the source document and on the appropriate eCRF. 
The following therapies are prohibited within the specified period and during the study: 
• Chronic opioid therapy defined as greater than 15 morphine-equivalent units per day for 
greater than 3 out of 7 days per week over a 1-month period within 12 months of IP 
initiation 
• Chaparral, comfrey, germander, jin bu huan, kava, pennyroyal, skullcap, St. John’s wort, 
or valerian within 14 days before surgery 
• Amphetamines, barbiturates, benzodiazepines, cocaine, opiates, phencyclidine, or 
tetrahydrocannabinol as indicated by positive urine drug screen test result 
• Concurrent therapy that could interfere with the evaluation of efficacy or safety, such as 
any drugs that in the investigator’s opinion may exert significant analgesic properties or 
act synergistically with the IP 
• Concurrent use of potent CYP1A2 inhibitors, including cimetidine, enoxacin, 
fluvoxamine, ciprofloxacin (Cipro), gemifloxacin (Factive), levofloxacin (Levaquin), 
moxifloxacin (Avelox), norfloxacin (Noroxin), or ofloxacin (Floxin) 
Subjects receiving excluded therapies will be ineligible for study enrollment. If subjects receive 
excluded therapies after enrollment, continuation in the study will be at the discretion of the safety 
monitoring group. 
9.7.3 Restrictions 
There will be no dietary restrictions during the study aside from the normal surgical dietary 
restrictions. Subjects must be at rest for a minimum of 15 minutes in the resting position before 
any assessments are performed, unless otherwise indicated in the schedule of events (Section 2.2). 
9.8 
Treatment After End of Study 
After the end of the study, each subject will be treated according to standard clinical practice. 
9.9 
Dispensing and Storage 
The test product supplied by CALI is to be used exclusively in the clinical study according to the 
instructions of this protocol. The investigator is responsible for dispensing the IP according to the 
dosage scheme and for ensuring its proper storage. 
The investigator must confirm the receipt of the IP with his or her signature. A copy of this receipt 
must be kept by the investigator and another copy will be stored at Rho. Until the IP is dispensed 
to subjects, CPL-01 must be stored at 2 to 8°C in a securely locked area that is not generally 
accessible. Placebo can be stored at room temperature in a securely locked area. 
The key to the storage area is to be kept by the investigator or designee responsible for the IP. The 
store will be accessible only to those persons authorized by the investigator to dispense the IP. 


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9.10 Drug Accountability 
The investigator must maintain adequate records showing the receipt, dispensing, return, or other 
disposition of the IPs, including the date, quantity, batch or code number, and identification of 
subjects (subject number and initials) who received them. The investigator will not supply the IPs 
to any person, except those named as subinvestigators on Form FDA 1572, designated study 
personnel, and subjects in this study. The investigator will not dispense the IPs from any study 
sites other than those listed on Form FDA 1572. The IPs may not be relabeled or reassigned for 
use by other subjects. If any of the IPs are not dispensed, are lost, stolen, spilled, unusable, or are 
received in a damaged container, this information must be documented and reported to the sponsor 
and appropriate regulatory agencies, as required. 
Drug accountability will be monitored by an unblinded CRA during the study. Their reports will 
go to an unblinded clinical manager who will review them for accuracy. These will not be provided 
to the sponsor during the study but will be placed in the eTMF until after the study is unblinded. 
9.11 Labeling and Packaging 
CPL-01 will be packaged in vials and labeled with study-specific information meeting all 
applicable regulatory requirements. 
Save all empty packaging or packaging containing unused IP for final disposition by the sponsor 
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10 STUDY PROCEDURES 
Subjects must provide written informed consent before any study-related procedures are initiated, 
including the cessation of prohibited concomitant therapy. 
For the timing of assessments and procedures throughout the study, refer to the schedule of events 
(Section 2.2). Throughout the study, every reasonable effort should be made by study personnel to 
follow the timing of assessments and procedures in the schedule of events for each subject. If a 
subject misses a study visit for any reason, the visit should be rescheduled as soon as possible. 
10.1 Study Duration 
The overall study duration is expected to be approximately 3 months. 
The planned sequence and maximum duration of the study periods for each subject will be as 
follows: 
1. Screening period: 42 days 
2. Surgical/anesthesia period: 1 day 
3. Post-anesthesia period: 4 days 
4. Post-treatment follow-up: 
Days 5 and 6 Assessments: 2 days 
Day 7-10 Follow-up Visit: 7 to 10 days after administration of IP 
Day 30 Follow-up Visit: 30 days after administration of IP 
The maximum study duration for each subject is approximately 73 days. 
10.2 Study Periods and Visits 
Subjects must be at rest for a minimum of 15 minutes in the resting position before any assessments 
are performed during each study visit, unless otherwise indicated. 
10.2.1 Screening Period (-42 Days to -1 Day Before Surgery) 
The subject must be screened within 42 days before surgery. The following procedures will be 
performed at Screening: 
• Obtain written informed consent. 
• Assess inclusion/exclusion criteria. 
• Collect demographic information. 
• Record medical history and concomitant medications. 
• Perform a full neurological examination.  
• Perform a complete physical examination.  
• Measure vital signs (resting blood pressure, heart rate, respiratory rate, and oral body 
temperature) after the subject has been in a resting position for 5 minutes. 
• Measure height, weight, and confirm BMI. 
• Perform 12-lead ECG. 


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• Collect blood and urine samples for clinical laboratory evaluations (hematology, 
chemistry, and urinalysis). 
• Collect blood samples for serology tests (HIV, hepatitis B surface antigen, and hepatitis C 
virus antibody). 
• For women of childbearing potential, perform serum pregnancy test. 
• Perform a urine drug screen to test for amphetamines, barbiturates, benzodiazepines, 
cocaine, opiates, phencyclidine, and tetrahydrocannabinol. 
• Train subjects how to use NRS. 
Prior to enrollment in the study subjects must not be taking prohibited therapies (see Section 9.7.2). 
10.2.2 Surgical/Anesthesia Period (Day 1 through Hour 1, Confinement) 
Subjects will be confined to the study site from Day 1 through Day 4. 
The following procedures will be performed on Day 1 through Hour 1: 
• At check-in, confirm inclusion/exclusion criteria. 
• At check-in, record medical history. 
• Any time prior to anesthesia induction, perform a full neurological examination. 
• At check-in, measure vital signs (resting blood pressure, heart rate, respiratory rate, and 
oral body temperature) after the subject has been in a resting position for 5 minutes. 
• For women of childbearing potential, perform urine pregnancy test at check-in. 
• At check-in, perform urine drug screen to test for amphetamines, barbiturates, 
benzodiazepines, cocaine, opiates, phencyclidine, and tetrahydrocannabinol. 
• Before surgery, train subjects how to use NRS. 
• Before surgery, assign randomization number. 
• Perform 12-lead ECG immediately prior to induction of anesthesia. 
• Administer general anesthesia according to a standard regimen (Appendix D) and perform 
mini-abdominoplasty. At the end of the surgical procedure but before the wound is closed, 
administer the IP by wound infiltration and instillation. Begin continuous pulse oximetry 
immediately after surgery, and continue throughout transport and in the post-anesthesia 
care unit until the subject switches from intravenous morphine to oral rescue analgesia 
medication. If O2 saturation drops below 93% or if the subject has clinical signs or 
symptoms that suggest respiratory depression while on the oral medication, or the subject 
switches back to intravenous morphine, keep the subject on continuous pulse oximetry as 
required. 
• Collect blood samples for PK analysis at baseline (before IP administration), 15, 30, and 
45 minutes after administration of IP (± 5 minutes). 
• Subjects with inadequately controlled pain symptoms may request rescue analgesia. Pain 
intensity using an NRS will be recorded just prior to receiving rescue analgesia. After 


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administration of the IP, rescue analgesia will be restricted to 2 to 4 mg of intravenous 
morphine every hour as needed until the subject is able to tolerate oral medication. 
• Record concomitant medications 
• Collect AEs. 


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10.2.3 Post-anesthesia Period (Day 1, Hour 1 through Day 4, Confinement) 
The following procedures will be performed at Day 1, Hour 1 through Day 4 during confinement 
at the study site: 
• Continue to monitor continuous pulse oximetry until the subject switches from intravenous 
morphine to oral rescue analgesia medication. If O2 saturation drops below 93% or if the 
subject has clinical signs or symptoms that suggest respiratory depression while on the oral 
medication, or subject switches back to intravenous morphine, keep the subject on 
continuous pulse oximetry as required. 
• Perform LAST assessment every 4 hours on Day 1 and at least once daily on Days 2 and 3 
using the following: vital signs (resting blood pressure, heart rate, respiratory rate, and oral 
body temperature), RASS assessment (Appendix A), and a focused neurological 
examination. Vital signs should be measured after the subject has been in a resting position 
for 5 minutes. If abnormal neurological findings are observed during the LAST assessment, 
a full neurological examination will be performed. If any signs or symptoms of LAST are 
observed, including a change in the ECG, the following will be performed: unscheduled 
PK sample collection, 12- lead ECG, and vital sign measurements.  
• Perform 12-lead ECG at 1, 2, 4, 8, 10, 12, 24, 48, and 72 hours after IP administration. 
• Assess pain intensity using an NRS at 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16, 24, 32, 40, 48, 56, 
64, and 72 hours after administration of IP. Additionally, pain intensity using an NRS will 
be recorded just prior to receiving rescue analgesia. 
• Subjects with inadequately controlled pain symptoms may request rescue analgesia.  
o After administration of the IP, rescue analgesia will be restricted to 2 to 4 mg 
intravenous morphine every hour as needed until the subject is able to tolerate oral 
medication.  
o Once oral medication can be tolerated, oxycodone 5 to 10 mg every 3 to 4 hours 
will be used as needed for analgesia.  
o After the subject’s pain intensity is ≤4, oral acetaminophen 1000 mg will be used 
every 6 to 8 hours as needed for analgesia (not to exceed 4 g within 24 hours).  
o For breakthrough pain intensity >4 that is not relieved by the oral acetaminophen, 
oral oxycodone 5 to 10 mg every 3 to 4 hours as needed for pain may continue to 
be used.  
o For breakthrough severe pain intensity >8, intravenous morphine 2 to 4 mg every 
hour as needed may be allowed. 
• Perform surgical wound site assessment by direct visualization, including photograph at 
24, 48, and 72 hours after administration of IP.  
o Record the numerical rating score on the eCRF (see Appendix B) and photograph 
the wound area (see Appendix C for instructions).  
o Instruct subjects to call with any concerns about the appearance of the wound after 
being discharged from the study site. If subjects call with concerns, they will be 
asked to return to the study site for an unscheduled visit. 


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• Collect PK blood samples at 1, 2, 4, 6, 8, 10, 12, 18, 24, 30, 36, 48 (Day 2), 60 (Day 3), 
and 72 hours (Day 4) after administration of IP (± 5 minutes for samples taken at 1 hour 
and ± 10 minutes for the remainder of the samples). 
• Record concomitant medications. 
• Collect AEs. 
• Give subject a diary to record their pain intensity (using NRS), and rescue medication usage 
when they are discharged from the study site. Instruct subjects to complete the diary daily 
until they return to the study site for the Day 7-10 Follow-up Visit (7 to 10 days after 
administration of IP or upon early termination).  


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10.2.4 Post-treatment Follow-up Period 
After discharge, on non-visit days prior to the Day 7-10 Follow-up Visit, conduct a brief daily 
telephone call to remind subjects to record their pain intensity (using NRS), and rescue medication 
usage in the diary. 
10.2.4.1 Days 5 and 6 
Subjects will return to the study site on Days 5 and 6 to have the following procedures performed: 
• Perform a 12-lead ECG on Day 5 only. 
• Collect PK blood sample at 96 (Day 5) and 120 (Day 6) hours after administration of IP 
(± 1 hour). 
• Assess pain intensity using an NRS at 96 (Day 5) and 120 hours (Day 6) after 
administration of IP. 
• Perform surgical wound site assessment by direct visualization including photograph 96 
(Day 5) and 120 hours (Day 6) after administration of IP. Record the numerical rating score 
on the eCRF (Appendix B) and photograph the wound area (see Appendix C instructions). 
Instruct subjects to call with any concerns about the appearance of the wound after being 
discharged from the study site. If subjects call with concerns, they will be asked to return 
to the study site for an unscheduled visit. 
• Collect AEs. 
10.2.4.2 Day 7-10 Follow-up Visit (7 to 10 days after Administration of Investigational 
Product or Upon Early Termination) 
The following procedures will be performed at the Day 7-10 Follow-up Visit: 
• Collect completed diary from the subject. 
• Perform a full neurological examination. 
• Perform abbreviated physical examination (changes since Screening). 
• Measure vital signs (resting blood pressure, heart rate, respiratory rate, and oral body 
temperature) after the subject has been in a resting position for 5 minutes. 
• Perform 12-lead ECG. 
• Collect blood for clinical laboratory evaluations  
• Perform surgical wound site assessment by direct visualization including photograph. 
Record the numerical rating score on the eCRF (see Appendix B) and photograph the 
wound area (see Appendix C for instructions). 
• Record concomitant medications 


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• Collect AEs. 
10.2.4.3 Day 30 Follow-up Visit (30 days After Administration of IP) 
Thirty days after administration of IP, record AEs and concomitant medications and perform 
surgical wound site assessment by direct visualization including photograph. Record the numerical 
rating score on the eCRF (see Appendix B) and photograph the wound area (see Appendix C for 
instructions). 
10.3 Assessments 
10.3.1 Safety  
Safety will be assessed based on AEs, vital signs, clinical laboratory assessments, 12-lead ECGs, 
physical examination, full neurological examination, LAST assessment, and wound evaluation. 
10.3.1.1 Clinical Laboratory Safety Assessments 
10.3.1.1.1 Clinical Laboratory Tests to be Performed 
Samples for the following laboratory tests will be collected at the time points specified in the 
schedule of events (Section 2.2). 
Hematology: 
hemoglobin, hemoglobin A1c, hematocrit, red blood cell (RBC) count, 
RBC indices, mean corpuscular hemoglobin, mean corpuscular 
hemoglobin concentration, platelet count (or estimate), white blood cell 
count including differential 
Serum Chemistry: 
albumin, total bilirubin, total protein, calcium, alkaline phosphatase, 
alanine aminotransferase, aspartate aminotransferase, blood urea nitrogen, 
creatinine, glucose, sodium, potassium, chloride, bicarbonate, lactate 
dehydrogenase, uric acid 
Coagulation Panel: prothrombin time, partial thromboplastin time, fibrinogen 
Urinalysis: 
pH, specific gravity, blood, glucose, protein, ketones 
Pregnancy test 
urine/serum: 
for women of childbearing potential only 
Urine Drug Screen: amphetamines, 
barbiturates, 
benzodiazepines, 
cocaine, 
opiates, 
phencyclidine, and tetrahydrocannabinol  
Blood and urine samples for hematology, serum chemistry, coagulation panel, serum pregnancy 
test, and urinalysis will be sent to a local laboratory for analyses. Urine drug screens and pregnancy 
tests will be conducted at the study site. 
10.3.1.1.2 Specimen Handling Requirements 
The transmission of infectious agents may occur through contact with contaminated needles and 
blood or blood products. Consequently, appropriate blood and body fluid precautions should be 
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both the clinic and laboratory settings. Refer to current recommendations of the appropriate 
authorities. 
In addition to appropriate handling of subject samples, specific regulations exist regarding the 
shipment of biologic/etiologic samples. The investigator is responsible for ensuring that all study 
samples that are to be transported to another location are packed and shipped appropriately 
according to the applicable regulations.  
10.3.1.1.3 Evaluation of Clinical Laboratory Values 
The normal ranges of values for the clinical laboratory assessments in this study will be provided 
by the responsible laboratory and submitted to CALI prior to the beginning of the study. They will 
be regarded as the reference ranges on which decisions will be made. 
If a laboratory value is out of the reference range, it is not necessarily clinically relevant. The 
investigator must evaluate the out-of-range values and record his or her assessment of the clinical 
relevance in the appropriate eCRF. 
All clinical laboratory values that in the investigator’s opinion show clinically relevant or 
pathological changes during or after termination of treatment must be reported as AEs and 
followed, as described in Section 11.2.5. 
All measurements described in this section are recognized standard methods. 
10.3.1.2 Clinical Examinations 
10.3.1.2.1 Pulse Oximetry 
Continuous pulse oximetry will be monitored immediately following surgery, throughout 
transport, and in the post-anesthesia care unit until subjects switch from intravenous morphine to 
oral rescue analgesia medication. If O2 saturation drops below 93% or if subjects have clinical 
signs or symptoms that suggest respiratory depression while on the oral medication, or subjects 
switch back to intravenous morphine, they will be kept on continuous pulse oximetry as required. 
Single-point pulse oximetry values will be recorded as part of each vital sign assessment. 
10.3.1.2.2 Vital Signs 
Vital signs (resting blood pressure, heart rate, respiratory rate, and oral body temperature) will be 
measured after the subject has been in a resting position for 5 minutes. 
Vital signs will be measured and recorded at Screening, at check-in on Day 1, every 4 hours after 
IP administration on Day 1 and at least once daily on Days 2 and 3 (as part of the LAST 
assessment), and at the Day 7-10 Follow-up Visit.  
10.3.1.2.3 Twelve-lead Electrocardiogram 
A standard 12-lead ECG will be performed after the subject has been resting for at least 5 minutes 
at Screening, immediately prior to induction of anesthesia, and at 1, 2, 4, 8, 10, 12, 24, 48, 72, and 
96 hours after IP administration; and at the Day 7-10 Follow-up Visit. All ECG recordings will be 


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identified with the subject number, initials, date, and time of the recording and will be attached to 
the subject’s eCRF. 
10.3.1.2.4 Physical Examination 
A complete physical examination will be performed at Screening (including height and weight). 
An abbreviated physical examination (changes since Screening), will be performed at the Day 7-10 
Follow-up Visit (7 to 10 days after administration of IP or upon early termination). 
10.3.1.2.5 Full Neurological Examination 
A full neurological examination will be performed at Screening, on Day 1 prior to anesthesia 
induction, and at the Day 7-10 Follow up Visit or upon early termination. The full neurological 
examination will include a mental status examination and evaluation of cranial nerve, motor, 
sensory, cerebellar function. 
The findings will be summarized in a neurologic assessment. The examiner will be asked to record 
whether the subject’s overall neurologic status is normal or abnormal. 
10.3.1.2.6 Local Anesthetic Systemic Toxicity Assessment 
Signs and symptoms of LAST will be monitored every 4 hours on Day 1 and at least once daily 
on Days 2 and 3 using the following: vital signs, RASS assessment (provided in Appendix A), and 
a focused neurological examination. If abnormal neurological findings are observed during the 
LAST assessment, a full neurological examination will be performed. If any signs or symptoms of 
LAST are observed, including a change in the ECG, the following will be performed: unscheduled 
PK sample collection, 12- lead ECG, and vital sign measurements. 
Vital signs (resting blood pressure, heart rate, respiratory rate, and oral body temperature) will be 
measured after the subject has been in a resting position for 5 minutes. The RASS is a validated 
and reliable method to assess patients’ level of agitation and sedation in the intensive care unit. 
The focused neurological examination will include a basic mental status examination and an 
evaluation to see if the subject is tremulous or complaining of any unusual symptoms (e.g., perioral 
paresthesias, metallic taste, or dizziness). 
10.3.1.2.7 Wound Evaluation 
Study site staff will evaluate the wound at 24, 48, 72, 96 (Day 5), and 120 hours (Day 6) after IP 
administration, at the Day 7-10 Follow-up Visit (7 to 10 days after administration of IP), and at 
the Day 30 Follow-up Visit. Surgical wound site assessment will be performed by direct 
visualization and recording the numerical rating score on the eCRF (see Appendix B). 
Additionally, study site staff will photograph the wound area following the standardized 
instructions (Appendix C). Subjects will be instructed to call with any concerns about the 
appearance of the wound after being discharged from the study site. If subjects call with concerns, 
they will be asked to return to the study site for an unscheduled visit. 


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10.3.1.3 Adverse Events 
The definitions and management of AEs, and any special considerations for AEs, are provided in 
Section 11. 
10.3.2 Pharmacokinetic Evaluation 
Blood samples (approximately 3 mL each) for PK assessments will be collected via indwelling 
intravenous catheter. Plasma ropivacaine concentrations will be quantified using a validated 
LC-MS/MS assay method. All samples for all time points should be collected within the scheduled 
sampling windows (± 5 minutes for samples taken during the first hour, ± 10 minutes for the 
samples taken at 2 through 72 hours after administration of IP, and ± 1 hour for samples taken at 
96 and 120 hours after administration of IP). The exact time of blood sampling will be recorded in 
the source documents. 
Pharmacokinetic samples will be shipped to a central laboratory for analysis. 
10.3.2.1 Pharmacokinetic Sampling Assessments 
Plasma ropivacaine concentrations will be measured from blood samples collected at the following 
time points: baseline (before IP administration), 15, 30, and 45 minutes, and at 1, 2, 4, 6, 8, 10, 12, 
18, 24, 30, 36, 48, 60, 72, 96, and 120 hours after administration of IP. 
10.3.2.1.1 Pharmacokinetic Parameters 
Pharmacokinetic parameter estimates will be completed using Phoenix WinNonlin, Version 6.4 or 
higher (Pharsight Corporation). Actual sampling times will be used for all parameter estimation. 
The following PK parameters will be calculated from ropivacaine: 
• Cmax: maximum (peak) plasma concentration 
• tmax: time to reach highest observed (peak) concentration in plasma following IP 
administration 
• t1/2: elimination half-life 
• λz: terminal elimination rate constant with the respective t1/2 
• AUC0-last: area under the plasma concentration-time curve (AUC) from Time 0 to time of 
last quantifiable plasma concentration (Time 0 is defined as the moment that IP is 
administered) 
• AUC0-∞: AUC from Time 0 to infinity 
Other parameters may be calculated as appropriate and if data permit. 


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10.3.3 Efficacy 
10.3.3.1 Numeric Rating Scale 
Pain intensity will be assessed using an NRS at 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16, 24, 32, 40, 48, 56, 
64, 72, 96, and 120 hours after administration of IP. Additionally, pain intensity using an NRS will 
be recorded just prior to receiving rescue analgesia. 
The NRS is an 11-point scale from 0 to 10. The subject will rate his or her current pain intensity 
using the following question: “On a scale from 0 to 10, where “zero” represents “no pain” and 
“10” represents “the worst possible pain,” how would you rate your current pain?” 
10.3.3.2 Opioid Rescue Analgesia Use 
The use of opioid rescue analgesia will be assessed as follows: 
• Total use of opioid rescue analgesia (morphine equivalents) over 1 to 24 hours 
• Total use of opioid rescue analgesia (morphine equivalents) over 1 to 48 hours 
• Total use of opioid rescue analgesia (morphine equivalents) over 1 to 72 hours 
• Time to first use of opioid rescue analgesia 
 
 


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11 ADVERSE EVENTS 
11.1 Definitions 
11.1.1 Adverse Events (AEs) 
An AE is defined as any untoward medical occurrence in a subject or clinical investigation subject 
administered a pharmaceutical product that does not necessarily have a causal relationship with 
this treatment. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding, for example), symptom, or disease temporally associated with the 
use of a medicinal product, whether or not related to the medicinal product. 
Pre-existing diseases or conditions will not be considered AEs unless there is an increase in the 
frequency or severity, or a change in the quality, of the disease or condition. (Worsening of a 
pre-existing condition is considered an AE.) 
Events that occur in subjects treated with placebo are also considered AEs. 
11.1.2 Serious Adverse Events (SAEs) 
An SAE is any untoward medical occurrence that at any dose: 
• Results in death 
• Is life-threatening 
NOTE: The term “life-threatening” in the definition of “serious” refers to an event in which 
the subject was at risk of death at the time of the event; it does not refer to an event that 
hypothetically might have caused death if it were more severe. 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
NOTE: An elective hospital admission to treat a condition present before exposure to the 
IP, or a hospital admission for a diagnostic evaluation of an AE, does not qualify the 
condition or event as an SAE.  
• Results in persistent or significant disability/incapacity 
• Is a congenital anomaly 
NOTE: A congenital anomaly in an infant born to a mother who was exposed to the IP 
during pregnancy is an SAE. However, a newly diagnosed pregnancy in a subject that has 
received IP is not considered an SAE unless it is suspected that the IP(s) interacted with a 
contraceptive method and led to the pregnancy.  
• Is an important medical event 
NOTE: Medical and scientific judgment should be exercised in deciding whether it is 
appropriate to consider other situations serious, such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may jeopardize 
the subject or may require intervention to prevent one of the other outcomes listed in the 
definition above. Examples of such events are intensive treatment in an emergency room 
or at home for allergic bronchospasm, blood dyscrasias, or convulsions that do not result 
in hospitalization, development of drug dependency, or drug abuse.  


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11.1.3 Treatment-Emergent Adverse Events 
An AE is defined as treatment emergent if the first onset or worsening is after administration of 
the IP (CPL-01 or placebo) and not more than 30 days after administration of IP. 
11.2 Event Assessment and Follow-up of Adverse Events 
The occurrence of an AE or SAE may come to the attention of study personnel during study visits 
and interviews of a study participant presenting for medical care or upon review by a study 
monitor. 
All AEs including local and systemic reactions not meeting the criteria for SAEs will be captured 
on the appropriate eCRF. Information to be collected includes event description, time of onset, 
clinician’s assessment of severity, relationship to study product (assessed only by those with the 
training and authority to make a diagnosis), and time of resolution/stabilization of the event. All 
AEs occurring while on study must be documented appropriately regardless of relationship. All 
AEs will be followed to adequate resolution. 
Any medical condition that is present at the time that the participant is screened will be considered 
as baseline and not reported as an AE. However, if the study participant’s condition deteriorates 
at any time during the study, it will be recorded as an AE.  
Changes in the severity of an AE will be documented to allow an assessment of the duration of the 
event at each level of severity to be performed. Adverse events characterized as intermittent require 
documentation of onset and duration of each episode. 
Adverse events will be collected from the time of signing the ICF through the Day 30 Follow-up 
Visit (30 days after administration of IP) or upon early termination, whichever occurs first. 
Throughout the study, the investigator will inquire about the occurrence of AE/SAEs since the last 
visit. Events will be followed for outcome information until resolution or stabilization. 
11.2.1 Assessment 
The investigator is responsible for the detection and documentation of events meeting the criteria 
and definition of an AE or SAE described previously. Throughout the study, the subject will be 
allowed time to spontaneously report any issues since the last visit or evaluation. The investigator 
will then monitor and/or ask about or evaluate AEs using nonleading questions, such as the 
following: 
• “How are you feeling?” 
• “Have you experienced any issues since your last visit?” 
• “Have you taken any new medications since your last visit?” 
Any clinically relevant observations made during the visit will also be considered AEs. 


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11.2.2 Evaluation 
11.2.2.1 Severity of Adverse Events 
The clinical severity of an AE will be classified as: 
Mild 
Usually transient and may require only minimal treatment or therapeutic 
intervention. The event does not generally interfere with usual activities of 
daily living. 
Moderate 
Usually alleviated with additional specific therapeutic intervention. The event 
interferes with usual activities of daily living, causing discomfort but poses no 
significant or permanent risk of harm to the subject. 
Severe 
Interrupts usual activities of daily living, or significantly affects clinical status, 
or may require intensive therapeutic intervention. 
It is important to distinguish between severe AEs and SAEs. Severity is a classification of intensity 
whereas an SAE is an AE that meets serious criteria, as described in Section 11.1.2. 
11.2.2.2 Seriousness 
The investigator is to evaluate whether the AE meets serious criteria, as described in 
Section 11.1.2. 
11.2.2.3 Action(s) Taken with Investigational Product 
Action(s) taken may consist of: 
None 
 
Not applicable 
Determination of a value is not relevant in the current context. 
Discontinued 
IP discontinued due to the adverse event 
11.2.2.4 Outcome at the Time of Last Observation 
The outcome at the time of last observation will be classified as: 
• Recovered/resolved 
• Recovered/resolved with sequelae 
• Recovering/resolving 
• Not recovered/not resolved 
• Fatal* 
• Unknown 
*Only select fatal as an outcome when the AE results in death. If more than 1 AE is judged to be 
possibly related to the subject’s death, the outcome of death should be indicated for each such AE. 
Although “fatal” is usually an event outcome, events such as sudden death or unexplained death 
should be reported as SAEs. 


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11.2.2.5 Adverse Event Relationship to the Investigational Product 
The investigator must make an assessment of each AE’s relationship to the IP. The categories for 
classifying the investigator’s opinion of the relationship are as follows: 
Not related 
An AE with sufficient evidence to accept that there is no causal relationship 
to IP administration (e.g., no temporal relationship to drug administration, 
because the drug was administered after onset of event; investigation shows 
that the drug was not administered; another cause was proven.) 
Unlikely 
related 
An AE, including laboratory test abnormality, with a temporal relationship to 
IP administration that makes a causal relationship possible but other drugs, 
events, or underlying disease provide a far more likely explanation. 
Potentially 
related 
An AE with a reasonable time sequence to administration of the IP, but that 
could also be explained by concurrent disease or other drugs or events. 
Information on drug withdrawal may be lacking or unclear. 
Probably 
related 
An AE with evidence to suggest a causal relationship, and the influence of 
other factors is unlikely. The clinical event, including an abnormal laboratory 
test result, occurs within a reasonable time after administration of the study 
intervention, is unlikely to be attributed to concurrent disease or other drugs 
or chemicals.  
Definitely 
related 
An AE occurring in a plausible time relationship to IP administration and that 
cannot be explained by a concurrent disease or other drugs or events.  
11.2.3 Documentation 
All AEs that occur within the period of AE collection for the study must be documented in the 
eCRF with the following information, where appropriate. (The period of AE collection for the 
study is described in Section 11.2.) 
• AE name or term 
• When the AE first occurred (start date and time) 
• When the AE stopped (stop date and time or an indication of “ongoing”) 
• Severity of the AE 
• Seriousness (hospitalization, death, etc.) 
• Actions taken 
• Outcome 
• Investigator opinion regarding the AE relationship to the IPs 
11.2.4 Treatment of Adverse Events 
Adverse events that occur during the study will be treated, if necessary, by established standards 
of care. The decision about whether the subject may continue in the study will be made by the 
sponsor after consultation with the investigator and/or medical monitor. 


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If AEs occur in a subject that are not tolerable, the investigator must decide whether to stop the 
subject’s involvement in the study and/or treat the subject. Special procedures may be 
recommended for the specific IP, such as the collection of a serum sample for determining blood 
concentrations of IP, or treatment regimens, as appropriate. 
For double-blinded studies, it is not necessary to unblind a subject’s treatment assignment in most 
circumstances, even if an SAE has occurred. If unblinding is necessary, see Section 9.6 for a 
description of the unblinding procedures. 
11.2.5 Follow-up 
All nonserious AEs that are not related or unlikely to be related to IP will be followed until the end 
of study participation. All SAEs or AEs possibly, probably, or definitely related to treatment will 
be followed until resolution or stabilization. All findings relevant to the final outcome of an AE 
must be reported in the subject’s medical record and recorded on the eCRF page.  
11.2.6 Reporting 
11.2.6.1 Serious Adverse Events 
The investigator or designee must report all SAEs promptly to Rho Product Safety (PS) within 
24 hours of first becoming aware of the event by completing the SAE eCRF in RAVE EDC. Rho 
PS contact information:  
Email: rho_productsafety@rhoworld.com 
SAE Fax number: 1-888-746-3293 
SAE Help Line: 1-888-746-7231 
Rho Medical Monitor email: MedicalMonitorSupport@rhoworld.com 
A paper report should only be submitted if RAVE is not available. A paper SAE form is provided 
for this purpose in the Study Operation’s Manual. At the time of first notification, the investigator 
or designee should provide the following information: 
• Reporter (study site and investigator) 
• Subject’s study number 
• Date of IP administration 
• AE term 
• Date of occurrence of the event 
• A brief description of the event, outcome to date, and any actions taken 
• The seriousness criteria(on) that were met 
• Investigator’s opinion of the relationship to the IP (“Is there a reasonable possibility that 
the IP caused the SAE? Yes or No?”) 
• Whether and when the investigator was unblinded as to the subject’s treatment 
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Any missing or additional relevant follow-up information concerning the SAE must be reported 
by the investigator via RAVE in the same timeframes.   
Specific information may be requested by Rho PS using a follow-up request form or via email 
communication. 
The investigator is required to comply with applicable regulations (including local laws and 
guidances) regarding the notification of his or her health authorities, institutional review board 
(IRB), principal and coordinating investigators, study investigators, and institutions. Each 
investigator is obligated to learn about the reporting requirements for investigators in his or her 
country. 
11.2.6.2 Nonserious Adverse Events 
Nonserious AEs will be recorded in the eCRF and each will be classified according to the 
aforementioned criteria. If a non-serious AE becomes serious, the SAE must be reported to Rho 
PS within 24 hours as described above.  
11.3 Special Considerations 
11.3.1 Adverse Events of Special Interest 
The following will be considered AEs of special interest because they are common symptoms 
of LAST.   
• Neurological signs/symptoms – circumoral and/or tongue numbness, metallic taste, 
lightheadedness and/or dizziness, visual (e.g. difficulty focusing vision) and/or 
auditory disturbances (e.g. tinnitus), disorientation, drowsiness (to an unexpected 
or unusual degree), agitation or seizures. 
• Cardiorespiratory signs/symptoms – hypotension that is clinically significant or sustained, 
clinically significant (new and/or sustained) arrhythmia, cardiac or respiratory arrest. 
11.3.2 Pregnancy 
All women of childbearing potential who participate in the study should be counseled on the need 
to practice adequate birth control and on the importance of avoiding pregnancy during study 
participation. Women should be instructed to contact the investigator or study staff immediately if 
pregnancy occurs or is suspected. 
For women of childbearing potential, pregnancy testing will be conducted at screening and at 
check-in. A woman who is found to be pregnant at the Screening Visit or at check-in will be 
excluded from the study and considered to be a screening failure. 
A woman who becomes pregnant within 30 days of administration of the IP, will continue in the 
study for follow-up safety assessments. The investigator must report the pregnancy within 
24 hours of learning of the pregnancy, to Rho PS. The pregnancy will be reported on the Pregnancy 
eCRF in RAVE EDC. The outcome of all pregnancies will be followed and documented by Rho 
PS.  
Early termination visit assessments are required as soon as possible after learning of the pregnancy. 
The investigator is also responsible for following the pregnancy until delivery or termination. 


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These findings must be reported on the Pregnancy eCRF in RAVE EDC. . The pregnancy event 
meets the SAE criterion only if it results in a spontaneous abortion or a congenital anomaly. 


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12 DATA SAFETY MONITORING BOARD 
A data safety monitoring board will not be used in this study.  


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13 STATISTICS 
13.1 Statistical Analysis 
This section presents a summary of the planned statistical analyses. A statistical analysis plan 
(SAP) that describes the details of the analyses to be conducted will be written prior to database 
lock.  
Unless otherwise indicated, all statistical tests will be carried out at a two-sided significance level 
of 5%. Given that all efficacy assessments are considered as exploratory only and are intended to 
in to inform future trials, no multiplicity adjustment shall be applied to these exploratory analyses. 
Summary statistics will be provided for the variables described below. For continuous variables, 
these statistics will typically include the number of subjects, mean, standard deviation (SD), 
median, minimum, and maximum. For categorical variables, these statistics will typically include 
the number and percentage of subjects in each category. 
Additional exploratory analyses may be carried out as deemed necessary and specified in the SAP. 
13.1.1 Analysis Populations 
The following 3 analysis populations are planned for this study:  
• Intent-to-treat (ITT) Population: all subjects who are successfully screened and 
randomized. The ITT population is the primary population for the efficacy analysis. 
• Safety Population: all subjects who are treated with IP. The Safety population is the 
population for all safety analyses. 
• PK Population: all subjects who receive IP during surgery and who have at least 
1 measurable plasma concentration. All PK analyses will be based on the PK population. 
In the event that a subject is administered the incorrect IP, analyses of the ITT population will be 
based on the randomized treatment, whereas analyses of the Safety population will be based on 
the actual treatment received. 
13.1.2 Study Subjects and Demographics 
13.1.2.1 Disposition and Withdrawals 
The numbers of subjects randomized, receiving IP, and withdrawing, along with reasons for 
withdrawal, will be tabulated overall and by treatment group. The number of subjects in each 
analysis population will be reported. 
13.1.2.2 Protocol Deviations 
A protocol deviation is any noncompliance with the clinical trial protocol or International Council 
for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Good 
Clinical Practice (GCP) requirements. The noncompliance may be either on the part of the 
participant, the investigator, or the study site staff. Protocol deviations will be recorded on the 
source documents and with an explanation for the deviation. All protocol deviations will also be 
recorded as specified in the monitoring plan. 


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Major protocol deviations are defined as those that result in harm to the study patients or 
significantly affect the scientific value of the reported results of the study. Other deviations will 
be considered minor. 
Major protocol deviations that meet the criteria for a serious breach of ICH GCP should be reported 
to the sponsor immediately. No deviation from the inclusion/exclusion criteria shall be permitted. 
Protocol deviations will be listed. 
13.1.2.3 Demographics and Other Baseline Characteristics 
Demographic and baseline characteristics (including age, gender, race, weight, height, and BMI) 
will be summarized for each treatment group and for the overall population using descriptive 
statistics. Medical history will be displayed in a listing. 
Prior and concomitant medications will be summarized by treatment group, by the number and 
percentage of subjects taking each medication, classified using World Health Organization Drug 
Dictionary Anatomical Therapeutic Chemical classes and preferred terms (PTs). 
13.1.3 Exposure and Compliance 
The number of subjects who successfully receive IP will be summarized as part of subject 
disposition. 
13.1.4 Pharmacokinetics 
The PK parameters will be estimated using non-compartmental PK analysis for each subject with 
sufficient data to characterize the administered dose. These parameters will be summarized and a 
mean concentration figure with plots will be produced both with a linear y-axis and with a 
log-y axis. Individual concentrations will be listed, graphed, and summarized by scheduled 
sampling time.  
13.1.5 Safety and Tolerability Analyses 
Summaries of safety results will be presented by treatment group for the safety analysis population 
(as defined in Section 13.1.1). Safety variables include treatment-emergent AEs, clinical 
laboratory values, vital signs, ECG readings, full neurological examination results, LAST 
assessment results, wound evaluation, and physical examination results. No formal inferential 
analyses will be conducted for safety variables, unless otherwise noted. 
13.1.5.1 Adverse Events 
All AEs will be coded using the latest version of the Medical Dictionary for Regulatory Activities.  
Treatment-emergent AEs are defined as: 
• AEs with onset at the time of or following administration of the IP through the Day 30 
Follow-up Visit or Early Termination Visit, whichever occurs first, or 
• AEs starting prior to the administration of the IP but increasing in severity or relationship 
at the time of, or following, administration of the IP through the Day 30 Follow-up Visit 
or Early Termination Visit, whichever occurs first. 


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The number and percentage of subjects with treatment-emergent AEs will be summarized for each 
treatment group by system organ class (SOC), PT, and treatment group. Serious AEs will be 
summarized in a similar fashion. Treatment-emergent AEs and SAEs will also be presented by 
severity and by relationship. All AEs will be presented in full in a comprehensive listing. Details 
of SAEs and AEs leading to withdrawal will be listed separately.  
13.1.5.2 Clinical Laboratory Evaluations 
Descriptive summaries (mean, SD, median, minimum, and maximum) of observed (absolute) 
values and changes from baseline values will be presented for clinical laboratory values for each 
treatment group at each time point. 
The number of subjects with clinical laboratory values categorized as below, within, or above 
normal ranges, will be tabulated showing change from baseline (shift tables) for each clinical 
laboratory analyte by treatment group and by study visit.  
Laboratory values that are outside the normal range will also be flagged in the data listings and 
presented with the corresponding normal ranges. Any out-of-range values that are identified by 
the investigator as being clinically significant will also be shown in a data listing. 
13.1.5.3 Vital Signs 
Descriptive summaries of observed values and changes from baseline for vital signs measurements 
will be presented by study visit and by study group.  
13.1.5.4 Twelve-lead Electrocardiograms 
The number and percentage of subjects with normal and abnormal ECG findings will be 
summarized for each treatment group at each time point. Abnormal results will be grouped as 
“abnormal, clinically significant” and “abnormal, not clinically significant,” and summarized in 
the same way. A by-subject listing of abnormal ECG findings will be provided. 
Descriptive summaries of observed values and changes from baseline will be presented for ECG 
measures of PR interval, QRS interval, QT interval, QTc interval (Bazett’s and Fridericia’s 
correction methods), and HR for each treatment group at each time point. In addition, the number 
and percent of subjects in each treatment group who experienced a change in QT and QTc interval 
of >30 ms or a change >60 ms will be presented. 
Descriptive summaries (mean, SD, median, minimum, and maximum) will be presented for ECG 
measures of PR interval, QRS interval, QT interval, QTc interval (both correction methods), and 
HR for each treatment group at each time point. 
13.1.5.5 Wound Evaluation 
A descriptive summary of the surgical wound site assessment findings (including wound infection 
and wound-related AEs) at the Day 7-10 Follow-up Visit (7-10 days after administration of IP) 
and the Day 30 Follow-up Visit (30 days after administration of IP) will be presented by treatment 
group. Surgical wound site assessment findings at 24, 48, 72, 96, and 120 hours after IP 
administration will be displayed in a listing. 


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13.1.5.6 Physical and Neurological Examination Findings 
Physical and neurological examination results will be displayed in a listing. 
13.1.5.7 Richmond Agitation and Sedation Scale Assessment 
A descriptive summary of the RASS assessment will be presented by study visit and by treatment 
group. 
13.1.6 Efficacy Analysis 
13.1.6.1 Efficacy Exploratory Endpoints 
The efficacy exploratory endpoints are the following: 
• Time-weighted summed pain intensity over 1 to 24 hours (SPI1-24) for CPL-01 subjects 
compared with placebo subjects 
• SPI at other time points: SPI1-6, SPI6-12, SPI1-12, SPI12-24, SPI24-48, SPI1-48, SPI48-72, and SPI1-72 
for CPL-01 subjects compared with placebo subjects 
• Total dose of opioid rescue analgesia (morphine equivalents) over 24, 48, and 72 hours after 
administration of IP 
• Time to administration of first dose of opioid rescue analgesia 
• The percentage of subjects who used no opioid rescue analgesia over 24, 48, and 72 hours after 
administration of IP 
• 
The percentage of subjects who remain pain free over 24, 48, and 72 hours after administration 
of IP (pain intensity ≤1). 
13.1.6.2 Analysis 
Individual NRS pain intensity scores will be tabulated for each time point and summarized 
descriptively by treatment group.  
The analysis of continuous efficacy endpoints will be performed using an analysis of variance 
(ANOVA) model. The ANOVA model will include the specific endpoint as the response variable 
(e.g., NRS SPI t, where t=1-6, 6-12, 1-12, 1-24, 12-24, 24-48, 1-48, 48-72, 1-72 hours, 
respectively) and will have Treatment as the main effect. Contrast tests will be carried out to 
compare CPL-01 against placebo. Since all exploratory analyses in this study are intended for 
hypothesis generation, there will be no adjustment for multiplicity and each analysis will be based 
on a 2-sided test at the significance level of 0.05. This approach will be used to analyze all 
continuous exploratory efficacy variables, including total dose of opioid (morphine equivalents) 
used over 24, 48, and 72 hours, respectively. 
Time to first use of rescue analgesia for postoperative surgical pain will be analyzed using the 
Kaplan-Meier method. The log-rank test will be used to test the hypothesis of overall treatment 
differences. In addition, a Cox proportional hazards model will be used to allow individual 
contrasts tests comparing CPL-01 against placebo. Hazard ratios and 95% confidence intervals 
will be generated for each contrast.  


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The percentage of subjects who used no opioid rescue analgesia and the percentage of subjects 
who remain pain free over 24, 28, and 72 hours will be analyzed using Fisher’s exact test. 
To assess the impact of missing data, multiple imputation will be used as a sensitivity analysis for 
the primary endpoint. 
Additional exploratory efficacy analyses may be conducted as required. 
13.1.7 Interim Analysis 
No interim analyses are planned.  
13.2 Sample Size Determination 
This is a proof-of-concept study with a primary goal of estimation rather than hypothesis testing. 
The sample sizes are consistent with similar studies of this type, but are not based on power 
considerations for specific treatment-effect sizes. 


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14 STUDY CONDUCT 
Steps to ensure the accuracy and reliability of data include the selection of qualified investigators 
and appropriate study sites, review of protocol procedures with the investigator and associated 
personnel before the study, periodic monitoring visits, and meticulous data management. 
14.1 Sponsor and Investigator Responsibilities 
14.1.1 Sponsor Responsibilities 
The sponsor is obligated to conduct the study in accordance with strict ethical principles 
(Section 16). The sponsor reserves the right to withdraw a subject from the study (Section 8.3), to 
terminate participation of a study site at any time (Section 14.7), and/or to discontinue the study 
(Section 14.6). 
CALI agrees to provide the investigator with sufficient material and support to permit the 
investigator to conduct the study according to the study protocol. 
14.1.2 Investigator Responsibilities 
By signing the Investigator’s Agreement (Section 18.1), the investigator indicates that he or she 
has read the protocol carefully, fully understands the requirements, and agrees to conduct the study 
in accordance with the procedures and requirements described in this protocol.  
The trial will be conducted in accordance with ICH GCP and applicable US Code of Federal 
Regulations (CFR) (Appendix E). The principal investigator will assure that no deviation from, or 
changes to, the protocol will take place without prior agreement from the Investigational New 
Drug (IND) sponsor, funding agency and documented approval from the IRB, except where 
necessary to eliminate an immediate hazard(s) to the trial participants. All personnel involved in 
the conduct of this study have completed Human Subjects Protection and ICH GCP training. 
Investigators should ensure that all persons who are delegated study-related responsibilities are 
adequately qualified and informed about the protocol, the IP(s), and their specific duties within the 
context of the study. Investigators are responsible for providing CALI with documentation of the 
qualifications, GCP training, and research experience for themselves and their staff as required by 
the sponsor and the relevant governing authorities. 
To ensure compliance with the guidelines, the study may be audited by an independent person. 
The investigator agrees, by written consent to this protocol, to cooperate fully with compliance 
checks by allowing access to all study documentation by authorized individuals. 
14.1.3 Confidentiality and Privacy 
Participant confidentiality and privacy is strictly held in trust by the participating investigators, 
their staff, and the sponsor(s) and their interventions. This confidentiality is extended to cover 
testing of biological samples and genetic tests in addition to the clinical information relating to 
participants. Therefore, the study protocol, documentation, data, and all other information 
generated will be held in strict confidence. No information concerning the study or the data will 
be released to any unauthorized third party without prior written approval of the sponsor.  
All research activities will be conducted in as private a setting as possible. 
The study monitor, other authorized representatives of the sponsor, representatives of the IRB, 
regulatory agencies, or pharmaceutical company supplying study product may inspect all 


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documents and records required to be maintained by the investigator, including, but not limited to, 
medical records (office, clinic, or hospital) and pharmacy records for the participants in this study. 
The clinical study site will permit access to such records. 
The study participant’s contact information will be securely stored at each clinical site for internal 
use during the study. At the end of the study, all records will continue to be kept in a secure location 
for as long a period as dictated by the reviewing IRB, institutional policies, or sponsor 
requirements. 
Study participant research data, which is for purposes of statistical analysis and scientific reporting, 
will be transmitted to and stored at Rho. This will not include the participant’s contact or 
identifying information. Rather, individual participants and their research data will be identified 
by a unique study identification number. The study data entry and study management systems used 
by clinical sites and by Rho staff will be secured and password protected. At the end of the study, 
all study databases will be de-identified and archived at Rho. 
14.2 Site Initiation 
Study personnel may not screen or enroll subjects into the study until after receiving notification 
from the sponsor or its designee that the study can be initiated at the study site. The study site will 
not be authorized for study initiation until: 
1. The study site has received the appropriate IRB approval for the protocol and the 
appropriate ICF. 
2. All regulatory documents have been submitted to and approved by the sponsor or its 
designee. 
3. The study site has a Clinical Trial Agreement in place. 
4. Study site personnel, including the investigator, have participated in a study initiation 
meeting. 
14.3 Screen Failures 
Subjects who fail inclusion and/or exclusion criteria may not be rescreened for the study. 
14.4 Study Documents 
All documentation and material provided by CALI for this study are to be retained in a secure 
location and treated as confidential material. 
14.4.1 Informed Consent 
A consent form describing in detail the study intervention, study procedures, and risks is given to 
the participant and written documentation of informed consent is required prior to starting 
intervention/administering study intervention. 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in the 
study and continues throughout the individual’s study participation. Consent forms will be 
IRB-approved and the participant will be asked to read and review the document. The investigator 
will explain the research study to the participant and answer any questions that may arise. A verbal 
explanation will be provided in terms suited to the participant’s comprehension of the purposes, 
procedures, and potential risks of the study and of their rights as research participants. Participants 


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will have the opportunity to carefully review the written consent form and ask questions prior to 
signing. The participants should have the opportunity to discuss the study with their family or 
surrogates or think about it prior to agreeing to participate. The participant will sign the informed 
consent document prior to any procedures being done specifically for the study. Participants must 
be informed that participation is voluntary and that they may withdraw from the study at any time, 
without prejudice. A copy of the informed consent document will be given to the participants for 
their records. The informed consent process will be conducted and documented in the source 
document (including the date) and the form signed before the participant undergoes any 
study-specific procedures. The rights and welfare of the participants will be protected by 
emphasizing to them that the quality of their medical care will not be adversely affected if they 
decline to participate in this study. 
14.4.2 Investigator’s Regulatory Documents 
The regulatory documents are listed in the study plan. 
The regulatory documents must be received from the investigator and reviewed and approved by 
CALI or its designee before the study site can initiate the study and before CALI will authorize 
shipment of IP to the study site. Copies of the investigator’s regulatory documents must be retained 
at the study site in a secure location. Additional documents, including a copy of the protocol and 
applicable amendment(s), eCRF completion guidelines, copies of regulatory references, copies of 
IRB correspondence, and IP accountability records should also be retained as part of the 
investigator’s regulatory documents. It is the investigator’s responsibility to ensure that copies of 
all required regulatory documents are organized, current, and available for inspection. 
14.4.3 Case Report Forms 
By signing the Investigator’s Agreement (Section 18.1), the investigator agrees to maintain 
accurate eCRFs and source documentation as part of the case histories for all subjects who sign an 
ICF. 
Case report forms are considered confidential documents and should be handled and stored 
accordingly. The sponsor or its designee will provide the necessary training on the use of the 
specific eCRFs system used during the study to ensure that the study information is captured 
accurately and appropriately. 
To ensure data accuracy, eCRF data for individual subject visits should be completed as soon as 
possible after the visit. All requested information must be entered in the electronic data capture 
(EDC) system according to the completion guidelines provided by the sponsor or its designee. 
The eCRFs must be signed by the investigator or a subinvestigator. These signatures serve to attest 
that the information contained in the eCRFs is accurate and true. 
14.4.4 Source Documents 
Information recorded in the EDC should be supported by corresponding source documentation. 
Examples of acceptable source documentation include, but are not limited to, hospital records, 
clinic and office charts, laboratory notes, and recorded data from automated instruments, 
memoranda, and pharmacy dispensing records. 


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14.5 Data Quality Control 
CALI and its designees will perform quality control checks on this clinical study. 
14.5.1 Monitoring Procedures 
CALI and/or its designee will conduct site visits to monitor the study and ensure compliance with 
the protocol, GCP, and applicable regulations and guidelines. The assigned CRA will visit the 
investigator and study site at periodic intervals and maintain periodic communication. The 
investigator agrees to allow the CRA(s) and other authorized CALI personnel access. The CRA(s) 
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. While on site, the CRA(s) will review the following: 
• Regulatory documents, directly comparing entries in the EDC system with the source 
documents 
• Consenting procedures 
• Adverse event procedures 
• Storage and accountability of IP and study materials (unblinded CRA only) 
The CRA will ask for clarification and/or correction of any noted inconsistencies. Procedures for 
correcting eCRF are described in the study plan. As representatives of the sponsor, CRAs are 
responsible for notifying project management of any noted protocol deviations. 
By signing the Investigator’s Agreement (Section 18.1), the investigator agrees to meet with the 
CRA(s) during study site visits; to ensure that study staff is available to the CRA(s) as needed; to 
provide the CRA(s) access to all study documentation, to the clinical supplies dispensing and 
storage area; and to assist the monitors in their activities, if requested. Further, the investigator 
agrees to allow CALI or designee auditors or inspectors from regulatory agencies to review records 
and to assist the inspectors in their duties, if requested. 
For additional information, please refer to the clinical monitoring plan. 
14.5.2 Data Management 
CALI or designee will be responsible for activities associated with the data management of this 
study. The standard procedures for handling and processing records will be followed per GCP and 
Rho’s standard operating procedures. A comprehensive data management plan will be developed, 
including a data management overview, description of database contents, annotated eCRF, 
pre-entry review list, self-evident correction conventions, query contacts, and consistency checks. 
Study site personnel will be responsible for providing resolutions to all data queries. The 
investigator will be required to document electronic data review to ensure the accuracy of the 
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14.5.3 Quality Assurance/Audit 
This study will be subject to audit by CALI or its designee. Audits may be performed to check 
compliance with GCP guidelines and can include: 
• Site audits 
• Trial Master File audits 
• Database audits 
• Document audits (e.g., protocol and/or clinical study report [CSR]) 
CALI or its designee may conduct additional audits on a selection of study sites, requiring access 
to subject notes, study documentation, and facilities or laboratories used for the study. 
The study site, facilities, all data (including source data), and documentation will be made available 
for audit by quality assurance auditors and for IRB or regulatory authorities according to GCP 
guidelines. The investigator agrees to cooperate with the auditor during the visit and will be 
available to supply the auditor with CRFs or other files necessary to conduct that audit. Any 
findings will be strictly confidential. 
If a regulatory authority informs the investigator that it intends to conduct an inspection, the 
investigator shall notify CALI immediately. 
14.6 Study Termination 
The study may be terminated at CALI’s discretion at any time and for any reason. 
14.6.1 Premature Study Termination 
The study may be temporarily suspended or terminated prematurely if there is sufficient reasonable 
cause at any time by CALI, IRBs, regulatory authorities, respective steering committees, or the 
coordinating investigator.  
Written notification, documenting the reason for study suspension or termination, will be provided 
by the suspending or terminating party to study participants, investigator, the IND sponsor, and 
regulatory authorities. If the study is prematurely terminated or suspended, the principal 
investigator will promptly inform study participants, the IRB, and sponsor and will provide the 
reason(s) for the termination or suspension. Study participants will be contacted, as applicable, 
and be informed of changes to study visit schedule. 
Circumstances that may warrant termination or suspension include, but are not limited to: 
• Determination of unexpected, significant, or unacceptable risk to participants 
• Demonstration of efficacy that would warrant stopping 
• Insufficient compliance to protocol requirements 
• Data that are not sufficiently complete and/or evaluable 
• Determination that the primary endpoint has been met 
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AE-related criteria that may warrant termination of the study include, but are not limited to: 
• One subject has a generalized seizure or a hemodynamically significant cardiac arrhythmia 
• One subject has multiple signs and/or symptoms that, in aggregate, suggest that LAST is 
occurring. 
• Two or more subjects have an SAE that is assessed as related to investigational product 
• Two or more subjects show evidence of severe local drug product reaction or clearly 
impaired wound healing 
• One subject death occurs possibly related to study drug 
Study sites may be asked to have all subjects currently participating in the study complete all of 
the assessments for the Early Termination Visit. 
The study may resume once concerns about safety, protocol compliance, and data quality are 
addressed and satisfy the sponsor, IRB, and/or Food and Drug Administration (FDA). 
14.7 Study Site Closure 
At the end of the study, all study sites will be closed. CALI may terminate participation of a study 
site at any time. Examples of conditions that may require premature termination of a study site 
include, but are not limited to, the following: 
• Noncompliance with the protocol and/or applicable regulations and guidelines 
• Inadequate subject enrollment 
14.7.1 Record Retention 
The investigator shall retain and preserve 1 copy of all data generated in the course of the study, 
specifically including, but not limited to, those defined by GCP as essential until: 
• At least 2 years after the last marketing authorization for the IP has been approved or the 
sponsor has discontinued its research with the IP, or 
• At least 2 years have elapsed since the formal discontinuation of clinical development of 
CPL-01. 
These documents should be retained for a longer period, however, if required by the applicable 
regulatory requirement(s) or if needed by the sponsor. 
At the end of such period, the investigator shall notify the sponsor in writing of his or her intent to 
destroy all such material. The sponsor has 30 days to respond to the investigator’s notice, and the 
sponsor has further opportunity to retain such materials at the sponsor’s expense. 
14.7.2 Sample Retention 
Samples may be used for purposes related to this research. The samples will be stored until the 
sponsor has determined that specimens are no longer needed, and the decision has been made that 
none of the samples needs to be reanalyzed. In addition, identifiable samples can be destroyed at 
any time at the request of the subject. 


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14.8 Changes to the Protocol 
This protocol cannot be altered or changed except through a formal protocol amendment, which 
requires the written approval of CALI. The protocol amendment must be signed by the investigator 
and approved by the IRB before it may be implemented. Protocol amendments will be filed with 
the appropriate regulatory agency(s) having jurisdiction over the conduct of the study. 
14.9 Use of Information and Publication 
All information concerning CPL-01, CALI’s operations, patent applications, formula, 
manufacturing processes, basic scientific data, and formulation information supplied by CALI or 
its designee to the investigator, and not previously published, is considered confidential and 
remains the sole property of CALI. Case report forms also remain the property of CALI. The 
investigator agrees to use this information for purposes of study execution through finalization. 
The information developed in this study will be used by CALI in connection with the continued 
development of CPL-01 and thus may be disclosed as required to other clinical investigators or 
government regulatory agencies. 
The information generated by this study is the property of CALI. Publication or other public 
presentation of CPL-01 data resulting from this study requires prior review and written approval 
of CALI. Abstracts, manuscripts, and presentation materials should be provided to CALI for 
review at least 30 days prior to the relevant submission deadline. 
It is agreed that the results of the study will not be submitted for presentation, abstract, poster 
exhibition, or publication by the investigator until CALI has reviewed and commented on such a 
presentation or manuscript for publication. If applicable, this study will be registered at 
ClinicalTrials.gov, and results information from this study will be submitted to ClinicalTrials.gov. 


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15 FINAL CLINICAL STUDY REPORT 
CALI will retain ownership of the data. 
The final CSR will be written within 6 months of completion of the clinical part of the study. This 
report will include a summary of the study results based on a statistical evaluation and clinical 
assessment of the protocol-defined endpoints. 
The final CSR may be submitted to the regulatory authorities.  


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16 ETHICAL AND LEGAL CONSIDERATIONS 
16.1 Good Clinical Practice 
This study will be conducted in compliance with the April 1996 ICH Guidance for Industry GCP 
E6 (including archiving of essential study documents), the Integrated Addendum to ICH E6 (R2) 
of November 2016, and the applicable regulations of the country in which the study is conducted. 
16.2 Subject Information and Informed Consent 
A properly constituted, valid IRB must review and approve the protocol, the investigator’s ICF, 
and related subject information and recruitment materials before the start of the study. 
It is the responsibility of the investigator to ensure that written informed consent is obtained from 
the subject before any activity or procedure is undertaken that is not part of routine care. 
16.3 Approval by Institutional Review Board 
For IND studies, the minimum standards of conduct and requirements for informed consent are 
defined in the FDA regulations. 
A valid IRB must review and approve this protocol before study initiation. Written notification of 
approval is to be provided by the investigator to the sponsor’s representative before shipment of 
investigational drug supplies, and will include the date of the committee’s approval and the 
chairperson’s signature. This written approval must consist of a completed IRB Approval Form or 
written documentation from the IRB containing the same information. 
Until written approval by the IRB has been received by the investigator, no subject may undergo 
any procedure not part of routine care for the subject’s condition. 
Protocol amendments must also be reviewed and approved by the IRB. Written approval from the 
IRB, or a designee, must be received by CALI before implementation. This written approval will 
consist of a completed IRB Approval Form or written documentation from the IRB containing the 
same information. 
16.4 Finance and Insurance 
Details on finance and insurance will be provided in a separate agreement between the investigator 
and the sponsor. 


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17 REFERENCES 
1. Dahl J, Moiniche S, Kehlet H. Wound infiltration with local anaesthetics for postoperative 
pain relief. Acta Anaesthesiol Scand. 1994; 38(1):7-14. 
2. Moiniche S, Mikkelsen Wetterslev J, et al. A qualitative systematic review of incisional 
local anaesthesia for postoperative pain relief after abdominal operations. Br J Anaesth. 
1998;81(3):377-383. 
3. Kehlet H., Andersen LO. Local infiltration analgesia in joint replacement: the evidence and 
recommendations for clinical practice. Acta Anaesthesiol Scand. 2011;55(7):778-784. 
4. Rawal N. Analgesia for day-case surgery. Br J Anaesth. 2001;87(1):73-87. 
5. NAROPIN® (ropivacaine HCl Injection, USP) Package Insert. Lake Zurich, IL, Fresenius 
Kabi USA, LLC, 2015. 
6. Pettersson N, Emanuelsson B-M, Reventlid H, Hahn RG. High-dose ropivacaine wound 
infiltration for pain relief after inguinal hernia repair: A clinical and pharmacokinetic 
evaluation. Reg Anesth Pain Med. 1998 March-April;23(2):189-196. 
 


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18 ATTACHMENTS 
18.1 Investigator’s Agreement 
PROTOCOL 
NUMBER: 
CPL-01_AB_001 
PROTOCOL TITLE: 
Phase 2a, Randomized, Double-blind, Placebo-controlled Study to 
Evaluate the Safety and Pharmacokinetic Profile of CPL-01 in the 
Management 
of 
Acute 
Postoperative 
Pain 
After 
Mini-abdominoplasty Surgery 
FINAL PROTOCOL: 
V3.0 25-Nov-2019 
 
 
I have read this protocol and agree to conduct this clinical study as outlined herein. I will ensure 
that all subinvestigators and other study staff members have read and understand all aspects of this 
protocol. I agree to cooperate fully with CALI Pharmaceuticals and Rho during the study. I will 
adhere to all FDA, ICH, and other applicable regulations and guidelines regarding clinical studies 
on an IP during and after study completion. 
Principal Investigator: 
 
Printed Name: 
 
 
 
 
 
 
 
 
 
 
Signature: 
 
 
 
 
 
 
 
 
 
 
Date: 
 
 
 
 
 
 
 


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19 APPENDICES 
A. Richmond Agitation and Sedation Scale 
B. Surgical Wound Site Assessment 
C. Wound Photography Instructions 
D. Standardized General Anesthesia Regimen 
E. Regulations and Good Clinical Practice 
 
 


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A. Richmond Agitation and Sedation Scale 
 
 


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B. Surgical Wound Site Assessment 
The surgical wound will be examined and scored by the investigator or designee using a 5-point 
numerical rating scale as follows: 
Numerical Rating 
Description 
1-Normal healing 
Findings that may include bruising, erythema, edema and drainage 
at expected normal levels based upon the time point of the wound 
assessment.a 
2-Delayed healing 
Findings that may include bruising, erythema or edema beyond 
expected normal levels based upon the timepoint of the wound 
assessment. 
3-Excessive Drainage 
Any purulent drainage. Serous or hemoserous drainage beyond 
expected normal levels based upon the time point of the wound 
assessment.b 
4-Infection 
Evidence of cellulitis such as excessive heat, spreading erythema, 
purulent discharge. 
5-Tissue breakdown 
Complete wound dehiscence, hematoma any of which would require 
surgical intervention 
a Inflammation - (bruising, erythema and edema) are normal post-operative findings and may be present at the 
timepoint evaluated. 
b Drainage - Postoperative wound drainage may refer to the following: Serous exudate – drainage of a clear, thin, 
watery fluid from a surgical wound. This type of wound ooze is a normal and expected part of the healing process. 
- Haemoserous (serosanguinous) exudate – drainage of a thin, watery, pink colored fluid composed of blood and 
serum and may be a normal and expected part of the healing process based upon the time point evaluated. 
 
This numerical rating will be included in the electronic Case Report Form. Any rating of 2 or 
above will be reported as an AE. Refer to Section 11.1.1 for additional information regarding AEs. 
For further guidance regarding normal versus impaired healing refer to Table 1 from the 2018 
World Union of Healing Societies Consensus Document. 


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Table 1: 
Signs of Progression and Impaired Incision Healing 
Source: Excerpt from World Union of Wound Healing Societies Consensus Document: Surgical wound dehiscence, 
Improving prevention and outcomes, 2018, page 12. Free download available from www.woundsinternational.com. 
 


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C. Wound Photography Instructions 
 
Materials 
• Camera (specify type and model, identify camera settings) 
• Memory card for each subject 
• Background cloth 
• Identification tag: Complete for Protocol #, Subject #, Study visit, date, time, and location 
“abdomen” 
• Adhesive backed decal ruler (on a roll) 
Instructions 
1. Ensure the batteries in the camera are charged. If low, replace the batteries prior to using the 
camera. 
2. Place the subject’s memory card in the camera. 
3. Expose the entire abdomen to be photographed and place the background cloth under the area 
to be photographed. 
4. Remove any dressing and place the completed identification tag adjacent to the area to be 
photographed, taking care not to obscure any area of the wound itself. 
5. Apply the adhesive backed ruler decal in an area of the abdomen not obscuring the wound area 
itself. 
6. Take 3 photographs with the camera, looking down at the abdomen so that the abdominal area 
fills the camera window, showing the entire surgical abdominal incision, the identification tag 
information and the ruler. 
7. Remove the subject’s memory card. 
 
 
 


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D. Standardized General Anesthesia Regimen 
 
Protocol Number:  CPL-01_AB_001  
General Anesthesia Regimen 
 
Monitors 
• All routine required ASA monitors 
IV Fluids 
• Lactated Ringer at 1-3 cc/kg/h at discretion of 
anesthesia provider 
Premedication 
• Midazolam 1-3 mg IVP as needed 
Induction 
• Propofol 1-3 mg/kg IV 
• Rocuronium 0.6-1.2 mg/kg IV 
• Fentanyl 1-2 ug/kg IV 
Maintenance 
• No N2O 
• Air/O2 as required to maintain intraoperative 
O2 saturation >95%  
• Sevoflurane or desflurane are preferred agents 
at 0.8 to 1.2 MAC as tolerated  
• Isoflurane at 0.8 to 1.2 MAC as tolerated can 
be used only if both sevoflurane and 
desflurane are not available 
• Rocuronium 0.1 to 0.2 mg/kg as needed per 
train-of four monitoring and at discretion of 
anesthesia provider 
• Fentanyl 2-4 ug/kg IV as needed 
AW device 
• Oral endotracheal tube or supraglottic device 
(laryngeal mask airway, etc.) at discretion of 
anesthesia provider 
Reversal of NMB if needed 
• Neostigmine 0.025 to 0.05 mg/kg IVP per 
TOF monitoring 
• Glycopyrrolate 0.01 mg/kg IVP or atropine 
0.02 mg/kg IVP 
ASA = American Society of Anesthesiologists; IV = intravenous; IVP = intravenous push; MAC = minimum 
alveolar concentration; NMB = neuromuscular blockade. 
 
 


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E. Regulations and Good Clinical Practice 
 
1. Regulations 
Refer to the following US Code of Federal Regulations (CFR): 
• FDA Regulations 21 CFR, Parts 50.20 – 50.27 
Subpart B – Informed Consent of Human Subjects 
• FDA Regulations 21 CFR, Parts 56.107 – 56.115 
Part 56 – Institutional Review Boards 
Subpart B – Organization and Personnel 
Subpart C – IRB Functions and Operations 
Subpart D – Records and Reports 
• FDA Regulations 21 CFR, Parts 312.50 – 312.70 
Subpart D – Responsibilities of Sponsors and Investigators 
2. Good Clinical Practice Guidelines 
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for 
Human Use GCP guidelines can be found at the following URLs: 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6/E6_R1_G
uideline.pdf 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6/E6_R2__
Step_4.pdf 
 

SAP_001.pdf: 
CALI Pharmaceuticals LLC 
CPL-01_AB_001 
Page 1 of 38 
Version Date: 2020-03-07 
Version: <1.0>  
 
 
STATISTICAL ANALYSIS PLAN 
 
STUDY TITLE:  
PHASE 2A, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED 
STUDY TO EVALUATE THE SAFETY AND PHARMACOKINETIC 
PROFILE OF CPL-01 IN THE MANAGEMENT OF ACUTE 
POSTOPERATIVE PAIN AFTER MINI-ABDOMINOPLASTY SURGERY 
 
PROTOCOL NUMBER:  
CPL-01_AB_001 
 
 
SPONSOR: 
CALI Pharmaceuticals LLC 
IND NUMBER: 
136759 
PREPARED BY: 
Rho 
2635 E NC Hwy 54 
Durham, NC 27713 
Telephone: (919) 408-8000 
Fax: (919) 408-0999 
 
 
 
 
 
This document is confidential and proprietary to Cali. This study is being conducted in compliance with good 
clinical practice, including the archiving of essential documents. Acceptance of this document constitutes 
agreement by the recipient that no unpublished information contained herein will be reproduced, published, or 
otherwise disclosed without the prior written approval of Cali, except that this document may be disclosed to 
appropriate Institutional Review Boards under the condition that they keep the information confidential. 
 
 
 
 


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Version Date: 2020-03-07 
Version: <1.0>  
 
ACKNOWLEDGEMENT AND SIGNATURE SHEET 
 
Approved: 
________________________________ 
Date: 
_______________ 
 
Ben Vaughn, MS 
 
 
 
Chief Strategist Biostatistics and Protocol 
Design 
Rho, Inc. 
 
 
 
Approved: 
________________________________ 
Date: 
_______________ 
 
Christine Pan, MS 
 
 
 
DM and Biostatistics Lead 
Cali Pharmaceuticals, LLC 
 
 
 
Approved: 
________________________________ 
Date: 
_______________ 
 
Lee Chen, PhD 
 
 
 
COO, Cali Pharmaceuticals, LLC 
 
 
 
 
 
 


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VERSION HISTORY 
 
SAP Version 
Version Date 
Change(s) 
Rationale 
1.0 
2020-03-07 
First draft 
 
 
 
 
 
 
 


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TABLE OF CONTENTS 
1. 
LIST OF ABBREVIATIONS .......................................................................................7 
2. 
PURPOSE OF THE ANALYSES ................................................................................9 
3. 
PROTOCOL SUMMARY ..........................................................................................10 
4. 
GENERAL ANALYSIS AND REPORTING CONVENTIONS ..............................12 
4.1. 
Assessment Time Windows ........................................................................................13 
5. 
ANALYSIS SAMPLES ..............................................................................................14 
6. 
STUDY SUBJECTS ...................................................................................................15 
6.1. 
Disposition of Subjects ...............................................................................................15 
6.2. 
Demographic and Other Baseline Characteristics ......................................................15 
6.3. 
Prior and Concomitant Medications ...........................................................................16 
6.3.1. 
Prior Medications ........................................................................................................16 
6.3.2. 
Concomitant Medications ...........................................................................................16 
6.4. 
Medical History ..........................................................................................................16 
7. 
STUDY OPERATIONS .............................................................................................17 
7.1. 
Protocol Deviations ....................................................................................................17 
7.2. 
Randomization ............................................................................................................17 
7.3. 
Measures of Treatment Compliance ...........................................................................17 
8. 
ENDPOINT EVALUATION .....................................................................................18 
8.1. 
Overview of Efficacy Analysis Methods ....................................................................18 
8.1.1. 
Multicenter Studies .....................................................................................................18 
8.1.2. 
Timing of Analyses .....................................................................................................18 
8.1.3. 
Multiple Comparisons/Multiplicity ............................................................................18 
8.2. 
Primary Efficacy Endpoint .........................................................................................18 
8.2.1. 
Computation of the Primary Endpoint ........................................................................18 
8.2.2. 
Primary Analysis of the Primary Endpoint .................................................................19 
8.2.3. 
Sensitivity Analyses of the Primary Analysis ............................................................19 
8.3. 
Secondary Endpoints ..................................................................................................19 
8.3.1. 
Time Weighted Sum Pain Intensities .........................................................................19 
8.3.2. 
Pain Intensities by Time Point ....................................................................................19 
8.3.3. 
Total Opioid Usage (Morphine Equivalents)..............................................................20 
8.3.4. 
Time to First Rescue ...................................................................................................20 


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8.3.5. 
Any Opioid Use ..........................................................................................................20 
8.3.6. 
Pain Free Subjects .......................................................................................................20 
8.3.7. 
Diary Rescue Medication Use ....................................................................................20 
8.4. 
Examination of Subgroups .........................................................................................21 
9. 
SAFETY EVALUATION ..........................................................................................22 
9.1. 
Overview of Safety Analysis Methods .......................................................................22 
9.2. 
Adverse Events ...........................................................................................................22 
9.3. 
Deaths, Serious Adverse Events (SAE), and Other Significant Adverse 
Events .........................................................................................................................23 
9.4. 
Wound AEs and Infections .........................................................................................23 
9.5. 
Clinical Laboratory Evaluation ...................................................................................24 
9.6. 
Vital Signs, Physical Findings, and Other Observations Related to Safety ...............24 
9.6.1. 
Vital Signs ..................................................................................................................24 
9.6.2. 
Physical and Neurological Examinations ...................................................................24 
9.6.3. 
Local Anesthetic Systemic Toxicity Assessment .......................................................24 
9.6.4. 
Richmond Agitation and Sedation Scale Assessment ................................................25 
9.6.5. 
ECGs ...........................................................................................................................25 
9.6.6. 
Wound Healing ...........................................................................................................25 
10. 
PHARMACOKINETIC EVALUATION ...................................................................27 
10.1. 
Pharmacokinetic Endpoints ........................................................................................27 
11. 
OTHER ANALYSES .................................................................................................28 
12. 
INTERIM ANALYSES AND DATA MONITORING .............................................29 
13. 
CHANGES TO THE ANALYSES PLANNED IN THE PROTOCOL .....................30 
14. 
REFERENCES ...........................................................................................................31 
15. 
APPENDIX .................................................................................................................32 
15.1. 
Schedule of Events .....................................................................................................33 
15.2. 
Random Seeds ............................................................................................................36 
15.3. 
Wound AEs .................................................................................................................36 
16. 
ATTACHMENTS .......................................................................................................38 
 
 


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LIST OF TABLES 
Table 1: 
List of Abbreviations ....................................................................................................7 
 


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1. 
LIST OF ABBREVIATIONS 
Table 1: 
List of Abbreviations 
Abbreviation 
Term 
AE 
Adverse Event 
ANOVA 
Analysis of Variance 
ATC 
Anatomical Therapeutic Chemical 
BMI 
Body Mass Index 
Cm 
Centimeters 
CRF 
Case Report Form 
ECG 
Electrocardiogram 
g 
Gram 
GCP 
Good Clinical Practice 
ICH 
International Council for Harmonization 
IP 
Investigational Product  
ITT 
Intent-to-treat 
kg 
Kilograms 
LAST 
Local Anesthetic Systemic Toxicity 
LS 
Least Squares 
m 
Meters 
mg 
Milligram 
MAR 
Missing at Random 
MCMC 
Markov Chain Monte Carlo 
MedDRA 
Medical Dictionary for Regulatory Activities 
MEQ 
Morphine Equivalent 
MI 
Multiple Imputation 
MNAR 
Missing Not at Random 
NRS 
Numeric Rating Scale 
PK 
Pharmacokinetic 
RASS 
Richmond Agitation and Sedation Scale 
SAP 
Statistical Analysis Plan 
SAE 
Serious Adverse Event 
SD 
Standard Deviation 


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SE 
Standard Error 
SOC 
System Organ Class 
SPI 
Summed Pain Intensity 
TEAE 
Treatment Emergent Adverse Events 
WHO-DD 
World Health Organization Drug Dictionary 
 


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2. 
PURPOSE OF THE ANALYSES 
This statistical analysis plan (SAP) provides a detailed description of the strategy and statistical 
methodology to be used for analysis of data from the CPL-01_AB_001 protocol, version 3.0, 
dated 25NOV2019. 
The purpose of the SAP is to describe the pre-specified statistical approaches to the analysis of 
study data prior to database lock. This analysis plan is meant to supplement the study protocol. If 
differences occur between analyses described in the SAP and the current protocol, those found in 
this SAP will assume primacy. Any deviations from this plan will be described in the Clinical 
Study Report. 


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3. 
PROTOCOL SUMMARY 
 
This is a randomized, double-blind, single-site study to evaluate the safety, pharmacokinetic 
(PK) profile, and analgesic duration of action of CPL-01 in men and women ≥18 and ≤70 years 
of age for the management of postoperative pain after mini-abdominoplasty surgery.  
The study will evaluate approximately 20 subjects who will be enrolled and randomly assigned 
in a 3:1 ratio to either 2% CPL-01 (200 mg ropivacaine [10 mL]) or placebo (0.9% NaCl).  
The study will include 4 periods: Screening Period, Surgical/Anesthesia Period (Confinement), 
Post-anesthesia Period (Confinement); and Post-treatment Follow up Period. 
Screening Period (Day -42 up to Day -1): Subjects will be screened within 42 days before the 
planned surgery; however, Screening can be performed as late as on the morning of the surgery 
if all inclusion/exclusion criteria can be verified. Subjects who give written informed consent 
will be assessed for eligibility. Screening evaluations will include collection of demographic 
information, medical history, full neurological examination, complete physical examination, vital 
signs (resting blood pressure, heart rate, respiratory rate, and oral body temperature), height, 
weight, body mass index (BMI), 12-lead electrocardiogram (ECG), clinical laboratory tests 
(hematology, chemistry, and urinalysis), serology tests, serum pregnancy test (women of 
childbearing potential only), urine drug screen, and recording of concomitant medications. 
Additionally, subjects will be trained on the use of the numeric rating scale (NRS) for pain 
assessment at Screening. 
Surgical/Anesthesia Period (Day 1 through Hour 1, Confinement): On Day 1, at check in, 
inclusion/exclusion criteria will be confirmed and medical history, full neurological examination, 
vital signs, 12 lead ECG, urine pregnancy test, urine drug screen, and concomitant medications 
will be updated. Before surgery, subjects will be trained again on the NRS and assigned a 
randomization number.  
Subjects will be administered general anesthesia according to a standard regimen (Appendix D 
of the protocol), during which they will undergo a mini-abdominoplasty. At the end of the 
surgical procedure but before the wound is closed, the investigational product (IP) will be 
administered by wound infiltration and instillation (Time 0). Blood samples will be collected for 
PK analysis at baseline (before IP administration) and 15, 30, and 45 minutes after 
administration of IP. Continuous pulse oximetry will be monitored immediately following 
surgery, throughout transport, and in the post-anesthesia care unit, until subjects switch from 
intravenous morphine to oral rescue analgesia medication. If O2 saturation drops below 93% or if 
subjects have clinical signs or symptoms that suggest respiratory depression while on the oral 
medication, or subjects switch back to intravenous morphine, they will be kept on continuous 
pulse oximetry as required. Following surgery, subjects will be admitted and confined to the 
study site through Day 4 (72 hours). 
Post-anesthesia Period (Day 1, Hour 1 [1 hour after administration of IP] through Day 4, 
Confinement): Assessments during the Post-anesthesia Period will include local anesthetic 
systemic toxicity (LAST) assessment (including vital signs, Richmond Agitation and Sedation 
Scale [RASS] assessment (Appendix A of the protocol), and focused neurological examination), 
12 lead ECG, pain intensity assessments, surgical wound site assessment (including photograph), 


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concomitant medications, and adverse events (AEs). Continuous pulse oximetry will be 
conducted in the post-anesthesia care unit until subjects switch from intravenous morphine to 
oral rescue analgesia medication. If O2 saturation drops below 93% or subjects have clinical 
signs or symptoms that suggest respiratory depression while on the oral medication, or subjects 
switch back to intravenous morphine, they will be kept on continuous pulse oximetry as required. 
Subjects will also receive a diary to record their pain intensity (using NRS) and rescue 
medication usage when they are discharged from the study site on Day 4. On non-visit days prior 
to the Day 7-10 Follow up Visit, a brief daily telephone call will be conducted to remind subjects 
to record their pain intensity (using NRS), and rescue medication usage in the diary. Subjects 
will be instructed to return their completed diary at the Day 7-10 Follow-up Visit (7 to 10 days 
after administration of IP or upon early termination). 


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4. 
GENERAL ANALYSIS AND REPORTING CONVENTIONS 
This section discusses general policies to be employed in the analysis and reporting of the data 
from the study. Departures from these general policies will be described, if applicable, in the 
appropriate sections of this SAP. When this situation occurs, the rules set forth in the specific 
section take precedence over the general policies. 
 
For categorical variables, summary statistics will consist of the number and percentage of 
subjects in each category; percentages will be out of the number of subjects in the population 
being reported, unless otherwise noted. All percentages will be rounded to one decimal point. 
The number and percentage of subjects will always be presented in the form XX (XX.X%) 
where the percentage is in parentheses. To ensure completeness, all summaries for categorical 
and discrete variables will include all categories, even if none of the subjects had a response in a 
particular category. Denominators for each analysis will be based on the population of interest 
(e.g., safety population; subjects with non-missing data). 
 
For continuous variables, summary statistics will consist of the number of subjects with data, 
mean, median, standard deviation (SD), minimum, and maximum values. The summary statistic 
n will be the number of subjects with non-missing values. All means and medians will be 
reported to one more significant digit than the values being analyzed. Standard errors (SE) and 
standard deviations will be reported to two more significant digits than the values being 
analyzed. The minimum and maximum will be reported to the same number of significant digits 
as the values being analyzed. 
 
For tests of hypothesis of treatment group differences, the associated p-value will be reported. 
All p-values will be rounded to three decimal places; p-values that round to 0.000 will be 
presented as “<0.001”. P-values are descriptive.  
 
In general, the baseline value will be considered the last non-missing measurement observed 
prior to the first dose of study treatment. 
 
For efficacy, subjects will be analyzed according to randomized treatment. For safety analyses, 
subjects will be analyzed according to the actual treatment received. 
 
Data will be listed by treatment and subject. In general, listings will be sorted in the order that 
columns are displayed, starting with the first column on the left (treatment). Subject listings of 
data will be presented for all randomized subjects unless specified otherwise. 


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Unless otherwise specified, summaries will include the following treatment groups:  
• 
CPL-01 
• 
Placebo 
 
SAS statistical software, version 9.4 or higher, will be used for all analyses.  
4.1. 
Assessment Time Windows 
Assessments should be performed within the windows stated in the protocol and will be analyzed 
by the visit/time point that they are entered into the case report form (CRF) under. For 
assessments other than the NRS pain, if an assessment is missing and an unscheduled or early 
termination assessment falls within the protocol-specified window, it will be assigned to that 
visit/time point for the purposes of summarization. If more than one unscheduled visit/ early 
termination visit falls into a window, the one closest to the scheduled time point will be used 
(with the earlier one used in case of a tie); again, scheduled visits will always take precedence, 
regardless of timing. 
NRS assessments will use the actual times of collection; see section 8.2.1for additional details. 
 


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5. 
ANALYSIS SAMPLES 
The following 3 analysis populations are planned for this study: 
• Intent-to-treat (ITT) Population: all subjects who are successfully screened and 
randomized. The ITT population is the primary population for the efficacy analysis. 
• Safety Population: all subjects who are treated with IP. The Safety population is the 
population for all safety analyses. 
• PK Population: all subjects who receive IP during surgery and who have at least 1 
measurable plasma concentration. All PK analyses will be based on the PK population. 
In the event that a subject is administered the incorrect IP, analyses of the ITT population will be 
based on the randomized treatment, whereas analyses of the Safety population will be based on 
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6. 
STUDY SUBJECTS 
6.1. 
Disposition of Subjects 
The number and percentage of subjects screened, enrolled, randomized, received treatment, 
completed the study (through day 30), and discontinued from the study, will be reported, along 
with the reason for discontinuation (counts only will be reported for screened and enrolled 
subjects).  Percentages will be out of the number of subjects randomized. Additionally, the 
number and percentage of subjects that complete the confinement period (through day 4) will be 
reported.  Subjects screened and enrolled will be reported overall; the remaining items will be 
reported by treatment group and overall.  Subjects randomized will include all subjects for whom 
randomization is checked on the CRF; subjects receiving treatment will include all subjects that 
had any IP administered; subjects completing the study will be based on the recorded disposition; 
subjects completing the confinement period will include those that have a termination date on or 
after day 4. 
Reasons for discontinuation include the following: 
• Adverse Event 
• Death 
• Lack of Efficacy 
• Lost to Follow-up 
• Physician Decision 
• Pregnancy 
• Protocol Deviation 
• Study Terminated by Sponsor 
• Technical Problem 
• Withdrawal by Subject 
• Other 
Additionally, the number and percent of subjects in each analysis population will be reported by 
treatment. Screen failures will also be included in a by-subject listing.  
6.2. 
Demographic and Other Baseline Characteristics 
Demographic and baseline characteristics will be collected during the Screening Visit. 
Descriptive statistics will be provided for all demographic and baseline characteristics based on 
the Safety Population. For categorical variables, the number and percentage of subjects in each 
category will be presented. For continuous variables, summaries will include the number of 
subjects with data, mean, median, standard deviation, minimum, and maximum.  
Variables to be summarized include:  
• Age at screening (years) as recorded on the CRF 
• Sex at birth 
• Ethnicity  
• Race  
• Weight (kg) 


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• Height (cm) 
• BMI (kg/m2) 
All demographic and other baseline characteristics will be provided in a listing. 
6.3. 
Prior and Concomitant Medications 
All medications taken during the screening period prior to the surgery through the end of the 
study or early termination will be recorded in the concomitant medications log in the CRF, with 
the exception of rescue analgesic medications, which are collected on the rescue medications 
page. All medications will be coded using the World Health Organization Drug Dictionary 
(WHO-DD) Version GLOBALB3Sep19.  Rescue medications will be limited to 2 to 4 mg of 
intravenous morphine per hour; 5 or 10 mg oral oxycodone (every 3-4 hours); or 1000mg 
acetaminophen every 6-8 hours (not to exceed 4g per day) and recorded separately. 
6.3.1. 
Prior Medications 
Prior medications are defined as all medications recorded in the CRF initiated prior to the 
administration of IP. Prior medications will be summarized in a table by treatment group using 
the Safety Population. Medications will be reported by drug class (Anatomical Therapeutic 
Chemical [ATC] Level 3) and preferred term; a subject will be counted only once for each 
medication.  
6.3.2. 
Concomitant Medications 
Concomitant medications are defined as all medications recorded in the CRF taken after the 
administration of IP, including those that were initiated prior to administration of IP and 
ongoing. Concomitant medications will be summarized in a table by treatment group using the 
Safety Population. Medications will be reported by drug class (Anatomical Therapeutic 
Chemical [ATC] Level 3) and preferred term; a subject will be counted only once for each 
medication.  
 
6.4. 
Medical History 
Medical history will be coded using Medical Dictionary for Regulatory Activities (MedDRA) 
Version 22.1. Conditions will be listed, including the verbatim investigator description of the 
relevant medical condition, the coded terms (system organ class, preferred term), start date, end 
date, and whether or not the condition is ongoing. 


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7. 
STUDY OPERATIONS 
7.1. 
Protocol Deviations 
A protocol deviation is any noncompliance with the clinical trial protocol or International 
Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use 
(ICH) Good Clinical Practice (GCP) requirements. The noncompliance may be either on the part 
of the participant, the investigator, or the study site staff. Protocol deviations will be recorded on 
the source documents and with an explanation for the deviation. All protocol deviations will also 
be recorded as specified in the monitoring plan. 
Protocol deviations will be identified by site staff, through medical reviews, and by clinical 
research associates during site monitoring. Deviations will be classified as minor or major prior 
to the database lock. Major protocol deviations are defined as those that result in harm to the 
study patients or significantly affect the scientific value of the reported results of the study. Other 
deviations will be considered minor. 
All protocol deviations will be summarized in a table and well as presented in a listing, including 
their assigned severity (major/minor). 
7.2. 
Randomization 
Prior to surgery, subjects will be assigned a sequential randomization number corresponding to a 
sealed envelope containing a card displaying the assigned treatment, the randomization number 
and an area for the subject ID to be recorded. A member of the unmasked surgery team will 
retrieve study materials corresponding to the assigned treatment for use during surgery. Subjects 
will be assigned in a 3:1 ratio to either 2% CPL-01 (200 mg ropivacaine [10 mL]) or placebo 
(0.9% NaCl). A by-subject listing of randomized treatment group and randomization number will 
be presented. 
7.3. 
Measures of Treatment Compliance 
Following surgery, CPL-01 or Placebo will be administered by wound infiltration and 
instillation; IP will be delivered by 4 syringes in order with the following volumes: 1ml, 4ml, 
4ml, and 1ml. Per the protocol, it is expected that all syringes will be used and whether each was 
administered will be recorded on the CRF. The number and percent of subjects receiving each 
syringe will be reported for the safety population, as well as the number and percent receiving all 
syringes.  Additionally, summary statistics will be reported for the assumed total volume (for 
example, if the final 1ml syringe is not marked as being administered but the remainder are, the 
assumed volume would be 9ml). 
 


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8. 
ENDPOINT EVALUATION 
8.1. 
Overview of Efficacy Analysis Methods 
8.1.1. 
Multicenter Studies 
This is a single-center study and no special considerations are required for pooling of data. 
8.1.2. 
Timing of Analyses 
All final, planned analyses will be performed after the last participant has completed all study 
assessments, all relevant study data have been processed and integrated into the analysis 
database, and the database has been locked.  
Any post-hoc, exploratory analyses completed to support planned study analysis, which were not 
identified in this SAP, will be documented and reported in appendices to the CSR. Any results 
from these unplanned analyses (post-hoc) will also be clearly identified in the text of the CSR. 
8.1.3. 
Multiple Comparisons/Multiplicity 
Unless otherwise indicated, all statistical tests will be carried out at a two-sided significance 
level of 5%. Given that all efficacy assessments are considered as exploratory only and are 
intended to inform future trials, no multiplicity adjustment shall be applied to these exploratory 
analyses. 
8.2. 
Primary Efficacy Endpoint 
All efficacy endpoints are exploratory. However, the primary endpoint of interest is the time-
weighted summed pain intensity over 1 to 24 hours (SPI1-24) for CPL-01 subjects compared with 
placebo subjects. 
8.2.1. 
Computation of the Primary Endpoint 
The time weighted SPI will be calculated using the trapezoidal rule and the available NRS pain 
scores. Missing values will not be imputed (with the exception of the final timepoint) for the 
primary analysis of the primary endpoint; the trapezoidal rule will implicitly perform a linear 
interpolation between the two observed values on either side of a missing value. Actual times of 
each NRS score will be used for calculating the SPIs. 
NRS scores will be recorded just prior to administration of rescue medications. Following the 
administration of morphine, NRS values will be censored for two hours for the purposes of 
calculating the SPI; likewise, NRS values will be censored for four hours following 
administration of oxycodone. These values will be retained in the database, but will not be 
utilized for the SPI calculations, since they will be influenced by the rescue medications.  
Assuming that a subject has a 24-hour nominal value, their SPI will be normalized to exactly 
24hrs. Should the subject be missing the nominal 24-hour value, but have a subsequent NRS 
recorded, linear interpolation will be performed to impute the 24-hour value by connecting the 
prior and subsequent values and calculating where the 24-hour value would fall on that line. The 
above rules will be applied should the 24-hour value be censored due to rescue medication use; 


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the NRS collected from the associated rescue medication use will serve as the prior point for the 
imputation and the first subsequent non-censored value will be serve as the other anchor. If a 
subject withdraws from the study or has no values following the missing/censored 24-hour value, 
last observation carried forward will be employed using the last observed NRS. 
8.2.2. 
Primary Analysis of the Primary Endpoint 
An analysis of variance (ANOVA) model with a main effect for the treatment group will be used 
to compare the time weighted SPI1-24 between the treatment groups. Summary statistics will be 
reported as well as the least square (LS) means, difference in the LS means, 95% confidence 
intervals and p-value for the contrast comparing the LS means. 
8.2.3. 
Sensitivity Analyses of the Primary Analysis 
As a sensitivity analysis to the primary endpoint, the SPI will be calculated using multiple 
imputation (MI) instead of the procedures described above. The censoring rules for rescue 
medications will remain as above, but missing values will be imputed using MI within treatment 
group conditioned on the observed values, assuming missing at random (MAR). Nominal time 
points will be used for the purposes of the multiple imputation. Where values are censored for 
rescue medication use, the NRS score recorded just prior to the rescue administration will be 
substituted. The MI will use 20 repeats performed using Markov Chain Monte Carlo (MCMC) 
assuming non-monotone missing (Carpenter, 2013; Mallinckrodt, 2013).  A list of random seeds 
to be used is given in Appendix 15.2. 
The above estimates from the primary ANOVA model will be combined using SAS proc MI 
ANALYZE and the resulting least square (LS) means, difference in the LS means, 95% 
confidence intervals and p-value for the contrast comparing the LS means will be reported. 
 
8.3. 
Secondary Endpoints 
 
8.3.1. 
Time Weighted Sum Pain Intensities 
An approach identical to the primary computation for the SPI1-24 above will be employed for the 
cumulative SPI for hours 1-6, 1-12, 1-48, and 1-72.  Additionally, intervals 6-12, 12-24, 24-48, 
and 48-72 will be calculated by subtracting the associated cumulative values (so SPI6-12 will be 
calculated as SPI1-12 minus SPI1-6).  Summary statistics and results from an ANOVA modeling 
approach identical to the primary analysis will be reported. 
8.3.2. 
Pain Intensities by Time Point 
For each scheduled time point of collection, descriptive statistics will be reported for the pain 
intensities collected at that time point, both with all values included and with values censored 
due to rescue medication consumption; for the latter, the number of censored values will be 
reported. 
This presentation will also include daily NRS scores recorded in the take-home diary; no special 
data handling will be performed to account for recue medications on the daily diaries. 


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8.3.3. 
Total Opioid Usage (Morphine Equivalents) 
The total mg of opioids in morphine equivalents (MEQ) administered to each subject will be 
calculated through 24, 48 and 72 hours. Oxycodone mg will be converted to MEQ by 
multiplying by 1.5. Per the protocol, only morphine and oxycodone will be used as opioid rescue 
medications, but should another opioid moiety be used, the MEQ will be calculated using the 
CDC conversion guide (https://www.cdc.gov/drugoverdose/pdf/calculating_total_daily_dose-
a.pdf). 
The total MEQ through each time point will be reported with summary statistics and compared 
between the two groups using an ANOVA approach identical to that for the primary efficacy 
analysis. 
8.3.4. 
Time to First Rescue 
Time to first use of any rescue analgesia for postoperative surgical pain and the time to first 
opioid use will each be analyzed using the Kaplan-Meier method. The log-rank test will be used 
to test the hypothesis of overall treatment differences. If estimable, quantiles (25%, median, 
75%) will be reported; in the case of sparse rescue medication usage, the number and percentage 
of subjects will be reported along with summary statistics of the time to first use among those 
with use. 
8.3.5. 
Any Opioid Use 
The number and percentage of subjects who used no opioid rescue through 24, 48, and 72 hours 
will be reported for each treatment group and compared using Fisher’s exact test. Subjects that 
drop out prior to the given reporting period will be displayed. 
This will also be reported for those that remain opioid free through the end of the confinement 
period starting at 24, 48, and 72 hours. 
8.3.6. 
Pain Free Subjects 
The number and percentage of subjects who report pain intensity <=1 for all recorded NRS 
evaluations through 24, 48, and 72 hours will be reported for each treatment group and compared 
using Fisher’s exact test. Subjects that drop out prior to the given reporting period will be 
displayed. 
This will also be reported for those that remain pain free through the end of the confinement 
period starting at 24, 48, and 72 hours. 
8.3.7. 
Diary Rescue Medication Use 
Usage of rescue medications recorded in the take-home diary will be presented in a listing. 
 
 
 
 
 


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8.4. 
Examination of Subgroups 
There are no preplanned analyses of subgroups; exploratory analyses of subgroups may be 
performed, but will be post-hoc. 
 


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9. 
SAFETY EVALUATION 
 
9.1. 
Overview of Safety Analysis Methods 
Safety assessments will include AEs, vital signs, clinical laboratory assessments, 12-lead ECGs, 
physical examination, full neurological examination, local anesthetic systemic toxicity (LAST) 
assessment, and wound evaluation. 
 
9.2. 
Adverse Events 
An AE is defined as any untoward medical occurrence in a subject or clinical investigation 
subject administered a pharmaceutical product that does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding, for example), symptom, or disease temporally 
associated with the use of a medicinal product, whether or not related to the medicinal product. 
Pre-existing diseases or conditions will not be considered AEs unless there is an increase in the 
frequency or severity, or a change in the quality, of the disease or condition. (Worsening of a 
pre-existing condition is considered an AE.) 
Events that occur in subjects treated with placebo are also considered AEs. 
An AE is considered to be a treatment-emergent adverse event (TEAE) if the first onset or 
worsening is after administration of the IP (CPL-01 or placebo) and not more than 30 days after 
administration of IP. 
All AEs will be coded using Medical Dictionary for Regulatory Activities (MedDRA) Version 
22.1. 
 
An AE summary table will be presented for the following: 
• TEAEs 
• TEAEs by severity 
• TEAEs leading to study discontinuation  
• TEAEs by relationship 
• Serious AEs (defined below) 
Summaries of incidence rates (frequencies and percentages) of individual AEs by MedDRA 
System organ class (SOC) and preferred term will be prepared. Such summaries will be 
displayed for all TEAEs, TEAEs by maximum severity, and TEAEs by strongest relationship to 
study drug. 
Each participant will be counted only once within each summation level (SOC; preferred term). 
If a participant experiences more than one TEAE within each summation level only, the TEAE 
with the strongest relationship or the maximum severity, as appropriate, will be included in the 
summaries of relationship and severity. 


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In the AE data listings, all AEs will be displayed. AEs that are treatment-emergent will be 
flagged. 
 
 
9.3. 
Deaths, Serious Adverse Events (SAE), and Other Significant 
Adverse Events 
An adverse event is considered to be an SAE if it meets any of the following criteria: 
• Results in death 
• Is life-threatening 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability/incapacity 
• Is a congenital anomaly 
• Is an important medical event 
A summary of incidence rates (frequencies and percentages) of SAEs by treatment group, SOC, 
and preferred term will be prepared for the Safety Population. A data listing of SAEs will also be 
provided, displaying details of the event(s) captured on the CRF. Likewise, AEs resulting in 
study discontinuation and AEs resulting in death will be listed separately.  
 
Additionally, a summary of incidence rates (frequencies and percentages) of adverse events of 
special interest by treatment group, SOC, and preferred term will be prepared for the Safety 
Population.  
 
The following will be considered AEs of special interest because they are common symptoms of 
LAST. 
• Neurological signs/symptoms - circumoral and/or tongue numbness, metallic taste, 
lightheadedness and/or dizziness, visual (e.g. difficulty focusing vision) and/or auditory 
disturbances (e.g. tinnitus), disorientation, drowsiness (to an unexpected or unusual 
degree), agitation or seizures. 
• Cardiorespiratory signs/symptoms - hypotension that is clinically significant or sustained, 
clinically significant (new and/or sustained) arrhythmia, cardiac or respiratory arrest. 
Occurrences of LAST and AEs that may be signs and symptoms of LAST will be displayed in an 
identical manner on a separate table. 
9.4. 
Wound AEs and Infections 
A summary of incidence rates (frequencies and percentages) of wound AEs (including surgical 
site infections) by treatment group, SOC, and preferred term will be prepared for the Safety 
Population. A data listing of wound AEs will also be provided, displaying details of the event(s) 
captured on the CRF. A partial list of preferred terms is given in appendix 15.3, but at a 
minimum AEs where the preferred term includes “wound”, “incision”, “post-procedural”, 
“seroma” and “abscess” will be considered and reviewed as possible wound AEs. 


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9.5. 
Clinical Laboratory Evaluation 
Clinical laboratory values will be collected at the Screening Visit and the Follow-up Visit. 
Values collected at Screening will serve as the baseline. 
Descriptive summaries (mean, SD, median, minimum, and maximum) of observed (absolute) 
values and changes from baseline values will be presented for clinical laboratory values for each 
treatment group at each time point. 
The number of subjects with clinical laboratory values categorized as below, within, or above 
normal ranges, will be tabulated showing change from baseline to follow-up (shift tables) for 
each clinical laboratory analyte by treatment group. Only laboratory values that are outside the 
normal range will be flagged in the data listings and presented with the corresponding normal 
ranges. The original units for normal ranges provided the study’s local lab will be utilized in 
determining whether parameters are in range; that is, no conversions or rounding will be 
performed prior to this determination. Any out-of-range values that are identified by the 
investigator as being clinically significant will also be shown in a data listing. 
Serology tests (for HIV, Hepatitis B, Hepatitis C), pregnancy tests, and urine drug screens will 
be presented in a listing. 
 
9.6. 
Vital Signs, Physical Findings, and Other Observations Related to 
Safety 
9.6.1. 
Vital Signs 
Vital signs including blood pressure, heart rate, respiratory rate and temperature will be collected 
at the Screening Visit, Baseline Visit (at check-in) and the Follow-up Visit. Values collected at 
Baseline Visit will serve as the baseline; if missing, the Screening Visit or last unscheduled visit 
prior to baseline will be used. Additional vital signs will be collected as part of the LAST 
assessments (see below), but will not be summarized. 
Descriptive summaries (mean, SD, median, minimum, and maximum) of observed (absolute) 
values and changes from baseline values will be presented for vital sign values for each 
treatment group at each time point. 
9.6.2. 
Physical and Neurological Examinations 
Any abnormal findings from the neurological examination results will be displayed in a listing. 
Physical Exam findings will be recorded in medical history if present at screening and as adverse 
events if emergent at later assessments. 
9.6.3. 
Local Anesthetic Systemic Toxicity Assessment  
Subjects will be evaluated for local anesthetic systemic toxicity (LAST) throughout the 
confinement period. This includes AEs that may be signs and symptoms of LAST, ECG 
findings, vital signs, the Richmond Agitation Sedation Scale.  If the clinician determines the 
subject to be presenting with LAST, an AE will be recorded reflecting this finding. Subjects that 
have a LAST AE recorded will have all their LAST assessments presented in a listing. 


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9.6.4. 
Richmond Agitation and Sedation Scale Assessment 
The Richmond Agitation and Sedation Scale (RASS) is used in hospitalized patients to describe 
their level of alertness or agitation.  The clinician observes the subject and ranks their level of 
sedation/agitation using the following scale and scores: 
• Combative +4 
• Very agitated +3 
• Agitated +2  
• Restless +1  
• Alert and calm 0 
• Drowsy -1 
• Light sedation -2 
• Moderate sedation -3 
• Deep sedation -4 
• Unarousable sedation -5 
The descriptive summaries (mean, SD, median, minimum, and maximum) of observed values 
using the above scores will be presented for each treatment group at each time point. 
9.6.5. 
ECGs 
The number and percentage of subjects with normal and abnormal ECG findings will be 
summarized for each treatment group at each time point. Abnormal results will be grouped as 
“abnormal, clinically significant” and “abnormal, not clinically significant,” and summarized in 
the same way. A by-subject listing of abnormal ECG findings will be provided.  
Descriptive summaries of observed values and changes from baseline will be presented for ECG 
measures of PR interval, QRS interval, QT interval, QTc interval (Bazett’s and Fridericia’s 
correction methods), and HR for each treatment group at each time point. In addition, the number 
and percent of subjects in each treatment group who experienced an increase in QT and QTc 
interval of >30 ms or a change >60 ms at any time point will be presented. 
9.6.6. 
Wound Healing 
In addition to the wound infection and wound-related AEs presentations described in section 9.4, 
the subject’s wound site will be evaluated using a 1 to 5 scale as follows: 
1-Normal healing 
2-Delayed healing 
3-Excessive Drainage 
4-Infection 
5-Tissue breakdown 
Descriptive statistics of the surgical wound site assessment findings at the Day 7-10 Follow-up 
Visit (7-10 days after administration of IP) and the Day 30 Follow-up Visit (30 days after 
administration of IP) will be presented by treatment group as well as the count and percentage of 
subjects with each level of the response. 


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Surgical wound site assessment findings at 24, 48, 72, 96, and 120 hours after IP administration 
will be displayed in a listing. 
 
 


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10. 
PHARMACOKINETIC EVALUATION 
Blood samples (approximately 3 mL each) for PK assessments will be collected via indwelling 
intravenous catheter. Plasma ropivacaine concentrations will be quantified using a validated LC-
MS/MS assay method. All samples for all time points should be collected within the scheduled 
sampling windows (± 5 minutes for samples taken during the first hour, ± 10 minutes for the 
samples taken at 2 through 72 hours after administration of IP, and ± 1 hour for samples taken at 
96 and 120 hours after administration of IP). The exact time of blood sampling will be recorded 
in the source documents. 
Pharmacokinetic samples will be shipped to a central laboratory for analysis. 
10.1. 
Pharmacokinetic Endpoints 
PK analyses is not in the scope of this SAP, and will be documented in a PK analysis plan 
separately by a third party vendor MicroConstants, Inc.. 


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11. 
OTHER ANALYSES 


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12. 
INTERIM ANALYSES AND DATA MONITORING 
No interim analyses are planned. 


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13. 
CHANGES TO THE ANALYSES PLANNED IN THE PROTOCOL 
The protocol stated that a Cox proportional hazards model would be used for the analysis of time 
to first rescue medication use in addition to the Kaplan-Meier analysis. The Kaplan-Meier 
analysis was determined to be sufficient. 
The protocol describes physical exams findings as being recorded separately; as described above, 
they will be recorded with medical history or adverse events per the current CDISC 
recommendations. 
The analyses of any opioid use and pain free time have been expanded to look both at subjects 
free of opioids and pain through the described time points (included in the protocol) and subjects 
free of opioids/pain starting at those time points through the end of the confinement. 
 


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14. 
REFERENCES 
Carpenter, J. R. and Kenward, M. G. (2013), Multiple Imputation and Its Application, New 
York: John Wiley & Sons. 
Mallinckrodt C, Roger J, Chuang-Stein C, Molenberghs G, Lane PW, O’Kelly M, Ratitch B, Xu 
L, Gilbert S, Mehrotra DV, Wolfinger R, Thijs H. (2013), Missing Data: Turning Guidance Into 
Action, Statistics in Biopharmaceutical Research, 5:4, 369-382 


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15. 
APPENDIX 


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15.1. 
Schedule of Events 
 
Screenin
g Period 
(-42 days 
to -1 day 
before 
surgery)a 
Surgical/ 
Anesthesia 
Period 
(Confinemen
t)b 
Post-anesthesia Period 
(Confinement) 
Post-treatment Follow-up Period 
Day 1 
through 
Hour 1  
Day 1, Hour 1 
(1 hour after 
administration 
of IP) 
to Hour 24 
Day 2 
Day 3 
Day 4 
Days 5 
and 6 
Day 7-10  
Follow-up Visit 
(7 to 10 days after 
administration of 
IP or upon early 
termination)c 
Day 30 
Follow-up 
Visit 
(30 days after 
administration 
of IP) 
Written informed consent 
X 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X (at check-
in) 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Medical history 
X 
X (at check-
in) 
 
 
 
 
 
 
 
Full neurological examinationd 
X 
X 
 
 
 
 
 
X 
 
LAST assessmente 
 
 
X 
X 
X 
 
 
 
 
Physical examinationf 
X 
 
 
 
 
 
 
X 
 
Vital signsg 
X 
X (at check-
in) 
 
 
 
 
 
X 
 
Height, weight, and BMI 
X 
 
 
 
 
 
 
 
 
12-lead electrocardiogram 
X 
Xh 
Xh 
Xh 
Xh 
Xh 
Xh (Day 5 
only) 
X 
 
Clinical laboratory evaluationsi 
X 
 
 
 
 
 
 
X 
 
Serology testsj 
X 
 
 
 
 
 
 
 
 
Pregnancy testk 
X 
X (at check-
in) 
 
 
 
 
 
 
 
Urine drug screenl 
X 
X (at check-
in) 
 
 
 
 
 
 
 
Train subjects how to use NRS 
X 
X (before 
surgery) 
 
 
 
 
 
 
 
Dispense diary and dischargem 
 
 
 
 
 
X 
 
 
 
Assign randomization number 
 
 
X (before 
surgery) 
 
 
 
 
 
 
 


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Screenin
g Period 
(-42 days 
to -1 day 
before 
surgery)a 
Surgical/ 
Anesthesia 
Period 
(Confinemen
t)b 
Post-anesthesia Period 
(Confinement) 
Post-treatment Follow-up Period 
Day 1 
through 
Hour 1  
Day 1, Hour 1 
(1 hour after 
administration 
of IP) 
to Hour 24 
Day 2 
Day 3 
Day 4 
Days 5 
and 6 
Day 7-10  
Follow-up Visit 
(7 to 10 days after 
administration of 
IP or upon early 
termination)c 
Day 30 
Follow-up 
Visit 
(30 days after 
administration 
of IP) 
 
 
 
 
 
 
Mini-abdominoplasty and IP 
administrationn 
 
X 
 
 
 
 
 
 
 
Rescue analgesiao 
 
X 
X 
X 
X 
X 
 
 
 
Continuous pulse oximetryp 
 
X 
X 
X 
X 
X 
 
 
 
Pain intensity assessmentsq 
 
 
X 
X 
X 
X 
X 
 
 
Wound evaluation, including 
photographr 
 
 
 
X 
X 
X 
X 
X 
X 
PK blood sample collections 
 
X 
X  
X 
X 
X 
X 
 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse eventst 
 
X 
X 
X 
X 
X 
X 
X 
X 
Subject returns completed diary 
 
 
 
 
 
 
 
X 
 
Abbreviations: AE = adverse event; BMI = body mass index; ECG = electrocardiogram; HIV = human immunodeficiency virus; IP = investigational product; LAST = local anesthetic 
systemic toxicity; NRS = numeric rating scale; PK = pharmacokinetic; RASS: Richmond Agitation and Sedation Scale  
a 
Screening can be performed as late as on the morning of the surgery if all inclusion/exclusion criteria can be verified. Subjects must be at rest for a minimum of 15 minutes in 
the resting position before any assessments are performed during each study visit, unless otherwise specified. 
b 
Subjects will be admitted to the study site on the morning of the scheduled surgery and confined at the study site through Day 4. 
c 
On non-visit days prior to the Day 7-10 Follow-up Visit, a brief daily telephone call will be conducted to remind subjects to record their pain intensity (using NRS), and rescue 
medication usage in the diary. 
d 
A full neurological examination will be performed at Screening, on Day 1 any time prior to anesthesia induction, and at the Day 7-10 Follow-up Visit or upon early termination. 
The full neurological examination will include a mental status examination and evaluation of cranial nerve, motor, sensory, and cerebellar function. In addition, the findings 
will be summarized in a neurologic assessment. The examiner will be asked to record whether the subject’s overall neurologic status is normal or abnormal. 
e 
Signs and symptoms of LAST will be monitored every 4 hours on Day 1 and at least once daily on Days 2 and 3 using the following: vital signs (resting blood pressure, heart 
rate, respiratory rate, and oral body temperature), RASS assessment, and a focused neurological examination. The focused neurological examination will include a basic mental 


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status examination and an evaluation to see if the subject is tremulous or complaining of any unusual symptoms (e.g., perioral paresthesias, metallic taste, or dizziness). If 
abnormal neurological findings are observed during the LAST assessment, a full neurological examination will be performed. If any signs or symptoms of LAST are observed, 
including a change in the ECG, the following will be performed: unscheduled PK sample collection, 12- lead ECG, and vital sign measurements. 
f 
A complete physical examination will be performed at Screening (including height and weight), and an abbreviated physical examination (changes since Screening), will be 
performed at the Day 7-10 Follow-up Visit (7 to 10 days after administration of IP or upon early termination). 
g 
Vital signs (resting blood pressure, heart rate, respiratory rate, and oral body temperature) will be measured after the subject has been in a resting position for 5 minutes. Vital 
signs will be measured and recorded at Screening, at check-in on Day 1, and at the Day 7-10 Follow-up Visit. 
h 
A 12-lead ECG will be performed immediately prior to induction of anesthesia and at 1, 2, 4, 8, 10, 12, 24, 48, 72, and 96 hours after IP administration. 
i 
The clinical laboratory evaluations will be hematology, chemistry, and urinalysis. 
j 
The serology tests will be HIV, hepatitis B surface antigen, and hepatitis C virus antibody. 
k 
For women of childbearing potential only, a serum pregnancy test will be done at Screening and a urine pregnancy test will be done at check-in on Day 1. 
l 
The urine drug screen will test for amphetamines, barbiturates, benzodiazepines, cocaine, opiates, phencyclidine, and tetrahydrocannabinol. 
m 
Subjects will receive a diary to record their pain intensity (using NRS) and rescue medication usage when they are discharged from the study site on Day 4. They will be 
instructed to complete the diary daily until they return to the study site for the Day 7-10 Follow-up Visit (7 to 10 days after administration of IP or upon early termination). 
n 
Subjects will be administered general anesthesia according to a standard regimen, during which they will undergo a mini-abdominoplasty. At the end of the surgical procedure 
but before the wound is closed, the IP will be administered by wound infiltration and instillation. 
o 
Subjects with inadequately controlled pain symptoms may request rescue analgesia. Pain intensity using an NRS will be recorded just prior to receiving rescue analgesia. After 
administration of the IP, rescue analgesia will be restricted to 2 to 4 mg of intravenous morphine every hour as needed until the subject is able to tolerate oral medication. Once 
oral medication can be tolerated, oxycodone 5 to 10 mg every 3 to 4 hours will be used as needed for analgesia. After the subject’s pain intensity is ≤4, oral acetaminophen 
1000 mg will be used every 6 to 8 hours as needed for analgesia (not to exceed 4 g within 24 hours). For breakthrough pain intensity >4 that is not relieved by the oral 
acetaminophen, oral oxycodone 5 to 10 mg every 3 to 4 hours as needed for pain may continue to be used. For breakthrough severe pain intensity >8, intravenous morphine 2 to 
4 mg every hour as needed may be allowed. Subjects should receive a prescription for rescue analgesia for use after they are discharged from the study site. 
p 
Continuous pulse oximetry will be monitored immediately following surgery, throughout transport, and in the post-anesthesia care unit until subjects switch from intravenous 
morphine to oral rescue analgesia medication. If O2 saturation drops below 93% or if subjects have clinical signs or symptoms that suggest respiratory depression while on the 
oral medication, or subjects switch back to intravenous morphine, they will be kept on continuous pulse oximetry as required.  
q 
Pain intensity will be assessed using an NRS at 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16, 24, 32, 40, 48, 56, 64, and 72 hours after administration of IP. Additionally, pain intensity using 
an NRS will be recorded just prior to receiving rescue analgesia. The pain intensity will also be recorded when subjects return to the study site at 96 and 120 hours after 
administration of IP. 
r 
Study site staff will evaluate the wound by direct visualization and record the numerical rating score on the eCRF at 24, 48, 72, 96 (Day 5), and 120 hours (Day 6) after 
administration of IP, and also at the Day 7-10 and Day 30 Follow-up Visits. Additionally, study site staff will photograph the wound area following the standardized instructions. 
Subjects will be instructed to call with any concerns about the appearance of the wound after being discharged from the study site. If subjects call with concerns, they will be 
asked to return to the study site for an unscheduled visit. 
s 
Blood samples will be collected for PK analysis at baseline (before IP administration), 15, 30, and 45 minutes, and at 1, 2, 4, 6, 8, 10, 12, 18, 24, 30, 36, 48, 60, and 72 hours 
after administration of IP (± 5 minutes for samples taken during the first hour and ± 10 minutes for the remainder of the samples). Subjects will return to the study site for 
collection of PK blood samples at 96 and 120 hours after administration of IP (± 1 hour) (Days 5 and 6). 
t 
Adverse events will be monitored throughout the study. If a subject has an AE after being discharged from the study site, he or she will return to the study site for safety 
assessments, including a photograph of the wound. 


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15.2. 
Random Seeds 
The following list of number will be used in order for programming tasks that require random 
seeds. If additional numbers are required, programming will return to the start of the list and add 
one to each value for additional seeds. 
95757437 
73846758 
65831589 
86284444 
90876999 
43543977 
78974612 
22334268 
66674922 
78467583 
 
 
15.3. 
Wound AEs 
The following is a partial list of potential preferred terms to identify wound AEs: 
Abdominal abscess 
Burning sensation 
Cellulitis 
Incision site cellulitis 
Incision site complication 
Incision site erythema 
Incision site haematoma 
Incision site haemorrhage 
Incision site hypoaesthesia 
Incision site infection 
Incision site inflammation 
Incision site pain 
Incision site pruritus 
Incision site rash 
Incision site swelling 
Local swelling 
Post procedural contusion 
Post procedural discharge 
Post procedural haematoma 
Post procedural haemorrhage 
Postoperative wound infection 
Scar 
Secretion discharge 


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Seroma 
Skin induration 
Suture related complication 
Wound complication 
Wound dehiscence 
Wound infection 
Wound secretion 


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16. 
ATTACHMENTS