Clinical trial NCT04774328
Conditions: Postsurgical Pain
Sponsor: Concentric Analgesics
Start date: 2020-09-09; Completion date: 2021-06-15
Enrollment: 34 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A Three-Part, Phase 1/2, Randomized, Double-blind, Placebo-Controlled, Adaptive Safety, Pharmacokinetics, and Preliminary Efficacy Study of CA-008 (Vocacapsaicin) in Patients Undergoing Ventral Hernia Repair

Detailed description:

Arms: arm 1: Single administration arm 2: Single administration
Interventions: intervention 1: CA-008 (vocacapsaicin) intervention 2: Placebo
Intervention descriptions: intervention 1: Single administration of CA-008 (vocacapsaicin) versus placebo intervention 2: Single administration of CA-008 (vocacapsaicin) versus placebo

Protocol documents:
Prot_000.pdf: 
Concentric Analgesics, Inc. 
 
Protocol Name:  CA-PS-209  
Protocol Title:  A Three-Part, Phase 1/2, Randomized, Double-blind, Placebo Controlled, Adaptive Safety, 
Pharmacokinetics, and Preliminary Efficacy Study of CA-008 (Vocacapsaicin) in Patients Undergoing 
Ventral Hernia Repair  
Investigational Product: CA-008 by Injection/Instillation  
IND: 129114 
NCT:  04774328 
Study Protocol, version dated 15 March 2021 
 


Clinical Trial Protocol CA-PS-209 
 
Confidential 
Amendment 2: March 15, 2021 
Page 1 of 147 
 
 
CLINICAL TRIAL PROTOCOL 
 
 
A Three-Part, Phase 1/2, Randomized, Double-blind, 
PlaceboControlled, Adaptive Safety, Pharmacokinetics, and 
Preliminary Efficacy Study of CA-008 (Vocacapsaicin) in Patients 
Undergoing Ventral Hernia Repair 
 
Investigational Product: CA-008 by Injection/Instillation 
IND: 129114 
 
Concentric Analgesics, Inc. 
Original Protocol Date: 27 July 2020 
Amendment 1 Date: 13 January 2021 
Amendment 2 Date: 15 March 2021 
 
 
CONFIDENTIAL 
This protocol is the property of Concentric Analgesics, Inc. (Concentric) and is intended 
solely for the guidance of the clinical investigation. This protocol may not—in full or part—
be passed on, reproduced, published, or distributed to any person or entity who is not bound 
by written confidentiality agreement, for any purpose, without the prior consent of 
Concentric. 
 
 
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SIGNATURE PAGE 
A Three-Part, Phase 1/2, Randomized, Double-blind, Placebo-Controlled, Adaptive 
Safety, Pharmacokinetics, and Preliminary Efficacy Study of CA-008 (Vocacapsaicin) 
in Patients Undergoing Ventral Hernia Repair 
 
Approved by: 
 
 
 
 
 
 
_____________________________________ 
_______________________ 
 
Nancy Wu 
 
Date 
 
Head of Clinical Operations 
 
 
Concentric Analgesics, Inc. 
 
 
Authored and Approved by: 
 
 
 
 
 
 
_____________________________________ 
_______________________ 
 
Sam Teichman, MD 
 
Date 
 
VP of Clinical Development 
 
Concentric Analgesics, Inc. 
 
 
 
 
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3/16/2021
3/16/2021


Clinical Trial Protocol CA-PS-209 
 
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1 
KEY PERSONNEL CONTACT INFORMATION 
Sponsor 
Concentric Analgesics, Inc. (Concentric) 
Carrie Khouri 
Sr Clinical Trial Manager 
ckhouri@concentricanalgesics.com 
310-617-6886 
 
Sam L. Teichman, M.D. 
VP of Clinical Development 
steichman@concentricanalgesics.com 
925-437-2067 
 
CRO 
Lotus Clinical Research, LLC 
Primary 
Contact 
 Teresa Shields 
Sr Project Manager 
tshields@lotuscr.com 
612-236-7455 
CRO Medical 
Monitors 
Primary: Jon L. Ruckle, MD, CPI 
 
MedicalMonitorCA-PS-209@Lotuscr.com 
808-349-9812 
Secondary: Royce Morrison, MD 
 
MedicalMonitorCA-PS-209@Lotuscr.com 
206-799-7386 
 
 
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Summary of Changes for protocol CA-PS-209 Version 1.0 to 2.0  
 
Substantive Changes 
Not Applicable 
 
Other Changes: 
Clarifications and Additions: 
• Updated study title for consistency (Synopsis) 
• Updated Overall Study Design – Part B dose of CA-008 will be decreased to 24 mg 
delivered as 80 mL of a 0.3 mg/mL solution (Synopsis and Section 7.1) 
• Updated Primary Study Objectives for Part B to reflect dose and dose volume change 
(Synopsis and Section 6.1) 
• Updated Secondary Study Objectives for Part B to reflect dose change (Synopsis and 
Section 6.2) 
• Updated Inclusion Criteria #1 to reduce maximum length of ventral hernia allowed 
for enrollment into study (Synopsis and Section 8.2.1) 
• Updated Dose Groups – Parts B and C for study drug volumes and delivery (Synopsis 
and Section 9.1.2) 
• Updated Preoperative, Anesthesia and Perioperative Care to clarify dosing for 
bupivacaine in Parts A, B and C (Synopsis, Sections 9.2.1, and 10.1.2.2) 
• Clarified Sample Size Stratification - Part C (Synopsis and Section 13.1) 
• Updated Dose Escalation - Part B to reflect dose change (Section 7.3)Updated Study 
Treatment Description to reflect dose change (Section 9.1.2)Updated Injection of 
Study Treatment – Parts B and C to reflect decreased volume of 80 ml and volume of 
amount administered to each site (Synopsis) 
• Updated Surgery Phase: Administration of Study Medication into the Surgical Site – 
Parts B and C to reflect decreased volume of 80 ml and volume amount administered 
to each site (Synopsis and Section 10.1.3) 
• Updated Investigator Protocol Agreement Page to remove version number 
• Clarified Pharmacokinetic Endpoints to reflect that the analysis will be found in the 
analysis plan (Synopsis and Section 10.3.20) 
 
Administrative: 
• Corrected minor grammatical errors throughout protocol 
• Updated study contact personnel and information 
 
 
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Summary of Changes from CA-PS-209 original protocol to V1.0 
 
Substantive Changes: 
1. Bupivacaine dose 
Rationale: Clarified local anesthetic techniques so that the total dose of bupivacaine 
hydrochloride will not exceed 175 mg (Synopsis, Sections 9.2, and 10.1.2.2) 
 
2. CA-008 dose  
Rationale: Previous animal models and clinical trial studies, along with the characterization 
of the pharmacology, PK, and toxicology profiles and the anticipated benefits and potential 
risks support the dosage for CA-008 (Section 5.5.1)  
 
Other Changes: 
Clarifications and Additions: 
• Updated sample size for Parts A, B, and C (Synopsis and Section 13.1)  
• Clarification of study population for primary ventral hernia repair (Synopsis and 
Section 8.1) 
• Made laparoscopic assistance optional for all Parts (Synopsis and Sections 8.2.1, and 
10.1.3) 
• Updated Overall Study Design - Part A dose is CA-008 15 mg and Part B dose of 
CA-008 will be increased to 30 mg if the formal safety from Part A is favorable 
(Synopsis and Section 7.1) 
• Clarified Primary Study Objectives for Parts A and B (Synopsis and Section 6.1) 
• Updated Secondary Study Objectives for Parts A and B to evaluate the PK profile for 
both Parts and the ECG QT interval for Part B (Synopsis and Section 6.2) 
• Clarification Parts A, B, and C Dose Groups - study drug volumes and delivery 
(Synopsis and Section 9.1.2) 
• Specified the injection of Study Treatment for all Parts (Synopsis and Section 10.1.3) 
• Clarified language regarding intraoperative IV fluid volume (Synopsis and Section 
9.2.2) 
• Clarification of Inclusion Criteria # 2 regarding TAP block (Synopsis and Section 
8.2.1) 
• Clarification of antibiotic use (Exclusion # 5c). (Synopsis, Sections 8.2.2 and 9.5) 
• Updated Vital Signs to include O2 saturation [SpO2] (Synopsis and Section 10.4.1) 
• Clarification of Exploratory efficacy endpoints (Synopsis and Section 10.4.3.5) 
• Clarification of Pharmacokinetic endpoints (Synopsis and Section 10.3.20) 
• Updated Stopping Rules to apply to any grade 3 TEAE (Synopsis and Section 7.4) 
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• Added independent medical monitor to team to review relevant data for dose 
escalation or cohort expansion (Synopsis, Sections 7.3, 7.4, and 13.3) 
• Updated the timing of the Pharmacokinetic draws (Synopsis, Schedule of 
Assessments and Section 10.3.20) 
• Updated text for tests of statistical significance (Section 13.3) 
• Updated definition of PKT0 to “Pre-IP Dose” (Synopsis, Schedule of Assessments, 
Section 10.1.4, Section 10.3.20 and Section 13.4.5) 
• Added details to the ongoing clinical trials (Table 9, Section 5.3) 
• Corrected language that patients must abstain from THC-containing products for 7 
days prior to surgery (Section 10.3.13) 
• Modification of Intent-to-treat (MITT) Population to consist of all patients who 
received any dose of study treatment (Synopsis and Section 13.2)  
• Corrected the location of the neurosensory examination form (Section 17.12) 
• Updated Schedule of Assessments – vital signs, Holter monitor, and PK blood sample 
timepoints (Table 1) 
 
Administrative: 
• Corrected minor grammatical errors throughout protocol 
• Updated study contact personnel and information 
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2 
PROTOCOL SYNOPSIS 
Sponsor:  
Concentric Analgesics, Inc. (Concentric) 
101 California Street, Suite 1210 
San Francisco, CA 94111 
CRO: 
Lotus Clinical Research, LLC 
Protocol 
Number: 
CA-PS-209  
IND# 
129114 
Study Title: 
A Three-Part, Phase 1/2, Randomized, Double-blind, Placebo-Controlled, 
Pharmacokinetics, Adaptive Safety and Preliminary Efficacy Study of CA-008 
(Vocacapsaicin) in Patients Undergoing Ventral Hernia Repair 
Study 
Treatment 
CA-008 (also known as vocacapsaicin) and placebo 
Planned Study 
Center(s): 
Part A and Part B: 1 US site 
Part C: Up to 5 US sites 
Indication: 
Acute postsurgical pain 
Background 
Information: 
CA-008 is a prodrug of the analgesic capsaicin being developed to reduce 
postsurgical pain and reduce the need for opioids. The drug is delivered into the 
surgical site during the operative procedure. An open laparotomy procedure 
using an abdominal incision through all abdominal layers to repair a ventral 
hernia is a standard surgical model for the evaluation of experimental anesthetic 
and analgesic therapies. 
Sample Size: 
The total number of patients to be enrolled in Parts A and B together will not 
exceed ~48. 
Part A – Open-label, feasibility and safety assessment: 
N = At least 8 with an acceptable range of up to N=16  
Part B – Double-blind, placebo-controlled pilot: 
Expected N = 24 with an acceptable range of up to N = 32 (randomized 1:1 
active to placebo). 
Part C – Double-blind, placebo-controlled efficacy: 
In Part C, a total of up to N = ~100 patients will be randomized 1:1 
active:placebo in 2 parallel arms to bring the total number of patients enrolled 
in the study to up to ~150.  
Population: 
Adults 18 to 80 years of age, inclusive, who are planning to undergo an elective 
open laparotomy for ventral hernia repair (VHR), with retromuscular, 
preperitoneal mesh repair (i.e., Rives-Stoppa technique or equivalent), with or 
without laparoscopic assistance, and who otherwise meet eligibility criteria may 
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be considered for enrollment into the study. 
Study Duration: 
Approximately 90 days per patient from screening to Day 29 (D29) + 2 days 
(however, this could be longer to follow any adverse event [AE] to resolution 
or to establishment of a new baseline). 
Overall Study 
Design: 
 
This is a three-part, Phase 1/2, randomized, double-blind, placebo-controlled, 
pharmacokinetics (PK), and adaptive safety study of CA-008 in patients 
undergoing VHR. 
In Part A, CA-008 15 mg will be administered in an open-label exploration of 
different delivery techniques. The objective is to determine the safety, 
feasibility, PK and appropriateness of administration of a single dose of 
CA-008 infiltrated/instilled during surgery in patients undergoing VHR. It is 
expected that 8-12 patients will be enrolled in Part A, but it may be up to 16 
patients so that at least 8 patients receive the optimal delivery technique which 
will allow a formal safety assessment of the 15 mg dose of study drug. 
In Part B, if the formal safety assessment from Part A of CA-008 15 mg is 
favorable, then the active study drug dose will be increased. The single dose 
selected for Part B is 24 mg, based on the experience in Part A, delivered as 80 
mL of a 0.3 mg/mL solution. Using the general delivery technique identified in 
Part A, this dose, concentration and volume will be assessed compared to a 
placebo in a pilot, double-blind, randomized, parallel-group design (see Figure). 
The objective of Part B is to determine preliminarily the tolerability of planned 
study drug administration as well as the pain profile of the placebo control 
group. It is expected that approximately 24 patients (up to 32) will be enrolled 
in Part B. The results of Part B will be unblinded for analysis prior to the 
initiation of Part C. 
 
In Part C, the active dose level of CA-008 from Part B will be evaluated 
compared to placebo in a larger randomized, double-blind, parallel-group 
design to evaluate efficacy and safety. It is expected that ~100 patients will be 
enrolled in Part C to bring the total number of patients enrolled in the study to 
up to ~150.  
For each patient, the study will be conducted in two periods: 
• 
Inpatient period which continues from check-in on D1 until discharge 
(4 days or 96 hours [h] following surgery [T96 ± 4 h], [D5]). Discharge 
may be delayed, if needed, for medical reasons. 
• 
Outpatient period which begins on discharge from the inpatient unit 
through follow up visits to D29 + 2 days. Note that additional follow up 
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visits may occur at any time or even after D29 to follow AEs to resolution 
or to establish a new baseline. 
During the inpatient period, patients will undergo VHR including study drug 
treatment (CA-008 or placebo) followed by serial assessments of safety, PK, 
and drug effect, in particular focusing on reported pain and need for analgesia. 
During the outpatient period, patients will have serial assessments of safety and 
drug effect.  
Study 
Objectives: 
Part A: 
Primary Objective: 
• 
Evaluate the safety, tolerability and feasibility of a single intraoperative 
administration of CA-008 15 mg in patients undergoing an elective VHR. 
Secondary Objectives: 
• 
Evaluate the PK profile of a single intraoperative administration of CA-008 
15 mg in patients undergoing an elective VHR.  
 
Part B: 
Primary Objective:  
• 
Evaluate the safety, tolerability and feasibility of a single intraoperative 
administration of a fixed dose of CA-008, 24 mg in patients undergoing an 
elective VHR. 
Secondary Objectives: 
• 
Determine the pain profile of patients undergoing an elective VHR. 
• 
Determine the appropriateness of progression to Part C. 
• 
Assessment of opioid consumption.  
• 
Evaluate the PK profile of a single intraoperative administration of CA-008 
24 mg in patients undergoing an elective VHR.  
• 
Explore the relationship between CA-008 and its metabolite plasma 
concentrations and electrocardiogram (ECG) QT interval using a 
concentration-QT (cQT) analysis. 
 
Part C: 
Primary Objective: 
• 
Evaluate the efficacy of CA-008 on reported pain in patients undergoing an 
elective VHR during a specified post-operative time interval. 
Secondary Objectives: 
• 
Evaluate the efficacy of CA-008 on reported pain in patients undergoing an 
elective VHR during additional specified post-operative time intervals. 
• 
Evaluate the effect of CA-008 on opioid consumption. 
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• 
Evaluate the effect of CA-008 on patient-reported outcomes (PROs). 
• 
Evaluate, preliminarily, the effect of CA-008 on performance-based 
outcome measures (PBOMs). 
• 
Evaluate the safety and tolerability of CA-008 or placebo in patients 
undergoing an elective VHR. 
Study 
Treatment 
Dosing 
Schedule: 
Study treatment is to be administered intraoperatively as a single administration 
via infiltration/instillation into the “surgical site” prior to wound closure. 
In general, the intent is to deliver local anesthetic into the surgical site “on the 
way in” (upon adequate exposure of and prior to incision/dissection of target 
tissues). Conversely, study drug (active or placebo) delivery to the same and 
other areas will be administered by infiltration (injected) and/or 
instillation/irrigation (dripped) to the surgical site “on the way out” (prior to 
and at the time of surgical closure). 
The “surgical site” is defined as the area extending approximately at least 
2-3 cm in all directions (lateral/medial/proximal/distal/deep) from the margins 
of substantially all tissue traumatized by the surgical procedure, i.e., all tissue 
dissected, cut, electrocauterized (bovied), sutured or tacked, including both 
deep and superficial areas. The surgical site will include the full area of surgical 
mesh placement. 
Dose Groups: 
In Part A, CA-008 15 mg (50 ml of a 0.3 mg/mL solution) will be delivered and 
used to explore the optimal technique of delivery, i.e., location and volumes of 
delivery to the different areas and layers of the surgical procedure. The dose of 
CA-008 delivered in Part A will not exceed 15 mg. 
In Parts B and C, CA-008 at a fixed dose of 24 mg (80 mL of a 0.3 mg/mL 
concentration) or blinded placebo will be delivered using the general technique 
identified in Part A.  
Injection of 
Study 
Treatment: 
Note: Intent is to distribute study drug by infiltration (injected) and/or 
instillation/irrigation (dripped/spread) into/onto substantially all areas in the 
“surgical site.” “Surgical site” is defined as the area extending approximately at 
least 2−3 cm in all directions (lateral/medial/proximal/distal/deep) from the 
incision site and will include all deep and superficial tissue traumatized by the 
surgical procedure, i.e., tissue that has been dissected, cut, electrocauterized 
(bovied), sutured, tacked areas and surrounding tissues and includes the full 
area of surgical mesh. The surgical site includes those areas accessed directly 
via the surgical incision and also via laparoscopic access. 
 
Note: The technique for all tissue infiltration described below should include 
multiple microinjections. The needle may be inserted deeply at first and as the 
needle is withdrawn, the study drug can be injected slowly along the needle 
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track. The intent is to distribute the study drug widely in the surgical site where 
transient receptor potential cation channel, subfamily V (vanilloid) member 
1 (TRPV1) receptor targets are located, to act as a conduction block in intact 
nerves and not in a single, deep depot injection. Substantially all tissue 
traumatized by the surgical procedure should be exposed to study drug. 
 
If laparoscopic assistance is used, study drug will also be delivered to the site of 
the laparoscopic incisions requiring surgical closure. 
The general technique to be used is to allocate the total study drug volume to 
the different tissue layers as follows: 
• 
Deep midline/peritoneal layer – approximately up to 25% of the total 
volume 
• 
Mesh/fascia layer – at least approximately 50% of the total volume 
• 
Anterior layer – approximately up to 25% of the total volume 
If laparoscopy is utilized, then a few milliliters of study drug intended for the 
anterior later will be infiltrated into the laparoscopy ports. 
 
Part A: 
The initial total study drug volume administered per patient will be 50 mL 
delivered during the surgical procedure in divided aliquots. Modifications to the 
total study drug dose, volume, drug concentration, and allocation for 
subsequent patients may occur based on information from prior patients. 
• 
Deep midline/peritoneal layer –10 mL 
• 
Mesh/fascia layer –30 mL 
• 
Anterior layer – 10 mL 
Parts B and C: 
The allocation will be as follows, equating to a total study drug volume of 80 
mL (details follow in the protocol):  
• 
Deep midline/peritoneal layer – approximately 10 mL 
• 
Mesh/fascia layer –approximately 60 mL 
• 
Anterior layer – approximately 10 mL (up to 5 mL of this volume may be 
delivered to the laparoscopy port(s)) 
Preoperative, 
Anesthesia and 
Perioperative 
Care:  
At check-in (pre-operatively), at least 1-2 hours before surgery: 
• 
Celecoxib 200 mg orally (PO) 
• 
Acetaminophen 1000 mg PO 
After these medications have been administered, no additional non-opioid 
analgesics are to be administered during the inpatient phase (through T96). 
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The surgery will be performed under general anesthesia:  
• 
Inhaled anesthetic or propofol infusion with or without nitrous oxide 
(N2O).  
• 
Adequate optional premedication typically with midazolam (up to 5 mg), 
fentanyl (up to 100 mcg), more can be given if indicated 
• 
Supplemental anesthesia and sedation will be per institutional guidelines 
• 
Intra-operative titration of intravenous (IV) fentanyl, including during 
emergence, will be per institutional guidelines.  
In addition, patients will receive bupivacaine hydrochloride (BupiHCl) 175 mg 
delivered as follows:  
• 
Prior to start of surgery under ultrasound guidance: 
o BupiHCl 0.25%, 30 mL (75 mg) diluted with 10 mL of normal 
saline to a volume of 40 mL delivered as a rectus block with 20 mL 
on each side. 
Note: In Part A, the adequacy of the anesthetic regimen is part of the 
assessment of the technique feasibility. If patients report excessive pain during 
the immediate post-operative period, a TAP block may be added for subsequent 
patients but the total dose of bupivacaine will not exceed 175 mg. 
• 
Immediately before/after surgical incision:  
o PART A: BupiHCl 0.25%, 40 mL (100 mg), may be diluted in up 
to 110 mL of normal saline to a total volume of not more than 150 
mL: Infiltration of abdominal wall, anterior rectus abdominis 
sheath, posterior rectus abdominis sheath, other fascia, peritoneum 
(including circumferential areas of intended mesh placement)  
o PARTS B and C: BupiHCl 0.25%, 40 mL (100 mg), to be diluted 
in 40 mL of normal saline to a total volume of 80 mL: 
Infiltration of abdominal wall, anterior rectus abdominis sheath, 
posterior rectus abdominis sheath, other fascia, peritoneum 
(including circumferential areas of intended mesh placement) 
Standard supplemental anesthetic and perioperative care will be provided per 
institutional guidelines. This will typically include (but not be limited to) steps 
to ensure preservation of intraoperative normothermia (including the use of 
preoperative and intraoperative forced-air warming) and deep venous 
thrombosis prophylaxis. 
Intraoperative 
Analgesia and 
Care: 
Patients will receive general anesthesia and bilateral rectus blocks (see 
Section 9.2.1 Preoperative, Anesthesia and Perioperative Care). 
During surgery, ensure that patients receive the following:  
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• 
3–500 mL IV fluid, more can be given if indicated 
• 
Ondansetron 4 mg IV 
Note: Ondansetron should not be given to patients in Part B undergoing 
24 hours of 12-lead Holter monitoring to assess the effects of study drug on the 
QT interval. 
 
Within 15 minutes prior to the end of surgery, administer the following: 
• 
IV hydromorphone, 0.5 mg  
• 
Note: IV morphine 2.0 mg can be used if IV hydromorphone is not 
available 
 
Patients who develop clinically significant hemodynamic instability or other 
anesthesia complication prior to study drug administration should not receive 
study drug; in Parts A and B, these patients will be replaced. Replacement 
patients will be assigned the same treatment as the original patient. A 
‘replacement’ randomization list matching that of the main list will be created 
to facilitate this process. 
Rescue 
Medication 
during the 
Inpatient 
Period: 
Patients will be encouraged to use rescue medication only for 
moderate-to-severe pain (NRS ≥ 4); however, rescue medication may be 
requested at any time (i.e., even when NRS < 4) and medication will be 
provided when requested. Conversely, patients may refuse rescue medication 
even when the NRS is ≥ 4. Time intervals for all rescue medication use are 
guidelines that can be modified by Investigator discretion. 
• 
From the time of post-anesthesia care unit (PACU) discharge through T12:  
o Administer IV hydromorphone 0.5 mg, Q15 minutes PRN for pain 
of NRS ≥ 4.  
o Note: IV morphine 2.0 mg can be used if IV hydromorphone is not 
available 
• 
After T12–48:  
o Administer PO oxycodone 10 mg, Q 4 hours (h) PRN for pain NRS 
≥ 4. 
o Only PO oxycodone may be used as rescue. If a patient still requires 
IV opioid rescue after T12, then the patient will revert to IV opioid 
analgesia management per institutional guidelines. These patients 
will still also be followed for NRS, safety, and all other assessments.  
• 
After T48–96: 
o Administer PO oxycodone 5 mg, Q 4 h PRN pain NRS 5–10. 
o Only PO oxycodone may be used as rescue. If a patient still requires 
IV opioid rescue after T12, then the patient will revert to IV opioid 
analgesia management per institutional guidelines. These patients 
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will still also be followed for NRS, safety, and all other assessments. 
An NRS pain score should be recorded prior to any dose of rescue medication 
NRS scores recorded for PRN pain medication will not replace the recording of 
scheduled NRS scores. However, if PRN rescue medication has recently been 
administered and persistent pain is reported in a scheduled NRS record prior to 
rescue medication taking effect, a second dose of rescue medication should not 
be administered. 
Postsurgical 
Care: 
After surgery, patients will be transferred to the post-anesthesia care unit 
(PACU) where patients will be monitored for at least 90 minutes during which 
time pain assessments can begin once the patient is awake. T0 is the time of 
admission into the PACU (as recorded in notes by the PACU nurse). The time 
of extubation will be recorded, if applicable. 
Patients will use the 0 to 10 numerical rating scale (NRS) to report their current 
pain intensity multiple times per day during the remainder of the inpatient part 
of the study. Scheduled times for serial pain assessments are outlined in the 
protocol.  
Rescue medication will always only be administered upon request, i.e., 
independent of the currently reported pain score. That is, an NRS pain score 
alone does not trigger rescue medication administration. 
If the patient reports pain spontaneously and requests analgesia at an 
unscheduled time (i.e., PRN), an NRS should be used to record the pain present 
at that time. This unscheduled NRS must be recorded just prior to 
administration of any PRN analgesia, i.e., within 5 minutes prior to any PRN 
IV analgesic treatment and within 15 minutes prior to any PRN oral analgesic 
treatment. NRS scores for PRN pain medication will not replace the recording 
of scheduled NRS scores. 
Medication for moderate to severe pain (NRS ≥ 4) will be administered upon 
request as follows: 
• 
From T0 to T25 minutes: 
o IV fentanyl 50 mcg, every (Q) 5 minutes for pain NRS ≥ 4 
• 
From T26 minutes to PACU discharge: 
o IV hydromorphone 0.5 mg, Q 10 minutes for pain NRS ≥ 4 
o Note: IV morphine 2.0 mg can be used if IV hydromorphone is not 
available 
After discharge from the PACU, patients are followed through T96 (± 4 h) as 
inpatients in the inpatient unit where safety and activity/efficacy evaluations 
will be performed. Patients will be required to meet standard criteria for 
discharge to outpatient status. Patients will continue to be monitored as 
outpatients after discharge from the inpatient unit through D29 + 2 days for 
various safety and efficacy assessments, and later if necessary, for safety follow 
up. 
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Analgesia 
during the 
Outpatient 
Period: 
 
Following discharge from the hospital through the D15 visit, pain will be 
managed with the following regimen only:  
• 
Scheduled medication: 
o Celecoxib, 100 mg PO twice daily (BID) (unless contraindicated) 
• 
Rescue medications (for pain as needed):  
o Acetaminophen, 500-650 mg PO Q 6 h for mild pain (i.e., NRS 
< 4) (unless contraindicated) 
o Oxycodone, 5 mg – 1 or 2 tablets PO Q 4–6 h for moderate-severe 
pain (i.e., NRS ≥ 4). Discharge patient with a prescription for 
20 tablets. Use of this rescue medication [time, dose] must be 
recorded in the diary. Pre-rescue medication NRS for opioids will 
also be recorded in the diary. 
Note:  
• 
Instruct patients to use acetaminophen as the initial option for treating pain 
up to a total daily dose of 4,000 mg.  
Document the number of opioid tablets prescribed and document any additional 
prescriptions required if the patient’s pain continues to be an issue requiring 
additional opioid medication. 
Following D15, pain will be managed per institutional guidelines and standards 
of care. Pain medication use will be recorded as a concomitant medication from 
D15 through D29. 
Persistent pain or pain exacerbations during the outpatient period may suggest 
the need for an unscheduled in-person visit to assess the surgical site. If such a 
visit occurs, the Investigator should use clinical discretion regarding the 
adequacy of analgesic treatment, capture this occurrence as an AE, and 
document any required treatments 
Inclusion 
Criteria: 
In order to participate, patients must meet all inclusion criteria:  
1. Plan to undergo an elective, primary, open laparotomy with VHR, with 
retromuscular, preperitoneal synthetic (polypropylene) mesh placement, 
with midline fascial reconstruction (i.e., Rives-Stoppa technique or 
equivalent) and with optional laparoscopic assistance under general 
anesthesia with sedation, without collateral procedure or additional 
surgeries. Ventral hernia should not be longer than ~6 cm in length.  
2. Appropriate candidate for TAP block, including no contraindications, no 
anatomical constraints. Note: TAP block may replace or supplement rectus 
sheath block if rectus sheath block inadequate. 
3. Adults 18–80 years of age, inclusive. 
4. American Society of Anesthesiology (ASA) physical Class 1, 2, or 3 at the 
time of randomization (Section 17.2, Appendix B). 
5. If a male, be either sterile (surgically or biologically) or commit to an 
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acceptable method of birth control while participating in the study. The site 
personnel will provide instructions on what is an acceptable method. 
6. If a female, must meet all of the following: 
a. A female of child-bearing potential (FCBP) must have a negative 
serum pregnancy test at screening and negative urine pregnancy test 
before surgery; 
b. No plan to become pregnant or to breast feed during the study; and 
c. Be surgically sterile or at least one year post-menopausal (as 
documented by history and appropriate follicle stimulating hormone 
[FSH] level), or (one of the following must apply): 
i. is practicing double-barrier contraception;  
ii. is practicing abstinence (must agree to use double-barrier 
contraception in the event of sexual activity); 
iii. is using an insertable, injectable, transdermal or combination 
oral contraceptive approved by the FDA for at least 2 months 
prior to screening and commits to the use of an acceptable form 
of birth control while participating in the study. 
7. Have a body mass index ≤ 40 kg/m2. 
8. Be willing and able to sign the informed consent form (ICF) approved by an 
Institutional Review Board (IRB). 
9. Be willing and able to complete study procedures and pain scales and to 
return for outpatient follow up visits as required. 
10. Be willing and able to avoid foods containing capsaicin for 24 hours prior 
to surgery. 
Exclusion 
Criteria: 
If any of the following exclusion criteria apply, a patient may not 
participate in the study:  
1. In the opinion of the Investigator, the patient has: 
a. a concurrent chronic painful condition (i.e., daily pain) that may 
require analgesic treatment during the study period or may confound 
postsurgical pain assessments; 
b. active skin disease or other clinically significant abnormality at the 
anticipated site of surgery that could interfere with the planned 
surgery. 
2. The patient has taken opioids more than twice per week in any week within 
6 months of screening or has used any opioids during the 2 weeks prior to 
surgery. 
3. The patient has a known allergy (or contraindication) to any of the 
following: chili peppers, capsaicin or the components of CA-008, propofol, 
bupivacaine hydrochloride (HCl), midazolam, inhaled anesthetic, nitrous 
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oxide, ondansetron, acetaminophen, fentanyl, hydromorphone, morphine, 
oxycodone, or celecoxib.  
4. As determined by the Investigator (with input from the study’s medical 
monitor if requested by the Investigator), the patient has a history or 
clinical manifestation of significant medical, neuropsychiatric, or other 
condition, including a clinically significant existing arrhythmia, left bundle 
branch block or abnormal ECG, myocardial infarction, or coronary arterial 
bypass graft surgery within the prior 12 months, significant abnormal 
clinical laboratory test value, or known bleeding abnormality that could 
preclude or impair study participation or interfere with study assessments. 
5. Use of the following disallowed medications: 
a. Within 1 day prior to surgery and throughout the inpatient period, 
taking or using any capsaicin-containing products, such as dietary 
supplements or over the counter (OTC) preparations, including topical 
formulations, and prescription medications. 
b. Within the 7 days prior to surgery, taking any central nervous system 
active agent as an analgesic adjunct medication, such as 
anticonvulsants (e.g., gabapentin), antidepressants (such as SNRIs, 
SSRIs, and tricyclic antidepressants), benzodiazepines, sedative-
hypnotics, clonidine and other central alpha-2 agents (e.g., tizanidine), 
ketamine, or muscle relaxants.  
i. These drugs are permitted if prescribed for non-pain indications and 
the dose has been stable for at least 30 days prior to surgery. Note 
that the dose must remain stable throughout the study.  
ii. If the patient is taking centrally- and/or peripherally acting 
analgesic medications, such as acetaminophen, nonsteroidal anti-
inflammatory drug (NSAIDs), or pregabalin, the patient may 
participate in the study if the patient is willing to discontinue these 
medications 3 days prior to surgery. Note that (a) baby aspirin 
(81 mg/day) for cardiovascular prophylaxis or (b) regular or 
enteric-coated aspirin (up to 325 mg given up to twice daily) for 
venous thrombo-embolism prophylaxis is allowed during the study. 
c. Within the 7 days prior to the planned surgery taking (a) 
antiarrhythmics (except beta-blockers and digoxin); (b) warfarin or 
other anticoagulants (see exception above); (c) lithium; (d) 
aminoglycosides or other antibiotics for an infection (except for 
ophthalmic use); or (e) medical (or other) regular marijuana use.  
d. Within the 14 days prior to surgery, taking parenteral or oral 
corticosteroids (steroid inhaler for allergy or asthma treatment, topical 
steroid for a non clinically significant skin condition not involving the 
area of surgery, or ophthalmic steroids are permissible). 
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e. Taking an antianginal, antihypertensive agent or diabetic regimen at a 
dose that has not been stable for at least 30 days or which is not 
expected to remain stable while participating in the study. 
6. In the opinion of the Investigator, within the past year, the patient has a 
history of illicit drug use or prescription medicine or alcohol abuse 
(regularly drinks > 4 units of alcohol per day; where a unit = 8 oz. beer, 
3 oz. wine, or 1 oz. spirits).  
7. The patient has a disqualifying positive urine drug screen or alcohol 
breath/saliva test during screening or check-in (See Section 10.3.14). 
8. The patient has previously participated in a clinical study with CA-008. 
9. The patient has participated in another clinical trial or used an 
investigational product within 30 days or 5 half-lives (whichever is longer) 
prior to the planned surgery or is scheduled to receive an investigational 
product other than CA-008 while participating in the study. 
Visit Schedule: 
• 
Screening D -45 to Day Prior to Surgery: Patients undergo screening 
during this period. All screening assessments (including ICF) must be 
completed at least 1 day prior to surgery.  
• 
Site Unit Admission D1: Day of surgery, patients will be randomized, and 
baseline evaluations will be performed prior to surgery. Day 1 includes the 
day before surgery if check-in occurs at that time. 
• 
Surgery D1: VHR procedure is performed; study treatment is administered 
prior to wound closure. PK sample collection is to be done per 
protocol-specified time points through 48 h following the first study 
treatment instillation. 
• 
Post-surgery T0 to T96: T0 is the time of admission into the PACU (as 
recorded in notes by the PACU nurse). Patient remains in the PACU and 
then in the inpatient unit for study assessments. Discharge to outpatient 
status after T96 (± 4 h) [D5] assessments with follow up instructions, 
particularly on diary completion. 
• 
Follow Up D8 +1 day: clinic visit for study assessments. 
• 
Follow Up D15 +2 days: clinic visit for study assessments. 
• 
Follow Up D29 +2 days: clinic visit for study assessments and study 
completion visit, unless additional follow up for wound healing is needed. 
• 
If needed, Unscheduled Visits or Follow Up after D29: Clinic visit as 
needed for any ongoing safety issue occurring between scheduled visits or 
continuing after the D29 visit. 
• 
Early Termination (ET): For patients who terminate early, an ET visit 
will be required. 
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Monitored 
Parameters: 
• 
Treatment-emergent AEs (TEAEs) 
• 
Medical history  
• 
Physical examination (PE) findings, particularly neurosensory findings at 
the site of incision and the skin surrounding the incision 
• 
Surgical site assessment for wound healing, including a digital photograph 
if the patient has consented 
• 
Neurosensory testing near the surgical site 
• 
Clinical laboratory testing (standard chemistry, hematology, coagulation), 
drug and alcohol testing, pregnancy testing 
• 
12-lead ECGs 
• 
Blood draws for PK 
• 
NRS scores assessing rest pain and evoked pain (a) after coughing 3 times, 
(b) after sitting up from the supine position into a standardized position 
(both legs dangling on the side of the bed) and (c) during ambulation for 
approximately 10 yards using a 0 to 10 numeric rating scale for pain 
intensity 
• 
Patient-reported outcomes: 
o Activity Assessment Scale (AAS),  
o Patient Reported Outcomes Measurement Information System 
(PROMIS) 10 GLOBAL Health Questionnaire  
• 
Performance-based outcome measures (PBOMs):  
o Timed Up and Go (TUG) (Section 17.9, Appendix I)  
o Sit to Stand Test (Section 17.8, Appendix H) 
• 
Total postsurgical opioid consumption converted to an oral morphine 
equivalent dose (OME) 
• 
12-lead Holter monitors will be placed prior to surgery and record for 
24 hours to assess for effects on the QT interval and correlation with PK 
levels (Subset of at least 12 patients per randomized arm in Part B)  
Safety 
Endpoints:  
• 
Incidence of spontaneously reported TEAEs or serious AEs (SAEs) from 
study medication administration through D29 or later if necessary:  
o TEAEs are defined as AEs occurring post study medication 
administration 
o AEs recorded from the time the ICF is signed up to study 
medication administration will be recorded in medical history. 
o Note: An unscheduled PK sample should be collected where 
feasible during the inpatient phase of the study for all patients as 
part of the evaluation of any SAE or severe TEAE.  
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• 
PE: Full PE at Screening (without a breast, genital, or rectal examination). 
Interim targeted PE on D1 prior to surgery (can be done on the day before 
surgery if check-in occurs then), T96, and as an outpatient on D8, D15 and 
D29 (later if necessary). 
• 
Vital signs (heart rate [HR], blood pressure [BP], respiratory rate [RR], O2 
saturation [SpO2]) at screening, D1 prior to surgery, post-surgery T1, T2, 
T6, T12, and T24, and every 12 hours thereafter until T96, and as an 
outpatient on D8, D15 and D29 or later if necessary. Assess temperature on 
D1 prior to surgery. Temperature will be recorded daily along with vital 
signs per site SOPs at 2, 6, 12, 24, and every 12 hours thereafter until 
discharge from the inpatient facility (if awake at the time of assessment 
between hours of midnight and 6:00 AM).  
• 
Surgical site assessments at T96 prior to discharge from the inpatient unit 
and then as an outpatient on D8, D15 and D29 (later if necessary). If there 
are skin reactions atypical for the type of surgery, e.g., more than expected 
erythema, drainage, bruising or hematoma, induration, swelling, or other 
skin changes, they should be documented as AEs, graded for severity, and 
followed regularly until resolution or establishment of a new baseline. 
• 
Neurosensory testing near the incision will be performed at Screening visit, 
T96 (prior to discharge from the inpatient unit) and then as an outpatient on 
D8 and D29. 
o Numbness at or near, i.e., within 5 cm of the incision need not be 
considered a neurologic AE since this could occur because of tissue 
trauma and inflammation from the surgery. Persistent numbness 
would meet the criteria for an adverse event. 
o Sensory deficits or clinically significant persistent sensory change 
beyond the area proximal/distal to the incision at time of discharge, 
such as allodynia or hyperalgesia, must be designated as a 
neurologic AE. Patients will be followed until there is a return to 
baseline or establishment of a new baseline. 
• 
12-lead ECGs, and standard clinical laboratory tests at Screening and post-
surgery as specified in the Schedule of Assessments and outlined below. 
The Investigator is responsible for determining if out of range laboratory 
values are clinically significant or not. All clinically significant values will 
be recorded in the eCRF and followed until resolution.  
• 
12-lead ECG at Screening and T24 (± 2 h) 
• 
Clinical laboratory test results  
o Hematology/Coagulation at Screening and T48 (± 4 h): 
hemoglobin, hematocrit, white blood cell count with differential, 
red blood cell count, platelet count, activated partial thromboplastin 
time (aPTT), and prothrombin time (PT) or international 
normalization ratio (INR). 
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o Blood chemistry at screening and T48 (± 4 h) to include at least the 
following: alanine aminotransferase (ALT) and aspartate 
aminotransferase (AST), total bilirubin (Tot. Bili), gamma-
glutamyl transferase (GGT), albumin, blood urea nitrogen (BUN), 
creatinine, alkaline phosphatase (ALK), sodium, potassium, 
calcium, chloride, and glucose. 
o Serum and urine pregnancy test for FCBP: βhCG test at screening 
and urine test usually to be done within 24 hours prior to surgery. 
o Note: Safety laboratory assessments may be collected, as 
appropriate, as part of the evaluation of a SAE or severe TEAE. 
• 
In Part B, for at least 24 patients (i.e., 12 in each blinded, randomized arm), 
12-lead Holter monitors will be placed prior to surgery and will record for 
24 hours to assess for effects on the QT interval during study drug 
administration. Serial PK samples should be drawn in patients undergoing 
Holter ECG assessments.  
Activity/Efficacy 
Parameter 
Assessments:  
1. NRS scores will be assessed as follows: 
• 
During the inpatient stay, NRS at rest beginning with the PACU 
admission may be assessed once the patient is awake. T0 is the time of 
admission into the PACU (as recorded in notes by the PACU nurse). 
Obtain NRS scores T0 plus 1 hour (T1), T0 plus 2 hours (T2), T4, T6, 
T8, T12, T16, T20, T24, and every 4 hours thereafter (if awake at time 
of assessment) until discharge from the inpatient unit. Time windows: 
± 5 minutes for T1 and T2; ± 15 minutes for T4 onward. Scheduled NRS 
scores must be recorded regardless of timing of pre-rescue medication 
NRS scores and administration of rescue medication. The actual time of 
all NRS scores must be recorded, i.e., not the nominal time. 
• 
During the inpatient stay, as soon as feasible, obtain evoked NRS twice 
daily after 3 maneuvers: (a) coughing 3 times, and (b) sitting up from 
the supine position into a standardized position (both legs dangling on 
the side of the bed), and (c) ambulation for approximately 10 yards 
(30 feet). Obtain these NRS scores in the morning at 10:00 AM (± 1 h) 
and in the afternoon at 4:00 PM (± 1 h). 
• 
During the inpatient stay, pain scores may be skipped between the hours 
of midnight and 6:00 AM, but the patient may not miss two consecutive 
assessments. The T12, T24, T48, T72 and T96 assessments must be 
completed even if the patient must be awakened at these times. 
• 
During the inpatient stay, an additional NRS assessment must be 
obtained within 5 minutes prior to IV rescue medication administration 
and within 15 minutes prior to oral rescue medication administration. 
• 
During the outpatient period (after T96 and through D15), an additional 
NRS assessment must be obtained prior to oral rescue medication 
administration. If entered in the electronic diary, the timing of the 
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additional NRS assessment will be assumed to be coincident with the 
use of rescue medication. If not entered in the electronic diary, the 
additional NRS assessment should be within 15 minutes prior to use of 
rescue medication to be used for imputation. 
• 
During the outpatient period (after T96 and through D15), instruct the 
patient to document their NRS scores twice daily at 11:00 AM (± 1 h) 
and 7:00 PM (± 1 h) (a) at rest, (b) after coughing 3 times, (c) after 
sitting up from the supine position into a standardized position (both 
legs dangling on the side of the bed), and (d) during ambulation for 
approximately 10 yards. Note that the actual time of these assessments 
must be documented in the electronic diary. Instruct the patient to: 
o Obtain the morning NRS assessments;  
o 
Obtain the evening NRS assessments;  
o 
Opioid and non-opioid rescue medication (dose, date, time) must be 
recorded in the diary through D15, including a pre-rescue NRS 
score. 
2. Daily opioid consumption (specific drug, dose, date, time) will be recorded 
during the inpatient and outpatient periods (through D15) to allow calculation 
of total opioid consumption (OC) and daily opioid (rescue medication) 
consumption in OMEs.  
• 
Document daily use of opioid analgesia during the outpatient period 
through D15.  
• 
Document each opioid prescription provided to the patient and the 
number of and type of tablets provided to the patient for site records 
and reconciliation. 
3. PROs: AAS, PROMIS 10 Global at Screening, T48, T96, D8, D15, and D29. 
4. PBOMs: Sit to Stand Test, TUG at T48 (± 4 h), D5/Discharge, D8, D15, and 
D29. 
Efficacy 
Endpoints  
 
Part A: There are no efficacy endpoints for Part A 
Part B: There are no efficacy endpoints for Part B 
Part C: 
Primary efficacy endpoint:  
• 
Area under the curve (AUC) of the rest NRS from T0 to T96 
(AUC0-96h). AUC is the weighted sum of current pain intensity (SPI) 
assessments for a specified time interval. 
Key secondary efficacy endpoints:  
• 
Evoked pain NRS (three maneuvers): AUC0–96 
• 
Total opioid consumption (in daily OME) = OC from T0 to T96: OC0-96 
and from T0 to D8: OC0-D8 
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• 
Percentage of patients who do not require opioids after discharge (i.e., 
opioid-free or OF) from T96 to D15: OF96-D15 
• 
NRS at rest and evoked NRS (three maneuvers) from T0 to D8: AUC0-
D8 
 
Exploratory efficacy endpoints for Part C:  
• 
Using rest NRS: AUC12-96, AUC0-48, AUC48-96, and AUC0-D15; 
• 
Using evoked (three maneuvers) NRS: AUC12-96, AUC0-48, AUC48-96, 
and AUC0-D15; 
• 
Time-specific mean NRS scores at T48, T72, and T96; 
• 
Time-specific mean NRS scores daily from D5-D15; 
• 
Proportion of patients with NRS ≤ 3 during T0-T96, T0-48 and T48-96 
• 
OC12-96, OC24-96, OC0-D8, and OC0-D15; 
• 
OF0-96, OF0-D15, OF24-96, OF24-D15, OF48-D15, OF72-D15 and OFD8-D15 
• 
Time to cessation of opioid use; 
• 
Additional exploratory and sensitivity analyses rest/evoked NRS AUC, 
OC, and OF during different intervals may be undertaken, e.g., T48-
T168, T72-T168;  
• 
PRO questionnaire score improvement from Screening to D8, D15, and 
D29; and from T48 to D8, D15, and D29; 
• 
Improvement in PBOMs (Sit to Stand, TUG) from T48 (± 4 h), to 
D5/Discharge, to D8, to D15, and to D29; PBOM difference between 
groups at T48, T96, D8, D15 and D29; 
• 
Total non-opioid analgesic consumption (AC), i.e., rescue 
acetaminophen use for the indicated time intervals: AC96-D8 and 
AC96-D15; 
• 
Other endpoints to be defined in the statistical analysis plan (SAP). 
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Pharmacokinetic 
Endpoints: 
Part A: 
PK sampling will be performed on at least 8 patients at a single site. 
Part B:  
PK sampling will be performed on at least 24 patients receiving blinded study 
drug, i.e., 12 patients per randomized arm at a single site. All patients 
undergoing 24-hour Holter ECG recordings should have PK sampling. 
Part C: 
No PK sample collection is planned for Part C.  
The time points for whole blood collection will be at pre-dose pharmacokinetic 
time PKT 0 (Pre-IP Dose, 2-10 minutes prior to the first study treatment 
instillation), 0.03 h (2 min), 0.083 h (5 min), 0.167 h (10 min), 0.25 h (15 min), 
0.33 h (20 min), 0.5 h (30 min), 0.75 h (45 min), and at 1, 1.5, 2, 4, 8, 12, 16, 
24, 36 and 48 hours after the first study treatment instillation (total of 18 
samples).  
Plasma concentration for CA-008, capsaicin and CA-101 at PK sampling times 
will be summarized using descriptive statistics, including mean, standard 
deviation, median, minimum and maximum values, and coefficient of variation 
(CV%). PK parameters include (but are not limited to) maximum observed 
plasma drug concentration (Cmax), time to maximum plasma drug 
concentration (Tmax), half-life, and area under the plasma concentration-time 
curve (PK-AUC). Actual sampling times will be used to calculate plasma-
derived PK parameters.  
The PK analysis plan will be documented in the PK Analysis Plan. 
A concentration-QT (cQT) analysis (PK/PD) analysis will be performed to 
assess for drug effect on the QT interval. This analysis will be documented in 
the Analysis Plan. 
Note: An unscheduled PK sample should be collected where feasible during the 
inpatient phase of the study for all patients as part of the evaluation of any SAE 
or severe TEAE. 
Stopping Rules: 
Study enrollment will be paused if any patients experience any grade 3 TEAE, 
in particular in any of the categories shown in Table 19, Section 7.4, in 
Appendix A (Section 17.1) or found in the toxicity grading scale cited therein. 
Should a stopping rule be triggered, the Sponsor’s medical monitor, the CRO 
medical monitor, the relevant Principal Investigator and an independent 
medical monitor will review the relevant data to determine whether or not it is 
appropriate to resume enrollment with the same or a modified dose, modify the 
study or stop the study.  
The independent medical monitor will have the authority to unblind the 
treatment assignment for the affected patients as part of the safety review. 
The study will be stopped if a safety signal is detected that indicates an 
unacceptable risk to study participants. 
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Sample Size 
Justification: 
In Part A and Part B, no formal statistical hypothesis testing will be performed. 
The sample size of 8-12 initial patients in Part A, with the potential for 
expansion, and 24-32 patients in Part B have been selected empirically based on 
prior clinical trial experience with CA-008 and is considered sufficient for 
exploration of feasibility, tolerability, PK, preliminary efficacy and safety 
parameters. 
In Part C, a total of ~100 patients will be randomized in 2 parallel arms (1:1) 
with ~50 patients in each arm. Assuming a t-test for the difference in 2 
independent means, a sample size of approximately 40 patients per group 
would provide approximately 80% power to detect a standardized effect size 
(Cohen’s d) of ~0.55 at a one-sided level of significance, alpha, of 0.05 in the 
primary efficacy endpoint rest NRS AUC0-96.  
In Part C, randomization may be stratified based on the size of the ventral 
hernia: for example, < 4 cm vs. ≥ 4 cm. 
Alternative assumptions concerning the anticipated effect size lead to a 
different number of patients per group. The total number of patients to be 
enrolled in the study will not exceed ~150.  
Study 
Populations: 
The following 6 analysis populations are planned for this study:  
• 
Safety Population consists of all patients who received any part of a dose of 
study treatment. (Note this must include anyone who terminates early for 
lack of efficacy). 
• 
PK Population consists of all patients who received at least one dose of 
study treatment and have at least one PK sample. 
• 
PK/QT Population for cQT analysis consists of all patients with at least one 
time point with both PK and QT data. 
• 
Modified Intent-to-treat (mITT) Population consists of all patients who 
received any dose of study treatment 
• 
Per Protocol (PP) Population consists of all patients who received a full 
dose of study treatment and have evaluable NRS pain assessments at T12, 
24, 48, 72, and 96 and no two consecutive missing assessments among the other 
time points prior to T96 (± 4 h)/Discharge 
• 
Study Completers consists of all patients who received a full dose of study 
treatment and completed the entire study period through D29 + 2 days. 
Patients who discontinue study participation before or after randomization but 
prior to receiving study treatment will be replaced.  
Patients who are withdrawn or who elect to withdraw after receiving study 
treatment will not be replaced. Those who withdraw during the inpatient phase 
of the study, will be asked to continue with assessments through T96 if they 
have not elected to withdraw from all aspects of study participation (see 
Section 10.2). Patients who elect to discontinue participation on or prior to D8 
will be considered to have terminated as of the date of their election; however, 
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they will be asked to return to the site one time to ensure that adequate wound 
healing has occurred (see Section 10.2). 
Statistical 
Considerations:  
 
Progression from Part A to Part B will take place after a formal safety 
assessment has been completed showing that the total study drug dose, volume, 
allocation, and technique is acceptably safe and feasible. The formal safety 
assessment will be conducted by the Sponsor’s medical monitor, the CRO 
medical monitor, the relevant Principal Investigator, and an independent 
medical monitor. 
Progression from Part B to Part C will take place after an (“interim”) analysis 
of unmonitored, unblinded data from Part B occurs including data through 
Day 15. This analysis will assess preliminarily the safety and tolerability of the 
active study drug as well as the duration and severity of postsurgical pain in the 
control group.  
In general, descriptive statistics for continuous variables will include n, mean, 
SD, standard error of mean (SEM), (if appropriate), median, minimum, and 
maximum. Categorical variables will be described by frequency and 
percentage.  
All safety assessments and baseline characteristics will be summarized using 
the Safety Population. All safety summaries will be grouped by the actual 
treatment received.  
Safety and tolerability will be evaluated by examining the occurrence of AEs, 
including TEAEs. AEs leading to discontinuation from the study, AEs related 
to study treatment, and AEs by severity will be summarized by treatment group.  
Actual values and change from baseline in clinical laboratory measures, vital 
signs, and ECGs will also be assessed and summarized by treatment group. 
These data will be summarized using descriptive statistics. Abnormal values 
will be determined and flagged in the listings. Laboratory shift tables displaying 
the change (number of patients) relative to the normal range from baseline to 
each study visit will also be presented by treatment for each test. The 
Investigator should exercise medical and scientific judgment in deciding 
whether an abnormal laboratory finding, or other abnormal assessment is 
clinically significant.  
Efficacy, PK, and other assessments will be summarized using appropriate 
descriptive statistics. A detailed methodology for the statistical analyses of the 
data collected in this study will be documented in an SAP which will be signed 
prior to the database lock. 
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Table 1 
Schedule of Assessments – Parts A, B and C 
Study Period 
Screening 
Inpatient 
Follow-Up Clinic 
Visits 
Unscheduled 
Visit1 
Early 
Termination19 
Day of 
Surgery 
Surgery 
Post-
surgery 
T24 
T48 
T72 
T96 
± 4 h 
Study Day 
D -45 to 
Day Prior 
to Surgery 
D1 (prior 
to 
surgery) 
D1 
D1 
D2 
D3 
D4 
D5 
D8 
+ 1  
day 
D15 
+ 2 
days 
D29 
+ 2 
days 
Assessment 
Informed Consent 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Screening Medical 
and Surgical History 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/ Exclusion 
Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Screens for 
Alcohol/Drugs of 
Abuse 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Patient Pain 
Assessment Training 
X2 
X2 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test  
(or FSH if 
post-menopausal) 
X3 
(serum) 
X3  
(urine) 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs (supine) 
X 
X 
 
X4 
X4 
X4 
X4 
X4 
X 
X 
X 
X 
X19 
Temperature (oral) 
X 
X 
 
X4 
X4 
X4 
X4 
X4 
X 
X 
X 
X 
X19 
Physical Examination 
X5 
X5 
 
 
 
 
 
X5 
X5 
X5 
X5 
X5 
X5,19 
12-Lead ECG 
X 
 
 
 
X6 
 
 
 
 
 
 
 
 
Enroll/Randomize 
 
X 
 
 
 
 
 
 
 
 
 
 
 
12-lead Holter ECG 
(24h)7  
 
 
X 
X 
X 
 
 
 
 
 
 
 
 
Surgery 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Study treatment 
Infiltration/instillation 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Admission to PACU 
 
 
 
T0 
 
 
 
 
 
 
 
 
 
Surgical Site 
Assessment 
 
 
 
 
 
 
 
X8 
X8 
X8 
X8 
X8 
X8 
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Study Period 
Screening 
Inpatient 
Follow-Up Clinic 
Visits 
Unscheduled 
Visit1 
Early 
Termination19 
Day of 
Surgery 
Surgery 
Post-
surgery 
T24 
T48 
T72 
T96 
± 4 h 
Study Day 
D -45 to 
Day Prior 
to Surgery 
D1 (prior 
to 
surgery) 
D1 
D1 
D2 
D3 
D4 
D5 
D8 
+ 1  
day 
D15 
+ 2 
days 
D29 
+ 2 
days 
Assessment 
Neurosensory 
Examination  
X 
 
 
 
 
 
 
X9 
X9 
X9 
X9 
X9 
X9 
Blood Draw for 
Laboratory Tests 
X10 
 
 
 
 
X10 
 
 
 
 
 
 
 
Rescue Medication 
Consumption 
Recording 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
Concomitant 
Medication 
Assessment 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Adverse Event 
Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
NRS Pain 
Assessments 
 
 
 
X11 
X11 
X11 
X11 
X11 
X11 
X11 
 
 
X11 
Patient Home Diary 
Record (NRS) 
 
 
 
 
 
 
 
X12 
X12 
X12 
 
 
X12,19 
Electronic Diary 
(Review, Distribution 
and/or Collection) 
 
 
 
 
 
 
 
X13 
X13 
X13 
 
 
X13 
Patient Home Diary 
(Analgesic 
Consumption) 
 
 
 
 
 
 
 
X 
X 
X 
 
 
X 
Prescription for 
Outpatient Opioid 
Rescue 
 
 
 
 
 
 
 
X14 
 
 
 
 
 
PROs15 
X 
 
 
 
 
X 
 
X 
X 
X 
X 
 
 
PBOMs16 
 
 
 
 
 
X 
 
X 
X 
X 
X 
 
X 
Blood Draw for PK 
Analysis 
 
X17,18 
X17 
X17 
X17 
X17 
 
 
 
 
 
 
 
 
 
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FOOTNOTES: 
1 
Unscheduled visits may occur at any time and assessments are to be completed at the Investigator’s discretion. 
2 
Pain assessment training with test during screening; re-watch video only prior to surgery. 
3 
Note pregnancy tests are for FCBP; urine pregnancy test is to be performed within 24 hours of scheduled surgery. 
4 
Vital signs (HR, BP, RR (supine), SpO2) and temperature assessed together after T0 at T1, T2, T6, T12, T24, and every 12 hours thereafter (if awake at time 
of assessment between the hours of 12:00 AM and 6:00 AM) until discharge from the inpatient unit (may not miss two consecutive assessments). There will 
be a ± 5-minute window allowed for the collection of vital signs in the first 4 hours after the end of surgery, after which there will be a ± 15-minute window 
allowed. 
5 
A complete medical history and physical examination including all major body systems will be performed at Screening. In addition, at the following times, 
an interim medical history and targeted physical examination will be performed prior to surgery, and a physical examination to capture changes after 
Surgery, at T96 (± 4 hours), but prior to discharge from the inpatient unit, and D8, D15, and D29 or if the patient terminates early, at that time if allowed. 
Body weight (kg), in indoor clothing, but without shoes, will be measured at Screening and at T96. Height (cm) will be measured, and body mass index 
(BMI) will be calculated at Screening only. 
6 
Post-surgery ECG should be performed at T24 (± 2 hours). 
7 
In a subset of 12 patients per randomized arm at one site in Part C, 12-lead Holter monitors will be placed prior to surgery and record for 24 hours to assess 
for effects on the QT interval during study drug administration. Note: If the number of patients enrolled in Part B is increased, PK sampling and Holter 
monitoring as described above may be conducted in Part B instead of Part C. 
8 
Surgical site assessment: T96 (± 4 hours, but prior to discharge from the inpatient unit) and D8, 15, and 29. 
9 
Neurosensory examination of the area proximal to the surgical incision approximately 3 cm from the incision at Screening visit, T96 (± 4 hours, but prior to 
discharge from the inpatient unit) and D8, D15, and D29 or if the patient terminates early, at that time if allowed. 
10 
Clinical laboratory tests (chemistry, hematology, and coagulation) should be performed at Screening and T48 (± 4 hours. 
11 
During the inpatient stay, NRS at rest beginning with the PACU admission (T0) may be assessed once the patient is awake. Obtain NRS scores T0 plus 1 
hour (T1), T0 plus 2 hours (T2), T4, T6, T8, T12, T16, T20, T24, and every 4 hours (if awake at time of assessment) until discharge from the inpatient unit. 
Time windows: for T1 to T2 (± 5 min) and from T4 onward (± 15 min). Scheduled NRS scores must be recorded regardless of timing of pre-rescue 
medication NRS scores and administration of rescue medication. The actual time of all NRS scores must be recorded, i.e., not the nominal time. During the 
inpatient stay, as soon as feasible, evoked NRS twice daily after 3 maneuvers: (a) coughing 3 times, and (b) sitting up from the supine position into a 
standardized position (both legs dangling on the side of the bed), and (c) ambulation for approximately 10 yards (30 feet). Obtain these NRS scores in the 
morning at 10:00 AM (± 1 h) and in the afternoon at 4:00 PM (± 1 h). During the inpatient stay, pain scores may be skipped between the hours of midnight 
and 6:00 AM, but the patient may not miss two consecutive assessments. The T12, T24, T48, T72, and T96 assessments must be completed even if the 
patient must be awakened at these times. During the inpatient stay, an additional NRS assessment must be obtained within 5 minutes prior to IV rescue 
medication administration and within 15 minutes prior to oral rescue medication administration. During the outpatient period, (D8 and D15), instruct the 
patient to document their NRS scores twice daily at 11:00 AM (± 1 h) and 7:00 PM (± 1 h) (a) at rest, (b) after coughing 3 times, (c) after sitting up from the 
supine position into a standardized position (both legs dangling on the side of the bed), and (d) during ambulation for approximately 10 yards (30 feet). Note 
that the actual time of these assessments must be documented in the diary. Instruct the patient to: 
a. 
Obtain the morning NRS assessment. 
b. 
Obtain the evening NRS assessment. 
c. 
Opioid and non-opioid rescue medication must be recorded in the diary through D15, including a pre-rescue NRS score. 
12 
The patient is expected to document NRS pain scores at rest and on ambulation 2 ×/day through D15 (at the times and qualifications noted above).  
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13 
The diary and instructions are provided to the patient prior to discharge (T96). At each subsequent visit, review Patient Diary instructions with patient and 
collect the patient’s NRS scores and other study-related assessments. 
14 
Patients will be given a prescription for 20 tablets of oxycodone 5 mg one or two tablets PO Q 4–6 h PRN for moderate-severe pain (i.e., NRS 5–10).  
15 
PROs: PROMIS 10 Global (17.6 Appendix F) and Activities Assessment Scale (AAS) (17.7 Appendix G) 
16 
PBOMs: Sit to Stand Test (17.8 Appendix H), Timed Up and Go (TUG) Test (17.9 Appendix I). 
17 
Collect blood samples for PK. The time points for whole blood collection will be at PKT 0 (Pre-IP Dose, 2-10 minutes prior to the first study treatment 
instillation), 0.03 h (2 min), 0.083 h (5 min), 0.167 h (10 min), 0.25 h (15 min), 0.33 h (20 min), 0.5 h (30 min), 0.75 h (45 min), and at 1, 1.5, 2, 4, 8, 12, 16, 
24, 36 and 48 hours after the first study treatment instillation (total of 18 samples). There will be a ± 2-minute window allowed for the 10-, 15 and 20-minute 
collections, a ± 5-minute window allowed for collections at 30 minutes through 4 hours, and a ± 15-minute window for collections after 4 hours. In the event 
of a SAE or severe TEAE, an unscheduled PK draw will be performed. The actual time of collection will be recorded and used in any analysis. Out-of-
window collections will not be considered protocol deviations. 
18 
Patients must abstain from foods containing capsaicin for T24 prior to surgery. 
19 
If the patient terminates early, complete all procedures listed, as appropriate. The following assessments are done only if the Early Termination occurs prior 
to the D15 visit: Patients home diary review, vital signs, and targeted physical examination. 
Abbreviations: AAS = Activities Assessment Scale; AE = adverse event(s); ECG = electrocardiogram; FSH = follicle stimulating hormone; NRS = numeric 
rating scale of pain intensity; PACU = post-anesthesia care unit; PBOM = performance-based outcome measure; PK = pharmacokinetic(s); 
PKT = pharmacokinetic time; PO = orally (per os); PRN = as needed; PRO = patient-reported outcome; PROMIS = Patient Reported Outcomes Measurement 
Information System; T0 = time of admission into the PACU; TUG = Timed Up and Go. 
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3 
TABLE OF CONTENTS 
1 
KEY PERSONNEL CONTACT INFORMATION ................................................3 
2 
PROTOCOL SYNOPSIS ........................................................................................7 
3 
TABLE OF CONTENTS .......................................................................................31 
4 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ..........................36 
5 
INTRODUCTION .................................................................................................39 
5.1 
Background ......................................................................................................39 
5.2 
CA-008 Product Introduction ..........................................................................40 
5.3 
Previous Human Experience ............................................................................41 
5.3.1 
Adverse Events in Prior Clinical Studies .............................................41 
5.3.2 
Pharmacokinetic Exposures in Prior Clinical Studies .........................58 
5.3.3 
Estimated Exposures in VHR/Soft Tissue ...........................................63 
5.3.4 
Preclinical Supporting Data .................................................................65 
5.4 
Study Rationale ................................................................................................68 
5.5 
Dose Rationale .................................................................................................68 
5.5.1 
Selection of Doses................................................................................68 
5.5.2 
Selection and Timing of Dose..............................................................68 
6 
STUDY OBJECTIVES ..........................................................................................70 
6.1 
Primary Objectives...........................................................................................70 
6.2 
Secondary Objectives.......................................................................................70 
7 
INVESTIGATIONAL PLAN ................................................................................72 
7.1 
Overall Study Design and Plan ........................................................................72 
7.2 
Duration of Participation..................................................................................73 
7.3 
Dose Escalation and Cohort Expansion ...........................................................73 
7.4 
Study Stopping Rules .......................................................................................73 
8 
SELECTION OF STUDY POPULATION ...........................................................75 
8.1 
Study Population ..............................................................................................75 
8.1.1 
Number of Participants ........................................................................75 
8.2 
Eligibility Criteria ............................................................................................75 
8.2.1 
Inclusion Criteria .................................................................................75 
8.2.2 
Exclusion Criteria ................................................................................76 
9 
STUDY TREATMENTS .......................................................................................79 
9.1 
Study Treatment ...............................................................................................79 
9.1.1 
CA-008 HCl Description .....................................................................79 
9.1.2 
Study Treatment Description ...............................................................79 
9.1.3 
Study Treatment Storage......................................................................79 
9.1.4 
Study Treatment Accountability ..........................................................79 
9.1.5 
Control of Study Treatment and Rescue Medication ...........................80 
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9.2 
Other Interventions ..........................................................................................80 
9.2.1 
Preoperative, Anesthesia and Perioperative Care ................................80 
9.2.2 
Intraoperative Analgesia and Care .......................................................81 
9.2.3 
Inpatient Rescue Medications ..............................................................82 
9.2.4 
Postsurgical Care .................................................................................82 
9.2.5 
Outpatient Analgesic Medications .......................................................83 
9.3 
Method of Assigning Patients to Treatment Groups........................................84 
9.4 
Blinding............................................................................................................84 
9.5 
Prior and Concomitant Therapy .......................................................................85 
9.6 
Study Restrictions ............................................................................................85 
9.7 
Treatment Compliance .....................................................................................86 
10 
CONDUCT OF THE STUDY ...............................................................................87 
10.1 
Study Visits ......................................................................................................87 
10.1.1 
Screening Phase (Day -45 to Day Prior to Surgery): ...........................87 
10.1.2 
Surgery Phase: Admission to Unit for Surgery (Baseline) to End of 
Surgery .................................................................................................88 
10.1.3 
Surgery Phase: Administration of Study Medication into the 
Surgical Site .........................................................................................89 
10.1.4 
Postsurgery: T0 (Admission into the PACU) to T96 (Discharge) .......92 
10.1.5 
Outpatient Phase: T96 (after Discharge) through D15 ........................94 
10.1.6 
Outpatient Phase: D29 .........................................................................96 
10.1.7 
Early Termination ................................................................................97 
10.1.8 
Unscheduled Visit ................................................................................98 
10.2 
Patient Completion and Withdrawal ................................................................98 
10.2.1 
Patient Completion...............................................................................98 
10.2.2 
Patient Withdrawal...............................................................................98 
10.3 
Study Procedures and Assessments .................................................................99 
10.3.1 
Informed Consent.................................................................................99 
10.3.2 
Demographics ....................................................................................100 
10.3.3 
Medical and Surgical History ............................................................100 
10.3.4 
Medication History ............................................................................100 
10.3.5 
Contraceptive Requirements ..............................................................100 
10.3.6 
Patient Pain Assessment Training ......................................................100 
10.3.7 
Digital Photographs of the Surgical Site ............................................100 
10.3.8 
Numerical Rating Scale for Pain Intensity (NRS) .............................101 
10.3.9 
Patient-Reported Outcomes ...............................................................102 
10.3.10 
Performance-Based Outcome Measures (PBOMs) ...........................102 
10.3.11 
Rescue Medications ...........................................................................102 
10.3.12 
Clinical Laboratory Assessments .......................................................102 
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10.3.13 
Urine Drug Screen and Alcohol Test .................................................103 
10.3.14 
Vital Signs ..........................................................................................104 
10.3.15 
Electrocardiogram ..............................................................................104 
10.3.16 
Physical Examination.........................................................................104 
10.3.17 
Surgical Site Assessment ...................................................................105 
10.3.18 
Neurosensory Testing ........................................................................105 
10.3.19 
Assessment of Adverse Events ..........................................................106 
10.3.20 
Pharmacokinetic Assessments and Samples ......................................106 
10.4 
Safety, Tolerability, Pharmacokinetic, and Efficacy Endpoints ....................107 
10.4.1 
Safety Endpoints ................................................................................107 
10.4.2 
Pharmacokinetic Endpoints ...............................................................108 
10.4.3 
Efficacy Endpoints .............................................................................108 
11 
ADVERSE EVENTS ...........................................................................................110 
11.1 
Adverse Events and Serious Adverse Events ................................................110 
11.1.1 
Relationship to Study Treatment .......................................................110 
11.1.2 
Adverse Event Reporting ...................................................................111 
11.1.3 
Serious Adverse Event .......................................................................112 
11.2 
Severity Grading for AEs...............................................................................113 
11.3 
Pregnancy .......................................................................................................114 
12 
DATA QUALITY ASSURANCE .......................................................................115 
12.1 
Data Collection ..............................................................................................115 
12.2 
Study Auditing and Monitoring .....................................................................115 
13 
STATISTICAL METHODS ................................................................................117 
13.1 
Sample Size Justification ...............................................................................117 
13.2 
Analysis Populations ......................................................................................117 
13.3 
Planned Analyses ...........................................................................................118 
13.4 
Study Patients and Demographics .................................................................119 
13.4.1 
Disposition and Withdrawals .............................................................119 
13.4.2 
Protocol Deviations ............................................................................119 
13.4.3 
Demographics and Other Baseline Characteristics ............................120 
13.4.4 
Exposure ............................................................................................120 
13.4.5 
General Considerations ......................................................................120 
13.4.6 
Analysis of Efficacy Measures ..........................................................121 
13.4.7 
Handling of Dropouts or Missing Data ..............................................122 
13.4.8 
Analysis of Safety ..............................................................................122 
13.4.9 
Clinical Laboratory Evaluations ........................................................123 
13.4.10 
Vital Signs and ECG ..........................................................................123 
13.4.11 
Physical Examination Findings..........................................................124 
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14 
SITE AND INVESTIGATOR RESPONSIBILITIES .........................................125 
14.1 
Regulatory and Ethical Considerations ..........................................................125 
14.1.1 
Ethical Conduct of the Study .............................................................125 
14.1.2 
Ethics Approval .................................................................................125 
14.1.3 
Patient Informed Consent ..................................................................125 
14.2 
Privacy and Confidentiality ...........................................................................126 
14.3 
Study and Site Closure ...................................................................................126 
14.4 
Regulatory Documents and Records Retention .............................................127 
14.5 
Delegation of Responsibilities and Adequate Resources...............................128 
14.6 
Protocol Amendments ....................................................................................128 
14.7 
Financial Disclosure.......................................................................................128 
15 
INVESTIGATOR PROTOCOL AGREEMENT PAGE .....................................129 
16 
REFERENCES ....................................................................................................130 
17 
APPENDICES .....................................................................................................131 
17.1 
Appendix A: Toxicity Grading Scale for Systemic (General) Adverse 
Events .............................................................................................................131 
17.2 
Appendix B: American Society of Anesthesiologists Physical Status 
Classification System (ASA Class) ...............................................................132 
17.3 
Appendix C: Toxicity Grading Scale for Clinical Vital Sign Abnormalities 133 
17.4 
Appendix D: Toxicity Grading Scale for Clinical Laboratory 
Abnormalities .................................................................................................135 
17.5 
Appendix E: 0 to 10 Numerical Rating Scale of Pain Intensity (NRS) .........138 
17.6 
Appendix F: PROMIS 10 GLOBAL Health Questionnaire ..........................139 
17.7 
Appendix G: Activities Assessment Scale (AAS) .........................................141 
17.8 
Appendix H: Sit to Stand Test (30-Second Chair Stand) Assessment...........142 
17.9 
Appendix I: TUG Test ...................................................................................143 
17.10 
Appendix J: Surgical Site Assessment ...........................................................144 
17.11 
Appendix K: Surgical Wound Adverse Event Grading Guide ......................145 
17.12 
Appendix L: Neurosensory Examination Form .............................................146 
 
 
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LIST OF TABLES 
Table 1 
Schedule of Assessments – Parts A, B and C ............................................27 
Table 2 
Overall Summary of Adverse Events (CA-PS-201) ..................................42 
Table 3 
Summary of TEAEs by MedDRA System Organ Class / Preferred 
Term (CA-PS-201).....................................................................................42 
Table 4 
Overall Summary of TEAEs – (CA-PS-204).............................................46 
Table 5 
Summary of TEAEs by MedDRA System Organ Class / Preferred 
Term (CA-PS-204).....................................................................................46 
Table 6 
Summary of Serious Adverse Events – (CA-PS-204) ...............................48 
Table 7 
Overall Summary of TEAEs – (CA-PS-203).............................................49 
Table 8 
Summary of Serious Adverse Events – (CA-PS-203) ...............................49 
Table 9 
Summary of TEAEs by MedDRA SOC/PT (CA-PS-203) ........................50 
Table 10 
Summary of Treatment-Emergent Adverse Events (for Study CA-PS-
208) ............................................................................................................54 
Table 11 
Summary of Treatment Emergent Adverse Events Occurring in ≥10% 
Subjects by System Organ Class and Preferred Term for Study CA-PS-
208..............................................................................................................55 
Table 12 
Summary of PK Parameters by Dose Cohort for Study CA-PS-2017-
101 (BUN) and CA-PS-201 (BUN): 0.5 to 4.2 mg....................................59 
Table 13 
Summary of PK Parameters by Dose Cohort for Study CA-PS-203 
(TKA) and CA-PS-204 (ABD): 5 to 15 mg ...............................................60 
Table 14 
Summary of PK Parameters by Dose Cohort for Study CA-PS-208: 36 
to 90 mg .....................................................................................................62 
Table 15 
Supporting exposure data for administration of CA-008 up to 36 mg 
(0.3 mg/ml) in CA-PS-209 .........................................................................64 
Table 16 
Exposure from PS-208 vs. Predicted Exposures in Soft Tissue ................65 
Table 17 
Nonclinical Exposures and HED in Dog and Rat following SC 
administration of CA-008 ..........................................................................66 
Table 18 
Preclinical Exposure: Predicted Exposures in CA-PS-209 (VHR) Ratio ..67 
Table 19 
Study Stopping Rules .................................................................................74 
Table 20 
Clinical Laboratory Assessments .............................................................103 
 
TABLE OF FIGURES 
Figure 1 
Study Design ..............................................................................................72 
 
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4 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation Term 
AC 
Analgesic consumption 
ADaM 
Analysis Data Model 
AE 
Adverse event 
ALK 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
aPTT 
Activated partial thromboplastin time 
ASA 
American Society of Anesthesiologists 
AST 
Aspartate aminotransferase 
AUC 
Area Under the Curve 
AUC0-∞ 
Area Under the Curve from time 0 to infinity  
AUC0-last 
Area Under the Curve from time 0 to the last PK sample collection time 
BID 
Bis in die (twice daily) 
BMI 
Body mass index 
BP 
Blood pressure 
BUN 
Blood urea nitrogen 
CA-008 
Investigational product 
CA-101 
Cyclic urea 
CFR 
Code of Federal Regulations 
cm 
Centimeter 
Cmax 
Maximum observed plasma drug concentration 
CRF / eCRF 
Case Report Form (may include electronic data capture systems or paper forms) 
CRO 
Contract research organization 
CS 
Clinically significant 
D# or D-# 
Day # (study days after surgery), Day # prior to surgery 
ECG 
Electrocardiogram 
EDC 
Electronic data capture 
FCBP 
Female of childbearing potential 
FDA 
Food and Drug Administration 
FSH 
Follicle stimulating hormone 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transferase 
GLP 
Good Laboratory Practice 
h or hrs 
Hour(s) 
HCl 
Hydrochloride 
HR 
Heart rate 
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Abbreviation Term 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
INR 
International Normalized Ratio 
IP 
Investigational Product 
IRB 
Institutional Review Board 
IV 
Intravenous 
kg 
Kilogram 
LOCF 
Last pain score carried forward 
m 
Meter 
mcg 
Microgram 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
min 
Minutes 
mITT 
Modified Intent-to-treat 
mL 
Milliliter 
ms 
Millisecond 
NCS 
Not clinically significant 
NRS 
Numeric Rating Scale of Pain Intensity 
OC 
Opioid consumption  
OF 
Opioid free 
OME 
Oral morphine equivalent 
OTC 
Over the counter 
PACU 
Post-anesthesia care unit 
PBOM 
Performance-based outcome measure 
PDS 
Polydioxanone sutures 
PE 
Physical examination 
PI 
Principal Investigator 
PKT 
Pharmacokinetic time 
PK 
Pharmacokinetic(s) 
PO 
Per os (oral) 
PRN 
Pro re nata (as needed) 
PRO 
Patient-reported outcome 
PROMIS 
Patient Reported Outcomes Measurement Information System 
PT 
Prothrombin time 
Q 
Every 
RBC 
Red blood cell 
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Abbreviation Term 
RR 
Respiratory rate 
SAE 
Serious adverse event  
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SNRIs 
Serotonin-norepinephrine reuptake inhibitors 
SPI 
Sum of pain intensity 
SpO2 
Oxygen saturation 
SSRIs 
Selective serotonin reuptake inhibitors 
T# 
Time in hours since arrival in the PACU (T0 equals time of admission into the 
PACU) 
TEAEs 
Treatment emergent adverse event(s) 
THC 
Tetrahydrocannabinol 
TKA 
Total knee arthroplasty 
Tmax 
Time to maximum plasma drug concentration 
Tot. Bili 
Total bilirubin 
TRPV1 
Transient receptor potential subfamily V (vanilloid) member 1 
TUG 
Timed Up and Go 
ULN 
Upper limit of normal 
US 
United States 
VHR 
Ventral hernia repair 
W# 
Week # visit after surgery 
wLOCF 
Last prior pain score carried forward for a specified period (window) 
WOCF 
Worst prior pain score carried forward 
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5 
INTRODUCTION 
5.1 
Background 
Concentric Analgesics, Inc. (Concentric) is developing CA-008 (vocacapsaicin) to provide 
long-lasting pain relief of postsurgical pain following a single local administration. CA-008 
is a prodrug of trans-capsaicin (trans-8-methyl-N-vanillyl-6-nonenamide), the substance in 
chili peppers that produces the sensation of spiciness. Capsaicin is a transient receptor 
potential cation channel, subfamily V (vanilloid) member 1 (TRPV1) agonist. TRPV1 is a 
ligand-gated, nonselective, cation channel preferentially expressed most densely in C-fiber 
nociceptors and to a lesser extent on Aδ–fiber nociceptors (Babbar 2009, Caterina 2001). 
TRPV1 responds to noxious stimuli including capsaicin, heat, and extracellular acidification, 
and integrates simultaneous exposures to these stimuli (Suresh 2010, Surh 1995, Tominaga 
1998).  
Capsaicin exposure to TRPV-1-expressing nociceptor peripheral terminals results in initial 
excitation of the nociceptor followed by a functional desensitization which continues for 
some time after removal of capsaicin from the site. Capsaicin, however, is virtually insoluble 
in aqueous media or local anesthetic solutions which means that capsaicin formulations tend 
to be quite hydrophobic and viscous making them hard to inject and less likely to permeate 
surgical site tissues. Anesiva, which had been developing capsaicin for the management of 
postsurgical pain and osteoarthritis, solubilized capsaicin in polyethylene glycol 300 
(Hartrick 2011). The product was instilled into the open surgical site and after waiting for 
5 minutes, was removed via surgical suction. This simple administration technique limited 
exposure of capsaicin only to the exposed surfaces of cut tissue and bone with little to no 
ability to penetrate into the affected soft tissues. 
In order to work around the solubility limitations of capsaicin, the highly water-soluble 
capsaicin pro-drug CA-008 was developed for local infiltration. It avoids the 
physicochemical limitations of capsaicin while providing greater target engagement which 
theoretically would produce superior local analgesia, particularly after surgical trauma. Based 
upon this mechanism of action, local delivery of a TRPV1 agonist throughout the tissues 
around the surgical site prior to wound closure to maximize target engagement should result 
in a meaningful reduction of postsurgical pain over several days to weeks. This improved 
long-term pain relief has the ability to augment current multimodal analgesia or enhanced 
recovery programs which may help to avoid the need for supplemental opioid use after 
surgery.  
While no capsaicin products have been approved for injection or instillation into a wound site 
in the US, several companies have or had clinical development programs for such products. 
Centrexion Therapeutics has an active development program (CTNX-4975) for intraarticular 
injection of capsaicin for chronic osteoarthritis and Morton’s neuroma (see 
http://centrexion.com/our-pipeline/). Note that Centrexion is using the Anesiva highly 
viscous polyethylene glycol formulation for its intraarticular knee joint injections.  
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5.2 
CA-008 Product Introduction 
The active moiety of CA-008, capsaicin, has certain attractive properties for treatment of 
post-operative pain from a pharmaceutical perspective. CA-008 is water soluble and easy to 
inject through a 25 g needle or larger. It readily penetrates surgical site tissues where it 
releases capsaicin through a non-enzymatic pH-driven process. Local administration of 
CA-008 at or near the source of pain by infiltration or by instillation into a surgical site 
results in low systemic levels of capsaicin.  
CA-008 was created to improve delivery of capsaicin without having to account for its poor 
solubility profile in tissues. CA-008 provides an aqueous formulation that could be simply 
infiltrated in the wound site to achieve local capsaicin release to produce a maximal effect. 
The free base form of CA-008 rapidly breaks down at physiological pH to yield capsaicin 
and a cyclic urea, as shown in the scheme below: 
 
 
CA-008 was specifically selected for development due to its short half-life (< 5 min) at 
neutral pH. In Tris buffer at pH 7.4 and 37°C, it completely breaks apart to capsaicin and 
CA-101 as the sole degradants. 
The cyclic urea (CA-101) formed has not been previously evaluated for biological activity. 
While not a known compound in the clinical literature, its safety was evaluated in all 
nonclinical studies with CA-008 and it was shown to be inactive. The toxicokinetic profiles 
for CA-008, CA-101, and capsaicin were determined in Good Laboratory Practice (GLP) 
safety studies and the pharmacokinetic (PK) profile for various doses have been determined 
in multiple clinical trials conducted to date. 
In Concentric GLP toxicological Study CA-NC-008-TOX-019-CR, single-dose subcutaneous 
administration of CA-008 HCl was well-tolerated when administered to male and female 
anesthetized dogs at dose levels up to 3.24 mg/kg CA-008 HCl (3.00 mg/kg CA-008 free 
base). Test article was formulated in 0.5 mM citrate, 0.4 mg/mL mannitol in saline for 
injection, with a final pH of approximately 3.7 to 3.8. This study supports clinical doses up to 
100 mg of CA-008 (free base), with concentrations up to 2.00 mg/mL CA-008 (free base). 
Concentric Study CA-NC-008-WH-005-MP evaluated the effect of CA-008 on wound 
healing of a hernia defect surgically repaired with mesh. In the study, CA-008 was 
administered alone or in combination with bupivacaine or ropivacaine by wound infiltration 
to a hernia defect repaired with mesh, in male and female Yucatan minipigs. The dose of 
CA-008 HCl administered to each animal was 15 mg of CA-008 HCl/animal, which was 
equivalent to~0.375 mg/kg. The Human Equivalent Dose (HED) was ~ 20 mg/60 kg human 
and the concentration used in the study was ~0.87 mg/mL free base (16 mL). A 9-cm 
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circular Prolene Mesh (polypropylene) patch was placed into the hernia site, flattened, and 
attached to the muscle using 8 simple interrupted sutures of 2-0 Prolene. The hernia 
(muscle) was closed with 2-0 Prolene in a simple interrupted pattern. The subcutaneous 
tissue layer was closed with 2-0 polydioxanone sutures (PDS) in a continuous pattern. The 
subcuticular tissue layer was closed with 4-0 PDS in a continuous pattern. The skin was then 
closed with skin glue and the closed incisions were covered with Ioban. There were no 
unscheduled sacrifices, no related macroscopic findings at Days 30 and 57 and no 
histological findings at Day 30 and Day 57 that could be directly attributed to local wound 
infiltration of CA-008 HCl. 
Overall, treatment with CA-008 did not affect wound healing of a hernia defect surgically 
repaired with mesh. Furthermore, pre-treatment of the wound area with ropivacaine or 
bupivacaine prior to treatment with CA-008 did not impact the hernia wound healing process. 
5.3 
Previous Human Experience 
There is substantial clinical support for the potential safety of capsaicin, the active molecule 
released by CA-008 in vivo. In addition to consumption in hot spicy foods (chili peppers), 
capsaicin is an approved product for dermal applications for over-the-counter (OTC) and 
prescription use (Qutenza; 8% patch for management of neuropathic pain associated with 
post herpetic neuralgia), is frequently used intradermally in experimental pain models, and 
has been studied clinically for wound instillation for postsurgical analgesia (Anesiva; Adlea; 
capsaicin for instillation).  
5.3.1 
Adverse Events in Prior Clinical Studies 
A first-in-human study (Study CA-PS-2017-101) evaluated the safety and tolerability of 
CA-008 in 40 patients undergoing a unilateral transpositional first metatarsal osteotomy for 
correction of hallux valgus deformity, more commonly known as a bunionectomy. This study 
also evaluated PK and preliminary efficacy assessment of CA-008 to inform future studies in 
our clinical development plan. This study evaluated 5 different doses of CA-008 (0.5 mg, 
1 mg, 2 mg, 3 mg and 4.2 mg). The safety, efficacy and PK results for the Phase 1 
bunionectomy study are shown in the current Investigators’ Brochure.  
A Phase 2 bunionectomy study (CA-PS-201) was completed with 147 patients enrolled and 
randomized to one of 3 active doses: 0.05 mg/mL (0.7 mg, N = 36), 0.15 mg/mL (2.1 mg, 
N = 36) and 0.3 mg/mL (4.2 mg, N = 37) vs. placebo (N = 38) in a 1:1:1:1 randomization, 
respectively. The highest dose of 4.2 mg was statistically significantly superior to placebo for 
the primary efficacy endpoint of Pain AUC0-96 (p = 0.005) and key secondary efficacy 
endpoints: Pain AUC 0 to Week 1 (AUC0-W1) (p = 0.036); mean opioid consumption 
(reduced by 50%, p < 0.002); and percent of patients who were opioid free (OF) from 
0-96 hours (26% vs. 5% for placebo; p = 0.039).  
In CA-PS-201, low but measurable levels of CA-008 were documented in the systemic 
circulation for a few hours following study drug instillation with a Tmax of ~15 minutes. 
CA-008 was safe and well-tolerated at all doses. There were no treatment-emergent adverse 
events (TEAE) leading to patient discontinuation and no pattern of TEAEs that suggested a 
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drug-related safety concern. There were no serious adverse events (SAEs) reported. Table 2 
and Table 3 show the summary of safety for the study based upon summary tables and 
patient listings.  
Table 2 
Overall Summary of Adverse Events (CA-PS-201) 
 
 
Table 3 
Summary of TEAEs by MedDRA System Organ Class / Preferred 
Term (CA-PS-201) 
No. of Subjects 
Total 
N = 147 
n (%) 
CA-008 
Placebo 
(Standard of 
care alone) 
N = 37 
n (%) 
System Organ Class 
 Preferred Term 
0.7 mg 
(0.05 
mg/mL) 
N = 36 
n (%) 
2.1 mg 
(0.15 
mg/mL) 
N = 36 
n (%) 
4.2 mg (0.3 
mg/mL) 
N = 38 
n (%) 
No. of TEAEs 
287 
69 
82 
76 
60 
No. of Subjects with any 
TEAE1 
106 (72.1) 
27 (75.0) 
28 (77.8) 
26 (68.4) 
25 (67.6) 
Cardiac disorders 
6 (4.1) 
1 (2.8) 
2 (5.6) 
3 (7.9) 
0 
Angina pectoris 
1 (0.7) 
1 (2.8) 
0 
0 
0 
Bradycardia 
2 (1.4) 
0 
1 (2.8) 
1 (2.6) 
0 
Sinus tachycardia 
1 (0.7) 
0 
1 (2.8) 
0 
0 
Tachycardia 
2 (1.4) 
0 
0 
2 (5.3) 
0 
Eye disorders 
1 (0.7) 
0 
1 (2.8) 
0 
0 
Eye haematoma 
1 (0.7) 
0 
1 (2.8) 
0 
0 
Gastrointestinal disorders 
41 (27.9) 
8 (22.2) 
10 (27.8) 
10 (26.3) 
13 (35.1) 
Abdominal pain 
1 (0.7) 
0 
0 
0 
1 (2.7) 
Abdominal pain upper 
1 (0.7) 
1 (2.8) 
0 
0 
0 
Constipation 
10 (6.8) 
3 (8.3) 
2 (5.6) 
1 (2.6) 
4 (10.8) 
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No. of Subjects 
Total 
N = 147 
n (%) 
CA-008 
Placebo 
(Standard of 
care alone) 
N = 37 
n (%) 
System Organ Class 
 Preferred Term 
0.7 mg 
(0.05 
mg/mL) 
N = 36 
n (%) 
2.1 mg 
(0.15 
mg/mL) 
N = 36 
n (%) 
4.2 mg (0.3 
mg/mL) 
N = 38 
n (%) 
Diarrhoea 
1 (0.7) 
0 
1 (2.8) 
0 
0 
Dyspepsia 
1 (0.7) 
0 
1 (2.8) 
0 
0 
Flatulence 
1 (0.7) 
0 
0 
1 (2.6) 
0 
Nausea 
29 (19.7) 
6 (16.7) 
7 (19.4) 
7 (18.4) 
9 (24.3) 
Paraesthesia oral 
1 (0.7) 
0 
0 
0 
1 (2.7) 
Stomatitis 
1 (0.7) 
1 (2.8) 
0 
0 
0 
Vomiting 
12 (8.2) 
1 (2.8) 
4 (11.1) 
3 (7.9) 
4 (10.8) 
General disorders and 
administration site conditions 
20 (13.6) 
6 (16.7) 
3 (8.3) 
5 (13.2) 
6 (16.2) 
Administration site warmth 
2 (1.4) 
1 (2.8) 
0 
1 (2.6) 
0 
Application site pain 
1 (0.7) 
0 
0 
0 
1 (2.7) 
Application site rash 
1 (0.7) 
0 
0 
1 (2.6) 
0 
Chills 
1 (0.7) 
0 
0 
0 
1 (2.7) 
Feeling hot 
6 (4.1) 
1 (2.8) 
2 (5.6) 
1 (2.6) 
2 (5.4) 
Impaired healing 
1 (0.7) 
1 (2.8) 
0 
0 
0 
Infusion site oedema 
6 (4.1) 
3 (8.3) 
0 
1 (2.6) 
2 (5.4) 
Infusion site pain 
3 (2.0) 
1 (2.8) 
1 (2.8) 
0 
1 (2.7) 
Oedema peripheral 
2 (1.4) 
0 
0 
2 (5.3) 
0 
Pain 
4 (2.7) 
1 (2.8) 
1 (2.8) 
1 (2.6) 
1 (2.7) 
Infections and infestations 
9 (6.1) 
0 
5 (13.9) 
3 (7.9) 
1 (2.7) 
Cellulitis 
3 (2.0) 
0 
1 (2.8) 
1 (2.6) 
1 (2.7) 
Pharyngitis 
1 (0.7) 
0 
1 (2.8) 
0 
0 
Post procedural cellulitis 
1 (0.7) 
0 
1 (2.8) 
0 
0 
Post procedural infection 
1 (0.7) 
0 
1 (2.8) 
0 
0 
Postoperative wound 
infection 
3 (2.0) 
0 
1 (2.8) 
1 (2.6) 
1 (2.7) 
Tooth infection 
1 (0.7) 
0 
0 
1 (2.6) 
0 
Injury, poisoning and 
procedural complications 
18 (12.2) 
3 (8.3) 
5 (13.9) 
3 (7.9) 
7 (18.9) 
Foot fracture 
1 (0.7) 
0 
0 
0 
1 (2.7) 
Incision site erythema 
1 (0.7) 
0 
0 
0 
1 (2.7) 
Incision site haematoma 
2 (1.4) 
1 (2.8) 
1 (2.8) 
0 
0 
Scar 
1 (0.7) 
1 (2.8) 
0 
0 
0 
Wound 
1 (0.7) 
0 
0 
1 (2.6) 
0 
Wound dehiscence 
15 (10.2) 
2 (5.6) 
5 (13.9) 
3 (7.9) 
5 (13.5) 
Investigations 
7 (4.8) 
2 (5.6) 
2 (5.6) 
3 (7.9) 
0 
Alanine aminotransferase 
increased 
3 (2.0) 
0 
0 
3 (7.9) 
0 
Aspartate aminotransferase 
increased 
3 (2.0) 
0 
0 
3 (7.9) 
0 
Blood glucose increased 
1 (0.7) 
0 
1 (2.8) 
0 
0 
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No. of Subjects 
Total 
N = 147 
n (%) 
CA-008 
Placebo 
(Standard of 
care alone) 
N = 37 
n (%) 
System Organ Class 
 Preferred Term 
0.7 mg 
(0.05 
mg/mL) 
N = 36 
n (%) 
2.1 mg 
(0.15 
mg/mL) 
N = 36 
n (%) 
4.2 mg (0.3 
mg/mL) 
N = 38 
n (%) 
Blood pressure increased 
2 (1.4) 
2 (5.6) 
0 
0 
0 
Body temperature increased 
1 (0.7) 
0 
1 (2.8) 
0 
0 
Gamma-glutamyltransferase 
increased 
1 (0.7) 
0 
0 
1 (2.6) 
0 
Metabolism and nutrition 
disorders 
3 (2.0) 
0 
1 (2.8) 
2 (5.3) 
0 
Decreased appetite 
3 (2.0) 
0 
1 (2.8) 
2 (5.3) 
0 
Musculoskeletal and 
connective tissue disorders 
17 (11.6) 
7 (19.4) 
5 (13.9) 
4 (10.5) 
1 (2.7) 
Arthralgia 
2 (1.4) 
1 (2.8) 
1 (2.8) 
0 
0 
Back pain 
4 (2.7) 
2 (5.6) 
0 
2 (5.3) 
0 
Joint stiffness 
1 (0.7) 
0 
1 (2.8) 
0 
0 
Limb discomfort 
2 (1.4) 
2 (5.6) 
0 
0 
0 
Muscle spasms 
3 (2.0) 
0 
3 (8.3) 
0 
0 
Muscle twitching 
1 (0.7) 
1 (2.8) 
0 
0 
0 
Musculoskeletal pain 
1 (0.7) 
0 
0 
1 (2.6) 
0 
Musculoskeletal stiffness 
1 (0.7) 
0 
1 (2.8) 
0 
0 
Neck pain 
1 (0.7) 
0 
0 
1 (2.6) 
0 
Pain in extremity 
4 (2.7) 
1 (2.8) 
0 
2 (5.3) 
1 (2.7) 
Nervous system disorders 
53 (36.1) 
17 (47.2) 
14 (38.9) 
14 (36.8) 
8 (21.6) 
Burning sensation 
4 (2.7) 
2 (5.6) 
0 
2 (5.3) 
0 
Dizziness 
12 (8.2) 
4 (11.1) 
5 (13.9) 
1 (2.6) 
2 (5.4) 
Headache 
28 (19.0) 
7 (19.4) 
8 (22.2) 
7 (18.4) 
6 (16.2) 
Hyperaesthesia 
2 (1.4) 
1 (2.8) 
0 
1 (2.6) 
0 
Hypoaesthesia 
2 (1.4) 
0 
1 (2.8) 
1 (2.6) 
0 
Paraesthesia 
3 (2.0) 
1 (2.8) 
0 
1 (2.6) 
1 (2.7) 
Presyncope 
1 (0.7) 
1 (2.8) 
0 
0 
0 
Somnolence 
6 (4.1) 
2 (5.6) 
0 
2 (5.3) 
2 (5.4) 
Syncope 
1 (0.7) 
0 
1 (2.8) 
0 
0 
Psychiatric disorders 
1 (0.7) 
0 
0 
0 
1 (2.7) 
Depressed mood 
1 (0.7) 
0 
0 
0 
1 (2.7) 
Renal and urinary disorders 
4 (2.7) 
0 
4 (11.1) 
0 
0 
Polyuria 
4 (2.7) 
0 
4 (11.1) 
0 
0 
Urge incontinence 
1 (0.7) 
0 
1 (2.8) 
0 
0 
Reproductive system and 
breast disorders 
1 (0.7) 
0 
0 
1 (2.6) 
0 
Vaginal haemorrhage 
1 (0.7) 
0 
0 
1 (2.6) 
0 
Respiratory, thoracic and 
mediastinal disorders 
6 (4.1) 
3 (8.3) 
0 
3 (7.9) 
0 
Dysphonia 
1 (0.7) 
1 (2.8) 
0 
0 
0 
Hypoxia 
4 (2.7) 
2 (5.6) 
0 
2 (5.3) 
0 
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No. of Subjects 
Total 
N = 147 
n (%) 
CA-008 
Placebo 
(Standard of 
care alone) 
N = 37 
n (%) 
System Organ Class 
 Preferred Term 
0.7 mg 
(0.05 
mg/mL) 
N = 36 
n (%) 
2.1 mg 
(0.15 
mg/mL) 
N = 36 
n (%) 
4.2 mg (0.3 
mg/mL) 
N = 38 
n (%) 
Rhinorrhoea 
1 (0.7) 
0 
0 
1 (2.6) 
0 
Skin and subcutaneous tissue 
disorders 
13 (8.8) 
2 (5.6) 
4 (11.1) 
1 (2.6) 
6 (16.2) 
Dermatitis 
1 (0.7) 
0 
1 (2.8) 
0 
0 
Dry skin 
1 (0.7) 
0 
0 
1 (2.6) 
0 
Hyperhidrosis 
4 (2.7) 
2 (5.6) 
0 
0 
2 (5.4) 
Petechiae 
1 (0.7) 
0 
1 (2.8) 
0 
0 
Pruritus 
3 (2.0) 
0 
1 (2.8) 
0 
2 (5.4) 
Rash 
2 (1.4) 
0 
0 
0 
2 (5.4) 
Rash erythematous 
1 (0.7) 
0 
1 (2.8) 
0 
0 
Skin maceration 
3 (2.0) 
0 
1 (2.8) 
0 
2 (5.4) 
Surgical and medical 
procedures 
1 (0.7) 
1 (2.8) 
0 
0 
0 
Wound drainage 
1 (0.7) 
1 (2.8) 
0 
0 
0 
Vascular disorders 
9 (6.1) 
2 (5.6) 
3 (8.3) 
4 (10.5) 
0 
Deep vein thrombosis 
1 (0.7) 
0 
1 (2.8) 
0 
0 
Diastolic hypotension 
1 (0.7) 
1 (2.8) 
0 
0 
0 
Hot flush 
2 (1.4) 
0 
0 
2 (5.3) 
0 
Hypertension 
2 (1.4) 
0 
0 
2 (5.3) 
0 
Hypotension 
2 (1.4) 
0 
2 (5.6) 
0 
0 
Thrombophlebitis 
1 (0.7) 
1 (2.8) 
0 
0 
0 
 
A Phase 2, single-ascending dose study was completed in patients undergoing total 
abdominoplasty (CA-PS-204). A total of 54 patients received one of three active doses of 
CA-008: 5 mg as 0.05 mg/mL (N = 9), 10 mg as 0.1 mg/mL (N = 13), 15 mg as 0.15 mg/mL 
(N = 12) or placebo (N = 20). All doses of CA-008 were safe and well-tolerated (Table 4 and 
Table 5). Four SAEs occurred in 4 patients and all were considered unrelated to study drug: 
post-procedural hemorrhage in two patients, spontaneous abortion in one patient, and deep 
venous thrombosis in one patient (Table 6). No effect on pain relief was detected due to the 
small sample size and low doses of study drug administered. 
 
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Table 4 
Overall Summary of TEAEs – (CA-PS-204) 
 
Total Events / Number (No.) of Subjects with Any Event, n (%) 
Total 
(N = 54) 
Cohort 1 
Cohorts 2 and 3 
CA-008 
5 mg 
(N = 9) 
Placebo 
(N = 9) 
CA-008 
10 mg 
(N = 12) 
CA-008 
15 mg 
(N = 12) 
Pooled 
Placebo 
(N = 12) 
No. of TEAEs / 
135/ 
28/ 
28/ 
23/ 
32/ 
24/ 
No. of Subjects with any TEAE1 
49 (90.7%) 9 (100.0%) 8 (88.9%) 11 (91.7%) 10 (83.3%) 11 (91.7%) 
No. of Treatment Related AEs/ 
21/ 
2/ 
5/ 
8/ 
4/ 
2/ 
No. of Subjects with Any Related 
TEAE2 
16 (29.6%) 2 (22.2%) 2 (22.2%) 7 (58.3%) 3 (25.0%) 2 (16.7%) 
No. of Severe TEAEs/ 
7/ 
2/ 
0/ 
2/ 
2/ 
1/ 
No. of Subjects with Any Severe 
TEAE 
7 (13.0%) 
2 (22.2%) 
0 
2 (16.7%) 2 (16.7%) 
1 (8.3%) 
No. of SAEs/ 
4/ 
2/ 
0/ 
1/ 
1/ 
0/ 
No. of Subjects with Any SAE 
4 (7.4%) 
2 (22.2%) 
0 
1 (8.3%) 
1 (8.3%) 
0 
No. of TEAEs Leading to 
Discontinuation/ 
2/ 
0/ 
0/ 
 
1/ 
 
1/ 
 
0/ 
 
No. of Subjects with TEAEs 
Leading to Discontinuation 
2 (3.7%) 
0 
0 
1 (8.3%) 
1 (8.3%) 
0 
Abbreviations: AE = adverse events; N = total number of subjects; SAE = serious adverse event; 
TEAE = treatment-emergent adverse event 
1 
A TEAE is defined as any new AE or an existing AE that worsens in severity during or after study drug 
administration  
2 
Treatment-related TEAEs are defined as TEAEs as probably or possibly related to study drug. 
Source: Table 14.3.1 
 
Table 5 
Summary of TEAEs by MedDRA System Organ Class / Preferred 
Term (CA-PS-204) 
System Organ Class 
Preferred Term 
Number of subjects with at least 1 TEAE, n (%) 
Total 
(N = 54) 
Cohort 1 
Cohorts 2 and 3 
CA-008 
5 mg 
(N = 9) 
Placebo 
(N = 9) 
CA-008 
10 mg 
(N = 12) 
CA-008 
15 mg 
(N = 12) 
Pooled 
Placebo 
(N = 12) 
Subjects with at least TEAE 49 (90.7) 
9 (100.0) 
8 (88.9) 
11 (91.7) 
10 (83.3) 
11 (91.7) 
Gastrointestinal disorders 
33 (61.1) 
6 (66.7) 
8 (88.9) 
6 (50.0) 
6 (50.0) 
7 (58.3) 
Constipation 12 (22.2) 
3 (33.3) 
2 (22.2) 
1 (8.3) 
2 (16.7) 
4 (33.3) 
Diarrhoea 
1 (1.9) 
0 
0 
0 
1 (8.3) 
0 
Dyspepsia 
1 (1.9) 
0 
0 
0 
0 
1 (8.3) 
Lip oedema 
1 (1.9) 
0 
0 
0 
1 (8.3) 
0 
Nausea 27 (50.0) 
5 (55.6) 
8 (88.9) 
6 (50.0) 
5 (41.7) 
3 (25.0) 
Toothache 
1 (1.9) 
0 
0 
1 (8.3) 
0 
0 
Vomiting 
4 (7.4) 
0 
2 (22.2) 
0 
2 (16.7) 
0 
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System Organ Class 
Preferred Term 
Number of subjects with at least 1 TEAE, n (%) 
Total 
(N = 54) 
Cohort 1 
Cohorts 2 and 3 
CA-008 
5 mg 
(N = 9) 
Placebo 
(N = 9) 
CA-008 
10 mg 
(N = 12) 
CA-008 
15 mg 
(N = 12) 
Pooled 
Placebo 
(N = 12) 
Musculoskeletal and 
connective tissue disorders 
21 (38.9) 
3 (33.3) 
4 (44.4) 
4 (33.3) 
5 (41.7) 
5 (41.7) 
Back pain 19 (35.2) 
3 (33.3) 
4 (44.4) 
3 (25.0) 
4 (33.3) 
5 (41.7) 
Musculoskeletal chest pain 
1 (1.9) 
0 
0 
1 (8.3) 
0 
0 
Musculoskeletal pain 
1 (1.9) 
0 
0 
0 
1 (8.3) 
0 
Nervous system disorders 
12 (22.2) 
4 (44.4) 
1 (11.1) 
1 (8.3) 
2 (16.7) 
4 (33.3) 
Dizziness 
1 (1.9) 
0 
0 
0 
0 
1 (8.3) 
Headache 10 (18.5) 
4 (44.4) 
1 (11.1) 
1 (8.3) 
2 (16.7) 
2 (16.7) 
Sciatica 
1 (1.9) 
0 
0 
0 
0 
1 (8.3) 
Injury, poisoning and 
procedural complications 
10 (18.5) 
1 (11.1) 
1 (11.1) 
2 (16.7) 
4 (33.3) 
2 (16.7) 
Abdominal wound 
dehiscence 
1 (1.9) 
0 
0 
0 
1 (8.3) 
0 
Airway complication of 
anaesthesia 
1 (1.9) 
0 
0 
1 (8.3) 
0 
0 
Arthropod bite 
1 (1.9) 
0 
0 
1 (8.3) 
0 
0 
Flap necrosis 
2 (3.7) 
0 
0 
0 
1 (8.3) 
1 (8.3) 
Incision site pruritus 
1 (1.9) 
0 
0 
0 
1 (8.3) 
0 
Post procedural haematoma 
1 (1.9) 
0 
0 
0 
0 
1 (8.3) 
Post procedural haemorrhage 
2 (3.7) 
0 
0 
1 (8.3) 
1 (8.3) 
0 
Seroma 
1 (1.9) 
1 (11.1) 
0 
0 
0 
0 
Wound dehiscence 
1 (1.9) 
0 
1 (11.1) 
0 
0 
0 
Respiratory, thoracic and 
mediastinal disorders 
8 (14.8) 
1 (11.1) 
1 (11.1) 
1 (8.3) 
3 (25.0) 
2 (16.7) 
Cough 
2 (3.7) 
0 
0 
0 
2 (16.7) 
0 
Epistaxis 
1 (1.9) 
0 
0 
0 
0 
1 (8.3) 
Hypoxia 
4 (7.4) 
1 (11.1) 
1 (11.1) 
1 (8.3) 
0 
1 (8.3) 
Oropharyngeal pain 
1 (1.9) 
0 
0 
1 (8.3) 
0 
0 
Respiratory tract congestion 
1 (1.9) 
0 
0 
0 
1 (8.3) 
0 
Skin and subcutaneous tissue 
disorders 
8 (14.8) 
2 (22.2) 
1 (11.1) 
2 (16.7) 
3 (25.0) 
0 
Dermatitis contact 
1 (1.9) 
0 
0 
0 
1 (8.3) 
0 
Pruritus 
3 (5.6) 
0 
1 (11.1) 
1 (8.3) 
1 (8.3) 
0 
Pruritus generalised 
2 (3.7) 
1 (11.1) 
0 
1 (8.3) 
0 
0 
Rash 
2 (3.7) 
1 (11.1) 
0 
0 
1 (8.3) 
0 
Rash macular 
1 (1.9) 
0 
0 
0 
1 (8.3) 
0 
Abbreviations: AE = adverse events; MedDRA = Medical Dictionary for Regulatory Activities; N = total 
number of subjects; n = number of subjects reporting an event; PT = preferred term; SAE = serious adverse 
event; SOC = System Organ Class; TEAE = treatment-emergent adverse event 
Source: Table 14.3.1.1 
 
 
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Table 6 
Summary of Serious Adverse Events – (CA-PS-204) 
System Organ Class 
Preferred Term 
Subjects with at least 1 SAE, n (%) 
Total 
(N = 54) 
Cohort 1 
Cohorts 2 and 3 
CA-008 
5 mg 
(N = 9) 
Placebo 
(N = 9) 
CA-008 
10 mg 
(N = 12) 
CA-008 
15 mg 
(N = 12) 
Pooled 
Placebo 
(N = 12) 
Subjects with at least 1 SAE 
4 (7.4) 
2 (22.2) 
0 
1 (8.3) 
1 (8.3) 
0 
Injury, poisoning and 
procedural complications 
2 (3.7) 
0 
0 
1 (8.3) 
1 (8.3) 
0 
Post procedural 
haemorrhage 
2 (3.7) 
0 
0 
1 (8.3) 
1 (8.3) 
0 
Pregnancy, puerperium and 
perinatal conditions 
1 (1.9) 
1 (11.1) 
0 
0 
0 
0 
Abortion spontaneous 
1 (1.9) 
1 (11.1) 
0 
0 
0 
0 
Vascular disorders 
1 (1.9) 
1 (11.1) 
0 
0 
0 
0 
Deep vein thrombosis 
1 (1.9) 
1 (11.1) 
0 
0 
0 
0 
Abbreviations: MedDRA = Medical Dictionary for Regulatory Activities; N = total number of subjects; 
n = number of subjects reporting an event; PT = preferred term; SAE = serious adverse event; SOC = System 
Organ Class; TEAE = treatment-emergent adverse event 
Source: Table 14.3.1.3 
 
A Phase 2, single-ascending dose study was completed in patients undergoing total knee 
arthroplasty (TKA) (CA-PS-203). A total of 54 patients received one of three active doses of 
CA-008: 5 mg as 0.05 mg/mL (N = 9), 10 mg as 0.1 mg/mL (N = 13), 15 mg as 0.15 mg/mL 
(N = 12) or placebo (N = 20). All doses of CA-008 were safe and well-tolerated (Table 7 and 
Table 9). Four SAEs occurred in 3 patients and all were considered unrelated to study drug: 
perforated ulcer in one patient, cerebrovascular accident and seizure in one patient, and deep 
venous thrombosis in one patient (Table 8). No effect on pain relief was detected due to the 
small sample size and low doses of study drug administered.  
 
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Table 7 
Overall Summary of TEAEs – (CA-PS-203) 
 
Total Events / N of Subjects with Any Event, n (%) 
Total 
N = 54 
Cohort 1 
Cohorts 2 and 3 
CA-008 
5 mg 
N = 9 
Placebo 
N = 9 
CA-008 
10 mg 
N = 13 
CA-008 
15 mg 
N = 12 
Pooled 
Placebo 
N = 11 
No. of TEAEs / 
172/ 
35/ 
28/ 
36/ 
46/ 
27/ 
No. of Subjects with any 
TEAE1 
45 (83.3) 
7 (77.8) 
7 (77.8) 
12 (92.3) 
10 (83.3) 
9 (81.8) 
N of Treatment Related AEs/ 
11/ 
1/ 
3/ 
1/ 
1/ 
5/ 
N of Subjects with Any 
Related TEAE2 
8 (14.8) 
1 (11.1) 
3 (33.3) 
1 (7.7) 
1 (8.3) 
2 (18.2) 
N of Severe TEAEs/ 
1/ 
0/ 
0/ 
0/ 
0/ 
1/ 
N of Subjects with Any Severe 
TEAE 
1 (1.9) 
0 
0 
0 
0 
1 (9.1) 
N of SAEs/ 
4/ 
1/ 
0/ 
0/ 
2/ 
1/ 
N of Subjects with Any SAE 
3 (5.6) 
1 (11.1) 
0 
0 
1 (8.3) 
1 (9.1) 
N of TEAEs Leading to 
Discontinuation/ 
2/ 
0/ 
0/ 
0/ 
2/ 
0/ 
N of Subjects with TEAEs 
Leading to Discontinuation 
1 (1.9%) 
0 
0 
0 
1 (8.3) 
0 
1 
A TEAE is defined as any new AE or an existing AE that worsens in severity during or after study drug 
administration. 
2 
Treatment related TEAEs are defined as TEAEs with relationship to probably or possibly related. 
Source: Table 14.3.1 
 
Table 8 
Summary of Serious Adverse Events – (CA-PS-203) 
System Organ Class 
 Preferred Term 
Total Events / N of Subjects with Any Event, n (%) 
Total 
N = 54 
Cohort 1 
Cohorts 2 and 3 
CA-008 
5 mg 
N = 9 
Placebo 
N = 9 
CA-008 
10 mg 
N = 13 
CA-008 
15 mg 
N = 12 
Pooled 
Placebo 
N = 11 
No. of Subjects with any SAE 
3 (5.6) 
1 (11.1) 
0 
0 
1 (8.3) 
1 (9.1) 
General disorders and 
administration site conditions 
1 (1.9) 
0 
0 
0 
0 
1 (9.1) 
Perforated ulcer 
1 (1.9) 
0 
0 
0 
0 
1 (9.1) 
Nervous system disorders 
1 (1.9) 
0 
0 
0 
1 (8.3) 
0 
Cerebrovascular accident 
1 (1.9) 
0 
0 
0 
1 (8.3) 
0 
Seizure 
1 (1.9) 
0 
0 
0 
1 (8.3) 
0 
Vascular disorders 
1 (1.9) 
1 (11.1) 
0 
0 
0 
0 
Deep vein thrombosis 
1 (1.9) 
1 (11.1) 
0 
0 
0 
0 
Source: Table 14.3.1.3 
 
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Table 9 
Summary of TEAEs by MedDRA SOC/PT (CA-PS-203) 
 
Total Events / N of Subjects with Any Event, n (%) 
 
Total 
N = 54 
Cohort 1 
Cohorts 2 and 3 
System Organ Class 
 Preferred Term 
CA-008 
5 mg 
N = 9 
Placebo 
N = 9 
CA-008 
10 mg 
N = 13 
CA-008 
15 mg 
N = 12 
Pooled 
Placebo 
N = 11 
No. of Subjects with any 
TEAE 
45 (83.3) 
7 (77.8) 
7 (77.8) 
12 (92.3) 
10 (83.3) 
9 (81.8) 
Cardiac disorders 
16 (29.6) 
5 (55.6) 
0 
2 (15.4) 
3 (25.0) 
6 (54.5) 
Sinus tachycardia 
16 (29.6) 
5 (55.6) 
0 
2 (15.4) 
3 (25.0) 
6 (54.5) 
Gastrointestinal disorders 
30 (55.6) 
5 (55.6) 
5 (55.6) 
8 (61.5) 
8 (66.7) 
4 (36.4) 
Abdominal distension 
1 (1.9) 
0 
1 (11.1) 
0 
0 
0 
Constipation 
8 (14.8) 
2 (22.2) 
3 (33.3) 
0 
3 (25.0) 
0 
Dyspepsia 
2 (3.7) 
0 
0 
2 (15.4) 
0 
0 
Nausea 
27 (50.0) 
5 (55.6) 
5 (55.6) 
8 (61.5) 
5 (41.7) 
4 (36.4) 
Vomiting 
12 (22.2) 
1 (11.1) 
0 
4 (30.8) 
5 (41.7) 
2 (18.2) 
General disorders and 
administration site conditions 
17 (31.5) 
4 (44.4) 
3 (33.3) 
4 (30.8) 
2 (16.7) 
4 (36.4) 
Application site pain 
2 (3.7) 
0 
2 (22.2) 
0 
0 
0 
Instillation site induration 
1 (1.9) 
1 (11.1) 
0 
0 
0 
0 
Oedema peripheral 
3 (5.6) 
1 (11.1) 
0 
0 
1 (8.3) 
1 (9.1) 
Perforated ulcer 
1 (1.9) 
0 
0 
0 
0 
1 (9.1) 
Peripheral swelling 
1 (1.9) 
0 
0 
0 
0 
1 (9.1) 
Pyrexia 
12 (22.2) 
3 (33.3) 
2 (22.2) 
4 (30.8) 
2 (16.7) 
1 (9.1) 
Infections and infestations 
4 (7.4) 
2 (22.2) 
1 (11.1) 
0 
1 (8.3) 
0 
Respiratory tract infection 
1 (1.9) 
1 (11.1) 
0 
0 
0 
0 
Upper respiratory tract 
infection 
1 (1.9) 
0 
1 (11.1) 
0 
0 
0 
Urinary tract infection 
3 (5.6) 
1 (11.1) 
1 (11.1) 
0 
1 (8.3) 
0 
Injury, poisoning and 
procedural complications 
13 (24.1) 
2 (22.2) 
3 (33.3) 
2 (15.4) 
3 (25.0) 
3 (27.3) 
Contusion 
3 (5.6) 
1 (11.1) 
0 
0 
2 (16.7) 
0 
Deep vein thrombosis 
postoperative 
1 (1.9) 
0 
0 
1 (7.7) 
0 
0 
Incision site vesicles 
1 (1.9) 
0 
0 
0 
0 
1 (9.1) 
Lumbar vertebral fracture 
1 (1.9) 
0 
0 
0 
1 (8.3) 
0 
Post procedural haematoma 
4 (7.4) 
1 (11.1) 
2 (22.2) 
0 
0 
1 (9.1) 
Post procedural haemorrhage 
2 (3.7) 
1 (11.1) 
0 
0 
0 
1 (9.1) 
Post procedural oedema 
3 (5.6) 
1 (11.1) 
1 (11.1) 
1 (7.7) 
0 
0 
Postoperative wound 
complication 
3 (5.6) 
1 (11.1) 
1 (11.1) 
0 
1 (8.3) 
0 
Procedural pain 
2 (3.7) 
0 
0 
0 
1 (8.3) 
1 (9.1) 
Wound secretion 
1 (1.9) 
1 (11.1) 
0 
0 
0 
0 
Investigations 
1 (1.9) 
0 
0 
0 
1 (8.3) 
0 
Electrocardiogram QT 
prolonged 
1 (1.9) 
0 
0 
0 
1 (8.3) 
0 
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Total Events / N of Subjects with Any Event, n (%) 
 
Total 
N = 54 
Cohort 1 
Cohorts 2 and 3 
System Organ Class 
 Preferred Term 
CA-008 
5 mg 
N = 9 
Placebo 
N = 9 
CA-008 
10 mg 
N = 13 
CA-008 
15 mg 
N = 12 
Pooled 
Placebo 
N = 11 
Musculoskeletal and 
connective tissue disorders 
9 (16.7) 
1 (11.1) 
1 (11.1) 
3 (23.1) 
2 (16.7) 
2 (18.2) 
Arthralgia 
4 (7.4) 
0 
1 (11.1) 
1 (7.7) 
1 (8.3) 
1 (9.1) 
Back pain 
1 (1.9) 
0 
0 
0 
0 
1 (9.1) 
Groin pain 
3 (5.6) 
1 (11.1) 
0 
2 (15.4) 
0 
0 
Pain in extremity 
1 (1.9) 
0 
0 
0 
1 (8.3) 
0 
Nervous system disorders 
7 (13.0) 
2 (22.2) 
1 (11.1) 
2 (15.4) 
2 (16.7) 
0 
Allodynia 
1 (1.9) 
0 
1 (11.1) 
0 
0 
0 
Cerebrovascular accident 
1 (1.9) 
0 
0 
0 
1 (8.3) 
0 
Dizziness 
4 (7.4) 
1 (11.1) 
0 
1 (7.7) 
2 (16.7) 
0 
Dysarthria 
1 (1.9) 
0 
0 
0 
1 (8.3) 
0 
Headache 
1 (1.9) 
1 (11.1) 
0 
0 
0 
0 
Paraesthesia 
1 (1.9) 
1 (11.1) 
0 
0 
0 
0 
Seizure 
1 (1.9) 
0 
0 
0 
1 (8.3) 
0 
Tremor 
1 (1.9) 
0 
0 
1 (7.7) 
0 
0 
Psychiatric disorders 
1 (1.9) 
0 
0 
1 (7.7) 
0 
0 
Anxiety 
1 (1.9) 
0 
0 
1 (7.7) 
0 
0 
Renal and urinary disorders 
2 (3.7) 
0 
1 (11.1) 
0 
1 (8.3) 
0 
Pollakiuria 
1 (1.9) 
0 
1 (11.1) 
0 
0 
0 
Urinary retention 
1 (1.9) 
0 
0 
0 
1 (8.3) 
0 
Respiratory, thoracic and 
mediastinal disorders 
2 (3.7) 
0 
0 
1 (7.7) 
1 (8.3) 
0 
Hiccups 
1 (1.9) 
0 
0 
1 (7.7) 
0 
0 
Respiratory depression 
1 (1.9) 
0 
0 
0 
1 (8.3) 
0 
Skin and subcutaneous tissue 
disorders 
9 (16.7) 
0 
3 (33.3) 
2 (15.4) 
3 (25.0) 
1 (9.1) 
Blister 
1 (1.9) 
0 
0 
0 
1 (8.3) 
0 
Erythema 
1 (1.9) 
0 
0 
0 
0 
1 (9.1) 
Hyperhidrosis 
1 (1.9) 
0 
1 (11.1) 
0 
0 
0 
Pruritus 
2 (3.7) 
0 
1 (11.1) 
1 (7.7) 
0 
0 
Pruritus generalised 
3 (5.6) 
0 
1 (11.1) 
0 
2 (16.7) 
0 
Rash 
2 (3.7) 
0 
1 (11.1) 
1 (7.7) 
0 
0 
Surgical and medical 
procedures 
1 (1.9) 
0 
0 
0 
0 
1 (9.1) 
Post procedural drainage 
1 (1.9) 
0 
0 
0 
0 
1 (9.1) 
Vascular disorders 
15 (27.8) 
2 (22.2) 
2 (22.2) 
4 (30.8) 
5 (41.7) 
2 (18.2) 
Deep vein thrombosis 
1 (1.9) 
1 (11.1) 
0 
0 
0 
0 
Hot flush 
1 (1.9) 
0 
1 (11.1) 
0 
0 
0 
Hypertension 
8 (14.8) 
0 
0 
2 (15.4) 
4 (33.3) 
2 (18.2) 
Hypotension 
6 (11.1) 
1 (11.1) 
1 (11.1) 
2 (15.4) 
2 (16.7) 
0 
Source: Table 14.3.1.1 
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A two-part, Phase 1/2, randomized, double-blind, placebo-controlled study has been 
completed (final report pending) in subjects undergoing elective primary unilateral TKA 
(CA-PS-208). 
Part A was an exploratory, sequential, dose-escalation phase in which three doses of CA-008 
were evaluated versus placebo for safety, tolerability, and PK. Each cohort in Part A had 
8 subjects randomized 3:1 to active drug or placebo. Subjects received placebo or CA-008 in 
a 120 mL volume, delivered as 36 mg (0.3 mg/mL), 60 mg (0.5 mg/mL) and 90 mg 
(0.75 mg/mL). 
Two dose levels of CA-008 were chosen in Part B of the study, based on the most effective 
dose (0.3 mg/mL) in a prior positive bunionectomy postsurgical pain study (Study CA-PS-
201). CA-008 was evaluated at doses of 36 mg (delivered as 0.3 mg/mL) and a higher dose 
of 60 mg (delivered as 0.5 mg/mL) compared to placebo in a multicenter randomized, 
double-blind, parallel-group design with a 1:1:1 ratio. 
A total of 193 subjects (mean age 62.3 years) were enrolled in the combined Parts A and B of 
the study, with 61 in the combined 36 mg dose group, 62 in the combined 60 mg dose group, 
6 in the 90 mg dose group, and 64 in the combined placebo group. Results from Part A 
remained blinded until the end of the study and were therefore included with Part B for 
efficacy and safety analyses. Subjects who received 90 mg CA-008 in Part A were included 
in the safety analyses only. 
All doses of CA-008 (36 mg, 60 mg, 90 mg) were well tolerated. Overall, of the 193 subjects 
enrolled and randomized, 184 (95.3%) reported 624 TEAEs (Table 10). Most TEAEs were 
unrelated (96.9%) and all but 7 (3.6%) were mild or moderate in severity. There were no 
stopping-rule pauses during the study to investigate any specific TEAE. No deaths occurred 
during the study or the follow-up period and there were no TEAEs causing early termination 
from the study. 
No meaningful differences were present across treatment groups for the overall summary of 
TEAEs (Table 10).  
Related TEAEs were uncommon during the study and no pattern was observed across 
treatment groups. AEs probably or possibly related to study drug were reported for 2 subjects 
in the CA-008 36 mg group (mild pyrexia); 2 subjects in the CA-008 60 mg group (mild 
pyrexia and mild calf pain) and 2 subjects in the placebo group (mild incision site drainage 
and mild pruritus). All related AEs resolved, typically within a few days after surgery. 
The frequency of subjects with the TEAE of pyrexia was greater in all active treatment 
groups (16% to 33%) compared to the placebo group (6%) without a clear dose-response 
(Table 11). All cases in all groups except for one patient that received placebo were 
considered mild in severity. The AE of pyrexia typically occurred 12-48 hours following 
surgery and represented transient low-grade fever (~99-100°F) without any associated 
abnormal clinical signs or symptoms suggesting a safety concern. During the 12-48 hours 
following surgery, the mean temperature of the groups receiving active drug appeared to be 
about 0.1-0.2°C higher than the placebo-treated group (Post hoc Figure 14.3.3). 
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The frequency of patients with the TEAE of tachycardia showed an apparent dose-response 
across all groups treated with active drug with the frequency in the 36 mg group (22%) 
comparable to that in the placebo group (18%), representing a difference of one patient 
(Table 11). Tachycardia occurred in 17 (27.9%) subjects in the 60 mg group and in 3 (50.0%) 
subjects in the 90 mg group. All cases in all groups were considered mild in severity. The AE 
of tachycardia typically occurred 1-2 days following surgery, lasted 1-2 days and resolved 
without intervention. Tachycardia was not associated with any other abnormal clinical signs 
or symptoms or other AEs suggesting a safety concern.  
The frequency of patients with the TEAE of drug ineffective was higher in the group that 
received placebo (10%) than in the groups that received 36 or 60 mg of active drug (5%; 
Table 11).  
Five SAEs occurred during the study (Table 10); however, none of these events were related 
to study drug. In the CA-008 36 mg group, there was one event each of myocardial infarction 
and knee postoperative haematoma; in the CA-008 60 mg group one subject had an allergic 
reaction to lisinopril; and in the placebo group, there was one event each of pulmonary 
embolus and post procedural haematoma. 
There were no meaningful differences across the treatment groups for assessments of wound 
healing of the surgical site or neurosensory evaluations. 
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Table 10 
Summary of Treatment-Emergent Adverse Events (for Study CA-PS-208) 
No. of Subjects 
Total 
(N = 193)n 
(%) 
CA-008 
Placebo 
N = 37 
n (%) 
36 mg  
N = 60 
n (%) 
60 mg  
N = 61 
n (%) 
90 mg  
N = 6 
n (%) 
Number of TEAEs 
624 
194 
199 
24 
207 
Number (%) of subjects with at least 
one AE1 
184 (95.3%) 
54 (90.0%) 
58 (95.1%) 
6 (100.0%) 
66 (100.0%) 
Number of treatment related AEs 
6 
2 
2 
0 
2 
Number (%) of subjects with at least 
one treatment related TEAE2 
6 (3.1%) 
2 (3.3%) 
2 (3.3%) 
0 
2 (3.0%) 
Number of severe AEs3 
7 
2 
2 
1 
2 
Number (%) of subjects with severe, 
life-threatening or fatal TEAEs 
7 (3.6%) 
2 (3.3%) 
2 (3.3%) 
1 (16.7%) 
2 (3.0%) 
Number of SAEs 
5 
2 
1 
0 
2 
Number (%) of subjects with at least 
one SAE 
5 (2.6%) 
2 (3.3%) 
1 (1.6%) 
0 
2 (3.0%) 
Number of TEAEs leading to 
discontinuation 
0 
0 
0 
0 
0 
Number (%) of subjects with TEAEs 
leading to discontinuation 
0 
0 
0 
0 
0 
Abbreviations: AE = adverse event; SAE = serious adverse event; TEAE = treatment emergent adverse event. 
Note: Events with missing severity were imputed as severe. Events with missing relationship were imputed as probably related. Percentages are based on subjects in the Safety 
population. For subject counts, if a subject experienced 1 or more events, they were counted only once. 
1 
A TEAE is defined as any new AE or an existing AE that worsens in severity during or after study drug administration. 
2 
Treatment related TEAEs are defined as TEAEs with relationship of probably or possibly related. 
3 
No life-threatening or fatal TEAEs occurred. 
Source: Study CA-PS-208 Table 14.3.1.1; Listing 16.2.7.1. 
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Table 11 
Summary of Treatment Emergent Adverse Events Occurring in ≥10% Subjects by System Organ Class and 
Preferred Term for Study CA-PS-208 
System Organ Class 
Preferred Term 
Total (N = 193) 
n (%) 
CA-008 
Placebo 
N = 66 
n (%) 
36 mg  
N = 60 
n (%) 
60 mg  
N = 61 
n (%) 
90 mg  
N = 6 
n (%) 
Number of subjects with at least one TEAE1  
184 (95.3%) 
54 (90.0%) 
58 (95.1%) 
6 (100.0%) 
66 (100.0%) 
Gastrointestinal disorders 
138 (71.5%) 
39 (65.0%) 
45 (73.8%) 
6 (100.0%) 
48 (72.7%) 
Abdominal pain 
1 (0.5%) 
0 
1 (1.6%) 
0 
0 
Constipation 
95 (49.2%) 
29 (48.3%) 
32 (52.5%) 
4 (66.7%) 
30 (45.5%) 
Diarrhoea 
1 (0.5%) 
0 
1 (1.6%) 
0 
0 
Dyspepsia 
1 (0.5%) 
1 (1.7%) 
0 
0 
0 
Flatulence 
1 (0.5%) 
0 
1 (1.6%) 
0 
0 
Lip Swelling 
1 (0.5%) 
0 
1 (1.6%) 
0 
0 
Nausea 
93 (48.2%) 
24 (40.0%) 
28 (45.9%) 
5 (83.3%) 
36 (54.5%) 
Vomiting 
36 (18.7%) 
9 (15.0%) 
11 (18.0%) 
1 (16.7%) 
15 (22.7%) 
Cardiac disorders 
58 (30.1%) 
17 (28.3%) 
20 (32.8%) 
3 (50.0%) 
18 (27.3%) 
Atrial fibrillation 
1 (0.5%) 
0 
0 
0 
1 (1.5%) 
Bradycardia 
12 (6.2%) 
3 (5.0%) 
4 (6.6%) 
0 
5 (7.6%) 
Myocardial infarction 
1 (0.5%) 
1 (1.7%) 
0 
0 
0 
Supraventricular tachycardia 
1 (0.5%) 
0 
1 (1.6%) 
0 
0 
Tachycardia 
45 (23.3%) 
13 (21.7%) 
17 (27.9%) 
3 (50.0%) 
12 (18.2%) 
General disorders and administrative site 
conditions 
47 (24.4%) 
18 (30.0%) 
15 (24.6%) 
3 (50.0%) 
11 (16.7%) 
Chills 
2 (1.0%) 
1 (1.7%) 
1 (1.6%) 
0 
0 
Drug ineffective 
14 (7.3%) 
3 (5.0%) 
3 (4.9%) 
1 (16.7%) 
7 (10.6%) 
Infusion site pruritus 
1 (0.5%) 
0 
0 
0 
1 (1.5%) 
Injection site bruising 
1 (0.5%) 
1 (1.7%) 
0 
0 
0 
Injection site pain 
1 (0.5%) 
0 
1 (1.6%) 
0 
0 
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System Organ Class 
Preferred Term 
Total (N = 193) 
n (%) 
CA-008 
Placebo 
N = 66 
n (%) 
36 mg  
N = 60 
n (%) 
60 mg  
N = 61 
n (%) 
90 mg  
N = 6 
n (%) 
Injection site swelling 
1 (0.5%) 
0 
1 (1.6%) 
0 
0 
Non-cardiac chest pain 
1 (0.5%) 
0 
1 (1.6%) 
0 
0 
Oedema peripheral 
1 (0.5%) 
0 
0 
0 
1 (1.5%) 
Peripheral swelling  
7 (3.6%) 
5 (8.3%) 
1 (1.6%) 
0 
1 (1.5%) 
Pyrexia 
28 (14.5%) 
12 (20.0%) 
10 (16.4%) 
2 (33.3%) 
4 (6.1%) 
Nervous system disorders 
41 (21.2%) 
15 (25.0%) 
11 (18.0%) 
2 (33.3%) 
13 (19.7%) 
Dizziness 
19 (9.8%) 
8 (13.3%) 
2 (3.3%) 
2 (33.3%) 
7 (10.6%) 
Headache 
17 (8.8%) 
5 (8.3%) 
7 (11.5%) 
0 
5 (7.6%) 
Hypoaesthesia 
4 (2.1%) 
1 (1.7%) 
2 (3.3%) 
0 
1 (1.5%) 
Sinus headache 
1 (0.5%) 
1 (1.7%) 
0 
0 
0 
Tremor 
1 (0.5%) 
1 (1.7%) 
0 
0 
0 
Skin and subcutaneous tissue disorders 
37 (19.2%) 
10 (16.7%) 
10 (16.4%) 
2 (33.3%) 
15 (22.7%) 
Blister 
2 (1.0%) 
1 (1.7%) 
0 
0 
1 (1.5%) 
Ecchymosis 
1 (0.5%) 
1 (1.7%) 
0 
0 
0 
Erythema 
1 (0.5%) 
1 (1.7%) 
0 
0 
0 
Pruritus 
29 (15.0%) 
7 (11.7%) 
9 (14.8%) 
2 (33.3%) 
11 (16.7%) 
Rash 
5 (2.6%) 
0 
2 (3.3%) 
0 
3 (4.5%) 
Skin induration 
1 (0.5%) 
0 
0 
0 
1 (1.5%) 
Urticaria 
1 (0.5%) 
0 
1 (1.6%) 
0 
0 
Musculoskeletal and connective tissue 
disorder 
27 (14.0%) 
10 (16.7%) 
8 (13.1%) 
1 (16.7%) 
8 (12.1%) 
Arthralgia 
4 (2.1%) 
0 
1 (1.6%) 
0 
3 (4.5%) 
Back pain 
2 (1.0%) 
1 (1.7%) 
1 (1.6%) 
0 
0 
Groin pain 
2 (1.0%) 
1 (1.7%) 
1 (1.6%) 
0 
0 
Intervertebral disc protrusion 
1 (0.5%) 
1 (1.7%) 
0 
0 
0 
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System Organ Class 
Preferred Term 
Total (N = 193) 
n (%) 
CA-008 
Placebo 
N = 66 
n (%) 
36 mg  
N = 60 
n (%) 
60 mg  
N = 61 
n (%) 
90 mg  
N = 6 
n (%) 
Joint stiffness 
1 (0.5%) 
0 
1 (1.6%) 
0 
0 
Muscle spasms 
3 (1.6%) 
1 (1.7%) 
1 (1.6%) 
0 
1 (1.5%)0 
Musculoskeletal pain 
1 (0.5%) 
0 
1 (1.6%) 
0 
0 
Musculoskeletal stiffness 
1 (0.5%) 
1 (1.7%) 
0 
0 
0 
Myalgia 
1 (0.5%) 
0 
0 
0 
1 (1.5%) 
Pain in extremity 
16 (8.3%) 
5 (8.3%) 
5 (8.2%) 
1 (16.7%) 
5 (7.6%) 
Respiratory, thoracic and mediastinal 
disorders 
21 (10.9%) 
6 (10.0%) 
8 (13.1%) 
1 (16.7%) 
6 (9.1%) 
Bradypnoea 
1 (0.5%) 
0 
1 (1.6%) 
0 
0 
Cough 
1 (0.5%) 
0 
0 
0 
1 (1.5%) 
Dyspnoea 
1 (0.7%) 
0 
0 
0 
1 (1.5%) 
Hypoxia 
12 (6.2%) 
4 (6.7%) 
4 (6.6%) 
1 (16.7%) 
3 (4.5%) 
Oropharyngeal pain 
5 (2.6%) 
2 (3.3%) 
3 (4.9%) 
0 
0 
Pulmonary embolism 
1 (0.7%) 
0 
0 
0 
1 (1.5%) 
Vascular disorders 
21 (10.9%) 
7 (11.7%) 
6 (9.8%) 
0 
8 (12.1%) 
Deep vein thrombosis 
1 (0.5%) 
0 
0 
0 
1 (1.5%) 
Diastolic hypotension 
3 (1.6%) 
2 (3.3%) 
0 
0 
1 (1.5%) 
Haematoma 
3 (1.6%) 
0 
2 (3.3%) 
0 
1 (1.5%) 
Hypertension 
12 (6.2%) 
3 (5.0%) 
5 (8.2%) 
0 
4 (6.1%) 
Hypotension 
3 (1.6%) 
2 (3.3%) 
0 
0 
1 (1.5%) 
Source: Study CA-PS-208 Table 14.3.1.2 
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5.3.2 
Pharmacokinetic Exposures in Prior Clinical Studies 
Rich pharmacokinetic data has been collected at defined timepoints following the completion 
of CA-008 instillation or infiltration in each of the previous studies. Due to the inherent low 
levels of pH-labile prodrug expected systemically and limits of detection, the CA-008 
parameters are less well defined in the studies with lower CA-008 doses. Generally, CA-008 
has a rapid Tmax (< 0.25 hr) following the end of infusion. The capsaicin and CA-101 Tmax 
occur between approximately 0.2 to 1.5 hours after the end of administration. In preliminary 
results from CS-PS-208 (TKA) clinical study, CA-008 had a half-life of less than 0.2 hours 
in most cases. Topically applied capsaicin has an elimination half-life of 1.64 hours (Babbar 
et al., 2009). The t1/2 for capsaicin ranges from approximately 0.5 to 1.5 hours. CA-101 mean 
t1/2 ranges from approximately 1.5 to 2 hours (Table 12, Table 13, Table 14).  
CA-PS-201 (BUN) (CA-008 doses between 0.7 and 4.2 mg): When dose normalized, Cmax 
appeared to be dose proportional based on visual comparison of the box plots for CA-008, 
capsaicin and CA-101. CA-008 AUC0-t appeared to be dose proportional while CA-101 and 
capsaicin AUC0-t appeared to be slightly greater than dose proportional. Note a similar trend 
was observed in the bunionectomy study, CA-PS-2017-101 (CA-008 doses between 0.5 and 
4.2 mg [Table 13, Table 14]).  
CA-PS-203 (TKA) (CA-008 doses between 5 and 15 mg): CA-008 Cmax and AUC0-tt were 
low and not significantly different across dose groups. Capsaicin and CA-101 exposures 
appeared to be dose proportional based on visualization of the box plot between 5 and 15 mg, 
but the 10 mg dose group appeared to have greater variability (Table 13). 
CA-PS-204 (ABD) (CA-008 doses between 5 to 15 mg): Proportionality of CA-008 was 
difficult to determine due to many time points having values below the limits of quantitation. 
CA-101 Cmax increased proportionally with dose. AUC0-t for capsaicin and CA-101 appeared 
to be dose proportional, given the intercohort variability (Table 13). 
CA-PS-208 (TKA): (CA-008 doses between 36 and 90 mg): When normalized to dose, CA-008 
exposure at 90 mg was disproportionally higher than 36 and 60 mg. CA-101 and capsaicin 
exposure increased with increasing dose. When normalized to dose, Cmax and AUC0-t were 
approximately consistent at 36 and 90 mg, with the 60 mg mean Cmax and AUC0-t to dose ratios 
less than expected (Table 14). 
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Table 12 
Summary of PK Parameters by Dose Cohort for Study CA-PS-2017-101 (BUN) and CA-PS-201 (BUN): 0.5 
to 4.2 mg 
Study 
 
Dose 
 
 
CA-008 
Capsaicin 
CA-101 
Statistics 
tmax 
(hr) 
Cmax 
(ng/mL) 
AUC0-t 
(hr•ng/mL) 
t1/2 
(hr) 
tmax 
(hr) 
Cmax 
(ng/mL) 
AUC0-t 
(hr•ng/mL) 
t1/2 
(hr) 
tmax 
(hr) 
Cmax 
(ng/mL) 
AUC0-t 
(hr•ng/mL) 
t1/2 
(hr) 
 
0.5 
mg 
 
N 
3 
3 
0 
0 
6 
6 
6 
3 
6 
6 
6 
1 
 
Mean 
– 
0.0668 
NC 
NC 
– 
0.370 
0.566 
0.685 
– 
0.850 
1.69 
2.57 
CA-
PS-
2017-
101 
(BUN) 
SD 
– 
0.06 
NC 
NC 
– 
0.133 
0.312 
0.248 
– 
0.305 
1.80 
NC 
CV% 
– 
89.7 
NC 
NC 
– 
35.9 
55.2 
36.2 
– 
35.9 
107 
NC 
1 mg 
 
N 
3 
3 
2 
0 
6 
6 
6 
1 
6 
6 
6 
1 
Mean 
– 
0.142 
0.0524 
NC 
– 
0.374 
0.666 
0.703 
– 
1.07 
2.79 
1.96 
SD 
– 
0.0997 
0.0362 
NC 
– 
0.193 
0.294 
NC 
– 
0.256 
1.24 
NC 
CV% 
– 
69.9 
69 
NC 
– 
51.5 
44.2 
NC 
– 
24 
44.6 
NC 
2 mg 
 
N 
5 
5 
3 
0 
6 
6 
6 
4 
6 
6 
6 
3 
Mean 
– 
0.155 
0.0395 
NC 
– 
1.05 
1.46 
1.07 
– 
2.19 
5.4 
1.26 
SD 
– 
0.0586 
0.00936 
NC 
– 
0.532 
0.722 
0.765 
– 
0.445 
1.65 
0.514 
CV% 
– 
37.8 
23.7 
NC 
– 
50.5 
49.4 
71.1 
– 
20.4 
30.6 
40.7 
3 mg 
 
N 
6 
6 
5 
0 
6 
6 
6 
5 
6 
6 
6 
3 
Mean 
– 
0.247 
0.0925 
NC 
– 
1.52 
2.68 
0.743 
– 
4.26 
9.53 
1.10 
SD 
– 
0.337 
0.116 
NC 
– 
0.504 
0.828 
0.201 
– 
0.502 
1.95 
0.286 
CV% 
– 
136 
125 
NC 
– 
33.1 
30.9 
27.1 
– 
11.8 
20.4 
26.1 
4.2 
mg 
 
N 
6 
6 
6 
1 
6 
6 
6 
4 
6 
6 
6 
5 
Mean 
– 
0.572 
0.260 
0.167 
– 
2.42 
4.07 
0.843 
– 
8.91 
46.7 
2.41 
SD 
– 
0.407 
0.176 
NC 
– 
1.82 
1.74 
0.355 
– 
5.66 
69.4 
2.23 
 
CV% 
– 
71.2 
67.6 
NC 
– 
75.4 
42.9 
42.2 
– 
63.6 
149 
92.4 
 
0.7 
mg 
 
N 
12 
12 
10 
0 
12 
12 
12 
9 
12 
12 
12 
7 
 
Mean 
NC 
0.108 
0.0272 
NC 
NC 
0.723 
0.734 
0.760 
NC 
1.06 
1.73 
1.82 
 
CA-
PS-
201 
(BUN) 
 
SD 
NC 
0.100 
0.0169 
NC 
NC 
0.405 
0.285 
0.474 
NC 
0.442 
0.955 
0.709 
CV% 
NC 
92.5 
62 
NC 
NC 
56.1 
38.8 
62.3 
NC 
41.6 
57.1 
39 
2.1 
mg 
 
N 
13 
13 
13 
1 
13 
13 
13 
13 
13 
13 
13 
12 
Mean 
NC 
0.216 
0.0653 
0.248 
NC 
2.59 
3.32 
1.53 
NC 
2.95 
7.73 
1.82 
SD 
NC 
0.171 
0.0521 
NC 
NC 
1.62 
1.60 
0.777 
NC 
1.04 
3.50 
1.08 
CV% 
NC 
79.2 
79.8 
NC 
NC 
62.6 
48.1 
50.8 
NC 
35.4 
45.3 
59.4 
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Study 
 
Dose 
 
 
CA-008 
Capsaicin 
CA-101 
Statistics 
tmax 
(hr) 
Cmax 
(ng/mL) 
AUC0-t 
(hr•ng/mL) 
t1/2 
(hr) 
tmax 
(hr) 
Cmax 
(ng/mL) 
AUC0-t 
(hr•ng/mL) 
t1/2 
(hr) 
tmax 
(hr) 
Cmax 
(ng/mL) 
AUC0-t 
(hr•ng/mL) 
t1/2 
(hr) 
 4.2 
mg 
 
N 
14 
14 
14 
4 
14 
14 
14 
13 
14 
14 
14 
11 
Mean 
NC 
0.502 
0.149 
0.185 
NC 
4.87 
7.02 
1.38 
NC 
6.52 
18.9 
1.58 
SD 
NC 
0.414 
0.125 
0.0367 
NC 
2.43 
2.48 
0.505 
NC 
2.22 
6.64 
0.534 
 
CV% 
NC 
82.3 
84.3 
19.8 
NC 
49.9 
35.3 
36.5 
NC 
34 
35.1 
33.9 
 
Table 13 
Summary of PK Parameters by Dose Cohort for Study CA-PS-203 (TKA) and CA-PS-204 (ABD): 5 to 15 mg  
 Dose 
Statistics 
CA-008 
Capsaicin 
CA-101 
Tmax 
(hr) 
Cmax 
(ng/mL) 
AUC0-t 
(hr•ng/mL) 
t1/2 (hr) 
Tmax 
(hr) 
Cmax 
(ng/mL) 
AUC0-t 
(hr•ng/mL) 
t1/2 (hr) 
Tmax 
(hr) 
Cmax 
(ng/mL) 
AUC0-t 
(hr•ng/mL) 
t1/2 
(hr) 
CA-PS-203 (TKA) 
5 mg 
N 
- 
9 
9 
- 
9 
9 
9 
9 
9 
9 
9 
8 
Mean 
- 
0.524 
0.0660 
- 
NR 
9.09 
6.46 
0.878 
NR 
9.65 
22.5 
1.91 
SD 
- 
0.475 
0.113 
- 
NR 
5.54 
3.54 
0.466 
NR 
2.89 
8.51 
0.613 
Min 
- 
0.108 
0.00483 
- 
0.17 
1.82 
3.16 
0.492 
0.50 
5.8 
10.2 
1.30 
Median 
- 
0.424 
0.0156 
- 
0.23 
7.90 
5.28 
0.709 
0.73 
8.89 
23.6 
1.82 
Max 
- 
1.40 
0.337 
- 
0.50 
18.6 
12.8 
1.93 
2.0 
15.6 
38.5 
3.29 
 10 mg 
N 
- 
13 
12 
- 
13 
13 
13 
13 
13 
13 
13 
13 
Mean 
- 
1.63 
0.345 
- 
NR 
23.9 
18.8 
1.46 
NR 
29.8 
80.6 
1.92 
SD 
- 
1.80 
0.310 
- 
NR 
14.5 
8.83 
0.620 
NR 
15.1 
35.4 
0.485 
Min 
- 
0 
0.0347 
- 
0.22 
3.12 
2.80 
0.812 
0.28 
19 
40.0 
1.20 
Median 
- 
1.11 
0.243 
- 
0.32 
20.7 
18.3 
1.19 
0.50 
26.7 
73.9 
1.84 
Max 
- 
6.08 
0.970 
- 
0.83 
48.5 
35.1 
3.02 
1.4 
68.1 
170 
3.15 
15 mg 
N 
12 
12 
12 
2 
12 
12 
12 
12 
12 
12 
12 
12 
Mean 
- 
0.569 
0.116 
- 
NR 
21.0 
20.9 
1.61 
NR 
28.8 
75.5 
1.96 
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 Dose 
Statistics 
CA-008 
Capsaicin 
CA-101 
Tmax 
(hr) 
Cmax 
(ng/mL) 
AUC0-t 
(hr•ng/mL) 
t1/2 (hr) 
Tmax 
(hr) 
Cmax 
(ng/mL) 
AUC0-t 
(hr•ng/mL) 
t1/2 (hr) 
Tmax 
(hr) 
Cmax 
(ng/mL) 
AUC0-t 
(hr•ng/mL) 
t1/2 
(hr) 
SD 
- 
0.492 
0.0985 
- 
NR 
13.5 
10.6 
0.586 
NR 
9.16 
28.2 
0.654 
Min 
- 
0.0594 
0.0104 
- 
0.050 
4.27 
6.60 
0.594 
0.13 
15.7 
41.9 
1.12 
Median 
NR 
0.378 
0.111 
NR 
0.39 
20.6 
20.7 
1.51 
0.57 
28.2 
66.4 
1.75 
Max 
NR 
1.66 
0.292 
NR 
1.0 
50.1 
35.9 
2.62 
1.0 
44.6 
129 
3.25 
CA-PS-204 (ABD) 
5 mg 
N 
- 
9 
9 
- 
9 
9 
9 
9 
9 
9 
8 
8 
Mean 
- 
2.60 
0.321 
- 
0.21 
14.1 
10.5 
0.951 
0.40 
19.3 
47.6 
1.12 
SD 
- 
1.25 
0.193 
- 
0.13 
4.78 
3.98 
0.261 
0.27 
8.26 
11.8 
0.210 
Min 
- 
0.0313 
0.00809 
- 
0.083 
8.35 
6.16 
0.577 
0 
0 
36.4 
0.826 
Median 
- 
2.96 
0.286 
- 
0.17 
14.2 
9.06 
0.938 
0.47 
19.9 
43.9 
1.14 
Max 
- 
3.84 
0.629 
- 
0.52 
21.9 
18.0 
1.50 
0.77 
31.1 
67.4 
1.39 
10 mg 
N 
- 
12 
12 
- 
12 
12 
12 
12 
12 
12 
12 
11 
Mean 
- 
5.62 
0.619 
- 
0.19 
28.0 
22.0 
1.23 
0.65 
46.8 
136 
1.71 
SD 
- 
4.10 
0.532 
- 
0.12 
13.5 
9.49 
0.356 
0.78 
10.7 
121 
1.11 
Min 
- 
1.97 
0.210 
- 
0.067 
12.7 
12.3 
0.600 
0.17 
28.0 
54.5 
0.880 
Median 
- 
3.66 
0.328 
- 
0.18 
26.4 
18.4 
1.32 
0.50 
47.6 
97.9 
1.26 
Max 
- 
15.0 
1.82 
- 
0.5 
53.8 
41.2 
1.82 
3.0 
68.9 
489 
4.64 
15 mg 
N 
12 
12 
12 
7 
12 
12 
12 
12 
12 
12 
12 
12 
Mean 
0.11 
6.00 
0.773 
0.111 
0.17 
43.3 
32.9 
1.57 
0.32 
65.2 
147 
1.24 
SD 
0.034 
3.81 
0.493 
0.0328 
0.068 
16.5 
8.78 
0.551 
0.14 
24.5 
113 
0.415 
Min 
0.067 
1.04 
0.139 
0.0777 
0.067 
20.2 
19.6 
0.628 
0.10 
47.6 
71.9 
0.752 
Median 
0.1 
5.79 
0.793 
0.103 
0.17 
42.4 
32.8 
1.59 
0.26 
58.7 
121 
1.14 
Max 
0.18 
11.7 
1.68 
0.177 
0.28 
77.5 
49.8 
2.55 
0.52 
140 
501 
2.41 
 
 
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Table 14 
Summary of PK Parameters by Dose Cohort for Study CA-PS-208: 36 to 90 mg 
Dose 
  
Statistic 
 
CA-008 
Capsaicin 
CA-101 
Tmax 
Cmax 
AUC0-t 
Half-life 
Tmax 
Cmax 
AUC0-t 
Half-life 
Tmax 
Cmax 
AUC 0-t 
Half-life 
(h) 
(ng/mL) 
(h*ng/mL) 
(h) 
(h) 
(ng/mL) 
(h*ng/mL) 
(h) 
(h) 
(ng/mL) 
(h*ng/mL) 
(h) 
36 mg 
  
  
  
  
  
N 
15 
15 
15 
2 
15 
15 
15 
15 
15 
15 
15 
15 
Mean 
0.42 
3.64 
0.937 
0.148 
0.54 
51.4 
62.8 
2.65 
1.0 
68.9 
220 
1.73 
SD 
0.25 
4.58 
1.28 
0.0761 
0.21 
32.7 
27.6 
0.947 
0.60 
29 
68 
0.337 
CV% 
58.9 
125.8 
137 
51.5 
42.8 
63.6 
43.9 
35.7 
59.9 
42.1 
30.9 
19.5 
60 mg 
  
  
  
  
  
N 
14 
14 
14 
7 
14 
14 
14 
14 
14 
14 
14 
14 
Mean 
0.26 
5.99 
1.47 
0.514* 
0.54 
59.1 
91 
2.52 
0.91 
86.1 
281 
1.94 
SD 
0.12 
8.65 
2.54 
0.598 
0.36 
27.3 
42.1 
1.04 
0.44 
38.1 
105 
0.498 
CV% 
46.5 
144.5 
172.2 
116.3 
66.1 
46.2 
46.3 
41.4 
48.9 
44.3 
37.4 
25.6 
90 mg 
  
  
  
  
  
N 
6 
6 
6 
5 
6 
6 
6 
6 
6 
6 
6 
6 
Mean 
0.22 
15.8 
4.56 
0.145 
0.37 
108 
183 
3.67 
1.0 
170 
489 
1.44 
SD 
0.039 
12.3 
3.77 
0.0288 
0.17 
63 
91.3 
1.7 
0.44 
45.6 
209 
0.196 
CV% 
18.2 
78.1 
82.7 
19.9 
47.2 
58.5 
49.9 
46.2 
41.7 
26.9 
42.7 
13.6 
*two subjects had low but persistent CA-008 past 0.5 hours, resulting in a longer half-life calculation than most subjects. 
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5.3.3 
Estimated Exposures in VHR/Soft Tissue  
In the current study, a dose of 15 and 30 mg CA-008 may be explored initially. 
The projected PK data for a 15 mg dose (50 mL of 0.3 mg/ml solution) of CA-008 in patients 
undergoing ventral hernia repair (CA-PS-209) is expected to be similar to the PK profile for a 15 
mg dose of CA-008 in patients undergoing abdominoplasty (CA-PS-204). There are no reasons 
to expect the safety profile of a 15 mg dose in these two similar surgeries to be different, and the 
safety profile of the 15 mg dose was indistinguishable from placebo in CA-PS-204. As such, the 
Sponsor considers a starting dose of 15 mg of CA-008 in CA-PS-209 to be safe and appropriate 
with escalation to up to 30 mg (0.3 mg/ml in 100 mL).  
Table 15 includes the 15 mg exposure observed in CA-PS-203 (TKA), the 36-90 mg exposure in 
observed in CA-PS-208 (TKA; part A and B, preliminary data), and the 15 mg exposure 
observed in an abdominoplasty study, CA-PS-204 (ABD). The table also includes exposures 
predicted in CA-PS-209 (VHR) at 15 and 30 mg. 
It is assumed that a 15 mg dose of CA-008 in CA-PS-209 will lead to exposures similar to that 
observed in the abdominoplasty surgery, CA-PS-204. Both are soft tissue surgeries and both 
locations are similarly vascularized. To fully characterize the absorption phase in CA-PS-209, 
unlike in CA-PS-204, PK will be collected during dosing. This may impact the determination of 
Tmax and Cmax. To predict exposure at 30 mg, dose proportionality from 15 mg to 30 mg was 
assumed for CA-008 and CA-101. Capsaicin exposures were also independently modeled from 
PS-204 data PK. A two-compartment model with linear elimination and zero-order absorption 
adequately fit the observed capsaicin concentrations in women undergoing abdominoplasty. A 
Monte-Carlo simulation (via R) was performed for delivery of 30 mg CA-008 in a total of 1000 
virtual healthy subjects per dose level. 
As shown in Table 15, a dose of 15 mg is expected to produce exposures to CA-008, CA-101 
and capsaicin that are less than exposures from the 60 mg dose in CA-PS-208 (TKA), a dose 
shown to be safe. A dose of 30 mg is expected to produce exposures to CA-008, CA-101 and 
capsaicin that are less than exposures from the 90 mg dose in CA-PS-208 (TKA), a dose shown 
preliminarily to be safe. The 30 mg dose will not be administered unless the safety assessment of 
the 15 mg dose is supportive.  
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Table 15 
Supporting exposure data for administration of CA-008 up to 36 mg (0.3 mg/ml) in CA-PS-209 
Concentric 
Study 
Type of 
Study 
Dose 
(mg/kg) 
CA-008 
Cmax (ng/mL) 
CA-008 
AUC0-t 
(ng*h/mL) 
CA-101 
Cmax (ng/mL) 
CA-101 
AUC0-t (ng*h/mL) 
Cap 
Cmax (ng/mL) 
Cap 
AUC0-t 
(ng*h/mL) 
Previous Human Exposure 
15 mg CA-
PS-203  
TKA 
15 mg 
0.569 (±0.492, 
%CV 86.4)a 
0.116 (±0.985, 
%CV 84.7)a 
28.8 (±9.16,  
%CV 31.9) 
75.5 (±28.2,  
%CV 37.4) 
21 (±13.5,  
%CV 64.2) 
20.9 (±10.6, 
 %CV 50.8) 
15 mg CA-
PS-204  
ABD 
15 mg 
6 (±3.81, 
 %CV 63.6) 
0.773 (±0.493, 
%CV 63.8) 
65.2 (±24.5,  
%CV 37.7) 
147 (±113,  
%CV 77.1) 
43.3 (±16.5,  
%CV 38.2) 
32.9 (±8.78, 
 %CV 26.7) 
36 mg CA-
PS-208  
TKA 
36 mg 
3.64 (±4.58,  
%CV 125.8) 
0.937 (±1.28, 
%CV 137.0) 
68.9 (±29.0,  
%CV 42.1) 
220 (±68.0, 
 %CV 30.9) 
51.4 (±32.7, 
 %CV 63.6) 
62.8 (±27.6, 
 %CV 43.9) 
60 mg CA-
PS-208  
TKA 
60 mg 
5.99 (±8.65, 
 %CV 144.5) 
1.47 (±2.54, 
%CV 172.2) 
86.1 (±38.1,  
%CV 44.3) 
281 (±105, 
 %CV 37.4) 
59.1 (±27.3, 
 %CV 46.2) 
91.0 (±42.1,  
%CV 46.3) 
90 mg CA-
PS-208  
TKA 
90 mg 
15.8 (±12.3,  
%CV 78.1) 
4.56 (±3.77, 
%CV 82.7) 
170 (±45.6,  
%CV 26.9) 
489 (±209,  
%CV 42.7) 
108 (±63.0,  
%CV 58.5) 
183 (±91.3, 
 %CV 49.9) 
 
Predicted Human Exposure in CA-PS-209 (VHR) 
15 mg soft 
tissue  
(Same as 
CA-PS-
204) 
VHR / 
Soft tissue 
15 mg  
6 (±3.81, 
%CV 63.6)b 
0.77 (±0.493, 
%CV 63.8)b 
65.2 (±24.5,  
%CV 37.7)b 
147 (±113,  
%CV 77.1)b 
 
43.3 (±16.5, 
 %CV 38.2)b 
32.9 (±8.78,  
%CV 26.7)b 
30 mg soft 
tissue, 
projected 
VHR 
/Soft 
tissue 
30 mg  
12c 
1.55c 
130c 
294c 
96.8 (±29.4,  
%CV 30.4)d 
96.3 (±24,  
%CV 24.9)d 
a 
Many subjects had ≤ 3 quantifiable CA-008 time points thus there may be some error in the reporting of Cmax and AUC0-t.  
b 
Same as PS-204 
c 
Exposure in soft tissues scaled from CA-PS-204: 15 mg Cmax CA-PS-204 x 2 or AUC0-t_CA-PS-204 x 2  
d 
Exposure modeled and simulated: a population PK analysis of capsaicin was performed based on data collected in CA-PS-204. A two-compartment model 
with linear elimination and zero-order absorption adequately fit the observed concentrations in female undergoing abdominoplasty. Monte-Carlo simulations 
(via R) were performed for an infiltration of 30 and 60 mg CA-008 in a total of 1000 virtual healthy subjects per dose level. Rich capsaicin concentrations 
were simulated after a single dose up to 24 hours to derive the following: Cmax, AUC0-t (mean, SD, %CV) 
  
 
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Table 16 
Exposure from PS-208 vs. Predicted Exposures in Soft Tissue 
Proposed Soft Tissue Dose 
CA-008 Cmax 
ratioa 
CA-008 AUC0-t 
ratioa 
CA-101 
Cmax ratioa 
CA-101 AUC0-t 
ratioa 
Capsaicin 
Cmax 
ratioa 
Capsaicin 
AUC0-t 
ratioa 
Observed 60 mg exposure in CA-PS-208 (TKA) / predicted exposure in VHR 
15 mg 
1.0 
1.9 
1.3 
1.9 
1.3 
2.6 
30 mg 
0.5 
0.9 
0.7 
1.0 
0.6 
0.9 
Observed 90 mg exposure in CA-PS-208 (TKA)/ / predicted exposure in VHR 
15 mg 
2.6 
5.9 
2.6 
3.3 
2.5 
5.6 
30 mg 
1.3 
2.9 
1.3 
1.7 
1.1 
1.9 
Cells in grey indicate exposure in soft tissue is predicted to be less than that at 60 or 90 mg in CA-PS-208 
a 
Table 15 was used to calculate the ratio. 
 
5.3.4 
Preclinical Supporting Data 
Preclinical NOAEL exposures are presented in Table 17 along with human equivalent dose (HED). Two pivotal GLP toxicology 
studies are presented: dog study CA-NC-008-TOX-019-CR and rat study CA-NC-008-TOX-0179-CR. Another GLP rat study CA-
NC-008-RT-003-CO is also presented. It is a repeat dose EFD study and thus has slightly higher rat exposures, though it is 
acknowledged that this study is not a general toxicology study with histology. On a dose basis, the GLP dog single dose toxicology 
study (CA-NC-008-TOX-019-CR) supports human dosing up to 100 mg in a 60 kg human.  
 
 
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Table 17 
Nonclinical Exposures and HED in Dog and Rat following SC administration of CA-008 
Concentric 
Study 
Type of 
Study 
Species 
Dose 
Frequency 
NOAEL 
Dose 
(mg/kg) 
CA-008 
HCl 
CA-008 
Cmax 
(ng/mL) 
CA-008 
AUC0-t 
(ng*h/mL) 
CA-101 
Cmax 
(ng/mL) 
CA101 
AUC0-t 
(ng*h/mL) 
Cap Cmax 
(ng/mL) 
Cap 
AUC0-t 
(ng*h/mL) 
Free 
base 
HED 
(mg) 
(60kg 
human) 
CA-NC-
008-TOX-
019-CR 
Single dose 
toxicology 
GLP 
Dog 
Single 
3.24 
208 
78 
313 
359 
 
 
230 
467 
100 
CA-NC-
008-TOX-
017-CR 
Single dose 
toxicology 
GLP 
Rat 
Single 
1.9 
(Toxicology 
Group) /1.5 
(TK group) 
8.5# 
5.9# 
490 
1020 
134 
109 
17/13.5 
CA-NC-
008-RT-
003-CO  
Reproductive 
Toxicology 
(repeat dose) 
GLP 
Rat 
Daily (23-
29 days) 
M/F = ND 
Mating, 
fertility = 3 
26# 
12# 
685 
1883 
220 
206 
26.9 
Except in CA-NC-008-RT-003-CO, male and female exposures were averaged. 
#Due to limited time points, the Cmax may be under reported. 
M = Males 
F= Females 
ND – NOAEL not determined for maternal and paternal animals due to injection site reactions after repeat dosing 
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To ensure preclinical exposures provide at least a 2x margin over expected clinical exposure 
in CA-PS-209, Table 18 presents the ratio of the NOAEL Cmax and AUC0-t observed in the 
dog and rat to the predicted exposure in human following administration to soft tissue. In the 
pivotal dog study CA-NC-008-TOX-019-CR, dog exposures to CA-008, capsaicin and CA-
101 are expected to be equal to or exceed twice that predicted in CA-PS-209 at 15 and 30 
mg, except for CA-101 at 30 mg. The pivotal rat study CA-NC-008-TOX-017-CR was dosed 
to 1.9 mg/kg (HED of 8.5 mg) and exposures in this study are expected 2-fold above that 
expected at 15 mg in CA-PS-209 (VHR), except the CA-008 Cmax. It is possible the CA-008 
Cmax was missed in the rat studies due to the first time point being at 10 minutes post 
subcutaneous dose, as well as the toxicokinetic (TK) groups in this study were dosed at 
approximately 1.3-fold below that of the toxicology groups. Based on time-concentration 
curves in rat, dog and human, the rat appears to allow the conversion from CA-008 to 
capsaicin and CA-101 faster than humans and dogs, though in all cases, the elimination phase 
appears steep. The pivotal rat study is also expected to be 2-fold above that of 30 mg in CA-
PS-209, except the CA-008 Cmax and capsaicin exposure. While it lacks the full evaluation of 
a general toxicology study, a rat GLP FEED study (CA-NC-008-RT-003-CO) is also 
presented in Table 18. It has a higher dose and exposure than CA-NC-008-TOX-017-CR and 
are likely to be equal to or exceed twice that observed in humans following soft tissue 
administration up to 30 mg. 
Table 18 
Preclinical Exposure: Predicted Exposures in CA-PS-209 (VHR) 
Ratio 
Proposed Dose 
CA-008 
Cmax 
Ratioa 
CA-008 
AUC0-t 
ratioa 
CA-101 
Cmax 
ratioa 
CA-101 
AUC0-t 
ratioa 
Capsaicin 
Cmax 
Ratioa 
Capsaicin 
AUC0-t 
Ratioa 
CA-NC-008-TOX-019-CR NOAEL Exposure in Dog 3.24 mg/kg / Predicted exposure in VHR 
 
15 
35 
101 
4.8 
2.4 
5.3 
14 
30 
17 
50 
2.4 
1.2 
2.4 
4.8 
CA-NC-008-TOX-017-CR NOAEL Single Dose Rat (1.9 or 1.5 mg/kg, Tox or TK group respectively / 
Predicted exposure in VHR 
15 
1.4b,c 
7.7 
7.5 
6.9 
3.1 
3.3 
30 
0.74b,c 
3.8 
3.8 
3.5 
1.4 
1.1 
CA-NC-008-RT-003-CO mating and fertility NOAEL Repeat Dose Rat (3 mg/kg) / Predicted exposure 
in VHR 
15 
4.3 
16 
11 
13 
5.1 
6.3 
30 
2.2 
7.7 
5.3 
6.4 
2.3 
2.1 
Grey indicates exposure in preclinical studies are ≥ 2X expected human exposure in CA-PS-209 (VHR) 
a 
Table 15 and Table 17 were used to calculate ratios. 
b 
In most cases, Tmax was at the first time point, so it is possible the true Tmax following s.c. injection was 
likely missed, thus exposure may be underestimated.  
c 
The Tk group was dosed at 1.5 mg/kg rather than the 1.9 mg/kg used in the main toxicology group so 
exposures presented may be under reported by a factor of approximately 1.3.  
d 
Maternal and paternal NOAEL could not be determined due injection site reactions associated with repeat 
dosing. 
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5.4 
Study Rationale 
CA-008 is being investigated as a potential therapy for treatment of pain following surgery. 
Ventral hernia repair (VHR) is a standard surgical model for the assessment of postsurgical 
pain. 
5.5 
Dose Rationale 
5.5.1 
Selection of Doses 
The preliminary safety of CA-008 was established in relevant animal models and supported 
by two clinical studies of bunionectomy (CA-PS-2017-101 and CA-PS-201) with doses up to 
4.2 mg (concentration 0.3 mg/mL) and clinical studies after TKA (CA-PS-203, CA-PS-208) 
and total abdominoplasty (CA-PS-204) with doses up to 90 mg (concentration 0.75 mg/mL) 
(Section 5.3), as well as knowledge from prior human studies with an injectable formulation 
of capsaicin. Taken together, the characterization of the pharmacology, PK, and toxicology 
profiles and the anticipated benefits as well as the potential risks are considered appropriate 
to support the intended initial dose in Part A of 15 mg CA-008 (concentration of 0.3 mg/mL), 
and if well-tolerated, potentially followed in Parts B and C by a higher, fixed dose of 
between 15-30 mg (concentration of 0.3 mg/mL) in this study of acute postsurgical pain 
following VHR. The selection of the dose for Parts B and C will be based on the experience 
in Part A. 
To predict exposure at 30 mg, dose proportionality from 15 mg to 30 mg was assumed for 
CA-008 and CA-101. Capsaicin exposures were also independently modeled from CA-PS-
204 (ABD) PK data. A two-compartment model with linear elimination and zero-order 
absorption adequately fit the observed capsaicin concentrations in women undergoing 
abdominoplasty. Monte-Carlo simulations (via R) were performed for delivery of 30 mg 
CA-008 in a total of 1000 virtual healthy subjects per dose level (Section 5.3.2). The 
predicted exposures in this study following administration of 30 mg or less are expected to be 
within a range that has been shown to be acceptably safe in preclinical and prior clinical 
studies. 
5.5.2 
Selection and Timing of Dose 
CA-008 is a pH labile prodrug of capsaicin that rapidly releases capsaicin after 
administration into tissue. Decision for single administration at the time of surgery is based 
on capsaicin’s mechanism of action. Capsaicin exposure results in initial excitation followed 
by a functional desensitization of TRPV-1-expressing nociceptors which continues for some 
time after removal capsaicin from the site. Administration while the patient is under 
anesthesia for the procedure supplemented by a regional local anesthetic block or local 
anesthetic infiltration of the surgical site should sufficiently address any transient pain that 
results from TRPV1 agonism. Administration of CA-008 during the wound closure process is 
ideal for delivering therapy to the surgical site, thus optimizing target engagement. Study 
treatment is to be administered intraoperatively as a single administration via 
infiltration/instillation into the “surgical site” prior to wound closure. During closure, the 
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surgical tissue is exposed and visible which allows for complete and adequate delivery of 
CA-008 (and capsaicin) to the potential areas where noxious pain is generated. 
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6 
STUDY OBJECTIVES  
6.1 
Primary Objectives  
For Part A: 
• 
Evaluate the safety, tolerability, and feasibility of a single intraoperative 
administration of CA-008 15 mg in patients undergoing an elective VHR. 
For Part B: 
• 
Evaluate the safety, tolerability and feasibility of a single intraoperative 
administration of a fixed dose of CA-008, 24 mg in patients undergoing an 
elective VHR. 
For Part C: 
• 
Evaluate the efficacy of CA-008 on reported pain in patients undergoing an 
elective VHR during a specified post-operative time interval. 
6.2 
Secondary Objectives 
For Part A: 
• 
Evaluate the PK profile of a single intraoperative administration of CA-008 15 
mg in patients undergoing an elective VHR.  
For Part B: 
• 
Determine the pain profile of patients undergoing an elective VHR. 
• 
Determine the appropriateness of progression to Part C. 
• 
Assessment of opioid consumption. 
• 
Evaluate the PK profile of a single intraoperative administration of a fixed dose 
of CA-008, 24 mg in patients undergoing an elective VHR.  
• 
Explore the relationship between CA-008 and its metabolite plasma 
concentrations and electrocardiogram (ECG) QT interval using a concentration-
QT (cQT) analysis. 
For Part C: 
• 
Evaluate the efficacy of CA-008 on reported pain in patients undergoing an 
elective VHR during additional specified post-operative time intervals. 
• 
Evaluate the effect of CA-008 on opioid consumption. 
• 
Evaluate the effect of CA-008 on patient-reported outcomes (PROs). 
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• 
Evaluate, preliminarily, the effect of CA-008 on performance-based outcome 
measures (PBOMs). 
• 
Evaluate the safety and tolerability of CA-008 or placebo in patients undergoing 
an elective VHR. 
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7 
INVESTIGATIONAL PLAN 
7.1 
Overall Study Design and Plan 
This is a three-part, Phase 1/2, randomized, double-blind, placebo-controlled, adaptive safety, 
PK and preliminary efficacy study of CA-008 in patients undergoing VHR.  
In Part A, CA-008 15 mg will be administered in an open-label exploration of different 
delivery techniques. The objective of Part A is to determine the safety, feasibility, PK, and 
appropriateness of administration of a single dose of CA-008 infiltrated/instilled during 
surgery in patients undergoing VHR. It is expected that 8 to 12 patients will be enrolled in 
Part A but it may be up to 16 patients, so that at least 8 patients receive the optimal delivery 
technique which will allow a formal safety assessment of the 15 mg dose of study drug. 
In Part B, if the formal safety assessment from Part A of CA-008 15 mg is favorable, then the 
active study drug dose will be increased to a fixed dose of 24 mg. Using the general delivery 
technique identified in Part A, this dose, concentration, and volume will be assessed 
compared to a placebo in a pilot, double-blind, randomized, parallel-group design. The 
objective of Part B is to determine preliminarily the tolerability of planned study drug 
administration as well as the pain profile of the placebo control group. It is expected that 
approximately 24 patients (up to 32) patients will be enrolled in Part B (see Figure 1). The 
results of Part B will be unblinded for analysis prior to the initiation of Part C. 
Figure 1 
Study Design 
 
 
In Part C, the active dose level of CA-008 from Part B will be evaluated compared to placebo 
in a larger randomized, double-blind, parallel-group design to evaluate efficacy and safety. It 
is expected that ~100 patients will be enrolled in Part C to bring the total number of patients 
enrolled in the study to up to ~150.  
In Parts A, B and C for each patient, the study will be conducted in two periods: 
• 
Inpatient period which continues from check-in on Day 1 (D1) until discharge 
(4 days or 96 hours [h] following surgery [T96 ± 4 h], [D5]). Discharge may be 
delayed, if needed, for medical reasons. 
• 
Outpatient period which begins on discharge from the inpatient unit through 
follow up visits to D29 + 2 days. Note that additional follow up visits may occur 
at any time or even after D29 to follow AEs to resolution or to establish a new 
baseline. 
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During the inpatient period, patients will undergo VHR including study drug treatment 
(CA-008 or placebo) followed by serial assessments of safety, PK, and drug effect, in 
particular focusing on reported pain and need for analgesia. During the outpatient period, 
patients will have serial assessments of safety and drug effect.  
7.2 
Duration of Participation 
Approximately 90 days per patient from screening to Day 29 (D29) + 2 days (however, this 
could be longer to follow any AE to resolution or to establishment of a new baseline). 
7.3 
Dose Escalation and Cohort Expansion 
In Part A, it is expected that 8-12 patients will be enrolled but it may be up to 16 patients. 
CA-008 will be administered at a dose of 15 mg (delivered as a 50 mL solution at a 
concentration of 0.3 mg/mL) in an open-label exploration of different delivery techniques.  
In Part B, the active study drug dose will be increased to a fixed dose of 24 mg and tested vs 
placebo in a pilot phase. It is expected that approximately 24 patients (up to 32) will be 
enrolled in Part B. The results of Part B will be unblinded for analysis prior to the initiation 
of Part C. 
In general, dose escalation in Part B will be permitted if there have been no adverse effects 
on wound healing and no intolerable systemic side effects during Part A. Dose escalation, or 
cohort expansion decisions will be made by the Sponsor’s medical monitor, the CRO’s 
medical monitor, a relevant Principal Investigator (PI) and an independent medical monitor. 
This will be based on review of at least the following safety data: 
• Inpatient (i.e., through 96 h) safety and tolerability data from all 8–12 initial patients, 
including vital signs, physical examination (PE), neurosensory examination, surgery 
site assessment, laboratory assessments, and AEs; 
• D8 ambulatory visit safety and tolerability data from at least 4 of the initial 8 patients 
in the current cohort, including vital signs, PE, neurosensory examination, surgery 
site assessment, and AEs. 
 
In Part C, the active dose level of CA-008 from Part B will be evaluated compared to placebo 
in a larger randomized, double-blind, parallel-group design to evaluate efficacy and safety. It 
is expected that ~100 patients will be enrolled in Part C to bring the total number of patients 
enrolled in the study to up to ~150. 
7.4 
Study Stopping Rules 
Study enrollment will be paused if any patient experience any grade 3 TEAE, in particular in 
any of the categories shown in Table 19, in Appendix A (Section 17.1) or found in the 
toxicity grading scale cited therein. 
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Should a stopping rule be triggered, the Sponsor’s medical monitor, the CRO medical 
monitor, the relevant Principal Investigator, and an independent medical monitor will review 
the relevant data to determine whether or not it is appropriate to resume enrollment with the 
same or a modified dose, modify the study or stop the study. 
The independent medical monitor will have the authority to unblind the treatment assignment 
for the affected patients as part of the safety review.  
The study will be stopped if a safety signal is detected that indicates an unacceptable risk to 
study participants. 
Table 19 
Study Stopping Rules 
Category 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially 
Life 
Threatening 
(Grade 4) 
Abnormal 
Wound Healing: 
Infection 
Dehiscence 
Necrosis 
 
Mild symptoms; 
clinical or diagnostic 
observations only; 
intervention not 
indicated. No 
interference with age-
appropriate 
instrumental ADL 
Minimal, local or 
noninvasive 
intervention 
indicated; May 
require local 
wound care or 
medical 
intervention (e.g., 
dressings or 
topical 
medications) 
Severe or medically 
significant 
but not immediately 
life-threatening; 
hospitalization or 
prolongation of existing 
hospitalization 
indicated; limiting 
ADLs. May require 
intravenous (IV) 
antibiotics, antifungals, 
or antivirals or 
radiologic intervention. 
Life-threatening 
consequences; 
urgent 
intervention 
indicated 
ECG/Cardiac 
issues 
Vital Signs 
Labs 
Asymptomatic, 
intervention not 
indicated 
 
Non-urgent 
medical 
intervention 
indicated 
 
Severe or medically 
significant 
but not immediately 
life-threatening; 
hospitalization or 
prolongation of existing 
hospitalization 
indicated  
Life-threatening 
consequences; 
urgent 
intervention 
indicated 
Focused 
Neurosensory 
Testing 
(performed by 
trained 
Investigator) 
Mild symptoms  
 
Moderate 
symptoms; 
limiting 
instrumental 
ADL 
 
Severe symptoms 
requiring medical 
intervention; limiting 
self-care ADL 
Life-threatening 
and urgent 
intervention 
indicated 
 
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8 
SELECTION OF STUDY POPULATION 
8.1 
Study Population 
The study population consists of adults 18 to 80 years of age, inclusive, who are planning to 
undergo an elective, primary, open VHR, with retromuscular, preperitoneal mesh repair (i.e., 
Rives-Stoppa technique or equivalent), with or without laparoscopic assistance, and who 
otherwise meet eligibility criteria may be considered for enrollment into the study.  
8.1.1 
Number of Participants 
• Part A – Open-label, feasibility and safety assessment: 
o 
N = At least 8 with an acceptable range of up to 16 
• Part B – Double-blind, placebo-controlled pilot: 
o 
Expected N = 24 with an acceptable range of up to N = 32 (randomized 1:1 
active to placebo) 
• Part C – Double-blind, placebo-controlled efficacy: 
o 
In Part C, a total of up to N= ~100 patients will be randomized in a 1:1 ratio to 
active or placebo to bring the total number of patients enrolled in the study to up 
to ~150. 
8.2 
Eligibility Criteria 
8.2.1 
Inclusion Criteria 
Patients must meet all of the following criteria to be considered eligible to participate in the 
study: 
1. Plan to undergo an elective, primary, open laparotomy with VHR, with retromuscular, 
preperitoneal synthetic (polypropylene) mesh placement, with midline fascial 
reconstruction (i.e., Rives-Stoppa technique or equivalent) and with optional laparoscopic 
assistance under general anesthesia with sedation, without collateral procedure or 
additional surgeries. Ventral hernia should not be longer than ~6 cm in length.  
2. Appropriate candidate for TAP block, including no contraindications, no anatomical 
constraints. Note: TAP block may replace or supplement rectus sheath block if rectus 
sheath block is inadequate. 
3. Adults 18–80 years of age, inclusive. 
4. American Society of Anesthesiology (ASA) physical Class 1, 2, or 3 at the time of 
randomization (Section 17.2, Appendix B). 
5. If a male, be either sterile (surgically or biologically) or commit to an acceptable method 
of birth control while participating in the study. The site personnel will provide 
instructions on what is an acceptable method. 
6. If a female, must meet all of the following: 
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a. A female of child-bearing potential (FCBP) must have a negative serum 
pregnancy test at screening and negative urine pregnancy test before surgery; 
b. No plan to become pregnant or to breast feed during the study; and 
c. Be surgically sterile or at least one year post-menopausal (as documented by 
history and appropriate follicle stimulating hormone [FSH] level), or (one of the 
following must apply): 
i. is practicing double-barrier contraception;  
ii. is practicing abstinence (must agree to use double-barrier contraception in 
the event of sexual activity); 
iii. is using an insertable, injectable, transdermal or combination oral 
contraceptive approved by the Food and Drug Administration (FDA) for at 
least 2 months prior to screening and commits to the use of an acceptable 
form of birth control while participating in the study. 
7. Have a body mass index ≤ 40 kg/m2. 
8. Be willing and able to sign the informed consent form (ICF) approved by an Institutional 
Review Board (IRB). 
9. Be willing and able to complete study procedures and pain scales and to return for 
outpatient follow up visits as required. 
10. Be willing and able to avoid foods containing capsaicin for 24 hours prior to surgery. 
 
8.2.2 
Exclusion Criteria 
Patients will not be eligible to participate in this study if any one of the following exclusion 
criteria are met: 
1. In the opinion of the Investigator, the patient has: 
a. a concurrent chronic painful condition (i.e., daily pain) that may require analgesic 
treatment during the study period or may confound postsurgical pain assessments; 
b. active skin disease or other clinically significant abnormality at the anticipated 
site of surgery that could interfere with the planned surgery. 
2. The patient has taken opioids more than twice per week in any week within 6 months of 
screening or has used any opioids during the 2 weeks prior to surgery. 
3. The patient has a known allergy (or contraindication) to any of the following: chili 
peppers, capsaicin or the components of CA-008, propofol, bupivacaine hydrochloride 
(HCl), midazolam, inhaled anesthetic, nitrous oxide, ondansetron, acetaminophen, 
fentanyl, hydromorphone, morphine, oxycodone, or celecoxib.  
4. As determined by the Investigator (with input from the study’s medical monitor if 
requested by the Investigator), the patient has a history or clinical manifestation of 
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significant medical, neuropsychiatric, or other condition, including a clinically significant 
existing arrhythmia, left bundle branch block or abnormal ECG, myocardial infarction, or 
coronary arterial bypass graft surgery within the prior 12 months, significant abnormal 
clinical laboratory test value, or known bleeding abnormality that could preclude or 
impair study participation or interfere with study assessments. 
5. Use of the following disallowed medications: 
a. Within 1 day prior to surgery and throughout the inpatient period, taking or using 
any capsaicin-containing products, such as dietary supplements or OTC 
preparations, including topical formulations, and prescription medications. 
b. Within the 7 days prior to surgery, taking any central nervous system active agent 
as an analgesic adjunct medication, such as anticonvulsants (e.g., gabapentin), 
antidepressants (such as SNRIs, SSRIs, and tricyclic antidepressants), 
benzodiazepines, sedative-hypnotics, clonidine and other central alpha-2 agents 
(e.g., tizanidine), ketamine, or muscle relaxants.  
i. These drugs are permitted if prescribed for non-pain indications and the 
dose has been stable for at least 30 days prior to surgery. Note that the 
dose must remain stable throughout the study.  
ii. If the patient is taking centrally- and/or peripherally-acting analgesic 
medications, such as acetaminophen, nonsteroidal anti-inflammatory drug 
(NSAIDs), or pregabalin the patient may participate in the study if the 
patient is willing to discontinue these medications 3 days prior to surgery. 
Note that (a) baby aspirin (81 mg/day) for cardiovascular prophylaxis or 
(b) regular or enteric-coated aspirin (up to 325 mg given up to twice daily) 
for venous thrombo-embolism prophylaxis is allowed during the study. 
c. Within the 7 days prior to the planned surgery taking (a) antiarrhythmics (except 
beta-blockers and digoxin); (b) warfarin or other anticoagulants (see exception 
above); (c) lithium; (d) aminoglycosides or other antibiotics for an infection 
(except for ophthalmic use); or (e) medical (or other) regular marijuana use.  
d. Within the 14 days prior to surgery, taking parenteral or oral corticosteroids 
(steroid inhaler for allergy or asthma treatment, topical steroid for a non-clinically 
significant skin condition not involving the area of surgery, or ophthalmic steroids 
are permissible). 
e. Taking an antianginal, antihypertensive agent or diabetic regimen at a dose that 
has not been stable for at least 30 days or which is not expected to remain stable 
while participating in the study. 
6. In the opinion of the Investigator, within the past year, the patient has a history of illicit 
drug use or prescription medicine or alcohol abuse (regularly drinks > 4 units of alcohol 
per day; where a unit = 8 oz. beer, 3 oz. wine, or 1 oz. spirits).  
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7. The patient has a disqualifying positive urine drug screen or alcohol breath/saliva test 
during screening or check-in (See Section 10.3.14). 
8. The patient has previously participated in a clinical study with CA-008. 
9. The patient has participated in another clinical trial or used an investigational product 
within 30 days or 5 half-lives (whichever is longer) prior to the planned surgery or is 
scheduled to receive an investigational product other than CA-008 while participating in 
the study. 
 
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9 
STUDY TREATMENTS 
9.1 
Study Treatment  
Complete details of study drug packaging, storage, dispensation, preparation, and tracking 
are provided in the pharmacy manual. 
9.1.1 
CA-008 HCl Description 
CA-008, provided as the hydrochloride salt is a white solid, highly soluble in water. It 
degrades rapidly to capsaicin at neutral pH but is stable for several days at room temperature 
in aqueous solution at pH~3. Capsaicin is known to be irritating to mucous membranes when 
aerosolized and is a skin irritant. 
9.1.2 
Study Treatment Description 
CA-008 for injection, 15 mg per vial, is a white lyophilized powder. On the day of use the 
appropriate number of vials will be reconstituted in sterile saline. 
The placebo comparator is identical in appearance to the reconstituted CA-008 solution. 
In Part A, CA-008 will be delivered at a dose of 15 mg (50 mL of a 0.3 mg/mL solution) and 
used to explore the optimal technique of delivery i.e., location and volumes of delivery to the 
different areas and layers of the surgical procedure. The dose of CA-008 delivered in Part A 
will not exceed 15 mg. 
In Parts B and C, CA-008 at a fixed dose of 24 mg (80 mL of a 0.3 mg/mL concentration) or 
blinded placebo will be delivered using the general technique identified in Part A. 
An unblinded pharmacist or designee may use unblinded vials identified as to contents to 
prepare the study treatment solutions. The anesthesia and surgical team and study site 
personnel will be blinded as to study treatment; details will be presented in the Unblinding 
Plan and/or the Pharmacy Manual. 
9.1.3 
Study Treatment Storage 
Study treatments will be stored at 5°C (2°C to 8°C) until the day of surgery. All study 
treatments should be stored in a secured area and in accordance with the product labeling and 
all applicable laws, regulations, and local/institutional requirements. A description of storage 
conditions for all investigational products will be provided in the Pharmacy Manual. 
9.1.4 
Study Treatment Accountability 
All study treatment will be transported, received, stored, and handled strictly in accordance 
with the container or product label, the instructions provided to the research site, and 
applicable regulations. Detailed drug accountability records must be maintained, including 
the dates shipments are received, the quantity of material received, the dates dispensed, and 
the running inventory. All unused supplies will be checked against the drug accountability 
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records during the study and/or at the end of the study. Unused supplies will be returned to 
the Sponsor’s drug supply vendor at the end of the trial.  
Only eligible patients participating in the study will receive the study treatment. Only 
authorized research site staff may supply, prepare, or administer the study treatments. Once 
dispensed, study treatment may not be relabeled or reassigned for use by other patients.  
9.1.5 
Control of Study Treatment and Rescue Medication 
Mishandling, potential theft, significant loss of clinical supplies, including study treatments, 
systemic analgesia medications, and rescue medications at the site, or other suspected 
diversion must be reported to the Sponsor or designee within 24 hours of first knowledge of 
the issue.  
9.2 
Other Interventions 
9.2.1 
Preoperative, Anesthesia and Perioperative Care 
At check-in (pre-operatively), at least 1-2 hours before surgery: 
Celecoxib 200 mg orally (PO) 
Acetaminophen 1000 mg PO 
 
After these medications have been administered, no additional non-opioid analgesics are to 
be administered during the inpatient phase (through T96). 
The surgery will be performed under general anesthesia:  
Inhaled anesthetic or propofol infusion with or without nitrous oxide (N2O). 
Adequate optional premedication typically with midazolam (up to 5 mg) fentanyl (up 
to 100 mcg); more can be given if indicated. 
Supplemental anesthesia and sedation will be per institutional guidelines. 
Intra-operative titration of intravenous (IV) fentanyl, including during emergence, 
will be per institutional guidelines. 
 
In addition, patients will receive bupivacaine hydrochloride (BupiHCl) 175 mg delivered as 
follows: 
Prior to start of surgery under ultrasound guidance: 
◦ 
Bupivacaine 0.25%, 30 mL (75 mg) diluted with 10 mL of normal saline to a 
volume of 40 mL delivered as a rectus block with 20 mL on each side. 
Note: In Part A, the adequacy of the anesthetic regimen is part of the assessment 
of the technique feasibility. If patients report excessive pain during the immediate 
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postoperative period, a TAP block may be added or may replace the rectus sheath 
block in subsequent patients, but the total dose of bupivacaine will not exceed 
175 mg. 
Immediately before/after surgical incision:  
◦ 
PART A: BupiHCl 0.25%, 40 mL (100 mg), may be diluted in up to 110 mL of 
normal saline to a total volume of not more than 150 mL: Infiltration of abdominal 
wall, anterior rectus abdominis sheath, posterior rectus abdominis sheath, other 
fascia, peritoneum (including circumferential areas of intended mesh placement)  
◦ 
Parts B and C: Bupivacaine 0.25%, 40 mL (100 mg), which should be diluted in 
40 mL of normal saline to a total volume of 80 mL: Infiltration of abdominal wall, 
anterior rectus abdominis sheath, posterior rectus abdominis sheath, other fascia, 
peritoneum (including circumferential areas of intended mesh placement), and 
laparoscopy ports. 
Standard supplemental anesthetic and perioperative care will be provided per institutional 
guidelines. This will typically include (but not be limited to) steps to ensure preservation of 
intraoperative normothermia (including the use of preoperative and intraoperative forced-air 
warming) and deep venous thrombosis prophylaxis. 
9.2.2 
Intraoperative Analgesia and Care 
Patients will receive general anesthesia and bilateral rectus blocks (see Section 9.2.1).  
During surgery, ensure that patients receive the following:  
3–500 mL intravenous (IV) fluid; more can be given if indicated 
Ondansetron 4 mg IV 
 
Note: Ondansetron should not be given to patients in Part B undergoing 24 hours of 12-lead 
Holter monitoring to assess the effects of study drug on the QT interval. 
Within 15 minutes prior to the end of surgery, administer the following: 
Intravenous (IV) hydromorphone, 0.5 mg 
Note: IV morphine 2.0 mg can be used if IV hydromorphone is not available 
 
Patients who develop clinically significant hemodynamic instability or other anesthesia 
complication prior to study drug administration should not receive study drug; in Parts A and 
B, these patients will be replaced. Replacement patients will be assigned the same treatment 
as the original patient. A ‘replacement’ randomization list matching that of the main list will 
be created to facilitate this process. 
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9.2.3 
Inpatient Rescue Medications 
Patients will be encouraged to use rescue medication only for moderate-to-severe pain 
(numeric rating scale [NRS] ≥ 4); however, rescue medication may be requested at any time 
(i.e., even when NRS < 4) and medication will be provided when requested. Conversely, 
patients may refuse rescue medication even when the NRS is ≥ 4. Time intervals for all 
rescue medication use are guidelines that can be modified by Investigator discretion. 
From the time of post-anesthesia care unit (PACU) discharge through T12:  
◦ 
Administer IV hydromorphone 0.5 mg, Q15 minutes as needed (PRN) for pain 
NRS ≥ 4. 
◦ 
Note: IV morphine 2.0 mg can be used if IV hydromorphone is not available 
After T12–48:  
◦ 
Administer PO oxycodone 10 mg, Q 4 h PRN pain NRS ≥ 4. 
◦ 
Only PO oxycodone may be used as rescue. If a patient still requires IV opioid 
rescue after T12, then the patient will revert to IV opioid analgesia management 
per institutional guidelines. These patients will still also be followed for NRS, 
safety, and all other assessments. 
After T48–96: 
◦ 
Administer PO oxycodone 5 mg, Q 4 h PRN pain NRS 5–10. 
◦ 
Only PO oxycodone may be used as rescue. If a patient still requires IV opioid 
rescue after T12, then the patient will revert to IV analgesia management per 
institutional guidelines. These patients will still be followed for NRS, safety, and 
all other assessments. 
 
NRS scores recorded for PRN pain medication will not replace the recording of scheduled 
NRS scores. However, if PRN rescue medication has recently been administered and 
persistent pain is reported in a scheduled NRS record prior to rescue medication taking 
effect, a second dose of rescue medication should not be administered. 
9.2.4 
Postsurgical Care 
After surgery, patients will be transferred to the post-anesthesia care unit (PACU) where 
patients will be monitored for at least 90 minutes during which time pain assessments can 
begin once the patient is awake. T0 is the time of admission into the PACU (as recorded in 
notes by the PACU nurse). The time of extubation will be recorded, if applicable. 
Patients will use the 0 to 10 numerical rating scale (NRS) to report their current pain intensity 
multiple times per day during the remainder of the inpatient part of the study. Scheduled 
times for serial pain assessments are outlined in the Schedule of Assessments (Table 1). 
Rescue medication will always only be administered upon request i.e., independent of the 
currently reported pain score. That is, an NRS pain score alone does not trigger rescue 
medication administration. 
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If the patient reports pain spontaneously and requests analgesia at an unscheduled time 
(i.e., PRN), an NRS should be used to record the pain present at that time. This unscheduled 
NRS must be recorded just prior to administration of any PRN analgesia, i.e., within 
5 minutes prior to any PRN IV analgesic treatment and within 15 minutes prior to any PRN 
oral analgesic treatment. NRS scores for PRN pain medication will not replace the recording 
of scheduled NRS scores. 
Medication for moderate to severe pain (NRS ≥ 4) will be administered upon request as 
follows: 
From T0 to T25 minutes: 
◦ 
IV fentanyl 50 mcg, every (Q) 5 minutes for pain NRS ≥ 4 
From T26 minutes to PACU discharge: 
◦ 
IV hydromorphone 0.5 mg, Q 10 minutes for pain NRS ≥ 4 
◦ 
Note: IV morphine 2.0 mg can be used if IV hydromorphone is not available 
 
After discharge from the PACU, patients are followed through T96 (± 4 h) as inpatients in 
the inpatient unit where safety and activity/efficacy evaluations will be performed. Patients 
will be required to meet standard criteria for discharge to outpatient status. Patients will 
continue to be monitored as outpatients after discharge from the inpatient unit through 
D29 + 2 days for various safety and efficacy assessments, and later if necessary, for safety 
follow up. 
9.2.5 
Outpatient Analgesic Medications 
Following discharge from the hospital through the D15 visit, pain will be managed with the 
following regimen only: 
Scheduled medication: 
◦ 
Celecoxib, 100 mg PO BID (unless contraindicated) 
Rescue medications (for pain as needed):  
◦ 
Acetaminophen, 650 mg PO Q 6 h for mild pain (i.e., NRS < 4) (unless 
contraindicated) 
◦ 
Oxycodone, 5 mg – 1 or 2 tablets PO Q 4–6 h for moderate-severe pain 
(i.e., NRS ≥ 4). Discharge patient with 20 tablets. Use of this rescue medication 
[time, dose] must be recorded in the diary. Pre-rescue medication NRS for opioids 
will also be recorded in the diary. 
Note:  
Instruct patients to use acetaminophen as the initial option for treating pain up to a total daily 
dose of 4,000 mg.  
 
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Document the number of opioid tablets prescribed and also document any additional 
prescriptions required if the patient’s pain continues to be an issue requiring additional opioid 
medication. 
Following D15, pain will be managed per institutional guidelines and standards of care. Pain 
medication use will be recorded as a concomitant medication from D15 through D29. 
Persistent pain or pain exacerbations during the outpatient period may suggest the need for an 
unscheduled in-person visit to assess the surgical site. If such a visit occurs, the Investigator 
should use clinical discretion regarding the adequacy of analgesic treatment, capture this 
occurrence as an AE, and document any required treatments. 
9.3 
Method of Assigning Patients to Treatment Groups 
Randomization will be used to avoid bias in the assignment of patients to blinded treatments, 
to increase the likelihood that known and unknown patient attributes (e.g., demographics, 
baseline characteristics) are evenly balanced across treatment groups, and to enhance the 
validity of statistical comparisons across treatment groups.  
Patients who have provided written informed consent will be assigned a unique number in 
the screening process. This number will be used to identify the patient throughout the study. 
Patients in Parts B and C will be randomized in a ratio of 1:1, active to placebo, in a blocked 
randomization of 4 patients, so that successive groups of patients will include 2 patients 
receiving active drug and 2 patients receiving placebo.  
Treatment assignments will be determined by a computer-generated randomization schedule. 
Once any patient number or randomization number is assigned, it cannot be reassigned to any 
other patient.  
Patients may be rescreened if the screening window is exceeded due to scheduling issues.  
9.4 
Blinding 
In order to reduce the potential for bias in the study, treatment group assignments for Part B 
and Part C will be double-blinded during the study. The patient, investigational site personnel 
except for the unblinded pharmacist, Sponsor, and Sponsor designees directly involved in the 
conduct and/or monitoring of this study will not be aware of patients’ treatment group 
assignments. Note that the placebo is identical in appearance to CA-008 once reconstituted. 
Under normal circumstances, unless consistent with the protocol, the blind will not be broken 
until all participants have completed treatment. In case of emergency, and only if the 
information is required by the Investigator to ensure patient’s safety in managing a medical 
condition, the treatment may be unblinded at the site by using a code break module. The code 
break module will be provided by the Sponsor or designee. If possible, the Investigator 
should contact the Sponsor prior to unblinding and after any actions have been taken. 
Whenever a treatment assignment is prematurely unblinded, the reason, date and time of the 
unblinding, and the individual who broke the blind must be documented.  
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It is assumed that the need to unblind a study patient’s treatment assignment will occur in the 
setting of a SAE, and therefore, all procedures for the reporting of a SAE must be followed. 
9.5 
Prior and Concomitant Therapy 
All non-study medications, including prescription, OTC, or herbal therapies, used by the 
patient will be documented for the 30 days prior to screening (prior medications), during 
screening, and throughout the study (concomitant medications). The Investigator will 
determine if the prior/concomitant medication(s) affect the patient’s eligibility to participate 
or continue to participate in the study. 
The use of benzodiazepines and the non-benzodiazepines (eszopiclone, ramelteon, zaleplon, 
and zolpidem) are permitted to treat insomnia during the post-operative period. 
Within the 7 days prior to the planned surgery, antibiotics for an infection are permitted for 
ophthalmic use or for treatment or prophylaxis of post-operative surgical site infections. At 
the Investigator’s discretion, agents intended for deep venous thrombosis (DVT) prophylaxis 
after the surgery are allowed. 
On a case-by-case basis, the Investigator is permitted to allow the use of some concomitant 
medications, for example to treat an AE, if the Investigator determines that the medication 
will not affect the patient’s safety or study integrity. Wherever possible, the Investigator 
should obtain approval from the medical monitor prior to administering the medication.  
9.6 
Study Restrictions 
In addition to the criteria described in Sections 8.2, 9.2, 9.5, and 10.1.2 the patient must agree 
to abide by the following study restrictions:  
Abstain from the following during the inpatient portion of the study: 
Consuming any alcohol 
Smoking or vaping (nicotine-containing or other substances)  
Illicit drug use or non-medical use of therapeutic drugs not allowed by the protocol 
Any foods containing capsaicin for 24 hours prior to PK blood draws 
 
Abstain from the following during the outpatient portion of the study: 
Patients will be asked to abstain from consuming more than 1 (women) or 2 drinks 
(men) per day of alcohol  
Patients will be asked to abstain from illicit drug use or non-medical use of 
therapeutic drugs (See Section 10.3.13) 
Patients will be asked to abstain from taking prohibited medications  
 
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9.7 
Treatment Compliance  
Because all study medication is being administered by study personnel, no patient 
compliance procedures are necessary. Potential diversion of controlled opioid medication 
will be monitored and recorded through rescue medication accountability. Any suspected or 
confirmed diversion will be documented and reported. 
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10 
CONDUCT OF THE STUDY 
All study assessments will be performed at the visits and timepoints outlined in the Schedule 
of Assessments (Table 1); the following sections outline the detailed timing and procedures 
associated with the visits and assessments.  
10.1 
Study Visits 
10.1.1 
Screening Phase (Day -45 to Day Prior to Surgery):  
Patients will be screened for participation at the study within 45 days of surgery/study drug 
administration. The following will be completed at least 1 day prior to surgery: 
Informed consent; 
Inclusion/exclusion criteria evaluation; 
Demographics; 
Medical and surgical history; 
Prior/current medications; 
Complete PE (without a breast, genital, or rectal examination), including height and 
weight; 
Vital signs - heart rate (HR), blood pressure (BP), respiratory rate (RR), O2 saturation 
(SpO2) in the supine position, and temperature (oral) (Section 17.3, Appendix C); 
Baseline neurosensory exam; 
Clinical laboratory tests (Section 17.4, Appendix D): 
◦ 
Hematology/Coagulation: hemoglobin, hematocrit, white blood cell count with 
differential, red blood cell (RBC) count, platelet count, activated partial 
thromboplastin time (aPTT), and prothrombin time (PT) or international 
normalization ratio (INR). 
◦ 
Blood Chemistry: including alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), total bilirubin (Tot. Bili), gamma-glutamyl transferase 
(GGT), albumin, blood urea nitrogen (BUN), creatinine, alkaline phosphatase 
(ALK), sodium, potassium, calcium, chloride, and glucose. 
Urine drug screening;  
Alcohol breath/saliva test; 
Serum pregnancy test (FCBP), if applicable, (unless post-menopausal status 
confirmed by FSH);  
12-lead ECG; 
Patient reported outcomes (PROs; Section 10.3.9 and Section 10.3.10) 
◦ 
Patient Reported Outcomes Measurement Information System (PROMIS) 10 
Global Health questionnaire (Section 17.6, Appendix F)  
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◦ 
Activity Assessment Scale (AAS) (Section 17.7, Appendix G)  
Patient pain assessment training; 
AE assessment (record any current conditions as medical history); 
 
10.1.2 
Surgery Phase: Admission to Unit for Surgery (Baseline) to End of Surgery 
10.1.2.1 
Admission to Site Unit (D1) Prior to Surgery 
Patients who meet the selection criteria at the Screening Visit and are eligible to participate 
in the study will be required to return to the study center for surgery within 45 days of 
screening. The following will be performed on D1 prior to surgery: 
Confirm informed consent; 
Review of inclusion/exclusion criteria; 
Review medical and surgical history since screening; 
Review prior and current concomitant medications; 
Interim targeted PE 
Urine pregnancy test (FCBP), if applicable, (unless post-menopausal status confirmed 
by FSH), usually to be done within 24 hours prior to surgery; 
Urine drug screen;  
Alcohol breath/saliva test; 
Patient pain assessment training, patient to watch pain training video; 
Blood draws for PK analyses (See Section 10.1.4 for timing); 
Vital signs - HR, BP, RR (supine), and temperature (oral); 
Randomize the patient to treatment after confirmation of patient’s continued 
eligibility; 
AE assessment (record any current conditions as medical history); 
Patients will be asked to abstain from foods containing capsaicin for 24 hours prior to 
their surgery. 
 
10.1.2.2 
Anesthesia and Surgery (D1) 
The surgery will be performed under general anesthesia: 
Inhaled anesthetic or propofol infusion with or without nitrous oxide (N2O).  
Adequate optional premedication typically with midazolam (up to 5 mg) and fentanyl 
(up to 100 mcg). 
Supplemental anesthesia and sedation will be per institutional guidelines. 
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Intra-operative titration of intravenous (IV) fentanyl, including during emergence, 
will be per institutional guidelines. 
 
12-lead Holter monitors will be placed prior to surgery and record for 24 hours to assess for 
effects on the QT interval in a subset of patients in Part B. 
In addition, patients will receive bupivacaine 175 mg delivered as follows: 
Prior to start of surgery under ultrasound guidance: 
◦ 
Bupivacaine 0.25%, 30 mL (75 mg) diluted with 10 mL of normal saline to a 
volume of 40 mL delivered a rectus block with 20 mL on each side. 
Note: In Part A, the adequacy of the anesthetic regimen is part of the assessment 
of the technique feasibility. If patients report excessive pain during the immediate 
postoperative period, a TAP block may be added or may replace the rectus sheath 
block, but the total dose of bupivacaine will not exceed 175 mg. 
 
Immediately before/after surgical incision:  
◦ 
PART A: BupiHCl 0.25%, 40 mL (100 mg), may be diluted in up to 110 mL of 
normal saline to a total volume of not more than 150 mL: Infiltration of abdominal 
wall, anterior rectus abdominis sheath, posterior rectus abdominis sheath, other 
fascia, peritoneum (including circumferential areas of intended mesh placement)  
◦ 
PARTS B and C: BupiHCl 0.25%, 40 mL (100 mg), which should be diluted in 
40 mL of normal saline to a total volume of 80 mL: Infiltration of abdominal wall, 
anterior rectus abdominis sheath, posterior rectus abdominis sheath, other fascia, 
peritoneum (including circumferential areas of intended mesh placement) 
 
Standard supplemental anesthetic and perioperative care will be provided per institutional 
guidelines. This will typically include (but not be limited to) steps to ensure preservation of 
intraoperative normothermia (including the use of preoperative and intraoperative forced-air 
warming) and deep venous thrombosis prophylaxis. 
10.1.3 
Surgery Phase: Administration of Study Medication into the Surgical Site 
Study treatment is to be administered intraoperatively as a single administration via 
infiltration/instillation into the “surgical site” prior to wound closure. 
In general, the intent is to deliver local anesthetic into the surgical site “on the way in” (upon 
adequate exposure of and prior to incision/dissection of target tissues). Conversely, study 
drug (active or placebo) delivery to the same and other areas will be administered by 
infiltration (injected) and/or instillation/irrigation (dripped) to the surgical site “on the way 
out” (prior to and at the time of surgical closure). 
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The “surgical site” is defined as the area extending approximately at least 2–3 cm in all 
directions (lateral/medial/proximal/distal/deep) from the margins of substantially all tissue 
traumatized by the surgical procedure, i.e., all tissue dissected, cut, electrocauterized 
(bovied), sutured or tacked, including both deep and superficial areas. The surgical site will 
include the full area of surgical mesh placement. 
If laparoscopic assistance is used, study drug may also be delivered to the site of the 
laparoscopic incisions requiring surgical closure. 
Note: The technique for all tissue infiltration described below should include multiple 
microinjections. The needle may be inserted deeply at first and as the needle is withdrawn, 
the study drug can be injected slowly along the needle track. The objective is to distribute the 
study drug widely in the surgical site where TRPV1 receptor targets are located and not in a 
single, deep depot injection to act as a conduction block in intact nerves. The intent is that all 
tissue traumatized by the surgical procedure should be exposed to study drug. 
Note: If after the surgery is underway, it becomes evident that the surgical mesh must be 
placed intra-peritoneally (i.e., IPOM technique), then the patient will not receive study drug. 
In Parts B and C, this patient would be considered randomized but not treated. 
The total study drug volume administered per patient will be 50 mL in Part A and 80 mL in 
Parts B and C, delivered during the surgical procedure in divided aliquots. Modifications to 
the delivery technique for subsequent patients may occur based on information from prior 
patients. In fact, the purpose of Part A is to optimize the delivery technique and allocation of 
study drug for use in Parts B and C. 
Study drug will be delivered to (a) the midline deep, peritoneum layer which includes the 
closure of the peritoneal sac, (b) the mesh layer which includes both the dorsal and ventral 
aspects of the space created by the surgeon to accommodate placement of the surgical mesh, 
whether this space is anterior or posterior to the posterior rectus fascia and (c) the anterior 
fascia layer which includes the closure of the anterior rectus fascia and linea alba. In 
addition, a small amount of study drug will be delivered to laparoscopic portals requiring 
suture closure. 
The initial allocation and general approach to dosing will be as follows, though minor 
modifications are permissible based on surgeon judgment and experience with earlier 
patients in the trial:  
Deep midline/peritoneal layer – up to approximately 25% of the total volume:  
Infiltrate or instill 10 mL (Part A) or approximately 10 mL (Parts B and C), approximately 
half the volume per side, into the deep midline area where closure of the peritoneal sac has 
been completed, along with the posterior rectus sheath if not separated from (peeled off) the 
peritoneum. Use multiple, micro-injections to distribute study drug widely along the closure. 
Ensure that all dissected, resected and sutured areas of the peritoneum (and posterior rectus 
sheath) are exposed to study drug. 
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Note: Laparoscopic visualization can be used to ensure that induration of the peritoneum 
confirms targeted delivery of study drug. 
Mesh/fascia layer – at least approximately 50% of the total volume:  
The mesh layer includes the space created by dissection for placement of the surgical mesh. 
It can be in-between the peritoneum and the posterior rectus fascia or in-between the 
posterior rectus fascia and the rectus abdominis muscle. In either case, the intent is to deliver 
sufficient study drug to both the posterior (dorsal) and anterior (ventral) aspects of the space 
created for the mesh, including all tissues that will be in contact with the mesh after 
placement as well as the perimeter area around the mesh itself. 
The following is a general description of the delivery of study drug to the mesh/fascia layer 
and is a guide for the surgeon. The actual delivery technique may vary based on the 
individual patient anatomy encountered by the surgeon. 
Part A: 
Using micro-injections, infiltrate ~10 mL (Part A) into the posterior surface of the mesh layer 
space where the mesh will be placed on both sides of the midline peritoneal closure. Ensure 
that any areas where mesh fixation with sutures or tacks are to be placed are exposed to study 
drug. 
Instill (drip/irrigate) ~5 mL (Part A) onto the posterior surface of the mesh layer space where 
the mesh will be placed. Instill about half the volume (~2.5 mL) at first using a finger to 
spread it around to the entire area followed 2–3 minutes later by the remaining volume 
(~2.5 mL). 
Using micro-injections, infiltrate ~7.5 mL (Part A) into the circumferential perimeter, i.e., 
edges, of the mesh space, e.g., where the peritoneum and posterior rectus fascia remain 
attached. 
An additional ~7.5 mL (Part A) should be delivered to the anterior surface of the mesh layer 
space where the mesh will be placed on both sides of the intended midline closure. If the 
mesh space is in-between the peritoneum and posterior rectus fascia, then this volume should 
be delivered to the posterior rectus fascia by micro-injections. If the mesh space is in-
between the rectus abdominis muscle and the posterior rectus fascia, then this volume should 
be delivered by instillation using a finger to spread it around to the entire area. Instill about 
half this volume at first using a finger to spread it around to the entire area followed 
2-3 minutes later by the remaining half. 
Part B: 
Using micro-injections, and instillation (drip/irrigation) wherever appropriate and feasible to 
ensure maximum exposure, infiltrate ~30 mL into each side of the mesh/fascia layer. 
Depending on the placement of the mesh, this should include (a) the posterior surface of the 
mesh layer (preperitoneal/fascia layer), (b) the circumferential perimeter of the mesh space, 
i.e., edges of the mesh space, e.g., where the peritoneum and posterior rectus fascia remain 
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attached, (c) any areas of mesh fixation with sutures or tacks and (d) the anterior surface of 
the mesh layer space (retromuscular/fascia layer). 
Anterior layer – up to approximately 25% of the total volume: 
Infiltrate 10 mL (Part A) or approximately 10 mL (Parts B and C) into the primary closure of 
the anterior rectus sheath and linea alba, divide equally on each side. 
Laparoscopy ports – Up to 5 mL: 
If a laparoscopy port(s) will require a suture closure, then infiltrate ~2–5 mL from the 
anterior layer allocation into the deeper tissues of the port (1-2 mL per port) prior to closure 
using study drug from the volume allocated to the anterior layer.  
Minor modifications to study drug dosing will be described in the study Pharmacy Manual 
and patient-specific dosing memos but the general approach will not change substantively.  
10.1.4 
Postsurgery: T0 (Admission into the PACU) to T96 (Discharge) 
Following surgery, patients will be transferred to the PACU where they will undergo an 
assessment of safety and efficacy over the next 90 minutes. After discharge from the PACU, 
patients are followed through T96 (± 4 h) as inpatients in the inpatient unit where safety and 
activity/efficacy evaluations will be performed. T0 is the time of admission into the PACU 
(as recorded in notes by the PACU nurse). 
The schedule of assessments is as follows:  
If the patient reports pain spontaneously and requests analgesia at an unscheduled 
time (i.e., PRN), an NRS should be used to record the pain present at that time. This 
unscheduled NRS must be recorded just prior to administration of any PRN analgesia, 
i.e., within 5 minutes prior to any PRN IV analgesic treatment and within 15 minutes 
prior to any PRN oral analgesic treatment. NRS scores for PRN pain medication will 
not replace the recording of scheduled NRS scores. 
Medication for moderate to severe pain (NRS ≥ 4) will be administered upon request 
as follows: 
◦ 
From T0 to T25 minutes: 
▪ IV fentanyl 50 mcg, Q 5 minutes for pain NRS ≥ 4 
◦ 
From T26 minutes to PACU discharge: 
▪ IV hydromorphone 0.5 mg, Q 10 minutes for pain NRS ≥ 4 
▪ Note: IV morphine 2.0 mg can be used if IV hydromorphone is not 
available 
Pain intensity (assessed with NRS):  
◦ 
During the inpatient stay, NRS at rest beginning with the PACU admission (T0) 
may be assessed once the patient is awake. Obtain NRS scores at T0 plus 1 hour 
(T1), T0 plus 2 hours (T2), T4, T6, T8, T12, T16, T20, T24, and every 4 hours 
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thereafter (if awake at time of assessment) until discharge from the inpatient unit. 
Time windows: ± 5 minutes for T1 and T2; ± 15 minutes for T4 onward. 
Scheduled NRS scores must be recorded regardless of timing of pre-rescue 
medication NRS scores and administration of rescue medication. The actual time 
of all NRS scores, i.e., scheduled and pre-rescue, must be recorded, i.e., not the 
nominal time. 
◦ 
During the inpatient stay, as soon as feasible, obtain evoked NRS twice daily after 
3 maneuvers: (a) coughing 3 times, and (b) sitting up from the supine position into 
a standardized position (both legs dangling on the side of the bed), and 
(c) ambulation for approximately 10 yards (30 feet). Obtain these NRS scores in 
the morning at 10:00 AM (± 1 h) and in the afternoon at 4:00 PM (± 1 h). 
◦ 
During the inpatient stay, pain scores may be skipped between the hours of 
midnight and 6:00 AM, but the patient may not miss two consecutive assessments. 
The T12, T24, T48, T72, and T96 assessments must be completed even if the 
patient must be awakened at these times. 
Vital signs - HR, BP, RR (supine), SpO2 and temperature (oral) - are assessed 
together postsurgery at T1, T2, T6, T12, and T24, and every 12 hours thereafter until 
T96. Assessments between the hours of 12:00 AM and 6:00 AM may be skipped if 
the patient is sleeping; however, two consecutive assessments may not be skipped. 
The allowable window is ± 5 minutes for the first 4 hours postsurgery, and 
± 15 minutes for all other times. 
Targeted PE: T96 (± 4 h) and prior to discharge from the inpatient unit. 
12-lead ECG: T24 (± 2 h). 
Surgical site assessment: T96 (± 4 h) prior to discharge from the inpatient unit 
(Section 17.10, Appendix J). If the Investigator determines there are skin reactions 
atypical for the type of surgery, e.g., more than expected erythema, drainage, bruising 
or hematoma, induration, swelling, or other skin changes, they should be documented 
as AEs, graded for severity, and followed regularly until resolution or establishment 
of a new baseline (Section 17.11, Appendix K). A digital photograph of the wound 
site should be taken if the patient has consented. 
Neurosensory testing of the surgical area near the incision will be performed at 
T96 (± 4 h) prior to discharge from the inpatient unit. 
◦ 
Numbness at or near the incision need not be considered a neurologic AE since 
this could occur because of tissue trauma and inflammation from the surgery. 
◦ 
Sensory deficits or clinically significant persistent sensory change beyond the 
area proximal/distal to the incision at time of discharge, such as allodynia or 
hyperalgesia, must be designated as a neurologic AE. Patients will be followed 
until there is a return to baseline or establishment of a new baseline. 
Clinical laboratory tests T48 (± 4 h):  
◦ 
Hematology/Coagulation: hemoglobin, hematocrit, white blood cell count with 
differential, RBC count, platelet count, aPTT, and PT or INR. 
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◦ 
Blood Chemistry: including ALT, AST, Tot. Bili, GGT, albumin, BUN, 
creatinine, ALK, sodium, potassium, calcium, chloride, and glucose. 
Blood draw for PK analysis postsurgery and at T24. The time points for whole blood 
collection will be at pre-dose at pharmacokinetic time (PKT) 0 (Pre-IP dose, 2–10 
minutes prior to the first study treatment instillation), 0.03 h (2 min), 0.083 h (5 min), 
0.167 h (10 min), 0.25 h (15 min), 0.33 h (20 min), 0.5 h (30 min), 0.75 h (45 min), 
and at 1, 1.5, 2, 4, 8, 12, 16, 24, 36 and 48 hours after the first PK study treatment 
instillation (total of 18 samples). In the event of a SAE or severe TEAE, an 
unscheduled PK draw will be performed whenever feasible. The actual time of 
collection will be recorded and used in any analysis. Out-of-window collections will 
not be considered protocol deviations. 
Record rescue medication consumption and concomitant medications throughout the 
inpatient period. 
Record AEs throughout the inpatient period (Section 17.1, Appendix A may be useful 
to the Investigator for assessing systemic [general] AEs).  
PBOMs at T48 and at T96 (± 4 h) (Section 10.3.10):  
◦ 
Sit to Stand Test (also known as 30-Second Chair Stand) Assessment 
(Section 17.8, Appendix H); 
◦ 
Timed Up and Go (TUG) Test (Section 17.9, Appendix I). 
PROs at T48 and at T96 (± 4 h) (Section 10.3.9 and Section 10.3.10):  
◦ 
PROMIS 10 Global Health questionnaire (Section 17.6, Appendix F)  
◦ 
Activity Assessment Scale (AAS) (Section 17.7, Appendix G)  
 
After completing the assessments through T96, the diary for at-home use will be reviewed 
and patients will be discharged from the study center with the diary to record pain 
assessments and pain medication at home. Patients will be provided routine standard of care 
for pain management after discharge from the study center.  
Patients will be given a prescription for 20 tablets of oxycodone 5 mg one or two tablets PO 
Q 4–6 h PRN for moderate-severe pain (i.e., NRS 5–10).  
Patients will be instructed to return to the study center on D8 (+ 1 day) for follow-up 
assessments.  
10.1.5 
Outpatient Phase: T96 (after Discharge) through D15 
After discharge at T96 (± 4 h) and through D15, patients will assess their pain intensity in 
their diary.  
Instruct patients to document their NRS scores twice daily at 11:00 AM (± 1 h) and 7:00 PM 
(± 1 h) (a) at rest, (b) after coughing 3 times, (c) after sitting up from the supine position into 
a standardized position (both legs dangling on the side of the bed), and (d) during ambulation 
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for approximately 10 yards. Note that the actual time of these assessments must be 
documented in the diary. Instruct patients to: 
◦ 
Obtain the morning NRS assessment; 
◦ 
Obtain the evening NRS assessment; 
 
Opioid and non-opioid rescue medication (dose, date, time) must be recorded through D15, 
including a pre-rescue NRS score. If entered in the electronic diary, the timing of the 
additional NRS assessment will be assumed to be coincident with the use of rescue 
medication. If not entered in the electronic diary, the additional NRS assessment should be 
within 15 minutes prior to use of rescue medication to be used for imputation. 
Patients will return to the study center on D8 (+ 1 day) and Day 15 (+ 2 days) for the 
following assessments:  
Patient home diary review (pain intensity [NRS score] and pain medication; 
Section 10.3.8); 
Vital signs - HR, BP, RR (supine), SpO2 and temperature (oral); 
Targeted PE; 
Surgical site assessment (Section 17.10, Appendix J): If the Investigator determines 
there are skin reactions atypical for the type of surgery, e.g., more than expected 
erythema, drainage, bruising or hematoma, induration, swelling, or other skin 
changes, they should be documented as AEs, graded for severity, and followed 
regularly until resolution or establishment of a new baseline (Section 17.11, 
Appendix K). A digital photograph of the wound site should be taken if the patient 
has consented; 
Neurosensory testing of the surgical area near the incision. This evaluation will 
include the details described in Section 17.12, Appendix L:  
◦ 
Numbness or other sensory changes at or near the incision need not be 
considered a neurologic AE since these could occur because of tissue trauma 
and inflammation from the surgery. 
◦ 
Sensory deficits or clinically significant persistent sensory change beyond the 
area proximal/distal to the incision at time of discharge, such as allodynia or 
hyperalgesia, must be designated as a neurologic AE. Patients will be 
followed until there is a return to baseline for the neurosensory assessment or 
until there is a determination that it has reached a resolution or establishment 
of a new baseline. 
PBOMs (Section 10.3.10); 
◦ 
Sit to Stand Test (also known as 30-Second Chair Stand) Assessment 
(Section 17.8, Appendix H); 
◦ 
TUG Test (Section 17.9, Appendix I). 
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PROs: (Section 10.3.9and Section 10.3.10):  
◦ 
PROMIS 10 Global Health questionnaire (Section 17.6, Appendix F)  
◦ 
Activity Assessment Scale (AAS) (Section 17.7, Appendix G)  
Concomitant medication use/concomitant treatments; 
AE assessment. 
 
10.1.6 
Outpatient Phase: D29 
Patients will return to the study center on D29 (+ 2 days), or at the time of discontinuation, 
for the following assessments:  
Vital signs - HR, BP, RR (supine), SpO2 and temperature (oral); 
Targeted PE; 
Surgical site assessment (Section 17.10 Appendix J): If the Investigator determines 
there are skin reactions atypical for the type of surgery, e.g., more than expected 
erythema, drainage, bruising or hematoma, induration, swelling, or other skin 
changes, they should be documented as AEs, graded for severity, and followed 
regularly until resolution or establishment of a new baseline (Section 17.11, 
Appendix K). A digital photograph of the wound site should be taken if the patient 
has consented; 
Neurosensory testing of the surgical area near the incision. This evaluation will 
include the details described in Section 17.12, Appendix L:  
◦ 
Numbness or other sensory changes at or near the incision need not be 
considered a neurologic AE since these could occur because of tissue trauma 
and inflammation from the surgery. 
◦ 
Sensory deficits or clinically significant persistent sensory change beyond the 
area proximal/distal to the incision at time of discharge, such as allodynia or 
hyperalgesia, must be designated as a neurologic AE. Patients will be 
followed until there is a return to baseline for the neurosensory assessment or 
until there is a determination that it has reached a resolution or establishment 
of a new baseline. 
PBOMs: (Section 10.3.10):  
◦ 
Sit to Stand Test Assessment (Section 17.8, Appendix H); 
◦ 
TUG Test (Section 17.9, Appendix I). 
PROs: (Section 10.3.9 and Section 10.3.10):  
◦ 
PROMIS 10 Global Health questionnaire (Section 17.6, Appendix F)  
◦ 
Activity Assessment Scale (AAS) (Section 17.7, Appendix G) 
Concomitant medication use/concomitant treatments; 
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AE assessment.  
 
10.1.7 
Early Termination 
If prior to D15 visit, patients will return for the following assessments: 
Patient home diary review (pain intensity [NRS] and pain medication) 
(Section 10.3.8); 
Vital signs - HR, BP, RR (supine), SpO2 and temperature (oral); 
Targeted PE; 
Surgical site assessment (if the Investigator determines there are atypical wound 
healing or visible abnormal findings, a digital photograph of the wound site should be 
taken if the patient has consented; Section 17.10, Appendix J); 
Neurosensory testing of the surgical area (Section 10.3.18); 
PBOMs; 
Concomitant medication use/concomitant treatments; 
AE assessment. 
 
If after D15 visit, patients will return for the following assessments:  
Surgical site assessment (if the Investigator determines there are atypical wound 
healing or visible abnormal findings, a digital photograph of the wound site should be 
taken if the patient has consented; Section 17.10, Appendix J); 
Neurosensory testing of the surgical area (Section 10.3.18); 
PBOMs (Section 10.3.10), 
Concomitant medication use/concomitant treatments; 
AE assessment. 
 
If after D29 visit, the Investigator has clinical discretion as to what assessments are to be 
completed at the visit. The following are the minimum assessments:  
Surgical Site assessment (if the Investigator determines there are atypical wound 
healing or visible abnormal findings, a digital photograph of the wound site should be 
taken if the patient has consented; Section 17.10, Appendix J); 
Neurosensory testing of the surgical area (Section 10.3.18); 
Concomitant medication use/concomitant treatments; 
AE assessment. 
 
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10.1.8 
Unscheduled Visit 
Unscheduled visits may occur at any time and assessments are to be completed at the 
Investigator’s discretion based on the reason for the visit and entered into the electronic data 
capture (EDC). At a minimum, the following should be performed: 
Vital signs - HR, BP, RR (supine), SpO2 and temperature (oral); 
Targeted PE; 
Surgical site assessment: If the Investigator determines there are atypical wound healing or 
visible abnormal findings, a digital photograph of the wound site should be taken if the 
patient has consented; Section 17.10, Appendix J); 
Neurosensory testing of the surgical area (Section 10.3.18); 
AE assessment. 
10.2 
Patient Completion and Withdrawal 
10.2.1 
Patient Completion 
A patient is considered to have completed the study once all end-of-study assessments are 
completed at D29 (+ 2 days), or at the last visit upon early termination of the study. 
10.2.2 
Patient Withdrawal 
If a patient still requires IV opioid rescue after T12, then the patient will revert to IV 
analgesia management per institutional standard-of-care but will continue serial NRS, 
activity/efficacy and safety assessments. These patients will still be evaluated for pain and 
safety assessments as described in the Statistical Analysis Plan. 
A patient is free to withdraw his/her consent and discontinue participation in the study at any 
time for any reason. A patient’s participation must therefore be terminated immediately upon 
his/her request, and the reason(s) for discontinuation appropriately documented. Patients who 
elect to discontinue participation prior to D8 will be considered to have terminated as of the 
date of their election however, they will be asked to return to the site one time to ensure that 
adequate wound healing has occurred 
The degree to which a patient withdraws can vary, and efforts will be made to collect 
important safety data whenever feasible and if the patient agrees. Patients can: 
Withdraw from activity/efficacy assessments but agree to participate in all study 
safety assessments; 
Withdraw from activity/efficacy assessments but agree to participate in limited study 
safety assessments; 
Withdraw from study activity/efficacy and safety assessments. In this case, patients 
should still return for a surgical follow-up assessment of wound healing. 
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A patient may be discontinued from the study for any of the following reasons: 
Safety reasons, including AEs or significant concomitant illness, injury, or urgent 
surgeries/procedures that would, in the judgment of the Investigator, affect 
assessments of clinical status to a significant extent, require discontinuation of study 
drug, or both; 
At the request of the Sponsor, regulatory agency, or Institutional Review Board 
(IRB); 
Patient is lost to follow-up; 
Patient treatment allocation is unblinded (i.e., individual code break; Section 9.4); 
Death of patient. 
 
A patient may also be discontinued from the study, at the discretion of the Investigator and/or 
Sponsor, for any of the following reasons:  
Patient refuses or is unable to adhere to the study protocol; 
Major protocol violation; 
Pregnancy; 
Use of unacceptable concomitant medication(s); 
It is not considered in the best interest of the patient to continue; 
Administrative reasons (e.g., termination of enrollment or study). 
 
The Investigator must maintain a record of all patients who discontinue from the study prior 
to completion; the reason(s) for study discontinuation will be documented. If a patient 
chooses to withdraw from the study, the Investigator should make a reasonable attempt to 
obtain and record the reason(s) for withdrawal in as much detail as possible, although the 
patient is not obligated to provide such a reason.  
10.3 
Study Procedures and Assessments 
10.3.1 
Informed Consent 
The nature of the study and its risks and benefits will be explained to the patient by the 
Investigator or designated study personnel. The patient must voluntarily provide written 
informed consent on an IRB-approved ICF, prior to performing any study-related procedures. 
The patient’s source records must document that the consent process has been completed and 
that written informed consent has been obtained from the patient prior to the initiation of any 
study-specific procedures. Documentation that the patient was given adequate time to ask the 
Investigator (or designee) questions about their participation in the study and that a signed 
and dated copy of the ICF was provided to the patient should also be included in the medical 
records or clinical chart. 
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10.3.2 
Demographics 
The following demographic data will be recorded: age (birthdate), sex, race, and ethnicity.  
10.3.3 
Medical and Surgical History 
The complete medical and surgical history will include histories of acute, chronic, or 
infectious disease; surgical or oncologic histories; and any reported conditions affecting 
major body systems. All findings on medical history will be evaluated by the Investigator for 
impact on study eligibility. 
10.3.4 
Medication History  
All medications (prescription and non-prescription, herbal medications/natural health 
products, or investigational drugs) taken by the patients during the 30 days prior to Screening 
will be recorded in the source documentation as medication history.  
10.3.5 
Contraceptive Requirements 
Female patients of childbearing potential must be using and willing to continue using 
medically acceptable contraception during the study. Examples of medically acceptable 
forms of contraception include true abstinence, hormonal contraceptives (combined oral pill, 
patch or vaginal ring, intrauterine device or system, progestin implant or injection), bilateral 
tubal ligation, or double-barrier methods (i.e., male condom in addition to a diaphragm or a 
contraceptive sponge).  
Female patients of non-childbearing potential are not required to use contraception or 
undergo pregnancy tests; however, they must be surgically sterile (e.g., hysterectomy and/or 
bilateral oophorectomy or salpingo-oophorectomy, as determined by patient medical history) 
or congenitally sterile or must be post-menopausal. Post-menopausal is defined as being 
amenorrheic for at least one year without another cause with an FSH > 40 mIU/mL (or FSH 
above the relevant laboratory value for post-menopausal status) confirmed during screening. 
Male patients, unless in a relationship with a female partner who is of non-childbearing 
potential (see above), must either be sterile (surgically or biologically) or commit to using 
double-barrier methods (i.e., male condom in addition to a diaphragm or a contraceptive 
sponge) during study participation.  
10.3.6 
Patient Pain Assessment Training 
Patients will undergo study participation education on pain assessments and written testing 
procedures according to the Schedule of Study Procedures. 
10.3.7 
Digital Photographs of the Surgical Site 
During the informed consent process, patients will be asked if they are willing to allow 
digital photographs to be taken of the surgical site. This is optional, and their response will in 
no way affect their inclusion in the study. Their response will be included on the ICF.  
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10.3.8 
Numerical Rating Scale for Pain Intensity (NRS) 
The NRS is an 11-point scale with anchors 0 (no pain) and 10 (worst pain imaginable) 
(Section 17.5, Appendix E).  
Patients will report or record the intensity of their current pain at designated times during the 
study after administration of study treatment. Patients should be at rest for at least 5–10 
minutes prior to completing NRS resting assessment. 
During the inpatient stay, NRS at rest beginning with the PACU admission may be 
assessed once the patient is awake. T0 is the time of admission into the PACU (as 
recorded in notes by the PACU nurse). Obtain NRS scores at T0 plus 1 hour (T1), T0 
plus 2 hours (T2), T4, T6, T8, T12, T16, T20, T24, and every 4 hours thereafter (if 
awake at time of assessment) until discharge from the inpatient unit. Time windows: 
± 5 minutes for T1 and T2; ± 15 minutes for T4 onward. Scheduled NRS scores must 
be recorded regardless of timing of pre-rescue medication NRS scores and 
administration of rescue medication. The actual time of all NRS scores, i.e., 
scheduled and pre-rescue, must be recorded, i.e., not the nominal time. 
During the inpatient stay, as soon as feasible, obtain evoked NRS twice daily after: 
(a) coughing 3 times, and (b) sitting up from the supine position into a standardized 
position (both legs dangling on the side of the bed), and (c) ambulation for 
approximately 10 yards (30 feet). Obtain these NRS scores in the morning at 
10:00 AM (± 1 h) and in the afternoon at 4:00 PM (± 1 h). 
During the inpatient stay, pain scores may be skipped between the hours of 12:00 AM 
(midnight) and 6:00 AM, but the patient may not miss two consecutive assessments. 
The T12, T24, T48, T72, and T96 assessments must be completed even if the patient 
must be awakened at these times. 
During the inpatient stay, an additional NRS assessment must be obtained within 
5 minutes prior to IV rescue medication administration and within 15 minutes prior to 
oral rescue medication administration. 
During the outpatient period (after T96 and through D15), instruct the patient to 
document their NRS scores twice daily at 11:00 AM (± 1 h) and 7:00 PM (± 1 h) (a) 
at rest, (b) after coughing 3 times, (c) after sitting up from the supine position into a 
standardized position (both legs dangling on the side of the bed), and (d) during 
ambulation for approximately 10 yards. Note that the actual time of these assessments 
must be documented in the electronic diary. Instruct the patient to: 
◦ 
Obtain the morning NRS assessments;  
◦ 
Obtain the evening NRS assessments;  
◦ 
Opioid and non-opioid rescue medication (dose, date, time) must be recorded in 
the diary through D15, including a pre-rescue NRS score. If entered in the 
electronic diary, the timing of the additional NRS assessment will be assumed to 
be coincident with the use of rescue medication. If not entered in the electronic 
diary, the additional NRS assessment should be within 15 minutes prior to use of 
rescue medication to be used for imputation. 
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10.3.9 
Patient-Reported Outcomes 
Patients will complete the PROs at Screening, T48, T96, D8, D15, and D29. These 
questionnaires include: 
PROMIS 10 Global Health questionnaire (Section 17.6, Appendix F) 
Activity Assessment Scale (Section 17.7, Appendix G) 
 
10.3.10 
Performance-Based Outcome Measures (PBOMs) 
Patients will undergo PBOMs at T48, T96 (± 4 h)/Discharge, D8, D15, and D29. These 
measures include: 
Sit to Stand Test Assessment (Section 17.8, Appendix H); 
TUG Test (Section 17.9, Appendix I). 
 
10.3.11 
Rescue Medications 
The details of rescue analgesic medication (specific drugs, doses, dates, and times) will be 
recorded during the inpatient period beginning from the end of surgery through the outpatient 
period to D15 (+ 2 days) visit or to the Early Termination Visit, if applicable. Patients will be 
instructed on the proper use and timing of rescue medication. 
The statistician will use a standard conversion table to calculate the oral morphine equivalent 
(OME) dose of various opioids (see the Statistical Analysis Plan [SAP] for further details). 
Total opioid consumption (OC) and daily opioid (rescue medication) consumption in OMEs 
will be calculated during the inpatient period and up to the D15 visit.  
Document daily use of OTC analgesics (and oxycodone if prescribed) during the 
outpatient period through D15.  
Document each opioid prescription provided to the patient and the number of and 
type of tablets provided to the patient for site records and reconciliation.  
 
10.3.12 
Clinical Laboratory Assessments  
All protocol-specified laboratory tests on blood samples will be collected, processed, 
shipped, and analyzed according to instructions from a selected central laboratory. The 
laboratory will generate laboratory reports and forward them to the clinical site in a timely 
manner. It is the responsibility of the Investigator to review and sign all laboratory reports 
expeditiously to document appropriate safety monitoring of study patients. The Investigator 
should sign and date each laboratory report concurrent with her or his review. The 
Investigator should exercise medical and scientific judgment in deciding whether abnormal 
laboratory values are clinically significant or not and should indicate the clinical significance 
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of each abnormal/flagged value by noting “NCS” (not clinically significant) or “CS” 
(clinically significant). All clinically significant values will be recorded in the eCRF and 
followed until resolution. Notations indicating that a value is clinically significant should 
also include a brief description of the underlying disease or condition that is associated with 
the value, e.g., “CS/mild anemia.” In general, and as determined by the Investigator, 
abnormal, clinically significant laboratory values are expected to be associated with an item 
recorded in medical history or with an AE. 
Additional laboratory samples may be taken at the discretion of the Investigator if the results 
of any tests fall outside reference ranges or clinical symptoms necessitate testing to ensure 
safety. Specific hematology, coagulation, and chemistry assessments are listed in Table 20. 
Table 20 
Clinical Laboratory Assessments 
Hematology 
Chemistry 
Hematocrit 
Hemoglobin 
Red blood cell (RBC) count  
Total and differential (absolute) white blood 
cell count 
Platelet count 
Sodium 
Potassium  
Calcium  
Chloride 
Glucose  
Creatinine 
Blood urea nitrogen (BUN) 
Albumin 
Total bilirubin (Tot. Bili) 
Alanine aminotransferase (ALT) 
Aspartate aminotransferase (AST) 
Gamma-glutamyl transferase (GGT) 
Alkaline phosphatase (ALK) 
Coagulation 
Activated partial thromboplastin time (aPTT) 
Prothrombin time (PT) / International 
normalized ratio (INR) 
 
Endocrinology 
Follicle stimulating hormone (FSH), as 
appropriate 
 
The clinical laboratory tests will be completed per the Schedule of Assessments (Table 1). In 
addition to the clinical laboratory tests, a serum pregnancy test (β-hCG) will be performed at 
the Screening Visit and a urine pregnancy test will be performed prior to surgery for females 
of childbearing potential.  
ALT or AST > 3 × upper limit of normal (ULN), Tot. Bili > 2 × ULN, and ALK > 2 × ULN 
will be considered an AE, as well as any other changes deemed clinically significant by the 
Investigator.  
10.3.13 
Urine Drug Screen and Alcohol Test 
Urine drug screen and alcohol breath/saliva tests will be completed at screening and 
pre-procedure. All patients will be tested for drugs-of-abuse (e.g., amphetamines, 
barbiturates, benzodiazepines, cocaine, opiates, phencyclidine, tetrahydrocannabinol [THC], 
methadone, methamphetamine, tricyclic antidepressants, oxycodone, and others). 
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The drug and alcohol screens will be performed in-house at the inpatient unit. If any of these 
tests are positive, except as indicated below, the patient will not be allowed further 
participation in the trial. However, a positive test may be repeated at the discretion of the 
Investigator. 
In the case of a urine drug screen at screening that is positive for THC, if the patient is 
willing to abstain from use or consumption of THC-containing products from 7 days prior to 
surgery until the Day 15 visit, they may be allowed to participate in the study. In this case, a 
urine drug screen positive for THC at check-in will not exclude the patient. 
If other positive urine drug screen results can be explained by a current prescription or 
acceptable OTC medication (that does not otherwise exclude the patient as determined by the 
Investigator), then the patient may continue to participate in the study. 
10.3.14 
Vital Signs 
Vital signs (supine) will consist of HR, BP, RR, SpO2 and temperature (oral) following a rest 
period. Vital signs will be assessed per the Schedule Assessments (Table 1). One missed 
assessment between 12:00 AM and 6:00 AM will not be considered a protocol deviation. 
Two missed assessments of vital signs in a row is a protocol deviation. The allowable 
window is ± 5 minutes for the first 4 hours postsurgery, and ± 15 minutes for all other times. 
10.3.15 
Electrocardiogram  
10.3.15.1 
12-Lead Electrocardiogram 
All 12-lead ECGs will be performed per the Schedule of Assessments (Table 1) after the 
patient has been resting in a recumbent/supine position for at least 5 minutes. The ECG 
variables will include ventricular heart rate and the PR, QRS, QT, and QTcF intervals. ECGs 
will be signed and dated by a medically qualified individual to confirm review of the ECG 
and verify whether any abnormalities are clinically significant. In general, abnormal, 
clinically significant ECGs are expected to be associated with an item recorded in medical 
history (e.g., at Screening) or with an AE (if it occurred post study treatment). Note that for 
QTcF, clinically significant prolongation of QTcF should be > 450 ms for male patients and 
> 470 ms for female patients or an increase of QTcF of 30 ms or greater (compared to the pre 
surgical ECG), as well as any other changes deemed by the Investigator as significant. 
Clinically significant changes in ECG will be considered an AE. 
10.3.15.2 
12-lead Holter Monitor 
12-lead Holter monitors will be placed prior to surgery and record for 24 hours to assess for 
effects on the QT interval and correlation with PK levels in a subset of at least 12 patients per 
randomized arm in Part B. 
10.3.16 
Physical Examination 
A complete PE including all major body systems (general appearance, head, eye, ear, nose, 
throat (HEENT), neck, neurologic, cardiovascular, lungs, abdomen, skin, extremities, lymph 
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nodes, and musculoskeletal systems but without a breast, genital or rectal examination) will 
be performed at Screening. A focused interim or targeted PE will be performed pre-surgery 
and after surgery during the inpatient and outpatient periods (see Table 1).  
Body weight (kg), in indoor clothing, but without shoes, will be measured at Screening and at 
T96. Height in centimeters (cm) will be measured, and body mass index (BMI) will be 
calculated at Screening only. BMI shall be calculated as kg/m2. The site should use the 
National Institute of Health (NIH) website BMI calculator (available at: 
http://www.nhlbi.nih.gov/health/educational/lose_wt/BMI/bmi-m.htm). 
10.3.17 
Surgical Site Assessment  
The surgical site should be assessed per the Schedule of Assessments (Table 1) to determine 
if any site related AEs have occurred. The Investigator will evaluate their satisfaction with 
the healing of the wound during this Surgical Site assessment using an 11-point scale (010) 
where a score of 0 is “Completely unsatisfied,” and a score of 10 is “Completely satisfied” 
(Section 17.10, Appendix J). Assessments will also be performed at each of the follow-up 
visits or at the time of early discontinuation. Insufficient wound healing that is clinically 
significant should be recorded as an AE. A follow-up visit will be scheduled after the D29 
visit if the Investigator observes insufficient wound or bone healing or to ensure resolution of 
an ongoing AE.  
If there are skin reactions atypical for the type of surgery, e.g., more than expected erythema, 
drainage, bruising or hematoma, induration, swelling, or other skin changes, they should be 
documented as AEs, graded for severity, and followed regularly until resolution or 
establishment of a new baseline (the grading guide for atypical wound findings may be useful 
to the Investigator: Section 17.11, Appendix K). 
10.3.18 
Neurosensory Testing 
Neurosensory testing of the skin surrounding the incision (will be conducted per the 
Schedule of Assessments (Table 1). This evaluation will include the details described in 
Section 17.12, Appendix L.  
Numbness or other sensory changes at or near the incision need not be considered a 
neurologic AE since these could occur because of tissue trauma and inflammation 
from surgery. 
Sensory deficits or clinically significant persistent sensory change beyond the area 
proximal to the incision at time of discharge, such as allodynia or hyperalgesia, must 
be designated as a neurologic AE. Patients will be followed until there is full return to 
baseline for the neurosensory assessment or until there is a determination that it has 
reached a resolution or establishment of a new baseline. 
 
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10.3.19 
Assessment of Adverse Events 
All SAEs will be documented and followed from the time the patient has signed the ICF until 
D29 + 2 days after the completion of surgery or later, as necessary. All SAEs and non-serious 
AEs will be documented and followed from the time of administration of study treatment 
until D29 or until resolution or establishment of a new baseline. AEs that occur between 
Screening and the surgery should be considered medical history, and be added to the 
patient’s medical record, unless related to a study-related procedure (such as phlebotomy), in 
which case it will be recorded as a non-treatment emergent AE. SAEs and AEs that have 
been designated as possibly related to study drug will be followed until resolution or 
stabilization. Further details on AEs, including definitions, elicitation, and reporting are 
provided in Section 11. 
10.3.20 
Pharmacokinetic Assessments and Samples 
Details for the collection and processing of blood samples for measurement of PK (CA-008, 
capsaicin, and CA-101) are outlined in the Laboratory Manual. 
Part A: 
PK sampling will be performed on at least 8 patients at a single site. 
Part B: 
PK sampling will be performed on at least 24 patients receiving blinded study drug, i.e., 
12 patients per randomized arm at a single site. All patients undergoing 24-hour Holter ECG 
recordings should have PK sampling. 
There will be no PK sample collection in Part B (unless Holter monitoring is done).  
Part C: 
No PK sample collection is planned for Part C.  
The time points for whole blood collection will be pre-dose at PKT 0 (Pre-IP Dose, 2–10 
minutes prior to the first study treatment instillation), 0.03 h (2 min), 0.083 h (5 min), 0.167 h 
(10 min), 0.25 h (15 min), 0.33 h (20 min), 0.5 h (30 min), 0.75 h (45 min), and at 1, 1.5, 2, 
4, 8, 12, 16, 24, 36 and 48 hours after the first study treatment instillation (total of 18 
samples).  
The PK analysis plan will be documented in the PK Analysis Plan., 
A cQT analysis (PK/PD) analysis will be performed to assess for drug effect on the QT 
interval. This analysis will be documented in an Analysis Plan. 
Note: An unscheduled PK sample should be collected where feasible during the inpatient 
phase of the study for all patients as part of the evaluation of any SAE or severe TEAE. 
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10.4 
Safety, Tolerability, Pharmacokinetic, and Efficacy Endpoints  
10.4.1 
Safety Endpoints 
Safety endpoints include the following: 
Incidence of spontaneously reported TEAEs or serious AEs (SAEs) from study medication 
administration through D29 or later if necessary:  
◦ 
TEAEs are defined as AEs occurring post study medication administration 
◦ 
AEs recorded from the time the ICF is signed up to study medication 
administration will be recorded in medical history. 
◦ 
Note: An unscheduled PK sample should be collected where feasible during the 
inpatient phase of the study for all patients as part of the evaluation of any SAE or 
severe TEAE.  
PE: full PE at Screening (without a breast, genital, or rectal examination). Interim targeted 
PE on D1 prior to surgery (can be done on the day before surgery if check-in occurs then), 
T96, and as an outpatient on D8, D15 and D29 (later if necessary). 
Vital signs (HR, BP, RR], O2 saturation [SpO2]) at screening, D1 prior to surgery, 
postsurgery T1, T2, T6, T12, and T24, and every 12 hours thereafter until T96 (see 
Section 10.3.14), and as an outpatient on D8, D15 and D29 or later if necessary. Assess 
temperature on D1 prior to surgery. Temperature will be recorded daily along with vital signs 
per site SOPs at 2, 6, 12, 24, and every 12 hours thereafter until discharge from the inpatient 
facility (if awake at the time of assessment between hours of midnight and 6:00 AM).  
Surgical site assessments at T96 prior to discharge from the inpatient unit and then as an 
outpatient on D8, D15 and D29 (later if necessary). If there are skin reactions atypical for the 
type of surgery, e.g., more than expected erythema, drainage, bruising or hematoma, 
induration, swelling, or other skin changes, they should be documented as AEs, graded for 
severity, and followed regularly until resolution or establishment of a new baseline. 
Neurosensory testing near the incision will be performed at Screening visit, T96 (prior to 
discharge from the inpatient unit) and then as an outpatient on D8 and D29. 
◦ 
Numbness at or near, i.e., within 5 cm of the incision need not be considered a 
neurologic AE since this could occur because of tissue trauma and inflammation 
from the surgery. Persistent numbness would meet the criteria for an AE. 
◦ 
Sensory deficits or clinically significant persistent sensory change beyond the area 
proximal/distal to the incision at time of discharge, such as allodynia or 
hyperalgesia, must be designated as a neurologic AE. Patients will be followed 
until there is a return to baseline or establishment of a new baseline. 
12-lead ECGs, and standard clinical laboratory tests at Screening and postsurgery as 
specified in the Schedule of Assessments (Table 1)and outlined below. The Investigator is 
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responsible for determining if out of range laboratory values are clinically significant or not. 
All clinically significant values will be recorded in the eCRF and followed until resolution.  
12-lead ECG at Screening and T24 (± 2 h) 
Clinical laboratory test results  
Hematology/Coagulation at Screening and T48 (± 4 h): hemoglobin, hematocrit, white blood 
cell count with differential, RBC count, platelet count, aPTT, and PT or INR. 
◦ 
Blood chemistry at screening and T48 (± 4 h) to include at least the following: 
ALT and AST, Tot Bili, GGT, albumin, BUN, creatinine, ALK, sodium, 
potassium, calcium, chloride, and glucose. 
◦ 
Serum and urine pregnancy test for FCBP: βhCG test at screening and urine test 
usually to be done within 24 hours prior to surgery. 
◦ 
Note: Safety laboratory assessments may be collected, as appropriate, as part of the 
evaluation of a SAE or severe TEAE. 
 
In Part B, for at least 24 patients (i.e., 12 in each blinded, randomized arm), 12-lead Holter 
monitors will be placed prior to surgery and record for 24 hours to assess for effects on the 
QT interval during study drug administration. Serial PK samples must be drawn in patients 
undergoing Holter ECG assessments.  
 
10.4.2 
Pharmacokinetic Endpoints 
Full details of PK will be described in a separate PK Analysis Plan. The time points for 
whole blood collection are outlined in the Schedule of Assessments (Table 1) and 
Section 10.3.20.  
Plasma concentration for CA-008 and key metabolite(s) (including capsaicin and CA-101) at 
PK sampling times will be summarized using descriptive statistics, including mean, standard 
deviation (SD), median, minimum and maximum values, and coefficient of variation (CV%). 
PK parameters include (but are not limited to) maximum observed plasma drug concentration 
(Cmax), time to maximum plasma drug concentration (Tmax), half-life, and area under the 
plasma concentration-time curve (PK-AUC). Actual sampling times will be used to calculate 
plasma-derived PK parameters.  
For the cQT analysis, QTc intervals will be matched with plasma concentrations for CA-008, 
capsaicin, and CA-101 and analyzed to describe the relationship between concentration and 
QTc using nonlinear mixed effects modeling. Methodologic details and results will be 
reported separately. 
10.4.3 
Efficacy Endpoints 
10.4.3.1 
Primary Efficacy Endpoints for Part A 
There are no efficacy endpoints for Part A. 
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10.4.3.2 
Primary Efficacy Endpoints for Part B 
There are no efficacy endpoints for Part B. 
10.4.3.3 
Primary Efficacy Endpoints for Part C 
Area under the curve (AUC) of the rest NRS from T0 to T96 (AUC0-96) AUC is the weighted 
sum of current pain intensity (SPI) assessments for a specified time interval. 
10.4.3.4 
Key Secondary Efficacy Endpoints for Part C 
Evoked pain NRS (three maneuvers): AUC0–96 
Total opioid consumption (in daily OME) = OC from T0 to T96: OC0-96 and from T0 to D8: 
OC0-D8 
Percentage of patients who do not require opioids after discharge (i.e., opioid-free or OF) 
from T96 to D15: OF96-D15 
NRS at rest and evoked NRS (three maneuvers) from T0 to D8: AUC0-D8 
10.4.3.5 
Exploratory Endpoints for Part C 
Using rest NRS: AUC12-96, AUC0-48, AUC48-96, and AUC0-D15; 
Using evoked (three maneuvers) NRS: AUC12-96, AUC0-48, AUC48-96, and AUC0-D15; 
Time-specific mean NRS scores at T48, T72, and T96; 
Time-specific mean NRS scores daily from D5-D15; 
Proportion of patients with NRS ≤ 3 during T0-T96 , T0-48 and T48-96 
OC12-96, OC24-96, OC0-D8, and OC0-D15; 
OF0-96, OF0-D15, OF24-96, OF24-D15, OF48-D15, OF72-D15 and OFD8-D15. 
Time to cessation of opioid use; 
Additional exploratory and sensitivity analyses rest/evoked NRS AUC, OC, and OF during 
different intervals may be undertaken, e.g., T48-T168, T72-T168;  
PRO questionnaire score improvement from Screening to D8, D15, and D29; and from T48 
to D8, D15, and D29; 
Improvement in PBOMs (Sit to Stand, TUG) from T48 (± 4 h), to D5/Discharge, to D8, to 
D15, and to D29; PBOM difference between groups at T48, T96, D8, D15 and D29; 
Total non-opioid analgesic consumption (AC), i.e., rescue acetaminophen use for the 
indicated time intervals: AC96-D8 and AC96-D15; 
Other endpoints to be defined in the SAP. 
 
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11 
ADVERSE EVENTS 
11.1 
Adverse Events and Serious Adverse Events 
The following definitions, developed in accordance with the United States (US) Code of 
Federal Regulations (CFR) and the International Conference on Harmonisation (ICH) 
Clinical Safety Data Management Guidance for Industry, E2A, will be used to identify AEs 
in this study. 
An AE is any untoward medical occurrence in a patient 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 (e.g., including an abnormal laboratory 
finding), symptom, or increase in severity of a preexisting abnormality, temporally associated 
with the use of a medicinal (investigational) product, whether or not considered related to the 
medicinal (investigational) product. 
Since this is a study using a surgical pain model, findings that are “typical” for the surgery 
should not be captured as an AE. Atypical or worse than typical findings should be captured 
as AEs. 
A “suspected adverse reaction” means any AE for which there is a reasonable possibility that 
the drug caused the event. “Reasonable possibility” means there is evidence to suggest a 
causal relationship between the drug and the AE.  
11.1.1 
Relationship to Study Treatment 
A qualified Investigator must make the determination of relationship to the investigational 
product for each AE. The Investigator should decide whether, in his or her medical judgment, 
there is a reasonable possibility that the event may have been caused by the study treatment.  
Causality Category 
Description 
Not Related 
Temporal relationship to study treatment administration is missing or implausible, 
or there is an evident other cause. 
Unlikely related 
A clinical event, including laboratory test abnormality, with a temporal 
relationship to study treatment administration which makes a causal relationship 
improbable or if other drugs, chemicals or underlying disease provide more 
plausible explanations.  
While temporal sequence may be an important factor in determining causality: 
i.e., whether the observed reaction or event began after the study treatment, it may 
well be that the surgery, anesthesia, a concurrent medical condition or concomitant 
medications administered during or after surgery were more likely than not to be 
responsible for the AE. The Investigator should use clinical judgment to evaluate 
the evidence and determine whether there is a reasonable possibility that study 
treatment actually caused the AE or whether based upon the evidence it is more 
likely that something else is responsible. If the former, choose “possibly related” 
and if the latter, “unlikely related.”  
For the purpose of this protocol, the term “unlikely related” will be considered an 
AE not related to study treatment. 
Possibly related 
A clinical event, including laboratory test abnormality, with a temporal 
relationship to study treatment administration, which also may be explained by 
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Causality Category 
Description 
concurrent disease or other drugs or chemicals. In such cases, if the Investigator 
using clinical judgment is unable to rule out a reasonable possibility that study 
treatment was partly responsible, then choose “possibly related.”  
For the purpose of this protocol, an event that has possible relationship to study 
treatment will be defined as a “Suspected Adverse Drug Reaction”.  
Probably related 
A clinical event, including laboratory test abnormality, with a temporal 
relationship to study treatment administration, in which the Investigator has 
determined that the event is unlikely to be attributed to other factors. 
For the purpose of this protocol, an event that has probable relationship to study 
treatment will be defined as an “Adverse Drug Reaction”. 
 
11.1.2 
Adverse Event Reporting 
All AEs must be entered on the AE CRF, regardless of causality or severity. AEs include 
new AEs, worsening baseline conditions, clinically significant laboratory findings, disease-
related signs and symptoms that were not present at baseline, and any events or findings that 
the Investigator feels are clinically significant. 
Disease-related signs and symptoms that are present at baseline should not be recorded as 
AEs unless they worsen in severity or increase in frequency. 
Information collected concerning AEs will include the following: 
Name of the event 
Onset date 
Resolution date 
Severity (i.e., mild, moderate, or severe) 
Relationship to study treatment 
Action and outcome 
Seriousness of event 
 
All SAEs will be documented and followed from the time the patient has signed the ICF until 
D29 + 2 days after the completion of surgery. All SAEs and non-serious AEs will be 
documented and followed from the time of administration of study treatment until D29 or 
later if necessary. AEs that occur between Screening and the administration of study 
medication should be considered medical history and added to the patient’s medical record, 
unless the AE is due to a study-related procedure (such as phlebotomy), in which case it will 
be recorded as a non-treatment emergent AE. SAEs and AEs that have been designated as 
possibly related to study treatment will be followed until resolution or stabilization. 
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11.1.3 
Serious Adverse Event  
A SAE or reaction is any adverse drug experience occurring at any dose that results in any of 
the following outcomes: 
Death 
Is life-threatening (at the time of the event) 
Requires patient hospitalization or prolongation of existing hospitalization, 
Results in persistent or significant disability/incapacity 
Is a congenital anomaly/birth defect (in an offspring) 
An important medical event that may not result in death, be life-threatening, or 
require hospitalization may be considered a SAE when, based upon appropriate 
medical judgment, the event may jeopardize the patient and/or may require medical 
or surgical intervention to prevent one of the outcomes listed in this definition. 
 
All AEs requiring hospitalization or prolongation of a pre-existing hospitalization should be 
reported as SAEs unless they occur ≥ 14 days after the D29 visit, or 21 days after an early 
termination AND are not considered to be study treatment-related by the Investigator. 
Hospitalizations meeting the following criteria will not be reported as a SAE but must be 
recorded on the appropriate CRF: study specified hospitalization, short-term administrative 
hospitalization for procedures, tests or treatments of conditions that would not otherwise 
constitute a SAE, elective hospitalizations. 
11.1.3.1 
Serious Adverse Event Reporting 
Serious AEs must be reported to the Sponsor or designee within 24 hours of knowledge of 
the event. All SAEs that occur while a patient is receiving study treatment and within 14 days 
following the study completion visit (or 21 days following an early termination [ET] if 
applicable) are reportable within 24 hours. During this follow-up period beyond study 
completion or after an ET, only those SAEs considered to be possibly related to study 
treatment should be reported within 24 hours. 
The procedure for reporting a SAE is as follows: 
All SAEs must be reported immediately (within 24 hours of discovery) by email to 
the CRO medical monitor or designee. Calls related to SAEs should first be directed 
to the CRO medical monitor or designee.  
The Sponsor’s medical monitor is available for questions about safety-related issues 
or to request waivers to modify post-operative patient care.  
The initial report should include all information known at the time of the report 
(additional information can be reported as discovered). Do not delay the initial 
reporting to obtain resolution or follow-up information. 
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The site will enter into the electronic database a SAE report, or similar form, that 
includes the following information, as available: 
◦ 
Patient ID; 
◦ 
Basic demographic information (age, gender, weight); 
◦ 
Outcomes attributed to the event (death, life-threatening hospitalization [new 
or prolonged], disability, congenital anomaly, required medical intervention to 
prevent permanent impairment/damage, etc.); 
◦ 
Onset date and severity of the event; 
◦ 
Brief description of the event including frequency and severity of symptoms 
leading to diagnosis; 
◦ 
List of relevant test results and laboratory data; 
◦ 
Any other relevant history; 
◦ 
Whether the study treatment was discontinued; 
◦ 
Investigator’s assessment of causality. 
 
The CRO medical monitor or another representative of the Sponsor may contact the 
Investigator to request additional information regarding the event or to confirm information. 
All SAEs will be entered on the AE CRF. The same nomenclature should be used on both the 
SAE report and the AE CRF. The Investigator is responsible for the complete and timely 
reporting of all SAEs to the Sponsor (or designee), reporting pertinent follow-up information 
on the SAE, and notifying the appropriate IRB of the occurrence of and details surrounding 
the event. In the event there is a question as to whether the AE is serious, the event should be 
reported. 
11.2 
Severity Grading for AEs 
Grading the severity of AEs is per Investigator discretion (the guidance reflected in 
Sections 17.4, 17.3 and 17.1; Appendices I, J, and K, respectively, may be helpful). 
Additionally, the following general guideline may be helpful: 
Grade 1 (mild) = asymptomatic or mild symptoms requiring no treatment, only 
clinical or diagnostic observation 
Grade 2 (moderate) = event or symptoms limit age-appropriate activities of daily 
living (ADLs) more than is expected from the surgery itself, requiring minimal 
treatment or local noninvasive intervention indicated.  
Grade 3 (severe) = medically significant but not immediately life-threatening, 
significantly limiting of self-care ADLs, requiring of medical treatment and may 
require hospitalization or prolongation of hospitalization.  
Grade 4 (potentially life-threatening).  
 
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11.3 
Pregnancy 
If a female patient becomes pregnant at any time during the study, the Investigator must 
notify the CRO medical monitor or designee within 48 hours of learning about the 
pregnancy. The Investigator will be required to follow the patient through the pregnancy 
term, and report to the CRO medical monitor or designee the course of the pregnancy, 
including perinatal or neonatal outcome. Information on the status of the mother and the 
child will be forwarded to the CRO medical monitor or designee. Any premature termination 
of the pregnancy will also be reported on this form. Although pregnancy occurring in a 
clinical study is not considered to be a SAE, any pregnancy complication or elective 
termination of a pregnancy for medical reasons will be recorded as an AE and will be 
followed as such. A spontaneous abortion is considered to be a SAE. 
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12 
DATA QUALITY ASSURANCE 
This study will be conducted under Good Clinical Practice (GCP) and all applicable 
regulatory requirements. In order to ensure compliance, the Sponsor or designee may conduct 
a quality assurance audit, as outlined in Section 12.2.  
Actions to ensure the accuracy and reliability of data include the selection of qualified 
Investigators and appropriate study centers; the review of protocol procedures with the 
Investigator and study personnel prior to study start; the design of suitable source documents 
with appropriate instructions for use (where applicable); the internal audit of source data 
according to GCP and internal procedures to ensure their accuracy, completeness, and 
verifiability; as well as the periodic site monitoring by the Sponsor. The Sponsor or designee 
will review source documents for accuracy and completeness during on-site monitoring visits 
and after their return to the Sponsor; any discrepancies will be resolved with the Investigator, 
as appropriate.  
Significant and/or repeated non-compliance will be investigated, and remedial action 
instituted when appropriate. Failure to comply with remedial actions may result in 
investigational site termination and regulatory authority notification. 
12.1 
Data Collection  
Source documents include, but are not limited to, original documents, data and records such 
as hospital/medical records (including electronic health records), clinic charts, laboratory 
results, participant diaries, data recorded in automated instruments, microfilm or magnetic 
media, and pharmacy records, etc. This study will use EDC. At a minimum, all data required 
by the protocol should have supporting source documentation for entries in the EDC system. 
All eCRFs will be completed by the site staff prior to review by the Sponsor’s monitor or 
designated representative. The Sponsor’s monitor or designated representative will review all 
source records on-site and compare them to the data recorded on the eCRF. All entries, 
corrections, and alterations will be made by the Investigator or other authorized study 
personnel. All data entries will be verified for accuracy and correctness by independent 
monitors. The EDC system maintains a full audit trail.  
12.2 
Study Auditing and Monitoring 
Monitoring of the study site (including, but not limited to, reviewing eCRFs for accuracy and 
completeness) will be performed by the Sponsor’s designated monitor(s). The extent, nature, 
and frequency of on-site visits will be based on such considerations as the study objectives 
and/or endpoints, the purpose of the study, study design complexity, and enrollment rate. By 
signing the protocol, the Investigator agrees that, within local regulatory restrictions and 
institutional and ethical considerations, authorized representatives of the Sponsor, a 
regulatory authority, and/or an IRB may visit the site to perform audits or inspections, 
including the drug storage area, study drug stocks, drug accountability records, participant 
charts and source documents, and other records related to study conduct. The purpose of the 
Sponsor audit or inspection is to systematically and independently examine all study-related 
activities and documents to determine whether the study-related activities were conducted, 
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and data recorded, analyzed, and accurately reported according to the protocol, the site’s 
standard operating procedures, GCP guidelines of the ICH, and any applicable regulatory 
requirements. The Investigator should contact the Sponsor immediately if contacted by a 
regulatory agency regarding an inspection. 
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13 
STATISTICAL METHODS  
The statistical methods to be employed in assessing the safety and efficacy of CA-008 in 
patients undergoing VHR in accordance with this Phase 1/2 study protocol are outlined 
below. Detailed descriptions of all summaries and analyses to be performed, including all 
secondary efficacy analyses and all safety analyses, will be provided in a SAP that will be 
finalized prior to database lock. The SAP will supersede the protocol with respect to the 
analyses specified.  
13.1 
Sample Size Justification 
In Part A and Part B, no formal statistical hypothesis testing is currently planned. The sample 
size of 8–12 initial patients in Part A, with the potential for expansion to 16, and 24–32 
patients in Part B have been selected empirically based on prior clinical trial experience with 
CA-008 and is considered sufficient for exploration of feasibility, PK, preliminary efficacy, 
tolerability and safety parameters. 
In Part C, a total of up to ~100 patients will be randomized in 2 parallel arms (1:1) with 
~50 patients in each arm to bring the total number of patients enrolled to ~150. Assuming a 
t-test for the difference in 2 independent means, a sample size of approximately 40 patients 
per group would provide approximately 80% power to detect a standardized effect size 
(Cohen’s d) of ~0.55 at a one-sided level of significance, alpha, of 0.05 in the primary 
efficacy endpoint of rest NRS AUC0-96. 
In Part C, randomization may be stratified based on the size of the ventral hernia:  
for example, < 4 cm vs. ≥ 4 cm. 
Alternative assumptions concerning the anticipated effect size lead to a different number of 
patients per group. The total number of patients to be enrolled in the study will not exceed 
~150.  
13.2 
Analysis Populations 
The following 6 analysis populations are planned for this study:  
Safety Population consists of all patients who received any part of a dose of study 
treatment. (Note this must include anyone who terminates early for lack of efficacy). 
PK Population consists of all patients who received a full dose of study treatment and 
completed at least one PK assessment. 
PK/QT Population for cQT analysis consists of all patients with at least one time 
point with both PK and QT data. 
Modified Intent-to-treat (mITT) Population consists of all patients who received any 
dose of study treatment. Per Protocol (PP) Population consists of all patients who 
received a full dose of study treatment and have evaluable NRS pain assessments at 
least through T96 (± 4 h)/Discharge. 
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Study Completers consists of all patients who received a full dose of study treatment 
and completed the entire study period through D29 + 2 days. 
Patients who discontinue study participation before or after randomization but prior to 
receiving study treatment will be replaced.  
Patients who are withdrawn or elect to withdraw after receiving study treatment will not be 
replaced. Those patients who withdraw during the inpatient phase of the study, will be asked 
to continue with assessments through T96 if they have not elected to withdraw from all 
aspects of study participation (see Section 10.2). Patients who elect to discontinue 
participation on or prior to D8 will be considered to have terminated as of the date of their 
election to discontinue; however, they will be asked to return to the study site one time to 
ensure that adequate wound healing has occurred (see Section 10.2). 
13.3 
Planned Analyses 
The final data analysis will be performed after all patients have either completed or have 
been discontinued from the study. Note: If after the surgery is underway, it becomes evident 
that the surgical mesh must be placed intra-peritoneally (i.e., IPOM technique), then the 
patient will not receive study drug. In Parts B and C, this patient would be considered 
randomized but not treated. 
The study will be unblinded after patient membership in each of the various analysis 
populations has been determined at a blinded data review meeting and upon confirmation of 
database lock. 
Any deviations from the analyses presented in the SAP will be detailed in the clinical study 
report. 
Progression from Part A to Part B will take place after a formal safety assessment has been 
completed showing that the total study drug dose, volume, allocation and technique is 
acceptably safe and feasible. The formal safety assessment will be conducted by the 
Sponsor’s medical monitor, the CRO medical monitor, the relevant Principal Investigator, 
and an independent medical monitor. 
Progression from Part B to Part C will take place after an (“interim”) analysis of 
unmonitored, unblinded data from Part B occurs including data through Day 15. This 
analysis will assess preliminarily the safety and tolerability of the active study drug as well as 
the duration and severity of postsurgical pain in the control group.  
Efficacy, PK, and other assessments will be summarized using appropriate descriptive 
statistics. A detailed methodology for the statistical analyses of the data collected in this 
study will be documented in the SAP, PK Analysis Plan and cQT Analysis Plan, which will 
be signed prior to the database lock. 
All safety assessments and baseline characteristics will be summarized using the Safety 
Population. All safety summaries will be grouped by the actual treatment received. Data from 
all patients receiving vehicle placebo will be combined for summaries.  
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Safety and tolerability will be evaluated by examining the occurrence of AEs, including 
TEAEs. AEs leading to discontinuation from the study, AEs related to study treatment, and 
AEs by severity will be summarized by treatment group. 
Actual values and change from baseline in clinical laboratory measures, vital signs, and 
ECGs will also be assessed and summarized by treatment group. These data will be 
summarized using descriptive statistics. Abnormal values will be determined and flagged in 
the listings. Laboratory shift tables displaying the change (number of patients) relative to the 
normal range from baseline to each study visit will also be presented by treatment for each 
test. The Investigator should exercise medical and scientific judgment in deciding whether an 
abnormal laboratory finding or other abnormal assessment is clinically significant.  
All data recorded in the study database will be included in data listings. Any spurious or 
erroneous data will be queried and followed up until satisfactorily resolved; if not resolvable, 
the data will be set to missing. 
Summary statistics—number of patients (n), mean, SD, standard error of mean (SEM), (if 
appropriate), median, minimum, and maximum—will be presented for continuous variables. 
Frequencies and percentages will be presented for categorical variables. Unless otherwise 
noted, percentages will be calculated using the total number of patients in the appropriate 
population and/or subgroup and per treatment group, where applicable. Changes from 
baseline for continuous outcomes will be presented as their corresponding continuous 
measures for post-baseline visits. All study data will be listed by treatment group, patient, 
and time point.  
Statistical testing including p-values and confidence intervals (CIs) will be presented as 
described in each section below.  
Tests of statistical significance will be 1-sided or 2-sided (as described in the SAP) at the 
0.05 level of significance. Because preliminary assessments of efficacy are the focus of 
efficacy analyses, no adjustments in the level of significance will be made for multiple 
comparison tests.  
13.4 
Study Patients and Demographics 
13.4.1 
Disposition and Withdrawals 
The numbers of patients randomized, completing, and withdrawing, along with reasons for 
withdrawal, will be tabulated overall and by treatment group. The number of patients in each 
analysis population will be reported. 
13.4.2 
Protocol Deviations 
Protocol deviations will be adjudicated and classified as major or minor during a blinded data 
review performed by the Sponsor and medical monitor prior to database lock and will be 
presented in a data listing. Major protocol deviations will be discussed in the Clinical Study 
Report.  
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13.4.3 
Demographics and Other Baseline Characteristics 
Demographic and baseline characteristics (including age, sex, race, weight, and height) will 
be summarized for each treatment group and for the overall population by descriptive 
statistics. Medical history and clinical laboratory tests will be listed. 
Prior and concomitant medications will be summarized by treatment group, by the number 
and percentage of patients taking each medication, classified using World Health 
Organization Drug Dictionary Anatomical Therapeutic Chemical classes and preferred terms. 
13.4.4 
Exposure  
Since this is a single dose study, study drug administration will be summarized in terms of 
total exposure by cohort and treatment group. 
13.4.5 
General Considerations 
All analyses will be performed using SAS® version 9.3 or higher. The Clinical Data 
Interchange Standards Consortium (CDISC) SDTM (Study Data Tabulation Model) domain 
data sets and the ADaM (Analysis Data Model) analysis data sets employed in generating the 
tables, figures, and listings (TFLs) specified in the SAP will be provided to the Sponsor 
along with the generated TFLs. The specifications for the domain data sets and analysis data 
sets will be provided in a separate document. 
The following conventions will be used throughout the study analysis: 
Time T0 for efficacy measures is the time of admission into the PACU and will be 
designated by T0.  
The timing of PK assessments is based on the time at pre-dose (2-10 minutes prior to 
the first study treatment instillation) designated PKT = 0. 
For safety assessments, TEAEs will be considered those AEs with onset after the 
beginning of study treatment administration. 
Day of surgery/study treatment administration is defined as D1. 
Elapsed assessment visit times are defined by time elapsed from T0 or D1. 
The baseline value of any parameter is defined as the last valid measurement of that 
parameter prior to the beginning of study treatment administration. 
The change from baseline value of a parameter is defined as the post-baseline value 
minus the baseline value. 
Duration of an AE will be computed in days for AEs lasting longer than 24 hours, and 
as hours for AEs lasting less than 24 hours. Missing dates will be imputed as 
described in the SAP. 
 
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13.4.6 
Analysis of Efficacy Measures 
All efficacy endpoints using NRS scores will be summarized over time by cohort and 
treatment using descriptive statistics including confidence intervals as appropriate. 
There are no efficacy endpoints for Part A and Part B. 
In Part C, the primary efficacy endpoint is the area under the curve (AUC) for NRS at rest 
versus time from T0 to T96 (AUC0-96). NRS AUC is the weighted SPI assessments for a 
specified time interval. 
AUC calculations will be done using the standard trapezoidal rule:  
 
AUC𝑇1−𝑇2 = ∑
NRS𝑖−1 + NRS𝑖
2
𝑛
𝑖=1
(𝑡𝑖−𝑡𝑖−1) 
 
Where 𝑁𝑅𝑆𝑖 = NRS at time i, n is the number of minutes between T1 and T2, and (𝑡𝑖−𝑡𝑖−1) 
is the time difference in minutes between time i and time i − 1. A similar calculation and 
handling of missing data will be performed for the NRS scores with position changes. 
Missing NRS values will be handled as discussed in the SAP.  
The AUC analyses will be presented in a summary table with standard summary statistics for 
each dose cohort and placebo as well as active vs. placebo mean differences, standard errors, 
confidence intervals, and comparison p-values, as appropriate. Comparisons of individual 
dose cohorts for dose response may also be presented for certain secondary AUC endpoints. 
Mean NRS scores over time (in-clinic and diary) will be graphed over time by treatment 
group. NRS over time by each patient may also be displayed graphically as warranted. The 
individual NRS and the computed AUC values will be listed for all individual patients.  
In this study, patients are permitted to take rescue medication for analgesia. It is anticipated 
that patients randomized to placebo will take rescue medication more often than patients on 
active treatment. During both inpatient and outpatient portions of the studies, a pre-rescue 
NRS should be recorded just prior to taking rescue medication, i.e., reflecting the pain level 
triggering the need for rescue analgesia. 
For patients who take rescue medication a windowed last pain score carried forward 
(wLOCF) will be used in the calculation of the NRS AUC. The pre-rescue pain score will be 
used to impute scheduled assessments for 30 minutes following the rescue use when IV 
fentanyl is used, 2 hours when IV hydromorphone is used, and 4 hours when PO oxycodone 
is used. Intermittent missing pain scores (due to patient sleeping, etc.) will not be imputed, 
and AUC will be calculated based on non-missing values.  
Sensitivity analyses of the primary efficacy variable using additional methods of imputation 
for rescue medication may also be performed. Exploratory analyses of the primary efficacy 
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variable using alternative methods may also be performed, e.g., mixed effects modeling and 
Silverman Rank Analysis. In addition, exploratory analyses of combined active vs. placebo 
and high-dose active vs low-dose active may be performed. Information is provided in the 
SAP. 
For secondary continuous efficacy endpoints based on the NRS scores, similar methods as 
the primary analysis will be used.  
13.4.7 
Handling of Dropouts or Missing Data 
All efforts will be made to minimize missing data. These efforts will include the following: 
Data will be collected regardless of study status or rescue use unless patient 
withdraws consent or is lost to follow up; 
Continue data collection after patients take rescue medication. 
With the procedures above, it is expected that the missing data would be minimal and 
random. Additional sensitivity analyses may be performed to assess the robustness of 
analysis conclusions, if warranted; details will be presented in the SAP.  
For patients who drop out of the study prior to D15 due to lack of efficacy (LOE) or AEs, 
scheduled assessments may be imputed using worst prior pain score carried forward. For 
patients who drop out of the study prior to D15, scheduled NRS assessments will first be 
imputed using the worst prior pain score carried forward (WOCF).  
As sensitivity analyses, the NRS AUC may also be calculated where, for each patient, 
assessments after dropout will be imputed by: (1) using LOCF; (2) using the last scheduled 
non-missing NRS prior to drop out; (3) the median NRS of the patients continuing in the 
study who are from the same treatment group as the dropout patients; and (4) without 
imputation of missing data.  
For categorical endpoints, when assessments are to be imputed for data after a patient 
discontinues from the study, a WOCF method or Worst Case will be used (e.g., for the 
PROMIS 10 Global, imputed value would be ‘Poor’). Sensitivity analyses using additional 
methods of imputation may be performed.  
All imputation methods for pain intensity will be documented in the SAP. 
13.4.8 
Analysis of Safety  
Analysis of safety will be performed for the Safety population (as defined in Section 13.2).  
All safety summaries will be grouped by the actual treatment received. Data from all patients 
receiving vehicle placebo will be combined for summaries.  
Actual values and change from baseline clinical laboratory measures, vital signs, ECGs, PE, 
surgical site, and neurosensory assessments will be assessed and summarized by treatment 
group.  
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No formal statistical comparisons will be performed for safety endpoints. 
13.4.8.1 
Adverse Events 
Adverse events will be coded by system organ class (SOC) and preferred term using the 
Medical Dictionary for Regulatory Activities (MedDRA) reporting system. 
Treatment-emergent AEs are defined as any of the following: 
Non-serious AEs with onset on the date of treatment with the study drug through D29 
or Early Termination, whichever occurs first;  
Serious AEs with onset on the date of treatment with the study drug through 30 days 
after D29 or Early Termination, whichever occurs first; 
AEs that start before the start of treatment but increase in severity or relationship at 
the time of or following the start of treatment through D29 or Early Termination, 
whichever occurs first. 
 
Safety and tolerability will be evaluated by examining the occurrence of AEs, including 
TEAEs. AEs leading to discontinuation from the study, AEs related to study treatment, and 
AEs by the maximum severity will be summarized by treatment group. The number and 
percentage of patients with TEAEs will be displayed for each treatment group by SOC and 
preferred term. Additionally, TEAEs will be tabulated for each treatment group by severity 
and by relationship to the study drug. A listing of SAEs will be provided, if applicable. 
13.4.9 
Clinical Laboratory Evaluations 
For continuous laboratory parameters, descriptive statistics will be presented for the value at 
each assessment time and for the changes from baseline by treatment group.  
Additionally, clinical laboratory parameters will be categorized as low, normal, or high 
according to laboratory range specifications. Laboratory shift tables displaying the change 
(number of patients) relative to the normal range from baseline to each study visit will also 
be presented by treatment for each test.  
Laboratory values that are outside the normal range will also be flagged in the data listings, 
along with corresponding normal ranges. 
13.4.10 
Vital Signs and ECG 
Descriptive summaries (mean, SD, median, minimum, and maximum) of actual values and 
changes from Baseline will be calculated for vital signs and ECGs. A detailed description of 
these analyses will be included in the SAP. 
The incidence of abnormal ECG findings will be summarized for each visit.  
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The PK/PD relationship of CA-008, capsaicin and CA-101 will be investigated with respect 
to Holter evaluation of QT interval. A description of the analysis will be presented in a 
separate cQT Analysis Plan. 
13.4.11 
Physical Examination Findings 
Physical examination and surgical site examination data will be presented in the listings. 
Abnormal or clinically significant PE and surgical site examination findings will be recorded 
as AEs. 
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14 
SITE AND INVESTIGATOR RESPONSIBILITIES 
Additional details may be outlined in the Clinical Study Agreement between the Sponsor and 
the investigational site.  
14.1 
Regulatory and Ethical Considerations 
14.1.1 
Ethical Conduct of the Study 
The Investigator will conduct the study in accordance with GCP and all applicable 
regulations, including, where applicable, the Declaration of Helsinki. The study will also be 
carried out in keeping with applicable national and local laws and regulations. This may 
include an inspection by the Sponsor’s representatives and/or regulatory authority’s 
representatives at any time. 
14.1.2 
Ethics Approval 
The investigational site’s IRB must meet all relevant regulatory requirements. The study 
protocol and ICF will be reviewed by the IRB prior to enrolling participants into the study; 
written approval from the committee must be received by the Sponsor before drug will be 
released to the Investigator. The Investigator is responsible for submitting all protocol or ICF 
changes and SAE reports to the IRB according to local procedures. At a minimum, all SAEs 
requiring an investigational new drug safety report must be immediately reported. 
In accordance with applicable local regulatory requirements, the Investigator may be 
obligated to provide periodic safety updates on the conduct of the study at his or her research 
site and notification of study closure to the IRB. Such periodic safety updates and 
notifications are the responsibility of the Investigator and not of the Sponsor. The Sponsor 
will be provided with copies of all notifications sent to the IRB. 
All relevant correspondence from the IRB will be forwarded by the respective study site to 
the Sponsor in a timely fashion. 
14.1.3 
Patient Informed Consent 
The Investigator (or authorized designee) will ensure that the participant (or the participant’s 
legal representative) is given full and adequate oral and written information about the nature, 
purpose, potential and possible risks and benefits of the study. Each prospective patient will 
receive an IRB-approved ICF that summarizes the pertinent study information and will be 
given ample time to read the form and ask questions about the study. All information is to be 
provided in a language understandable to the participant and must not include any language 
that waives the participant’s legal rights. Prospective participants must also be informed of 
their right to withdraw consent without prejudice at any time during the study. If the 
participant chooses to participate, he/she must sign the ICF before any study-related 
procedures are performed.  
Significant changes to the protocol or product safety information may require a revision of 
the ICF, which must be reviewed and signed by all applicable study participants. 
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The time that informed consent is obtained must be documented. The Investigator must 
maintain the original, signed ICF in the participant’s source documents. A copy of the signed 
ICF must be given to the study participant. 
14.2 
Privacy and Confidentiality 
The Investigator is responsible for complying with applicable privacy regulations, per his or 
her jurisdiction. Only information identified in this protocol will be collected. The 
information collected will only be used for the purposes identified in this protocol. 
To ensure anonymity and to limit disclosure, participants will be assigned a unique identifier 
at their first assessment. This identifier will be cross-referenced in the participant’s chart. The 
identifier will not contain any potentially identifiable information. An identifier log will be 
maintained, linking each participant’s name to the corresponding identifier. This log will be 
stored at the research site in a secure location. 
The knowledge gained through this study is the property of the Sponsor. The Sponsor, 
representatives and affiliated companies of the Sponsor, the IRB, and regulatory agencies 
(such as the US FDA) may inspect medical records related to the study to check the validity 
and accuracy of the data gathered in this study. Participant medical records (with 
participant’s initials and/or date of birth) may be copied. Confidentiality of participant 
records will be maintained except where release of information is required by law.  
The results of this study will be reported in such a manner that participants will not be 
identifiable in any way. Published reports or presentations will refer to grouped data or coded 
individual data and not to any identifiable individuals. Study reports sent to the Sponsor or 
drug regulatory agencies will not include participant names. 
By signing the ICF, the participant consents to the collection, access, use, and disclosure of 
his or her information as described in the ICF document. If a participant withdraws consent, 
some of the patient’s information may still be collected, used, and disclosed by those 
involved in this study, per applicable laws.  
By signing this protocol, the Investigator affirms that he or she will maintain in confidence 
information furnished to him or her by the Sponsor and will divulge such information to his 
or her respective IRB or Independent Ethics Committee (IEC) under an appropriate 
understanding of confidentiality with such board. All data will be considered the sole 
property of the Sponsor. Please refer to the Clinical Study Agreement for details. 
14.3 
Study and Site Closure 
Upon completion of the study, all study data will be provided to the Sponsor following 
review of site study records for completeness, and data clarifications and resolutions. 
Accounting, reconciliation, and final disposition of used and unused study drugs, treatment 
codes, and emergency code break envelopes will be performed, as applicable. 
In addition, the Sponsor reserves the right to temporarily suspend or prematurely discontinue 
this study at any time and for any reason. If such action is taken, the Sponsor will discuss this 
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with the Investigator (including the reasons for taking such action) at that time. The Sponsor 
will promptly inform any other Investigators and/or institutions conducting the study, if the 
study is suspended or terminated for safety reasons and will inform the regulatory authorities 
of the suspension or termination of the study and the reason(s) for the action. If required by 
applicable regulations, the Investigator will inform the IRB promptly and provide the study 
participants with the reason for the suspension or termination. If the study is prematurely 
discontinued, all study data will be returned to the Sponsor.  
14.4 
Regulatory Documents and Records Retention 
The Investigator is responsible for creating and/or maintaining all study documentation 
required by 21 CFR 50, 54, 56 and 312, ICH E6 section 8, as well as any other 
documentation defined in the protocol or Clinical Study Agreement. The Investigator must 
provide key documents to the Sponsor prior to the start of the study. A complete list of 
required regulatory documents will be supplied by the Sponsor or its representative. 
Federal and local regulations require that the Investigator retain a copy of all regulatory 
documents and records that support the data for this study for whichever of the following is 
the longest period of time: 
A period of 2 years following the final date of approval by the FDA or other 
regulatory agency of the study drug for the purposes that were the patient of the 
investigation; or 
A period of 5 years following the date on which the results of the investigation were 
submitted to the FDA or other regulatory agency in support of, or as part of, an 
application for a research or marketing permit for the study drug for the purposes that 
were the patient of the investigation. 
 
The Sponsor will notify Investigators once one of the above 2 timeframes has been satisfied. 
If the investigation does not result in the submission of the data in support of, or as part of, an 
application for a research or marketing permit, records must be retained for a period of 
2 years following notification by the Sponsor that the entire clinical investigation (not merely 
the Investigator’s portion) is completed, terminated, or discontinued or 2 years following 
withdrawal of the Investigational New Drug application/Clinical Trial Authorization or 
request for marketing approval (New Drug Application/Marketing Authorization 
Application).  
If the Investigator retires, relocates, or for other reasons withdraws from the responsibility of 
keeping the study records, custody must be transferred to a person who will accept the 
responsibility. The Sponsor must be notified in writing of the name and address of the new 
custodian. Study records should not be destroyed without consultation with the Sponsor. 
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14.5 
Delegation of Responsibilities and Adequate Resources 
The Investigator should have adequate time to conduct the study properly and should have an 
adequate number of qualified staff to assist with the conduct of the study.  
The term “Investigator” used throughout this protocol refers to the PI and/or qualified 
sub-Investigators. However, the Investigator may delegate responsibilities to other 
investigational site personnel. The Investigator shall delegate tasks only to individuals 
qualified by education, training and experience to perform the delegated tasks. The 
Investigator shall have direct oversight of all delegated activities and shall document 
delegation of responsibilities. The Investigator is responsible for ensuring all delegated staff 
has been properly trained on the protocol and their assigned study responsibilities. A 
delegation log identifying all delegated duties and the individual to whom they have been 
delegated will be maintained at the investigational site.  
14.6 
Protocol Amendments 
Approval of a protocol amendment by the Investigator’s IRB must be obtained before 
implementation of the protocol amendment, unless a change is necessary to eliminate an 
apparent immediate hazard to the participant or when the change involves logistical or 
administrative aspects of the study. The protocol amendment must be signed and dated by 
both the Sponsor and the Investigator. The Sponsor or designee will submit protocol 
amendments to the appropriate regulatory authorities, if required. 
14.7 
Financial Disclosure 
Clinical Investigators are required to provide financial disclosure information for the 
submission of certification or disclosure statements required under 21 CFR § 54. As defined 
in 21 CFR § 54.2, a clinical Investigator is a listed or identified Investigator or 
sub-Investigator who is directly involved in the treatment or evaluation of research 
participants. The term also includes the spouse and each dependent child of the Investigator. 
In addition, Investigators must promptly update financial disclosure information if any 
relevant changes occur during the course of the investigation and for 1 year following 
completion of the study. 
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15 
INVESTIGATOR PROTOCOL AGREEMENT PAGE 
A Three-Part, Phase 1/2, Randomized, Double-blind, Placebo-Controlled, Adaptive Safety, 
Pharmacokinetics, and Preliminary Efficacy Study of CA-008 in Patients Undergoing 
Ventral Hernia Repair 
 
Amendment 2 
Date: March 15, 2021 
 
 
I have read this protocol and I agree to conduct the study in accordance with the protocol and 
with all applicable government regulations and International Conference on 
Harmonisation/Good Clinical Practice guidelines. 
 
Principal 
Investigator’s Name 
  
(please print or type) 
  
 
 
 
 
 
 
 
Principal Investigator’s Signature 
 
Date  
(DD-MMM-
YYYY) 
 
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16 
REFERENCES 
1. Babbar S, Marier JF, Mouksassi MS, et al. Pharmacokinetic analysis of capsaicin after 
topical administration of a high-concentration capsaicin patch to patients with peripheral 
neuropathic pain. Ther Drug Monit. 2009;31:502-10. 
2. Caterina MJ, Julius D. The vanilloid receptor: a molecular gateway to the pain pathway. 
Annu Rev Neurosci. 2001;24:487-517. 
3. Hartrick CT, Pestano C, Carlson N, Hartrick S. Capsaicin instillation for post-operative 
pain following total knee arthroplasty: a preliminary report of a randomized, double-
blind, parallel-group, placebo-controlled, multicentre trial. Clin Drug Investig. 2011 Dec 
1;31(12):877-82. 
4. Suresh D, Srinivasan K. Tissue distribution & elimination of capsaicin, piperine & 
curcumin following oral intake in rats. Indian J Med Res. 2010;131:682-91. 
5. Surh YJ, Lee RC, Park KK, et al. Chemoprotective effects of capsaicin and diallyl sulfide 
against mutagenesis or tumorigenesis by vinyl carbamate and N-nitrosodimethylamine. 
Carcinogenesis 1995;16:2467-71. 
6. Tominaga M, Caterina MJ, Malmberg AB, Rosen TA, Gilbert H, Skinner K, Raumann 
BE, Basbaum AI, Julius D. The cloned capsaicin receptor integrates multiple pain-
producing stimuli. Neuron 21, 1998;531-43. 
 
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17 
APPENDICES 
17.1 
Appendix A: Toxicity Grading Scale for Systemic (General) Adverse 
Events 
The following table is excerpted from the Guidance for Industry: Toxicity Grading Scale 
for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical 
Trials. The grading system can be “useful in defining a particular study’s stopping rules 
(e.g., a certain number of AEs, as defined in the table, may call for stopping the study.)”  
The Guidance may be found in its entirety at: 
https://www.fda.gov/downloads/BiologicsBloodVaccines/ucm091977. 
The Investigator may find this useful for grading common systemic (general) TEAEs 
reported after surgery. 
 
 
 
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17.2 
Appendix B: American Society of Anesthesiologists Physical Status 
Classification System (ASA Class) 
 
*The addition of “E” denotes Emergency surgery: (An emergency is defined as existing 
when delay in treatment of the patient would lead to a significant increase in the threat to life 
or body part)  
Available at: https://www.asahq.org/resources/clinical-information/asa-physical-status-
classification-system 
 
 
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17.3 
Appendix C: Toxicity Grading Scale for Clinical Vital Sign 
Abnormalities 
The following guidance is excerpted from the Common Terminology Criteria for Adverse 
Events (CTCAE) v5.0 (November 27, 2017) as a reference. CTCAE v5.0 and prior versions 
are available at https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
The grading system can be “useful in defining a particular study’s stopping rules (e.g., a 
certain number of AEs, as defined in the table, may call for stopping the study.)”  
 
 
 
 
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These excerpts are from various sections within CTCAE v5.0: 
 
 
 
 
 
 
 
 
 
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17.4 
Appendix D: Toxicity Grading Scale for Clinical Laboratory 
Abnormalities 
The following tables are excerpted from the Guidance for Industry: Toxicity Grading 
Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine 
Clinical Trials. The grading system can be “useful in defining a particular study’s stopping 
rules (e.g., a certain number of AEs, as defined in the table, may call for stopping the study.)”  
The Guidance may be found in its entirety at: 
https://www.fda.gov/downloads/BiologicsBloodVaccines/ucm091977. 
For clinical laboratory values not covered in this Guidance, the Common Terminology 
Criteria for Adverse Events (CTCAE) v5.0 (November 27, 2017) may be useful as a 
reference. CTCAE v5.0 and prior versions are available at: 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  
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17.5 
Appendix E: 0 to 10 Numerical Rating Scale of Pain Intensity (NRS) 
Pain Intensity - Numerical Rating Scale (NRS) 
On a scale of 0-10, please rate your pain by marking the appropriate box that best describes 
your pain NOW. 
 
£0 
£1 
£2 
£3 
£4 
£5 
£6 
£7 
£8 
£9 
£10 
No Pain 
 
 
 
 
 
 
 
 
Worst pain 
imaginable 
 
Patient Initials: __________ 
 
 
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17.6 
Appendix F: PROMIS 10 GLOBAL Health Questionnaire 
 
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PROMIS v.1.1 - Global 
 
 
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17.7 
Appendix G: Activities Assessment Scale (AAS) 
 
 
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17.8 
Appendix H: Sit to Stand Test (30-Second Chair Stand) Assessment 
 
 
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17.9 
Appendix I: TUG Test 
 
 
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17.10 
Appendix J: Surgical Site Assessment 
The Investigator should grade the level of satisfaction with wound healing using this 0-10 
scale with 0=completely unsatisfied and 10=completely satisfied. 
 
Post-Operative Surgical Site Assessment 
Instructions to Investigator: Please respond to the question below. When completed, please initial at the 
bottom of the page. 
On a scale of 0 to 10, please rate your clinical satisfaction with the wound healing.  
£0 
£1 
£2 
£3 
£4 
£5 
£6 
£7 
£8 
£9 
£10 
Completely 
unsatisfied 
 
 
 
 
 
 
 
Completely satisfied 
 
Investigator Initials: __________ 
 
The assessment of satisfaction with wound healing should be performed with what is 
typically observed for surgeries of this type in the Investigator’s clinical opinion. The 
surgical wound AE grading scale in Appendix K may be helpful if there is an atypical or 
abnormal finding. 
 
 
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17.11 
Appendix K: Surgical Wound Adverse Event Grading Guide  
The Investigator may find the following table to be a useful guide for grading specific AEs 
using this 4-point categorical scale for common wound complications. The Investigator 
should use clinical discretion in determining whether the particular parameter is atypical or 
unusual compared to what is expected as a typical healing process. 
 
PARAMETER 
GRADE 
DESCRIPTION 
ERYTHEMA 
0 
NONE 
1 
VERY SLIGHT (BARELY PERCEPTIBLE) 
2 
SLIGHT (WELL DEFINED) 
3 
MODERATE  
4 
SEVERE (BEET REDNESS) TO SLIGHT ESCHAR 
FORMATION (INJURIES IN DEPTH) 
DRAINAGE 
0 
NONE 
1 
SEROUS 
2 
SEROSANGUINOUS 
3 
BLOODY 
4 
PURULENT 
EDEMA 
0 
NONE 
1 
VERY SLIGHT (BARELY PERCEPTIBLE) 
2 
SLIGHT (EDGES WELL DEFINED) 
3 
MODERATE (RAISED APPROXIMATELY 1 MM) 
4 
SEVERE (RAISED >1 MM AND BEYOND AREA OF 
EXPOSURE) 
INDURATION 
0 
NONE 
1 
MINIMAL 
2 
MILD (SPONGY TISSUE) 
3 
MODERATE (FIRM, WARM) 
4 
SEVERE (HARD, RED, HOT, CREPITUS) 
HEMATOMA 
0 
NONE 
1 
MINIMAL 
2 
MILD 
3 
MODERATE 
4 
SEVERE 
 
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17.12 
Appendix L: Neurosensory Examination Form 
Was the neurosensory exam completed?  
___ Yes 
 ___ No 
Date of Assessment 
______________ 
Time of Assessment ___: ___ 
 
 
 
Neurosensory testing should be performed in an area approximately 5 cm above and below 
the surgical incision site compared to the control site. The instructions below may assist the 
Investigator or designee in performing neurosensory testing. 
Visual Examination of Surgical Site: For this examination, report any findings 
observed during visual inspection of the surgical site. 
Light Touch Testing: For this examination, using the tip of your finger or a piece of 
cotton, briefly touch rather than stroke the patient’s skin at the location to be assessed. 
Ask the patient to close their eyes and indicate when the touch is felt. 
Monofilament (von Frey) Testing: For this examination, the filament should 
initially be prestressed (4-6 perpendicular applications to the dorsum of the 
examiner’s first finger). The filament is then applied perpendicularly at the location to 
be assessed and briefly, (<1 second) with even pressure. When the filament bends, the 
force of 10 grams has been applied. The patient, whose eyes are closed, is asked to 
respond yes if he / she feels the filament. Eight correct responses out of 10 
applications is considered normal: one to seven correct responses indicate reduced 
sensation and no correct responses translates into absent sensation.  
Testing for Allodynia: Performed at the location to be assessed using a foam brush. 
Note that allodynia testing is best assessed by using the foam brush, and while it may 
be elicited using von Frey filament testing, document presence of allodynia only with 
brush stimulation. For allodynia assessment the foam brush will be lightly stroked 3 
times across the skin in the location to be assessed. Patient will be asked to compare 
Caudad to Wound 
Visual Exam of the surgical site ___ Normal ___ Abnormal, describe: _______________ 
Light Touch  
 
 
___ Normal ___Reduced ___ Absent 
Von Frey Stimulation 
 
___Normal ___ Reduced ___ Absent 
Brush Stimulation 
 
___ Normal ___ Reduced ___ Absent ___ Pain (Allodynia) 
Cephalad to Wound 
Visual Exam of the surgical site ___ Normal ___ Abnormal, describe: _______________ 
Light Touch  
 
 
___ Normal ___Reduced ___Absent 
Von Frey Stimulation 
 
___Normal ___ Reduced ___Absent 
Brush Stimulation 
 
___ Normal ___ Reduced ___ Absent ___ Pain (Allodynia) 
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sensation to the control site just distal to the costal margin. If the sensation is 
described as painful or very unpleasant then allodynia will be reported as present. If 
sensation is slightly unpleasant or mildly irritating compared to the control area, then 
hyperaesthesia will be reported as present. If patient reports the stimulus as the same 
as the control area, then sensation will be reported as normal. If sensation is less than 
the control area then sensation will be reported as reduced, and if sensation is not felt 
as all then it will be reported as absent.  
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SAP_001.pdf: 
Concentric Analgesics, Inc. 
Protocol Name:  CA-PS-209 
Protocol Title:  A Three-Part, Phase 1/2, Randomized, Double-blind, Placebo Controlled, Adaptive Safety, 
Pharmacokinetics, and Preliminary Efficacy Study of CA-008 (Vocacapsaicin) in Patients Undergoing 
Ventral Hernia Repair  
Investigational Product: CA-008 by Injection/Instillation 
IND: 129114 
NCT:  04774328 
Statistical Analysis Plan, dated 14 May 2021 


Sponsor: Concentric Analgesics, Inc. 
 
Statistical Analysis Plan  
Protocol Number: CA-PS-209 
 
Date: 14MAY2021 
 
CONFIDENTIAL 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN  
 
A Three-part, Phase 1/2, Randomized, Double-blind, Placebo-controlled, 
Adaptive Safety, Pharmacokinetics, and Preliminary Efficacy Study of CA-008 
(Vocacapsaicin) in Patients Undergoing Ventral Hernia Repair 
 
Protocol Number:  CA-PS-209 
Protocol Version Amendment 2 (15MAR2021) 
 
SPONSORED BY 
Concentric Analgesics, Inc. 
 
PREPARED BY 
Lotus Clinical Research®, LLC 
100 W California Blvd, Unit 25 
Pasadena, CA 91105 
626-397-2390 office 
info@LotusCR.com 
www.LotusCR.com 
 
This document is confidential and proprietary to Concentric Analgesics, Inc.  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 Concentric Analgesics, Inc., 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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Statistical Analysis Plan 
Protocol Number: CA-PS-209 
Date: 14MAY2021 
 
CONFIDENTIAL 
                                                                      Page 2 of 78 
 
DOCUMENT VERSION CONTROL 
Version Number 
Date 
Comments/Changes 
Final 1.0 
14MAY2021 
SAP  
 
 
 
 
 
 
 
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Sponsor: Concentric Analgesics, Inc. 
Statistical Analysis Plan 
Protocol Number: CA-PS-209 
Date: 14MAY2021 
 
CONFIDENTIAL 
                                                                      Page 3 of 78 
 
APPROVALS 
Author: 
 
 
 
 
__________________________________  
 
 
________________ 
 
Swarupa Changan 
 
 
 
 
 
 
Date 
 
Biostatistician 
 
Quartesian 
 
 
Reviewed: 
 
 
 
 
__________________________________  
 
 
________________ 
 
Isaac Briskin  
 
 
 
 
 
 
Date 
 
Biostatistician 
 
Lotus Clinical Research®, LLC 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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20-May-21


Sponsor: Concentric Analgesics, Inc. 
Statistical Analysis Plan 
Protocol Number: CA-PS-209 
Date: 14MAY2021 
 
CONFIDENTIAL 
                                                                      Page 4 of 78 
Approved: 
 
 
 
 
__________________________________  
 
 
________________ 
 
Sam Teichman, MD  
 
 
 
 
 
Date 
 
VP, Head of Clinical Development 
 
Concentric Analgesics, Inc. 
 
 
 
 
 
__________________________________  
 
 
________________ 
 
Henry C. Foehl, PhD  
 
 
 
 
 
Date 
 
Consultant to Concentric Analgesics, Inc. 
 
Foehl Statistics & Analytics LLC 
 
 
 
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Sponsor: Concentric Analgesics, Inc. 
Statistical Analysis Plan 
Protocol Number: CA-PS-209 
Date: 14MAY2021 
 
CONFIDENTIAL 
                                                                      Page 5 of 78 
 
TABLE OF CONTENTS 
 
1. 
PURPOSE OF THE ANALYSES .................................................................................... 10 
2. 
PROTOCOL SUMMARY ................................................................................................. 11 
2.1 
Study Objectives ................................................................................................. 11 
2.1.1 
Part A of the Study .............................................................................................. 11 
2.1.2 
Part B of the Study .............................................................................................. 11 
2.1.3 
Part C of the Study .............................................................................................. 12 
2.2 
Overall Study Design and Plan ........................................................................... 12 
2.2.1 
Study Assessment Schedule ............................................................................... 14 
2.2.2 
Study Population ................................................................................................. 14 
2.2.3 
Treatment Regimens ........................................................................................... 14 
2.2.4 
Treatment Group Assignments or Randomization .............................................. 19 
2.2.5 
Sample Size Determination ................................................................................. 19 
3. 
GENERAL ANALYSIS AND REPORTING CONVENTIONS .......................................... 21 
4. 
ANALYSIS POPULATIONS ............................................................................................ 24 
4.1 
Analysis Populations ........................................................................................... 24 
4.2 
Disposition of Patients ......................................................................................... 25 
4.3 
Protocol Deviations ............................................................................................. 25 
5. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ................................. 26 
5.1 
Demographics and Baseline Characteristics ....................................................... 26 
5.2 
Medical History .................................................................................................... 26 
6. 
MEASUREMENTS OF TREATMENT EXPOSURE AND COMPLIANCE ....................... 28 
7. 
EFFICACY EVALUATION ............................................................................................... 29 
7.1 
Handling of Dropouts or Missing Data ................................................................. 29 
7.2 
Efficacy Endpoints ............................................................................................... 29 
7.2.1 
Primary Efficacy Endpoint ................................................................................... 29 
7.2.2 
Key Secondary Efficacy Endpoints...................................................................... 29 
7.2.3 
Exploratory Efficacy Endpoints ............................................................................ 29 
7.2.4 
NRS Pain Intensity Measurements...................................................................... 30 
7.2.5 
Handling of NRS Pain Intensity Scores Post Rescue Medication 
Use ...................................................................................................................... 31 
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Protocol Number: CA-PS-209 
Date: 14MAY2021 
 
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7.2.6 
Imputation of Missing Data for Efficacy Assessments ......................................... 33 
7.2.7 
NRS AUC Calculation ......................................................................................... 34 
7.2.8 
Total Opioid Consumption ................................................................................... 35 
7.2.9 
Total Non-opioid Analgesic Consumption ........................................................... 35 
7.2.10 Performance-based Outcome Measures (PBOMs) ............................................. 35 
7.2.11 PROMIS 10 Global Health Questionnaire ........................................................... 36 
7.2.12 Activities Assessment Scale ................................................................................ 36 
7.3 
Analysis Methods ................................................................................................ 36 
7.3.1 
General Considerations ....................................................................................... 37 
7.3.2 
Pooling of Data .................................................................................................... 37 
7.3.3 
Primary Efficacy Endpoint ................................................................................... 37 
7.3.4 
Other AUC Endpoints, Total Opioid Consumption, and Total Non-
opioid Analgesic Consumption Endpoints ........................................................... 41 
7.3.5 
Time to Cessation of Opioid Use ......................................................................... 41 
7.3.6 
Patients Who Are Opioid-free .............................................................................. 42 
7.3.7 
Time-specific Mean Rest NRS Scores ................................................................ 42 
7.3.8 
Performance-Based Outcome Measure (PBOM). ............................................... 43 
7.3.9 
PROMIS 10 Global Health Questionnaire Scores and AAS ................................ 44 
7.3.10 Other Binary Endpoints ....................................................................................... 45 
8. 
SAFETY EVALUATION .................................................................................................. 47 
8.1 
Overview of Safety Analysis Methods ................................................................. 47 
8.2 
Adverse Events ................................................................................................... 47 
8.2.1 
Adverse Event Summaries .................................................................................. 49 
8.2.2 
Deaths, Serious Adverse Events, Adverse Events Leading to 
Withdrawal ........................................................................................................... 50 
8.3 
Clinical Laboratory Test Results .......................................................................... 50 
8.4 
Drugs of Abuse and Alcohol Screens, Pregnancy Test ....................................... 51 
8.5 
Vital Signs ........................................................................................................... 51 
8.6 
ECG ..................................................................................................................... 52 
8.7 
Physical Examination .......................................................................................... 52 
8.8 
Surgical Site Assessments .................................................................................. 52 
8.9 
Neurosensory Test .............................................................................................. 53 
8.10 
Prior and Concomitant Medications..................................................................... 53 
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Statistical Analysis Plan 
Protocol Number: CA-PS-209 
Date: 14MAY2021 
 
CONFIDENTIAL 
                                                                      Page 7 of 78 
8.11 
Patient Pain Assessment Training and Surgery Details ...................................... 54 
9. 
PHARMACOKINETIC EVALUATION ............................................................................. 55 
10. 
OTHER ANALYSES ........................................................................................................ 55 
11. 
DEVIATIONS FROM THE SAP ...................................................................................... 56 
12. 
CHANGES IN CONDUCT OR PLANNED ANALYSES FROM THE 
PROTOCOL .................................................................................................................... 57 
13. 
EXAMPLE SAS CODE .................................................................................................... 58 
14. 
REFERENCES ................................................................................................................ 60 
15. 
APPENDICES ................................................................................................................. 61 
15.1 
0 to 10 Numerical Rating Scale of Pain Intensity (NRS) ..................................... 61 
15.2 
Scoring of PROMIS 10 Questionnaire ................................................................. 62 
15.3 
Activities Assessment Scale (AAS) ..................................................................... 66 
15.4 
Sit to Stand Test (30-Second Chair Stand) Assessment ..................................... 67 
15.5 
TUG Test ............................................................................................................. 68 
15.6 
Surgical Site Assessment .................................................................................... 69 
15.7 
Planned Tables, Figures, and Listings ................................................................ 70 
15.7.1 Tables .................................................................................................................. 70 
15.7.2 Figures ................................................................................................................ 75 
15.7.3 Listings ................................................................................................................ 76 
16. 
DOCUMENT HISTORY .................................................................................................. 78 
 
 
 
LIST OF IN-TEXT TABLES 
Table 1. 
Schedule of Assessments – Part A,Part B and Part C ................... 15 
 
 
 
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Statistical Analysis Plan 
Protocol Number: CA-PS-209 
Date: 14MAY2021 
 
CONFIDENTIAL 
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LIST OF ABBREVIATIONS 
AC 
Analgesic Consumption 
ADaM 
Analysis Data Model 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
ANOVA 
Analysis of Variance 
ATC 
Anatomical Therapeutic Chemical 
AUC 
Area Under the Curve 
BMI 
Body Mass Index 
CI 
Confidence Interval 
cQT 
Plasma Concentration–QT 
CRO 
Clinical Research Organization 
CSR 
Clinical Study Report 
 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
ET 
Early Termination 
FDA 
Food and Drug Administration 
FSH  
Follicle Stimulating Hormone 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization  
IV 
Intravenous 
LOCF 
Last Observation Carried Forward 
LOE 
Lack of Efficacy 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified Intent-To-Treat 
NRS 
Numerical Rating Scale for Pain Intensity  
OC 
Opioid Consumption  
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Statistical Analysis Plan 
Protocol Number: CA-PS-209 
Date: 14MAY2021 
 
CONFIDENTIAL 
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OF 
Opioid Free  
OME 
Oral Morphine Equivalent  
PACU 
Post-Anesthesia Care Unit 
PBOM 
Performance-Based Outcome Measure 
PE 
Physical Examination 
PI 
Principal Investigator 
PK 
Pharmacokinetic(s) 
PO 
Per Os (oral) 
PP 
Per Protocol 
PRO 
Patient-Reported Outcome 
PROMIS 
Patient Reported Outcomes Measurement Information System 
PT 
Preferred Term 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SDTM 
Standard Data Tabulation Model 
SE 
Standard Error 
SOC 
System Organ Class 
SPI 
Sum of Pain Intensity 
TEAE 
Treatment Emergent Adverse Event 
TFLs 
Tables, Figures, and Listings 
TUG 
Timed Up and Go 
VHR 
Ventral Hernia Repair 
WHO  
World Health Organization 
wLOCF 
Windowed Last Observation Carried Forward 
WOCF 
Worst Observation Carried Forward 
 
 
 
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Protocol Number: CA-PS-209 
Date: 14MAY2021 
 
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1. PURPOSE OF THE ANALYSES 
This statistical analysis plan (SAP) is based on protocol number CA-PS-209 Amendment 2 
(15MAR2021) from Concentric Analgesics, Inc.  
The purpose of this statistical analysis plan is to provide details on study populations, how 
variables will be derived, how missing data will be handled, and the statistical methodologies to 
be used to analyze the safety and efficacy data from the study. The document may evolve over 
time, for example, to reflect the requirements of protocol amendments or regulatory requests. This 
SAP is written with due consideration of the recommendations outlined in the most recent 
International Conference on Harmonisation (ICH) Efficacy Guideline E9, Statistical Principles for 
Clinical Trials, and the most recent ICH Efficacy Guideline E3, Structure and Content of Clinical 
Study Reports. 
Presented in this SAP are the details of the specific statistical methods that will be employed in 
the summary and analysis of data from study CA-PS-209. 
 
 
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Statistical Analysis Plan 
Protocol Number: CA-PS-209 
Date: 14MAY2021 
 
CONFIDENTIAL 
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2. PROTOCOL SUMMARY 
This is a three-part, phase 1/2, randomized, double-blind, placebo-controlled, adaptive safety, 
pharmacokinetics (PK), and preliminary efficacy study of CA-008 in patients undergoing ventral 
hernia repair (VHR).  Part A is an open-label exploration of different delivery techniques of the 
study drug.   Part B is a randomized, double-blind, placebo-controlled pilot study and Part C is a 
larger randomized, double-blind, placebo-controlled efficacy study. 
2.1 
Study Objectives 
2.1.1 Part A of the Study 
2.1.1.1 Primary Objective  
• 
Evaluate the safety, tolerability, and feasibility of a single intraoperative administration of 
CA-008 15 mg in patients undergoing an elective VHR. 
2.1.1.2 Secondary Objective  
• 
Evaluate the pharmacokinetic (PK) profile of a single intraoperative administration of CA-
008 15 mg in patients undergoing an elective VHR. 
2.1.2 Part B of the Study  
2.1.2.1 Primary Objective 
• 
Evaluate the safety, tolerability, and feasibility of a single intraoperative administration of 
CA-008 24 mg in patients undergoing an elective VHR. 
2.1.2.2 Secondary Objectives 
• 
Determine the pain profile of patients undergoing an elective VHR. 
• 
Determine the appropriateness of progression to Part C. 
• 
Assessment of opioid consumption. 
• 
Evaluate the PK profile of a single intraoperative administration of CA-008 24 mg in 
patients undergoing an elective VHR. 
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Statistical Analysis Plan 
Protocol Number: CA-PS-209 
Date: 14MAY2021 
 
CONFIDENTIAL 
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• 
Explore the relationship between CA-008 and its metabolite plasma concentrations and 
electrocardiogram (ECG) QT interval (time from the start of the Q wave to the end of the 
T wave) using a concentration-QT (cQT) analysis. 
2.1.3 Part C of the Study  
2.1.3.1 Primary Objective 
• 
Evaluate the efficacy of CA-008 on reported pain in patients undergoing an elective VHR 
during a specified post-operative time interval. 
2.1.3.2 Secondary Objectives 
• 
Evaluate the efficacy of CA-008 on reported pain in patients undergoing an elective VHR 
during additional specified post-operative time intervals. 
• 
Evaluate the effect of CA-008 on opioid consumption. 
• 
Evaluate the effect of CA-008 on patient-reported outcomes (PROs). 
• 
Evaluate, preliminarily, the effect of CA-008 on performance-based outcome measures 
(PBOMs). 
• 
Evaluate the safety and tolerability of CA-008 or placebo in patients undergoing an elective 
VHR. 
2.2 
Overall Study Design and Plan 
This is a three-part, phase 1/2, randomized, double-blind, placebo-controlled, adaptive safety, 
PK, and preliminary efficacy study of CA-008 in patients undergoing VHR.  
In Parts A, B, and C for each patient, the study will be conducted in two periods: 
• 
An inpatient period which continues from check-in on Day 1 (D1) until discharge (4 days 
or 96 hours [h] following surgery [T96 ± 4 h], [D5]). Discharge may be delayed, if needed, 
for medical reasons. 
• 
An outpatient period which begins on discharge from the inpatient unit through follow up 
visits to D29 + 2 days. Note that additional follow up visits may occur at any time or even 
after D29 to follow Adverse Events (AEs) to resolution or to establish a new baseline. 
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Statistical Analysis Plan 
Protocol Number: CA-PS-209 
Date: 14MAY2021 
 
CONFIDENTIAL 
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During the inpatient period, patients will undergo VHR including study drug treatment (CA-008 or 
placebo) followed by serial assessments of safety, PK, and drug effect, focusing on reported pain 
and need for analgesia. During the outpatient period, patients will have serial assessments of 
safety and drug effect. 
The duration of participation is approximately 90 days per patient from screening to Day 29 (D29) 
+ 2 days (however, this could be longer to follow any AE to resolution or to establishment of a 
new baseline). 
In Part A, it is expected that 8-12 patients will be enrolled, but it may be up to 16 patients.  CA-
008 will be administered at a dose of 15 mg (delivered as a 50 mL solution at a concentration of 
0.3 mg/mL) in an open-label exploration of different delivery techniques.  In Part B, the active 
study drug dose will be increased to 24 mg, delivered as 80 mL of a 0.3 mg/mL solution, and 
tested vs placebo in a pilot phase.  It is expected that approximately 24 patients (up to 32) will be 
enrolled in Part B. 
The results of Part B will be unblinded for analysis prior to the initiation of Part C.  
Cohort expansion decisions will be made by the Sponsor’s medical monitor, the CRO’s medical 
monitor, a designated Principal Investigator (PI), and an independent medical monitor. 
Cohort expansion decisions will be based on review of at least the following safety data: 
• 
Inpatient (i.e., through 96 h) safety and tolerability data from all 8–12 initial patients, 
including vital signs, physical examination (PE), neurosensory examination, surgery site 
assessment, laboratory assessments, and AEs; 
• 
D8 ambulatory visit safety and tolerability data from at least 4 of the initial 8 patients in the 
current cohort, including vital signs, PE, neurosensory examination, surgery site 
assessment, and AEs. 
In Part C, the active dose level of CA-008 from Part B will be evaluated compared to placebo in 
a larger randomized, double-blind, parallel-group design to evaluate efficacy and safety.  It is 
expected that approximately 100 patients will be enrolled in Part C to bring the total number of 
patients enrolled in the study up to approximately 150. 
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Protocol Number: CA-PS-209 
Date: 14MAY2021 
 
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2.2.1 Study Assessment Schedule 
The Schedule of Assessments is presented in Table 1 below.  Note: Time 0 (T0) is further defined 
for analyses in Section 3. 
2.2.2 Study Population 
Adults aged 18 to 80 years of age, inclusive, who are planning to undergo an elective primary, 
open VHR, with retromuscular, preperitoneal mesh repair (i.e., Rives Stoppa technique or 
equivalent), with or without laparoscopic assistance, and who otherwise meet eligibility criteria 
described in Sections 8.2.1 and 8.2.2 of the study protocol, may be considered for enrollment into 
the study. 
2.2.3 Treatment Regimens 
Part A:  
CA-008 will be administered at a dose of 15 mg (delivered as a 50 mL solution at a 
concentration of 0.3 mg/mL) in an open-label exploration of different delivery techniques. 
Cohort #1: CA-008 15 mg  
Part B: 
In Part B, the active study drug dose will be increased to 24 mg (delivered as an 80 mL 
solution at a concentration of 0.3 mg/mL) and tested versus placebo in a pilot phase. 
Cohort #1: CA-008 24 mg 
Cohort #2: Placebo 
Part C: 
In Part C, 24 mg CA-008 will be evaluated compared to placebo. 
Cohort #1: CA-008 24 mg  
Cohort #2: Placebo 
 
Note: Treatment group for each study part will be labelled as “CA-008 XX mg” and/or “Placebo” 
in TLFs. In addition, the study part will be labeled clearly in output header (or output title). 
 
 
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Statistical Analysis Plan 
Protocol Number: CA-PS-209 
Date: 14MAY2021 
 
CONFIDENTIAL 
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Table 1. Schedule of Assessments – Part A, Part B, and Part C 
Study Period 
Screening 
Inpatient 
 
 
 
 
 
 
Follow-Up Clinic 
Visits 
Unscheduled   
Visit1 
Early 
Termination19 
Day of 
Surgery 
Surgery 
Post-
surgery 
T24 
T48 
T72 
T96 
± 4 h 
Study Day 
D -45 to 
Day Prior to 
Surgery 
D1 (prior 
to 
surgery) 
D1 
D1 
D2    
D3 
D4 
D5 
D8 + 
1 day 
D15 
+ 2 
days 
D29 
+ 2 
days 
Assessment 
Informed Consent 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Screening Medical 
and Surgical History 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Screens for 
alcohol/drugs of 
abuse 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Patient Pain 
Assessment Training 
X2 
X2 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test  
(or FSH if post-
menopausal) 
X3 (serum) 
X3 (urine) 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs (supine) 
X 
X 
 
X4 
X4 
X4 
X4 
X4 
X 
X 
X 
X 
X 
Temperature (oral) 
X 
X 
 
X4 
X4 
X4 
X4 
X4 
X 
X 
X 
X 
X 
Physical Examination 
X5 
X5 
 
 
 
 
 
X5 
X5 
X5 
X5 
X5 
X5 
12-Lead ECG 
X 
 
 
 
X6 
 
 
 
 
 
 
 
 
Enroll/Randomize 
 
X 
 
 
 
 
 
 
 
 
 
 
 
12-lead Holter ECG 
(24h)7 
 
 
X 
X 
X 
 
 
 
 
 
 
 
 
Surgery 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Study treatment 
Infiltration/instillation 
 
 
X 
 
 
 
 
 
 
 
 
 
 
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Statistical Analysis Plan 
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CONFIDENTIAL 
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Study Period 
Screening 
Inpatient 
 
 
 
 
 
 
Follow-Up Clinic 
Visits 
Unscheduled   
Visit1 
Early 
Termination19 
Day of 
Surgery 
Surgery 
Post-
surgery 
T24 
T48 
T72 
T96 
± 4 h 
Study Day 
D -45 to 
Day Prior to 
Surgery 
D1 (prior 
to 
surgery) 
D1 
D1 
D2    
D3 
D4 
D5 
D8 + 
1 day 
D15 
+ 2 
days 
D29 
+ 2 
days 
Assessment 
Admission to PACU 
 
 
 
T0nrs 
 
 
 
 
 
 
 
 
 
Surgical Site 
assessment 
 
 
 
 
 
 
 
X8 
X8 
X8 
X8 
X8 
X8 
Neurosensory Exam 
X 
 
 
 
 
 
 
X9 
X9 
X9 
X9 
X9 
X9 
Blood draw for 
laboratory tests 
X10 
 
 
 
 
 
 
X10 
 
 
 
 
 
Rescue Medication 
consumption 
Recording 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
Concomitant 
Medication 
Assessment 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Adverse Event 
Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
NRS pain 
assessments 
 
 
 
X11 
X11 
X11 
X11 
X11 
X11 
X11 
 
 
X11 
Patient home diary 
record (NRS) 
 
 
 
 
 
 
 
X12 
X12 
X12 
 
 
X12,19 
Electronic Diary 
(review, distribution 
and/or collection) 
 
 
 
 
 
 
 
X13 
X13 
X13 
 
 
X13 
Patient home diary 
(analgesic 
consumption) 
 
 
 
 
 
 
 
X 
X 
X 
 
 
X 
Prescription for 
outpatient opioid 
rescue if needed 
 
 
 
 
 
 
 
X14 
 
 
 
 
 
PRO15 
X 
 
 
 
 
X 
 
X 
X 
X 
X 
 
 
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Statistical Analysis Plan 
Protocol Number: CA-PS-209 
Date: 14MAY2021 
 
CONFIDENTIAL 
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Study Period 
Screening 
Inpatient 
 
 
 
 
 
 
Follow-Up Clinic 
Visits 
Unscheduled   
Visit1 
Early 
Termination19 
Day of 
Surgery 
Surgery 
Post-
surgery 
T24 
T48 
T72 
T96 
± 4 h 
Study Day 
D -45 to 
Day Prior to 
Surgery 
D1 (prior 
to 
surgery) 
D1 
D1 
D2    
D3 
D4 
D5 
D8 + 
1 day 
D15 
+ 2 
days 
D29 
+ 2 
days 
Assessment 
PBOMs16 
 
 
 
 
 
X 
 
X 
X 
X 
X 
 
 
Blood draw for PK 
analysis 
 
X17,18 
X17 
X17 
X17 
X17 
 
 
 
 
 
 
 
1 
Unscheduled visits may occur at any time and assessments are to be completed at the Investigator’s discretion. 
2 
Pain assessment training with test during screening; re-watch video only prior to surgery. 
3 
Note pregnancy tests are for FCBP; urine pregnancy test is to be performed within 24 hours of scheduled surgery. 
4 
Vital signs (HR, BP, RR (supine), SpO2) and temperature assessed together after T0 at T1, T2, T6, T12, T24, and every 12 hours thereafter (if awake at time 
of assessment between the hours of 12:00 AM and 6:00 AM) until discharge from the inpatient unit (may not miss two consecutive assessments).  There will be 
a ± 5-minute window allowed for the collection of vital signs in the first 4 hours after the end of surgery, after which for vital signs and temperatures there will be 
a ± 15-minute window allowed. 
5 
A complete medical history and physical examination including all major body systems will be performed at Screening.  In addition, at the following times, an 
interim medical history and targeted physical examination will be performed prior to surgery, and a physical examination to capture changes after Surgery, at 
96 hours (± 4 hours) after T0, but prior to discharge, and D8, D15, and D29 after T0 or if the patient terminates early, at that time if allowed.  Body weight (kg), 
in indoor clothing, but without shoes, will be measured at Screening and at T96 hours.  Height (cm) will be measured and BMI will be calculated at Screening 
only. 
6 
Post-Surgery ECG should be performed at 24 hours (± 2 hours) after T0. 
In a subset of 12 patients per randomized arm at one site in Part C, 12-lead Holter monitors will be placed prior to surgery and record for 24 hours to assess for 
effects on the QT interval during study drug administration. Note: If the number of patients enrolled in Part B is increased, PK sampling and Holter monitoring 
as described above may be conducted in Part B instead of Part C. 
7 
Surgical Site assessment: 96 hours (± 4 hours after T0 but prior to discharge from the inpatient unit) and D8, 15, and 29. 
8 
Neurosensory Exam of the area proximal to the surgical incision approximately 3 cm from the incision at Screening visit, 96 hours (± 4 hours, but prior to 
discharge) and D8, D15, and D29 after T0 or if the patient terminates early, at that time if allowed. 
9 
Clinical laboratory tests (chemistry, hematology, and coagulation) should be performed at Screening and T48 (± 4 hours.  
10 
During the inpatient stay, NRS at rest beginning with the PACU admission (T0) may be assessed once the patient is awake. Obtain NRS scores T0 plus 1 hour 
(T1), T0 plus 2 hours (T2), T4, T6, T8, T12, T16, T20, T24, and every 4 hours (if awake at time of assessment) until discharge from the inpatient unit. Time 
windows: for T1 to T2 (± 5 min) and from T4 onward (± 15 min). Scheduled NRS scores must be recorded regardless of timing of pre-rescue medication NRS 
scores and administration of rescue medication. The actual time of all NRS scores must be recorded, i.e., not the nominal time. During the inpatient stay, as 
soon as feasible, evoked NRS twice daily after 3 maneuvers: (a) coughing 3 times, and (b) sitting up from the supine position into a standardized position (both 
legs dangling on the side of the bed), and (c) ambulation for approximately 10 yards (30 feet). Obtain these NRS scores in the morning at 10:00 AM (± 1 h) and 
in the afternoon at 4:00 PM (± 1 h). During the inpatient stay, pain scores may be skipped between the hours of midnight and 6:00 AM, but the patient may not 
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miss two consecutive assessments. The T12, T24, T48, T72, and T96 assessments must be completed even if the patient must be awakened at these times. 
During the inpatient stay, an additional NRS assessment must be obtained within 5 minutes prior to IV rescue medication administration and within 15 minutes 
prior to oral rescue medication administration. During the outpatient period, (D8 and D15), instruct the patient to document their NRS scores twice daily at 11:00 
AM (± 1 h) and 7:00 PM (± 1 h) (a) at rest, (b) after coughing 3 times, (c) after sitting up from the supine position into a standardized position (both legs dangling 
on the side of the bed), and (d) during ambulation for approximately 10 yards (30 feet). Note that the actual time of these assessments must be documented in 
the diary. Instruct the patient to: 
a. 
Obtain the morning NRS assessment 
b. 
Obtain the evening NRS assessment 
c. 
Opioid and non-opioid rescue medication must be recorded in the diary through D15, including a pre-rescue NRS score. 
11 
The patient is expected to document NRS pain scores at rest and on ambulation 2 ×/day through D15 (at the times and qualifications noted above). 
12 
The diary and instructions are provided to the patient prior to discharge (T96). At each subsequent visit, review Patient Diary instructions with patient and collect 
the patient’s NRS scores and other study-related assessments. 
13 
Patients will be given a prescription for 20 tablets of oxycodone 5 mg one or two tablets PO Q 4–6 h PRN for moderate-severe pain (i.e., NRS 5–10). 
14 
PROs: PROMIS 10 Global (Appendix 15.2) and Activities Assessment Scale (AAS) (Appendix 15.3).PROMIS 10 Global will not be measured at T48. 
15 
PBOMs: Sit to Stand Test, Timed Up and Go (TUG) Test. 
16 
Collect blood samples for PK. The time points for whole blood collection will be at pre-dose (from check-in and up to 30PKT 0 (Pre-IP Dose, 2-10 minutes before 
the start of surgery), and at PKT 0 (at prior to the first study treatment instillation), 0.03 h (2 min), 0.083 h (5 min), 0.167 h (10 min), 0.25 h (15 min), 0.33 h (20 
min), 0.5 h (30 min), 0.75 h (45 min), and at 1, 1.5, 2, 4, 6, 8, 12, 16, 24, 36 and 2448 hours after the first study treatment instillation (total of 1618 samples)..). 
There will be a ± 2-minute window allowed for the 10- to-, 15 and 20-minute collections, a ± 5-minute window allowed for collections at 30 minutes through 4 
hours, and a ± 15-minute window for collections after 4 hours. In the event of ana SAE or severe TEAE, an unscheduled PK draw will be performed. The actual 
time of collection will be recorded and used in any analysis. Out-of-window collections will not be considered protocol deviations. 
17 
Patients must abstain from foods containing capsaicin for T24 prior to surgery. 
18 
If the patient terminates early, complete all procedures listed, as appropriate. The following assessments are done only if the Early Termination occurs prior to 
the D15 visit: Patients home diary review, vital signs, and targeted physical examination. 
 
Abbreviations: AAS = Activities Assessment Scale; AE = adverse event(s); ECG = electrocardiogram; FSH = follicle stimulating hormone; NRS = numeric rating 
scale of pain intensity; PACU = post-anesthesia care unit; PBOM = performance-based outcome measure; PK = pharmacokinetic(s); PKT = pharmacokinetic time; 
PO = orally (per os); PRN = as needed; PRO = patient-reported outcome; PROMIS = Patient Reported Outcomes Measurement Information System; T0 = time of 
admission into the PACU; TUG = Timed Up and Go. 
 
 
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2.2.4 Treatment Group Assignments or Randomization 
Randomization will be used to avoid bias in the assignment of patients to blinded treatments to 
increase the likelihood that known and unknown patient attributes (e.g., demographics, baseline 
characteristics) are balanced across treatment groups, and to enhance the validity of statistical 
comparisons across treatment groups. 
Patients who have provided written informed consent will be assigned a unique identifier in the 
screening process that will be used to identify the patient throughout the study. 
Patients in Parts B and C will be randomized in a 1:1 ratio, active to placebo, employing blocked 
randomization with 4 patients per block, so that successive groups of patients will include 2 
patients receiving active drug and 2 patients receiving placebo. 
Treatment assignments will be determined by a computer-generated randomization schedule. 
Once any patient identifier or randomization number is assigned, it cannot be reassigned to any 
other patient. 
Patients may be rescreened if the screening window is exceeded due to scheduling issues. 
Patients who discontinue study participation before or after randomization but prior to receiving 
study treatment will be replaced.  Patients who are withdrawn or elect to withdraw after receiving 
study treatment will not be replaced.  Replacement patients will be assigned the same treatment 
as the original patient.  A ‘replacement’ randomization list matching that of the main list will be 
created to facilitate this process. 
2.2.5 Sample Size Determination 
In Part A and Part B, no formal statistical hypothesis testing is planned.  The sample sizes of 8-12 
patients initially in Part A, with the potential for expansion to 16 patients, and 24-32 patients in 
Part B, have been selected empirically based on prior clinical trial experience with CA-008 and 
are considered sufficient for exploration of feasibility, PK, preliminary efficacy, tolerability, and 
safety. 
For the primary efficacy endpoint of rest NRS AUC0-96, assuming a t-test for the difference in the 
means of 2 independent groups, a sample size of approximately 50 patients per group provides 
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approximately 80% power to detect a standardized effect size (Cohen’s d) of 0.55 at a two-sided 
level of significance, alpha, of 0.05.  Therefore, in Part C, a total of up to 100 patients will be 
randomized in 2 parallel arms (1:1) with approximately 50 patients in each arm to bring the total 
number of patients enrolled to approximately 150. 
Alternative assumptions of the anticipated effect size may lead to different numbers of patients 
per group.  The total number of patients to be enrolled in the study will not exceed 150. 
 
 
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3. GENERAL ANALYSIS AND REPORTING CONVENTIONS 
General analysis and reporting conventions to be employed for study CA-PS-209 data are 
described below. If departures from these conventions are appropriate, details will be presented 
in the relevant sections of this SAP. 
Data will be summarized by study part, treatment group, and time point. The total number of 
patients in the treatment group (N) under the stated population will be displayed in the header of 
summary tables. 
Continuous variables will be summarized by study part, treatment group, and time point (as 
applicable) using descriptive statistics: the total number of patients with non-missing data within 
the specific category (n); mean; standard deviation (SD); median; and range (minimum and 
maximum). 
Categorical variables will be summarized by study part, treatment group, and time point (as 
applicable) using frequency counts (n) which indicate the actual number of patients with a 
particular value of a variable or event and rate of occurrence (%).  Unless specified otherwise, in 
the analysis of categorical variables, the denominator for percentages will be the total number of 
patients in the appropriate analysis population and treatment group (N) who have a non-missing 
value of the categorical variable.  Percentages will be calculated as (n/N)*100. 
Changes from baseline for continuous variables will be presented as their corresponding 
continuous measures for post-baseline visits, as applicable.  All study data will be listed by study 
part, treatment group, patient, and time point (as applicable).  
The statistic “Missing” will also be evaluated by enumerating the number of missing 
entries/patients, if any at that visit, and presented as a summary statistic only for the resulting 
time points.  Proportions will be calculated as (n/N). 
No preliminary rounding of numeric data values will be performed; rounding will only occur after 
the completion of an analyses when data or calculation results are formatted for display.  Means 
and medians will be presented to one more decimal place than the number of decimal places 
recorded in the data.  Standard deviations will be presented to two more decimal places than the 
number of decimal places recorded in the data.  Also, the least squares mean, standard error and 
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its confidence interval, and least squares mean differences will be presented to two more decimal 
places than the number of decimal places recorded in the data. Percentages will be presented to 
one decimal place.  A percentage of 100 calculated to any number of decimal places will be 
reported as 100%; a percentage of 0 calculated to any number of decimal places will be reported 
as 0.  Minimums and maximums will be presented with the same number of decimal places as 
the original data.  P-values will be presented to three decimal places; p-values less than 0.001 
will be presented as < 0.001 and p-values greater than 0.999 will be presented as > 0.999. 
Statistical testing including p-values and confidence intervals (CIs) will be presented as described 
in each section below.  Tests of statistical significance will be 2-sided at the 0.05 level of 
significance.  
Because preliminary assessments of efficacy are the focus of efficacy analyses, no adjustments 
to the level of significance will be made for multiple comparison tests. 
All dates will be displayed in DDMMMYYYY format. 
All analyses will be performed using SAS® version 9.3 or higher. The domain (Study data 
tabulation Model [SDTM]) and analysis (Analysis Data Model [ADaM]) data sets will be the source 
of input to the SAS programs that generate the submission-ready tables, figures, and listings 
(TFLs).  Submission-ready SDTM and ADaM data sets, define files, reviewer’s guide, and Open 
CDISC reports will be provided to the sponsor in addition to the TFLs.  
The following conventions will be used in the study analysis as needed for calculations: 
• 
Time 0 for safety assessments (T0) is the start time of study drug administration. 
• 
Time 0 for efficacy assessments (T0nrs) is the time of admission into the post-anesthesia 
care unit (PACU). 
• 
Time 0 for PK assessments (T0pk) is the stop time of study drug administration. 
• 
Day of surgery/study drug administration is defined as Day 1. 
• 
Elapsed assessment visit times are defined by time elapsed from the corresponding Time 
0 (T0, T0nrs, or T0pk) or Day 1. 
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• 
The baseline value of any parameter is defined as the most recent valid measurement of 
that parameter prior to the beginning of Time 0 (T0, T0nrs, or T0pk). 
• 
The change from baseline value of a parameter is defined as the post-baseline value 
minus the baseline value. 
• 
Duration of an AE will be computed in days for AEs lasting 24 or more hours, and as hours 
for AEs lasting less than 24 hours.  
 
 
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4. ANALYSIS POPULATIONS 
4.1 
Analysis Populations 
The following analysis populations will be used in this study:  
• 
Safety Population—consists of all patients who received any part of a dose of study 
treatment.  Patients in the Safety Population will be analyzed as treated. 
• 
PK Population—consists of all patients who received a full dose of study treatment and 
completed at least one PK assessment.  Patients in the PK Population will be analyzed 
as treated. 
• 
PK/QT Population—consists of all patients with at least one time point with both PK and 
QT data for use in concentration-QT response modeling. Patients in the PK/QT Population 
will be analyzed as treated. 
• 
Modified Intent-to-treat (mITT) Population—consists of all patients who were randomized 
and received any dose of study treatment.  Patients in the mITT Population will be 
analyzed as randomized.  
• 
Per Protocol (PP) Population—consists of all patients who received a full dose of study 
treatment and have evaluable NRS pain assessments at T12, 24, 48, 72, and 96 and no 
two consecutive missing assessments among the other time points prior to T96 (± 4 
h)/Discharge.  Patients in the PP Population will be analyzed as treated.  
• 
Study Completers—consists of all patients who received a full dose of study treatment 
and completed the entire study period through D29 + 2 days, whether or not they have 
complete sets of NRS scores. 
Analysis populations will be determined before the study data are unblinded for analysis.  
Efficacy analyses will be performed using the mITT and PP Populations as detailed below.  Safety 
analyses will be performed using the Safety Population.  PK analyses and cQT analysis will be 
performed using the PK Population and PK/QT Population, respectively.  
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4.2 
Disposition of Patients 
All patients and the analysis populations for which they qualify for will be presented in the listings.  
Patients who are screened and who fail screening, withdraw consent prior to randomization, or 
are randomized but not treated will be presented in a listing and included in the patient disposition 
summary table.  Patients who are randomized, patients who are included in each study 
population, patients who are treated, patients who complete the study, and patients who withdraw 
early from the study and the reason for withdrawal, will be included by treatment group and overall 
and presented for each study part A, B, and C separately in the patient disposition summary table. 
4.3 
Protocol Deviations 
Deviations from the study protocol will be categorized as deviations from protocol-specified 
requirements regarding: informed consent procedures, inclusion/exclusion criteria, study 
medication, prohibited medications, study procedures, study drug assignment/treatment, visit or 
assessment time windows, missed visits or assessments, and other.  All protocol deviations will 
be captured on the electronic case report forms (eCRFs) and/or documented in site specific logs 
throughout the study.  Deviations will be categorized as described above and classified as major 
or minor by the Sponsor and the medical monitor prior to database lock and before the unblinding 
of study data for analysis.  Major protocol deviations will be discussed in the clinical study report 
(CSR).  In general, major protocol deviations are deviations from the study protocol that may 
significantly impact the completeness, accuracy, and/or reliability of the study data or that may 
significantly affect a patient's rights, safety, or well-being.  The number of patients with protocol 
deviations, both minor and major, will be presented for each study part A, B, or C separately using 
All Randomized Patients in a data listing and will be summarized by category of deviation and 
major/minor classification. 
NOTE: In March 2020, (updated January 2021) the FDA issued guidance on the conduct of clinical 
trials during the COVID-19 pandemic to assure the safety of trial participants and to maintain 
study compliance with GCP.  The FDA provided information on alternative methods to complete 
serial, non-invasive study assessments that allow compliance with local shelter-in-place 
considerations, e.g., phone contact or virtual visit using video chat/conferencing. 
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Unavoidable protocol deviations involving study procedure scheduling delays, early or missed 
visits, and missing information might occur due to the COVID-19 situation.  In general, if a study 
procedure is completed, it might not be considered a protocol deviation, even if it is completed 
remotely, out-of-window, or using alternative methods.  If a procedure cannot be completed and 
results in missing data, it might be considered a protocol deviation. COVID-19 related Protocol 
deviations be documented, and specific information that explains the basis of missing data 
including relationship to CoVID-19 must be captured in the CSR. Missing data related to COVID-
19 will be treated as non-COVID-19 related missing data. Any causal relationship between the 
study drug and SAE’s in trial participants diagnosed with CoVID-19 must be submitted to the FDA. 
Sponsors and investigators are required to document how restrictions related to CoVID-19 led to 
changes in study conduct, duration of those changes, which trial participants were impacted and 
how they were impacted. 
5. DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
5.1 
Demographics and Baseline Characteristics 
Demographic and baseline characteristics (age, sex, race, ethnicity, weight (kg), height (cm), and 
body mass index (BMI; kg/m2)) will be summarized separately for each study part by treatment 
group and overall using the Safety Population. Categorical variables (sex, ethnicity, and race) will 
be summarized using frequency count and percentage while continuous variables (age, weight, 
height, and BMI) will be summarized using descriptive statistics: n, mean, SD, median, minimum, 
and maximum.  
Demographic and baseline data will be listed All Randomized Patients.  
5.2 
Medical History 
Medical history will include acute, chronic, or infectious disease history; surgical or oncologic 
history; and any reported conditions affecting major body systems.  Medical events that occur 
prior to the study procedure (i.e., initiation of any surgery or anesthesia-related procedure) will be 
categorized as medical history.  All findings in a patient’s medical history will be evaluated by the 
Investigator for their potential effect on a patient’s eligibility for study participation.  Medical history 
will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) version 24.0 and 
summarized for the Safety Population separately by each study part A, B, and C in a summary 
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table of the number and percentage of occurrences, within treatment groups and overall, by 
System Organ Class (SOC) and Preferred Term (PT).   
Patients will only be counted once for each SOC and PT. Counts will be presented in descending 
frequency of SOC term for the overall column unless otherwise specified. 
Medical histories will also be presented for the Safety Population in a by-patient listing. 
 
 
 
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6. MEASUREMENTS OF TREATMENT EXPOSURE AND COMPLIANCE 
Because study medication is administered as a single dose at the study center by trained study 
personnel, patient compliance with respect to study medication administration will not be 
calculated.  A by-patient listing of study drug administration and exposure data will be provided 
by each study part separately.  Individual instances of incomplete or problematic study medication 
delivery will be noted as protocol deviations. 
Descriptive statistics (n, mean, standard deviation, median, minimum, and maximum) for the 
volume (mL) of study drug administered in the Safety Population will be presented separately for 
each study Part A, B, and C in a summary table by treatment group and overall. 
 
 
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7. EFFICACY EVALUATION 
The analysis of the primary endpoint and key secondary endpoints will be performed for the mITT 
and PP Populations. The analysis of the exploratory efficacy endpoints will be performed for the 
mITT Population only.  In the following, AUC refers to the area determined by a plot of NRS pain 
intensity scores versus time over a given time interval. 
7.1 
Handling of Dropouts or Missing Data 
Imputation of missing data, where appropriate, will be performed as indicated in this SAP for a 
given analysis; in particular, imputation of missing NRS scores and PROMIS 10 Global 
questionnaire responses, is discussed in detail in section 7.2.6.  Any spurious or erroneous data 
will be queried and followed up until satisfactorily resolved; if not resolvable, the data will be set 
to missing.  Study procedures have been designed to minimize opportunities for data not to be 
captured as planned, hence missing data will be considered to be missing at random.  
7.2 
Efficacy Endpoints 
There are no efficacy endpoints specified for Part A and Part B. Efficacy Endpoints for Part C are: 
7.2.1 Primary Efficacy Endpoint  
• 
Rest NRS AUC from T0 to T96 (rest NRS AUC0-96) 
7.2.2 Key Secondary Efficacy Endpoints  
• 
Evoked NRS AUC (three maneuvers) from T0 to T96 (evoked NRS AUC0–96) 
• 
Total opioid consumption (OC), in daily oral morphine equivalent (OME) dose, from T0 to 
T96, and from T0 to D8 (OC0-96 and OC0-D8) 
• 
Patient is opioid-free (OF) after discharge from T96 to D15 (OF96-D15), (patient has 
discontinued opioid use prior to hospital discharge) 
• 
Rest NRS AUC from T0 to D8 (rest NRS AUC0-D8) 
• 
Evoked NRS AUC (three maneuvers) from T0 to D8 (evoked NRS AUC0-D8) 
7.2.3 Exploratory Efficacy Endpoints 
• 
Rest NRS AUC for the indicated time intervals: AUC12-96, AUC0-48, AUC48-96, and AUC0-D15 
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• 
Evoked NRS AUC (three maneuvers) for the indicated time intervals: AUC12-96, AUC0-48, 
AUC48-96, and AUC0-D15 
• 
Rest NRS scores at T48, T72, and T96 
• 
Rest NRS scores daily from D5-D15 
• 
Rest NRS ≤ 3 during T0-T96, T0-48, and T48-96 
• 
Total OC, in daily OME dose, for the indicated time intervals: OC12-96, OC24-96, OC0-D8, and 
OC0-D15 
• 
Patient is OF for the indicated time intervals: OF0-96, OF0-D15, OF24-96, OF24-D15, OF48-D15, 
OF72-D15, and OFD8-D15 
• 
Time to cessation of opioid use 
• 
Change in PRO questionnaire scores (PROMIS 10 Global and AAS) from Screening to 
D8, D15, and D29; and from T96 to D8, D15, and D29 
• 
Change in PBOMs (Sit to Stand, TUG) from T48 (± 4 h), to D5/Discharge, to D8, to D15, 
and to D29 
• 
Total non-opioid analgesic consumption (AC), i.e., rescue acetaminophen use, for the 
indicated time intervals: AC96-D8 and AC96-D15 
Additional exploratory and sensitivity analyses may be undertaken for rest NRS AUC, evoked 
NRS AUC, OC, and OF for different intervals, e.g., T48-T168 and T72-T168. 
7.2.4 NRS Pain Intensity Measurements 
At designated times during the study following the administration of study treatment, patients will 
report or record their pain intensity at the assessment time as follows: 
• 
During the inpatient stay, NRS at rest beginning with the PACU admission may be 
assessed once the patient is awake. T0NRS is the time of admission into the PACU.  If the 
patient was able to provide responses, NRS scores were to be obtained at T0NRS plus 1 
hour (T1), T0NRS plus 2 hours (T2), T4, T6, T8, T12, T16, T20, T24, and every 4 hours 
thereafter (if the patient was awake at the scheduled time of assessment) until discharge 
from the inpatient unit. Time windows: ± 5 minutes for T1 and T2; ± 15 minutes for T4 
onward. Scheduled NRS scores will be recorded regardless of timing of pre-rescue 
medication NRS scores and administration of rescue medication. The actual time, not the 
nominal time, of all NRS scores, i.e., scheduled and pre-rescue, will be recorded. 
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• 
During the inpatient stay, as soon as was feasible, evoked NRS scores will be obtained 
twice daily after: (a) coughing 3 times; (b) sitting up from the supine position into a 
standardized position (both legs dangling on the side of the bed); and (c) ambulation for 
approximately 10 yards (30 feet). These NRS scores will be obtained in the morning at 
10:00 AM (± 1 h) and in the afternoon at 4:00 PM (± 1 h). 
• 
During the inpatient stay, pain scores may be skipped between the hours of 12:00 AM and 
6:00 AM, but the patient was not to have missed two consecutive assessments. The T12, 
T24, T48, T72, and T96 assessments will be completed even if the patient had to be 
awakened at those times. 
• 
During the inpatient stay, an additional NRS assessment will be obtained within 5 minutes 
prior to IV rescue medication administration and within 15 minutes prior to oral rescue 
medication administration. 
• 
During the outpatient period (after T96 and through D15), an additional NRS assessment 
must be obtained prior to oral rescue medication administration. If entered in the electronic 
diary, the timing of the additional NRS assessment will be assumed to be coincident with 
the use of rescue medication. If not entered in the electronic diary, the additional NRS 
assessment should be within 15 minutes prior to use of rescue medication to be used for 
imputation. 
• 
During the outpatient period (after T96, and through D15), patients will be instructed to 
document their NRS scores twice daily at 11:00 AM (± 1 h) and 7:00 PM (± 1 h) (a) at rest, 
(b) after coughing 3 times, (c) after sitting up from the supine position into a standardized 
position (both legs dangling on the side of the bed), and (d) during ambulation for 
approximately 10 yards. Note that the actual time of these assessments will be 
documented in the electronic diary. Patients will be instructed to:  
o obtain the morning NRS assessments  
o obtain the evening NRS assessments 
o record opioid and non-opioid rescue medication use (dose, date, time, and pre-
rescue NRS score) in the diary through D15. 
7.2.5 Handling of NRS Pain Intensity Scores Post Rescue Medication Use  
When rescue medication was used, any scheduled rest NRS assessment is censored if the 
assessment was taken within:  
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• 
30 minutes after the start of IV fentanyl; 
• 
2 hours after the start of IV hydromorphone; 
• 
4 hours after the administration of PO opioids. 
If other opioid rescue medications are used, other censoring intervals will be documented, e.g., 3 
hours after the start of IV morphine.  In the special case of the use of IV hydromorphone after T12 
(defined as an adverse event of lack of efficacy), scheduled rest NRS assessments will be 
censored for 8 hours after the start of dosing.  Censored NRS assessments will be replaced by 
imputed values in summaries, derivations, and analyses as described below. 
• 
For patients who take rescue medication, a ‘windowed’ last NRS pain intensity score 
carried forward (wLOCF) will be used in the calculation of the rest NRS AUC.  Specifically, 
the most recent NRS score obtained prior to the administration of rescue medication, 
whether that score is the pre-rescue NRS assessment or a scheduled NRS assessment, 
will be used to impute an NRS score to replace the censored values of all scheduled rest 
NRS assessments occurring during the censoring window, i.e., all scheduled rest NRS 
assessments for 30 minutes following rescue use when IV fentanyl is used, for 2 hours 
when IV hydromorphone is used, and for 4 hours when PO oxycodone is used. 
• 
If a patient requested rescue medication at the time of a scheduled rest NRS assessment, 
the scheduled rest NRS assessment will also to be recorded as the pre-rescue NRS 
assessment.   
• 
If a patient requested rescue medication within a wLOCF imputation time window, and 
additional rescue medication was administered prior to the end of that time window, the 
imputation window clock resets to 0 at the time of administration of the newly requested 
rescue medication and the imputation time window associated with that rescue medication 
begins; censored values during this new censoring window will be imputed using the pre-
rescue NRS score obtained in response to the latest request for rescue medication or the 
most recent imputed NRS value if the pre-rescue NRS score is missing.  
• 
In case a rescue medication administration time is not recorded in the rescue medication 
page in eCRF, but the time of the most recent pre-rescue NRS assessment occurring prior 
to the administration of rescue medication is recorded, that time shall be assumed to be 
the rescue medication administration time.  Conversely, if the most recent pre-rescue NRS 
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assessment is recorded in the rescue medication eCRF, but the time is missing, the time 
will be assumed to be the time the rescue medication was administered.  Note, for the 
outpatient period, the time of pre-rescue NRS assessments is not captured in the diary; 
hence, the time of the pre-rescue NRS assessment will be assumed to be the time when 
the rescue medication was administered. 
• 
If a patient’s pre-rescue NRS assessment is missing, then the mean of the patient’s non-
missing pre-rescue NRS scores occurring prior to the missing score will be used to impute 
values for censored NRS scores during the ensuing wLOCF imputation time window. If 
the patient has no non-missing pre-rescue NRS scores prior to the missing score, then 
the mean value of all study patients’ pre-rescue NRS scores occurring within the first 48 
hours of entry into the PACU will be used to impute values for censored NRS scores during 
the ensuing wLOCF imputation time window. 
• 
Evoked NRS assessments occur twice daily at 10:00 AM (± 1 h) and 4:00 PM (± 1 h).  If 
an evoked NRS assessment is scheduled to occur during a wLOCF imputation time 
window, the evoked NRS score will not be censored and will not be replaced with an 
imputed value. 
7.2.6  Imputation of Missing Data for Efficacy Assessments 
For the primary analysis of the primary efficacy endpoint, intermittent missing NRS assessment 
scores (due to a patient sleeping, etc.) will not be imputed and AUCs will be calculated using the 
available NRS assessments, unless the missing NRS assessment is a rest NRS assessment 
occurring during a rescue medication imputation period, in which case the imputed value will be 
used. 
For a patient who dropped out of the study prior to D15, the score for scheduled rest NRS 
assessments after the date of discontinuation will be imputed using the worst rest NRS score 
recorded during the 24-hour period prior to the patient’s date of discontinuation; similarly, for all 
scheduled evoked NRS scores after the date of discontinuation.  If no rest NRS assessments 
exist prior to the patient’s date of discontinuation, all AUC calculations based on rest NRS scores 
for that patient will be set to missing; similarly, if no evoked NRS assessments exist on or prior to 
the date of discontinuation, all AUC calculations based on evoked NRS scores will be set to 
missing. 
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Note that the replacement via imputation of a censored post-rescue NRS assessment (as 
described in section 7.2.5) must be performed prior to the selection of imputed values as 
described in this section.  
7.2.7 NRS AUC Calculation 
AUC calculations will be done using the standard trapezoidal rule:  
AUC𝑇𝑇1−𝑇𝑇2 = ෍
NRS𝑖𝑖−1 + NRS𝑖𝑖
2
𝑛𝑛
𝑖𝑖=1
(𝑡𝑡𝑖𝑖−𝑡𝑡𝑖𝑖−1) 
Where NRSi = NRS at time i, n is the number of assessments between T1 and T2, and (ti − ti−1) is 
the time difference in hours between actual collection time i and actual collection time i − 1. 
The NRS is an 11-point scale with anchors 0 (no pain) and 10 (worst pain imaginable). NRS 
assessment scores, whether rest or evoked, from all available eCRFs, including “Pain Intensity 
Assessment 
(NRS),” 
“Morning/Night 
Pain 
Intensity 
Assessment 
(NRS)—Inpatient,” 
“Morning/Night Pain Intensity Assessment (NRS)—Outpatient,” and “Rescue Medications” will be 
used in AUC calculations as appropriate for a specific computation.  For an AUC covering a 
particular time interval, e.g., from time Tn1 to time Tn2, all uncensored NRS assessments recorded 
from the start of the protocol-allowed window for time Tn1, up to the end of the protocol-allowed 
window for time Tn2, will be used; censored values will be replaced as described in sections 7.3.2.  
For example, for AUC0-96, all uncensored NRS scores recorded from 12 hours minus 15 minutes 
to 96 hours plus 15 minutes relative to T0nrs (time of admission to the PACU) will be used. 
If the first NRS assessment, or the last NRS assessment, for the time interval specified for an 
AUC calculation is not recorded (i.e., no assessments occurred within the protocol-specified 
windows for these time points) then, if the score from an adjacent scheduled NRS assessment of 
the same type (rest or evoked) is recorded, the recorded score at the adjacent time will be used 
to impute the missing NRS score; if both an earlier and a later adjacent score are present, then 
the higher of these two scores will be used for imputing the missing score.  If the first two or last 
two consecutively scheduled NRS scores of the same type (rest or evoked) for the time interval 
specified for an AUC calculation are not recorded, then the AUC calculation will be set to missing. 
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7.2.8 Total Opioid Consumption 
Opioids taken as rescue medication will be converted into oral morphine equivalents (OME) using 
the conversion factors in Nielsen 2016.  Opioid use is recorded on the rescue medication eCRF 
from the end of surgery through T96/Discharge and following discharge either in the electronic or 
paper diary until the Day 15 (D15) visit or the Early Termination (ET) visit.  Following discharge 
to outpatient status, opioid use recorded in the patient paper diary is transferred to the eCRF at 
subsequent clinic visits and electronic diary data is integrated into the study database directly.   
The formula below will be used to convert daily rescue medication dose into daily OME dose: 
Total OME units per day = Rescue medication use #1 [(rescue medication strength per unit) × 
(number of units per day) × (OME conversion factor)] +  
Rescue medication use #2 [(rescue medication strength per unit) × (number of units per day) × 
(OME conversion factor)] + etc. 
The total opioid consumption (OC) for each patient will be calculated as the sum of the OMEs of 
all of the medications taken during a specified interval.  For example, if a patient takes 5 OME of 
hydromorphone on Day 1, 5 OME of hydromorphone and 10 OME of oxycodone on Day 2, then 
the total OC for Day 1 is 5 OME, and the total OC for Day 2 is 15 OME; the total OC for Day 1 
and 2 is 20 OME.  Patients that take no opioids in a day will have a total OC of zero for that day. 
Total OC will be determined for the following time periods:  T0nrs to T96, T0nrs to D8, T12 to T96, 
T48 to d8, T72 to D8, T24 to T96, T0nrs to D8, and T0nrs to D15. 
7.2.9 Total Non-opioid Analgesic Consumption 
Non-opioid analgesic use is recorded similarly to opioid rescue medication use (Section 7.3.5). 
Total non-opioid analgesic consumption (AC), i.e., total milligrams of rescue acetaminophen 
(including the acetaminophen component of Percocet) taken during the specified time intervals 
by each patient will be calculated for the following time periods: AC96-D8 and AC96-D15.  
7.2.10 Performance-based Outcome Measures (PBOMs) 
PBOMs will be assessed at T48 (D3), T96 (D5), D8, D15, and D29.  The following data will be 
collected: 
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• 
Sit to Stand test: the number of times the patient is able to stand up and sit back down 
again in 30 seconds is recorded. 
• 
Timed Up and Go (TUG) test: the time in seconds the patient takes to perform the test is 
recoded. 
7.2.11 PROMIS 10 Global Health Questionnaire  
The Patient-reported Outcomes Measurement Information System 10 (PROMIS 10) Global 
Health survey is a 10-item questionnaire for use in the assessment of health-related quality of life; 
instrument scores can be contrasted with normative scores (t-scores) for the US population. The 
PROMIS 10 consists of 5 domains: physical function, fatigue, pain, emotional distress, and social 
health; responses are recorded on a 5-point scale.  The PROMIS 10 questionnaire, version 1.1, 
is to be administered at Screening, T96 (D5), D8, D15, and D29. Global Physical Health and 
Global Mental Health subscale scores will be calculated.  Details of the scoring algorithm are 
provided in Appendix 15.2. 
7.2.12 Activities Assessment Scale  
The Activities Assessment Scale (AAS) is a postoperative functional activity scale validated in 
men who underwent hernia surgery. The AAS includes 13 items covering a broad sample of 
sedentary (e.g., lying in bed), movement-related (e.g., walking outdoors), and graded-intensity 
physical activities (extending from housekeeping to various forms of exercise to construction 
work).  The preoperative scale references the impact of the hernia itself, and the postoperative 
version assesses the effects of the hernia repair on functioning.  The time frame for all questions 
is the previous 24 hours.  Five categories ranging from “no difficulty” to “not able to do it” will be 
used for responses. A “did not do it for other reasons” category is included but is not scored.  The 
AAS scores are then numerically transformed to produce a range extending from 0 to 100, with 
higher values indicating better functional ability.  The final version of the Activities Assessment 
Scale with both preoperative and postoperative instructions is presented in the Appendix 15.3. 
The AAS will be completed when patients complete the PROs at screening, T48 (D3), T96 (D5), 
D8, D15, and D29. 
7.3 
Analysis Methods 
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7.3.1 General Considerations 
Per the study design, progression from Part A to Part B will take place after an empirical 
assessment has been completed showing that the total study drug dose, volume, allocation (of 
volume administered at locations within the surgical site), and technique is feasible. Progression 
from Part B to Part C will take place after an UNBLINDED analysis of unmonitored data from Part 
B occurs including data through Day 15.  The final data analysis for Part C will be performed after 
all patients in Part C have either completed or have been discontinued from the study, all data 
cleaning has been completed, and the study database has been locked.  Part C will be unblinded 
after patient membership in each of the various analysis populations has been determined at a 
blinded data review meeting and upon confirmation of database lock.  Any deviations from the 
analyses specified in this SAP will be detailed in the clinical study report. 
All data collected in the clinical database will be included in the data listings and displayed by 
each Study Part. 
Statistical testing including p-values and confidence intervals (CIs) will be presented as described 
in each section below.  The Type I error rate (alpha) for the primary analysis of the primary efficacy 
endpoint, primary endpoint sensitivity analyses, key secondary efficacy endpoint analyses and 
exploratory endpoint analyses is 0.05 (two-sided).   
For this proof-of-concept study, no adjustment of the level of significance will be made for multiple 
testing. 
See Section 13 for example SAS code for the analyses described in the following subsections. 
7.3.2 Pooling of Data 
No data pooling from different study parts will be done in this study but may be explored. Please 
refer to Section 10 of the SAP (Other Analyses). 
7.3.3 Primary Efficacy Endpoint 
7.3.3.1 Primary Efficacy Endpoint Hypothesis 
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The null hypothesis associated with the primary efficacy endpoint is that the mean rest NRS 
AUC0-96 does not differ between active treatment and placebo, tested against the alternative 
hypothesis that the mean rest NRS AUC0-96 is different for active treatment compared to placebo. 
7.3.3.2 Primary Analysis of the Primary Efficacy Endpoint 
The primary analysis of the primary efficacy endpoint will be performed for the mITT Population 
using a analysis of variance (ANOVA) model with treatment group as main effect and hernia size 
may be included as an additional covariate.   
The analysis result will be reported as the Estimates (LS means, 95% CI) and standard error (SE) 
from the model for each treatment group.  The difference in LS means for treatment group vs. 
placebo for rest NRS AUC0-96, 95% CI, and SE for the difference along with two-sided p-values 
will also be presented. Primary analysis of the primary efficacy endpoint will be repeated for PP 
Population. 
For the ANOVA of rest NRS AUC0-96 values, the Shapiro-Wilk test will be used to check normality 
of residuals, and Levene’s test will be used to check homogeneity of variances. If assumptions of 
normality are violated, then the primary analysis may be repeated after suitable transformation of 
the data or the analysis may be replaced with the non-parametric analysis Kruskal-Wallis test. 
7.3.3.3 Primary Efficacy Endpoint Sensitivity Analyses 
In order to assess the sensitivity of the primary analysis of the primary efficacy endpoint to the 
censoring and imputation scheme specified for calculating the primary endpoint rest NRS AUC0-96 
value following rescue medication administration, the primary analysis of the primary efficacy 
endpoint will be repeated in the mITT Population and PP Population in two ways: 
• 
No post rescue medication administration censoring and imputation is performed; the rest 
NRS AUC0-96 calculation will employ all scheduled rest NRS scores and pre-rescue rest 
NRS scores available in the interval T0 to T96. 
• 
No post rescue medication administration censoring and imputation is performed; the rest 
NRS AUC0-96 calculation will employ all available scheduled rest NRS scores only. Pre-
rescue rest NRS scores will not be considered for AUC0-96 calculation. 
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7.3.3.4 Exploratory Analyses of the Primary Efficacy Endpoint 
For the primary efficacy endpoint, two exploratory analyses will be performed as to explore 
different methods of accounting for the effect of rescue medication use in the primary analysis.  
Censoring of rest NRS scores post rescue medication use as described in Section 7.3.2 will not 
be included in these analyses. 
• 
Silverman Rank Analysis: Rank patients in the combined treatment groups according to 
their NRS AUC0-96 values; when ties occur, assign each of the tied observations the 
average of the ranks the tied observations would have if there were no ties.  Perform the 
above steps for total opioid use OME values.  Each rest NRS AUC0-96 rank and each total 
opioid use OME rank will be expressed as a percentage difference from the mean rank 
for that variable in the overall study population and plotted.  The integrated ranks of the 
active treatment and placebo groups will be compared using the Kruskal-Wallis test (non-
parametric ANOVA).  (See Silverman 1993.) 
• 
Analysis of Covariance (ANCOVA): The primary analysis of the primary efficacy endpoint 
will be revised with the addition of the patient’s Total Opioid Consumption as a covariate 
in the model as well as the treatment by Total Opioid Consumption interaction.  The 
interaction term will be omitted from the model if not significant at the 0.1 level. 
Should the ANCOVA assumptions of normality of rest NRS AUC0-96 values, residuals, or 
homogeneity of variances be significantly violated and the relationship between the dependent 
variable and the covariate is not linear, then the primary analysis may be performed using Rank 
ANCOVA. 
The exploratory analyses for the primary endpoint will be performed using mITT Population. 
7.3.3.5 Primary Efficacy Endpoint Reporting 
The primary efficacy endpoint analysis results will be presented in a summary for part B and C 
respectively and analysis table for part C.  The number of patients (n) included in the analysis, 
mean (SD) of rest NRS AUC0-96, LS mean of rest NRS AUC0-96 and its standard error (SE) will be 
presented for all treatment groups.  The difference in LS mean from placebo, the 95% confidence 
interval (CI) for the difference in LS means, and the corresponding p-value for the difference will 
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be presented by treatment group using ANOVA and ANCOVA as described in the Section 7.4.3.2 
and Section 7.4.3.4 respectively.   
The output of the Kruskal-Wallis test for the Silverman rank analysis will be presented in a 
summary and analysis table.  A plot of the Silverman analysis summed percentage differences 
(for rest NRS and total opioid consumption OME) over all treatment groups versus mean overall 
rank will be presented in a figure. 
NRS values by time point, and computed AUC values by type, will be presented in patient listings 
by treatment group.  Imputed NRS values will be flagged in the listing. 
In order to visualize the effect of censoring scheduled rest NRS scores due to the administration 
of rescue medication, three figures will be provided: 
• 
A plot of mean scheduled rest NRS scores by nominal time point, where in calculating the 
mean, wherever a patient has a scheduled rest NRS score falling within a censoring 
interval due to the administration of rescue medication, the observed rest NRS score is 
replaced by the imputed score for that patient at that nominal time point (i.e., the wLOCF 
value is imputed at that nominal time point), and the mean is then calculated over all such 
NRS scores for each nominal time point. Missing values due to early drop out are imputed 
using WOCF as specified in Section 7.2.6. 
• 
A plot of mean scheduled rest NRS scores by nominal time point, where in calculating the 
mean, no post rescue medication administration censoring and imputation is performed 
and missing NRS scores post drop out are imputed using WOCF as specified in Section 
7.2.6. 
• 
A plot of the mean observed scheduled rest NRS scores with no imputation due to rescue 
medication use or post-dropout. 
Each figure will display the plot of NRS score by time for each treatment group and the regions 
corresponding to rest NRS AUC0-96 will be indicated on the plot. These figures will be provided for 
both the mITT and PP Populations. The corresponding table with descriptive summaries at each 
time point will also be produced for each figure. 
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Similar figures (with or without post-dropout LOCF imputation) and the corresponding tables will 
be created for evoked NRS. 
Plots of NRS values over time may be displayed in figures, by patient, as warranted. 
7.3.4 Other AUC Endpoints, Total Opioid Consumption, and Total Non-opioid Analgesic 
Consumption Endpoints 
Other AUC-based endpoints, total opioid consumption endpoints, and total non-opioid analgesic 
consumption endpoints will be analyzed using the same ANOVA approach employed in the 
primary analysis of the primary efficacy endpoint Section 7.4.3.2 for both mITT and PP Population 
respectively (as appropriate). 
7.3.4.1 Other AUC Endpoints and Total Opioid Consumption Endpoints Reporting 
ANOVA output for other AUC-based endpoints, total opioid consumption endpoints, and total non-
opioid analgesic consumption endpoints will be presented in tables similar to those presented for 
the primary endpoint analysis. 
Figures will be provided displaying plots similar to those specified for the primary endpoint for 
mean rest NRS values and mean evoked NRS values; regions corresponding to AUC for the 
relevant time periods will be indicated on the plots.  
A figure displaying total opioid consumption OME values for each treatment group in a bar chart 
will be provided.  A similar figure for total non-opioid analgesic consumption will also be provided. 
7.3.5 Time to Cessation of Opioid Use 
Time to cessation of opioid use (in hours from T0nrs to the last recorded use of opioid analgesics 
through D15) will be analyzed via a log-rank test. A Kaplan-Meier plot will be provided by 
treatment group. Median time to cessation and the 95% confidence interval of the median times 
to cessation will be presented, if estimable.  
In this time to event analyses, patients with ongoing opioids up to Day 15 or discontinuing from 
the study prior to Day 15 with ongoing opioid use will be censored at Day 15 or the day of last 
follow up, respectively.  
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This endpoint will be analyzed for mITT Population and will be repeated for the PP Population. 
7.3.6 Patients Who Are Opioid-free 
The number and percentage of patients who are opioid-free (yes/no) from T24 to D8 (T168), will 
be presented in an analysis table, by treatment group.  A Fisher’s exact test will be used to test 
the null hypothesis of no difference between each active treatment group and placebo in the 
proportion of opioid-free patients in the mITT Population from T24 to D8 (T168); the analysis will 
be repeated for the following time intervals: OF0-96, OF0-D15, OF24-96, OF24-D15, OF48-D15, OF72-D15, 
OF96-D15, and OFD8-D15.  Each of the OF analyses will be repeated for the PP Population. 
Treatment versus placebo odds ratios with 95% CI, the difference in proportions (active treatment 
minus placebo) with 95% CI, and Fisher’s exact test p-values for the comparisons of active 
treatment versus placebo will be presented in the analysis table. 
7.3.7 Time-specific Mean Rest NRS Scores 
The mean rest NRS scores at T48, T72, and D5(T96), will be summarized descriptively by time 
point and treatment group and presented in a summary table. 
For this analysis, post-rescue assessments will be imputed as described in Section 7.3.3.  
However, post-dropout missing NRS scores (described in section 7.2.6) will not be imputed. In 
case several NRS scores were collected for the same scheduled time point, the highest score 
recorded will be used. 
The difference in mean rest NRS scores between treatment groups at T48, T72, T96, D5-AM, D5-
PM, D6-AM, D6-PM, D7-AM, D7-PM, etc. to D15-AM, D15-PM, will be analyzed in the mITT 
Population using a linear mixed-effects model repeated measures ANOVA with fixed effects for 
treatment, time point, and the interaction of treatment and time point.  The Kenward-Roger 
method for computing the denominator degrees of freedom will be used.  An unstructured 
covariance matrix will be assumed; if convergence issues are experienced with this matrix type, 
then Toeplitz, first-order auto-regressive, and compound symmetry types will be tried in order and 
the first matrix to result in successful convergence will be used.  Least Squares (LS) means, with 
95% confidence intervals and the corresponding p-value, will be presented for each time point for 
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the difference between each active treatment group and placebo.  The analysis will be repeated 
for the PP Population.  
In addition, a plot of mean NRS scores versus nominal time point, by treatment group, will be 
presented in a figure. 
For the ANOVA of the difference in mean rest NRS scores between treatment groups, the 
Shapiro-Wilk test will be used to check normality of residuals and Levene’s test will be used to 
check homogeneity of variances. If the assumptions of normality are violated, then the ANOVA 
for the difference in mean rest NRS scores may be performed using generalized estimating 
equations (GEE). 
In the GEE approach, mean rest NRS scores will be analyzed as repeated measures over time. 
The GEE model with normal distribution and Identity link will include treatment group, time point, 
and interaction between treatment group and time point as fixed effects. To model the covariance 
structure, the exchangeable covariance matrix will be selected initially; if the exchangeable 
covariance structure leads to non-convergence, Quasi-Likelihood Information Criterion (QIC) will 
be used to select the best covariance structure. The adjusted least squares means (LS means) 
and standard error (SE) from the model will be presented for each active treatment group and 
placebo. The LS means estimates for the difference of each treatment group versus placebo, SE, 
95% CI, and p-value will also be provided. 
For each analysis, only measurements up to T48, T72, T96, D5-AM, D5-PM, D6-AM, D6-PM, D7-
AM, D7-PM, etc. to D15-AM, D15-PM will be included in the model, respectively. 
7.3.8 Performance-Based Outcome Measure (PBOM). 
The results of PBOM measurements at T48 (± 15 min), T96 (± 4 h)/Discharge, D15, and D29 will 
be summarized descriptively by time point and treatment group and presented in separate 
summary tables for each of the PBOMs—sit to stand and timed up and go (TUG). 
The difference in mean PBOM score between treatment groups at T48 (± 15 min), T96 (± 4 
h)/Discharge, D8, D15, and D29 will be analyzed in the mITT Population using a linear mixed-
effects model repeated measures ANOVA with fixed effects for treatment, time point, and the 
interaction of treatment and time point, similar to the model in Section 7.4.7. Least Squares (LS) 
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means, with 95% confidence intervals and the corresponding p-value, will be presented for each 
time point for the difference between each active treatment group and placebo.  The analysis will 
be repeated for the PP Population. 
7.3.9 PROMIS 10 Global Health Questionnaire Scores and AAS 
The PROMIS 10 questionnaire Global Physical Health and Global Mental Health subscale scores 
(see Appendix 15.2) at Screening (baseline), D8, D15, and D29 and their changes from baseline 
will be summarized descriptively by time point and treatment group for each subscale. 
The change from baseline in each subscale score will be analyzed in the mITT Population using 
a linear mixed-effects model with fixed effects for treatment, time point, the interaction of treatment 
and time point, and the corresponding baseline value, similar to the model in Section 7.4.7.  For 
each treatment group, the change from baseline mean (SD), LS mean (SE), and difference in LS 
mean from placebo with 95% CI and the corresponding p-value, will be presented, by subscale, 
for each time point and treatment group; the analysis will be repeated for the PP Population. 
The above analysis will be repeated for the sensitivity analysis of the PROMIS 10 questionnaire 
Global Physical Health and Global Mental Health subscale scores when assessments are to be 
imputed for data after a patient discontinues from the study, using WOCF. The responses to the 
PROMIS 10 questionnaire items will be listed separately by patient.  
The Activities Assessment Scale (see Appendix 15.3) overall AAS score and the Sedentary 
Activities, Ambulatory Activities, and Work/Exercise Activities subscale scores at Screening 
(baseline), D8, D15, and D29 and their changes from baseline will be summarized descriptively 
by time point and treatment group. 
The overall AAS score will be calculated as follows: 
1) Answers of 1=No difficulty, through 5=Not able to do it, will be summed across questions 
1-13.  Answers of 6=Did not do it for other reasons, will not be included in the sum. 
2) The mean will be calculated by dividing the sum from step 1 by the number of answers 
contributing to the sum. 
3) The mean from step 2 will be multiplied by 13.  The result will be the raw score. 
4) The raw score will be scaled from 0 to 100 using the following formula:  
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5) (65 – raw score)/52 x 100. Note: 65 is the maximum raw score, and 52 is the range of 
possible scores (65-13=52). 
6) If more than 6 questions out of 13 did not contribute to the sum in step 1, then the overall 
AAS score will be set to missing. 
Three subscales will be scored using the following steps: 
1) Answers of 1=No difficulty, through 5=Not able to do it, will be summed across the 
questions included in the subscale (see below). Answers of 6=Did not do it for other 
reasons, will not be included in the sum. 
2) The mean will be calculated by dividing the sum from step 1 by the number of answers 
contributing to the sum. 
3) The mean from step 2 will be multiplied by the number of questions in the subscale (3 for 
the ambulatory subscale, or 4 for the sedentary activities and work/exercise subscales). 
4) The raw score will be scaled from 0 to (number of subscale items*100/11) using the 
following formulas. Note: 11 is the total number of items contributing to the 3 subscales, 
and the subscales will sum to a maximum of 100 points. 
5) 3-item subscale: (15-raw score)/12 x 3x100/11. Note: 15 is the maximum raw score, and 
12 is the range of possible scores. 
6) 4-item subscale: (20-raw score)/16 x 4x100/11. Note: 20 is the maximum raw score, and 
16 is the range of possible scores. 
Subscales: 
Sedentary Activities subscale: items 1-4 (4 items) 
Ambulatory Activities subscale: items 6-8 (3 items) 
Work/Exercise Activities subscale: items 10-13 (4 items) 
A listing will be provided for AAS scores by patient within treatment group. 
7.3.10 Other Binary Endpoints 
For the following binary endpoint, the number and percentage of patients achieving the endpoint 
will be presented in an analysis table by time point (if applicable) and treatment group: 
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• 
Patients with NRS ≤ 3 during T0 to T96, T0 to T48, and T48 to T96 
A Fisher’s exact test will be used to test the null hypothesis of no difference between active 
treatment group and placebo in the proportion of patients who met the endpoint in the mITT 
Population for the relevant time period, where applicable. 
Treatment versus placebo odds ratios with 95% CI, the difference in proportions (active treatment 
minus placebo) with 95% CI, and Fisher exact test p-values for the comparisons of active 
treatment versus placebo will be presented in the analysis table. 
 
 
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8. SAFETY EVALUATION 
8.1 
Overview of Safety Analysis Methods 
Analysis of safety will be performed for the Safety Population. All safety summaries will be 
grouped by the actual treatment received.  Actual values and change from baseline clinical 
laboratory measures, vital signs, ECGs, physical examination, surgical site, and neurosensory 
assessments will be assessed and summarized by treatment group within each study Part A, B, 
and C. 
No formal statistical comparisons will be performed for safety endpoints.  
Safety outcomes include: 
• 
Incidence TEAEs or SAEs 
• 
Clinical laboratory test results 
• 
Vital sign measurements 
• 
12-lead ECG results 
• 
PE findings  
• 
Surgical site wound assessment findings 
• 
Neurosensory testing results 
• 
Concomitant medication use/concomitant treatments 
8.2 
Adverse Events 
All AEs are documented and followed from the time the patient signed the informed consent form 
(ICF) until Day 29 or later as necessary.  AEs will be coded by system organ class (SOC) and 
preferred term (PT) using the Medical Dictionary for Regulatory Activities (MedDRA Version 24.0) 
reporting system.  All coding will be reviewed prior to database lock.  All recorded AEs will be 
listed, but only TEAEs will be summarized. 
Treatment-emergent AEs are defined as any of the following:  
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• 
Non-serious AEs with onset on or after the date of treatment with the study drug through 
Day 29 or Early Termination. 
• 
Serious AEs with onset on or after the date of treatment with the study drug through 30 
days after Day 29 or Early Termination. 
• 
AEs that start before the start of treatment but increase in severity or relationship at the 
time of or following the start of treatment through Day 29 or Early Termination.  
In case an AE start date is partial, when comparing this date to the date of treatment, the latest 
possible date consistent with the known portion of the date will be imputed. However, when 
comparing the start date to the Day 29/Early Termination date, the earliest possible date 
consistent with the known portion of the date will be imputed. 
For evaluation of causal relatedness to treatment, the categories are probably related, possibly 
related, unlikely related, and not related.  For categorization in the summary tables, AEs 
designated as probably or possibly related will be considered to be related. 
For the evaluation of event severity, the criteria are mild, moderate, severe, and potentially life-
threatening. 
Safety summaries will include the incidence of treatment emergent adverse events (TEAEs).  AEs 
recorded on the CRF which began prior to treatment with study drug will not be included in the 
summary tables but will be included in the AE data listings.  TEAEs will be evaluated for severity 
and causality.  All TEAE summaries will be based on the number of patients experiencing an 
event, not the number of AEs experienced.  For example, if a patient reports the same AE on 
three separate occasions that patient will be counted only once for that preferred term.  Patients 
reporting more than one AE in a SOC will be counted only once in the SOC total. 
AEs and serious adverse events (SAEs) will be summarized separately and presented by 
treatment group.  The number and percentage of patients experiencing any event, and the 
number of events, will be presented.  Only TEAEs will be included in the summaries.  Non-
treatment emergent events will be included in the patient listings and flagged, but they will not be 
included in the AE summaries. 
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Summaries classifying AEs according to severity (i.e., mild, moderate, severe, potentially life-
threatening, or missing severity) and relationship to study drug (i.e., probably related, possibly 
related, unlikely related, not related, or relationship is missing) will be presented.  If a patient 
experiences the same AE at more than one severity or with more than one relationship to study 
drug, the most severe rating or the stronger causal relationship to study drug will be given 
precedence.  Any missing severity, causality, or outcome will not be imputed and will be classified 
as unknown. 
The denominator used for calculation of the safety summary percentages will be the number of 
patients in the Safety Population in the appropriate group.  AEs will be summarized for any 
exposure to study treatment by treatment group. 
8.2.1 Adverse Event Summaries 
The following AE summaries will be provided: 
• 
A summary of the number and percentage of patients reporting any TEAE will be 
presented by treatment group and by each study Part A, B, and C separately. Each 
summary will include: 
Number (%) of patients with at least one TEAE 
Number (%) of patients with at least one treatment related TEAE  
Number (%) of patients with at least one severe or potentially life-threatening TEAE  
Number (%) of patients with at least one Serious TEAE  
Number (%) of patients with a TEAE leading to discontinuation from the study 
Number (%) of patients with a TEAE leading to death 
• 
A summary of the number and percentage of patients reporting a TEAE by treatment 
group, system organ class, and preferred term. 
• 
A summary of the number and percentage of patients reporting a TEAE by treatment 
group, system organ class, preferred term, and maximum severity (for each patient and 
each TEAE, the maximum reported severity recorded will be attributed and used in the 
summary). 
• 
A summary of the number and percentage of patients reporting a TEAE by treatment 
group, system organ class, preferred term, and maximum toxicity grade (for each patient 
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and each TEAE, the maximum reported severity recorded will be attributed and used in 
the summary). 
• 
A summary of the number and percentage of patients reporting a TEAE by treatment 
group, system organ class, preferred term, and relationship to study drug (the worst 
relationship to study drug will be attributed and used in the summary). 
8.2.2 Deaths, Serious Adverse Events, Adverse Events Leading to Withdrawal 
The following summaries will be provided: 
• 
A summary of the number and percentage of patients reporting a serious TEAE by 
treatment group, system organ class, and preferred term. 
• 
A summary of the number and percentage of patients reporting a serious TEAE by 
treatment group, system organ class, preferred term, and relationship to study drug. 
• 
A summary of the number and percentage of patients reporting a TEAE leading to study 
discontinuation  by treatment group, system organ class, and preferred term. 
• 
A summary of the number and percentage of patients reporting a SAE outcome of death 
by treatment group and preferred term. 
All AEs (including non-TEAEs) reported during the study will be present in a by-patient listing. 
Separate by-patient listings will be generated to present AEs, SAEs, AEs leading to 
discontinuation from the study, and SAEs leading to death. 
8.3 
Clinical Laboratory Test Results 
Clinical laboratory tests (chemistry, hematology, and coagulation) will be collected at screening 
and before discharge from the inpatient unit (T48). All results will be presented in listings by patient 
and treatment group separately for study Part A, Part B, and Part C. 
For continuous laboratory parameters, descriptive statistics will be presented for the value at 
Baseline and Day 3 (T48), and for the changes from baseline to Day 3 (T48), by treatment group. 
Values reported as “< xx” or “> xx” (where xx is a number) will be treated as xx for the purposes 
of these summaries. 
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Additionally, clinical laboratory parameters will be categorized as low, normal, or high according 
to laboratory range specifications.  Laboratory shift tables displaying the change (number and 
percentage of patients) relative to the normal range from baseline to T48 will also be presented 
by treatment group for each test.   
Laboratory values that are outside the normal range will also be flagged in the data listings, along 
with corresponding normal ranges. 
8.4 
Drugs of Abuse and Alcohol Screens, Pregnancy Test 
Pregnancy tests (for female patients of childbearing potential), the follicle stimulating hormone 
(FSH) test, and alcohol (breath or saliva) tests will be performed at screening and on D1 pre-
surgery.  
Results will be presented in listings by patient.  Each test result will be recorded as “negative” or 
“positive”. 
8.5 
Vital Signs 
Vital signs (supine position) including blood pressure (systolic and diastolic; mmHg), heart rate 
(beats per minute), respiration rate (breaths per minute), SpO2, and temperature (°C) will be 
assessed at screening, D1 (pre-surgery) and after T0 at 1, 2, 6, 12, 24, and every 12 hours 
thereafter (if awake at time of assessment between the hours of 12:00 AM and 6:00 AM) until 
discharge from the inpatient unit (a patient may not miss two consecutive assessments) and as 
an outpatient on D8, D15, and D29 or later if necessary. There will be a ± 5-minute window allowed 
for the collection of vital signs in the first 4 hours after the end of surgery, after which a ± 15-minute 
window is allowed. 
Body weight (kg) will be measured at Screening and at T96.  Height (cm) was to be measured at 
screening only.  Body mass index (BMI) will be calculated for the Screening visit only. 
Vital signs (including weight) and their changes from baseline will be summarized descriptively 
by time point and treatment group.  
Vital signs data will be presented in a listing by patient and date and time of assessment for each 
parameter. 
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8.6 
ECG 
12-lead ECG: 
12-lead ECG will be performed at Screening and 24 hours (± 2 hours) after study medication 
administration. ECG parameters and their changes from baseline will be summarized 
descriptively by treatment group. Overall interpretation (Normal, Abnormal Not Clinically 
Significant, or Abnormal Clinically Significant) is recorded in the eCRF. The number and 
percentage of patients with each interpretation will be summarized by time point and treatment 
group. 
12-lead ECG Holter: 
12-lead Holter monitors will be placed prior to surgery and record for 24 hours to assess for 
effects on the QT interval and correlation with PK levels in a subset of at least 12 patients per 
randomized arm in Part B.  All patients undergoing 24-hour Holter ECG recordings should have 
PK sampling.  
Details of 12-lead ECG Holter analysis will be described in a separated cQT analysis plan. 
8.7 
Physical Examination  
A complete physical examination including all major body systems will be performed at Screening.  
In addition, a targeted physical examination will be performed prior to surgery, then a physical 
examination to capture changes after surgery at T96 (± 4 hours), but prior to discharge from the 
inpatient unit, and D8, D15, and D29 or at the time a patient terminates early, if permitted.   
Abnormal or clinically significant physical examination results will be recorded as AEs.  Physical 
examination results will be presented in a data listing by patient and treatment group.  
8.8 
Surgical Site Assessments 
Surgical sites will be assessed at 96 hours (prior to discharge from the PACU) and then at the 
D8, D15, and D29 visits.  The investigator will have evaluated wound healing during this surgical 
site assessment using an 11-point scale (0-10) where a score of 0 is “completely unsatisfied” and 
a score of 10 is “completely satisfied”.  Any clinically significant wound healing issues are captured 
as AEs and followed until resolution. 
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Assessment results and change from baseline will be summarized descriptively by time point and 
data will be listed by patient and treatment group.   
8.9 
Neurosensory Test 
Neurosensory testing near the incision (compared to a similar site on the opposite leg) will be 
performed at screening, T96h (prior to discharge from the unit), and then at the D8, D15, and D29 
visits. 
Two sides of the wound will be examined: cephalad (upper) and caudad (lower).  For each side, 
the following assessments were to be recorded: 
• 
Visual Examination of the Surgical Site (Normal or Abnormal) 
• 
Light Touch (Normal, Reduced, or Absent) 
• 
Von Frey Stimulation (Normal, Reduced, or Absent) 
• 
Brush Stimulation (Normal, Reduced, Absent, or Pain [Allodynia]) 
The neurosensory assessment results will be listed and the number and percentage of patients 
with each response will be summarized by treatment group, time point, wound side (cephalad or 
caudad), and assessment.  
8.10 Prior and Concomitant Medications 
Prior medications/therapies are those that stop prior to the start of the study drug administration.  
Any medication/therapy that stops at or is ongoing or starts after the start of the study drug 
administration is considered concomitant medication/therapy.  Prior and concomitant medications 
are collected for the 30 days prior to screening and throughout the study.  Prior and concomitant 
medications will be coded using World Health Organization Drug Dictionary Anatomical 
Therapeutic Chemical (WHO/ATC) classification index version March, 2020.  The number and 
percentage of patients who take concomitant medications will be summarized by the drug class 
(the highest available ATC level) and preferred term, overall and by treatment group for each 
study Part A, B & C separately using the Safety Population.  All medications and non-medical 
therapies captured in eCRFs will be presented by patient in listings by treatment group. 
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8.11 Patient Pain Assessment Training and Surgery Details 
Pain assessment training will be provided to patients during screening.  Patients were to re-watch 
the video prior to surgery.  Patient pain assessment training and surgery details were to be 
documented in eCRFs and will be presented by patient in listings by treatment group. 
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9. PHARMACOKINETIC EVALUATION 
PK sampling will be performed on at least 8 patients at a single site. PK sampling will be performed 
on at least 24 patients receiving blinded study drug, i.e., 12 patients per randomized arm at a 
single site.  All patients undergoing 24-hour Holter ECG recordings should have PK sampling. 
No PK sample collection is planned for Part C.  
The time points for whole blood collection will be at pre-dose pharmacokinetic time PKT 0 (Pre-
IP Dose, 2-10 minutes prior to the first study treatment instillation), 0.03 h (2 min), 0.083 h (5 min), 
0.167 h (10 min), 0.25 h (15 min), 0.33 h (20 min), 0.5 h (30 min), 0.75 h (45 min), and at 1, 1.5, 
2, 4, 8, 12, 16, 24, 36 and 48 hours after the first study treatment instillation (total of 18 samples).  
Unscheduled PK samples will be collected where feasible during the inpatient phase of the study 
for all patients incurring an SAE or severe TEAE as part of the evaluation of those AEs.  
There will be a ± 2-minute window allowed for the 10-, 15-, and 20-minute collections, a ± 5-
minute window allowed for collections at 30 minutes through 4 hours, and a ± 15-minute window 
for collections after 4 hours. In the event of a SAE or severe TEAE, the actual time of collection 
of any unscheduled PK draw will be recorded for use in any analyses.  Out-of-window collections 
will not be considered protocol deviations. 
PK Analysis will be handled by an external vendor. 
10. OTHER ANALYSES 
Additional analyses involving the pooling treatment groups (from Parts B and C) may be carried 
out for exploratory purposes. 
 
 
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11. DEVIATIONS FROM THE SAP 
Any deviations from the final version of this SAP will be described and justified in the final CSR. 
 
 
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12. CHANGES IN CONDUCT OR PLANNED ANALYSES FROM THE PROTOCOL 
None. 
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13. EXAMPLE SAS CODE 
Primary endpoint analysis, one-way ANOVA: 
proc mixed data=auc_data; 
  class patient treatment; 
  model auc = treatment; 
  lsmeans trt / diff cl alpha=0.05; 
   
run; 
 
 
Primary endpoint analysis, ANCOVA: 
proc mixed data=auc_data; 
  class patient treatment; 
  model auc = treatment total_OME treatment*total_OME; 
  lsmeans trt / diff cl alpha=0.05; 
   
   
run; 
 
 
Primary endpoint exploratory analysis, non-parametric ANOVA (Silverman rank test): 
proc npar1way wilcoxon correct=no data=integ_ranks;  
  class treatment;  
  var int_rank;  
run; 
 
 
Example SAS code for ANOVA by time point analyses: 
proc mixed data=scores; 
  class subjid trt time; 
  model score = trt time trt*time/ ddfm=kr; 
  repeated time / subject = subjid type = UN; 
  lsmeans trt*time / diff cl; 
run; 
 
Note: if the model does not converge with Unstructured covariance matrix (type=UN), then 
try TOEP, AR(1), and CS, in this order, choose the first structure that converges. 
 
 
Example SAS code for the change from baseline linear mixed-effects model: 
proc mixed data=parameter_data;  
  class patient treatment timepoint;  
  model change=baseline treatment timepoint treatment*timepoint / ddfm=kr;  
  repeated timepoint / subject = subjid type = UN; 
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  lsmeans treatment*timepoint / diff cl; 
run; 
 
Note: if the model does not converge with Unstructured covariance matrix (type=UN), then 
try TOEP, AR(1), and CS, in this order, choose the first structure that converges. 
 
 
Example SAS code for Fisher’s exact test: 
proc freq data=parameter_data order=data;  
  tables treatment*outcome / fisher exact OR;  
run; 
 
 
Example SAS code for time to event analysis: 
proc lifetest data=event_data method=KM plots=survival(failure test atrisk);  
  time hours*status(0);  
  strata treatment; 
run; 
 
 
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14. REFERENCES 
Clinical Trial Protocol CA-PS-209, Amendment Version 2.0 / 15-Mar-2021. 
eCRF Version and Date: Specification Version 3.0 and 22-Mar-2021. 
US Federal Register. (1998) International Conference on Harmonization; Guidance for Industry:  
Statistical Principles for Clinical Trials. Department of Health and Human Services:  Food and 
Drug Administration. Federal Register, Vol. 63, No. 179, September 16, 1998, page 49583. 
US Federal Register. (1996) International Conference on Harmonization; Guidance for Industry:  
Structure and Content of Clinical Study Reports. Department of Health and Human Services:  
Food and Drug Administration. Federal Register Vol. 61, July 17, 1996, page 37320.  
Silverman, David G. et al., Integrated assessment of pain scores and rescue morphine use during 
studies of analgesic efficacy, Anesth Analg 1993;77:168-70 
Nielsen, Suzanne et al., A synthesis of oral morphine equivalents (OME) for opioid utilisation 
studies, Pharmacoepidemiology and Drug Safety 2016; 25: 733–737 
Martin McCarthy Jr, PhD, Olga Jonasson, MD, FACS, Chih-Hung Chang, PhD, A Simon Pickard, 
PhD, Anita Giobbie-Hurder, MS, James Gibbs, PhD, Perry Edelman, PhD, Robert Fitzgibbons, 
MD, FACS, Leigh Neumayer, MD, FACS, Assessment of Patient Functional Status after Surgery. 
https://www.portalbiocursos.com.br/ohs/data/docs/57/275Assessment_of_Patient_Functi
onal_Status_after_Surgery.pdf 
Activity Assessment Scale with Description of Scoring 
 https://cdn-links.lww.com/permalink/aog/b/aog_134_5_2019_09_12_boyd_19-
1019_sdc1.pdf 
 
 
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15. APPENDICES 
15.1 0 to 10 Numerical Rating Scale of Pain Intensity (NRS) 
 
 
 
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15.2 Scoring of PROMIS 10 Questionnaire 
Global Health 
Please respond to each item by marking one box per row. 
 
 
 
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This study employs PROMIS v1.1 questionnaire that is scored as follows. 
1. Recode the response to question 10 (How would you rate your pain on average) as 
follows: 
Response 
Recoded Response 
0 
5 
1, 2, 3 
4 
4, 5, 6 
3 
7, 8, 9 
2 
10 
1 
2. Reverse the response to questions 8 (How often have you been bothered by emotional 
problems such as feeling anxious, depressed or irritable?) and 9 (How often have you 
been bothered by emotional problems such as feeling anxious, depressed or irritable?) 
by subtracting them from 5. This way higher scores for responses always indicate 
better health. 
3. Calculate the Global Physical Health raw score by summing the responses for 
questions 3, 6, 7, 9, and 10. If not all of these questions are answered, the score will 
be missing. 
4. Calculate the Global Mental Health raw score by summing the responses for 2, 4, 5, 
and 8. If not all of these questions are answered, the score will be missing. 
5. Use the following tables to convert the global raw scores to the T-scores that will be 
used in analysis: 
Global Physical Health 
Raw summed score 
T-score 
4 
16.2 
5 
19.9 
6 
23.5 
7 
26.7 
8 
29.6 
9 
32.4 
10 
34.9 
11 
37.4 
12 
39.8 
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Global Mental Health 
Raw summed score 
T-score 
4 
21.2 
5 
25.1 
6 
28.4 
7 
31.3 
8 
33.8 
9 
36.3 
10 
38.8 
11 
41.1 
12 
43.5 
13 
45.8 
14 
48.3 
15 
50.8 
16 
53.3 
17 
56.0 
18 
59.0 
19 
62.5 
20 
67.6 
 
13 
42.3 
14 
44.9 
15 
47.7 
16 
50.8 
17 
54.1 
18 
57.7 
19 
61.9 
20 
67.7 
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15.3 Activities Assessment Scale (AAS) 
 
 
 
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15.4 Sit to Stand Test (30-Second Chair Stand) Assessment 
 
 
 
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15.5 TUG Test 
 
 
 
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15.6 Surgical Site Assessment 
 
 
 
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15.7 Planned Tables, Figures, and Listings 
15.7.1 Tables 
Table 14.1.1.1.1 
All Patients 
Summary of Patient Disposition for Part A  
Table 14.1.1.1.2  
All Patients 
Summary of Patient Disposition for Part B 
Table 14.1.1.1.3 
All Patients 
Summary of Patient Disposition for Part C 
Table 14.1.2.1 
Safety Population 
Summary of Demographics and Baseline Characteristics for 
Part A 
Table 14.1.2.2 
Safety Population 
Summary of Demographics and Baseline Characteristics for 
Part B 
Table 14.1.2.3 
Safety Population 
Summary of Demographics and Baseline Characteristics for 
Part C 
Table 14.1.3.1 
Safety Population 
Summary of Medical History, by System Organ Class and 
Preferred Term for Part A 
Table 14.1.3.2 
Safety Population 
Summary of Medical History, by System Organ Class and 
Preferred Term for Part B 
Table 14.1.3.3  
Safety Population 
Summary of Medical History, by System Organ Class and 
Preferred Term for Part C 
Table 14.1.4.1  
Safety Population 
Summary of Concomitant Medications, by ATC Class and 
Preferred Term for Part A 
Table 14.1.4.2  
Safety Population 
Summary of Concomitant Medications, by ATC Class and 
Preferred Term for Part B 
Table 14.1.4.3 
Safety Population 
Summary of Concomitant Medications, by ATC Class and 
Preferred Term for Part C 
Table 14.1.5.1  
All Randomized 
Population 
Summary of Protocol Deviations for Part A 
Table 14.1.5.2  
All Randomized 
Population 
Summary of Protocol Deviations for Part B 
Table 14.1.5.3  
All Randomized 
Population 
Summary of Protocol Deviations for Part C 
Table 14.1.6.1 
Safety Population 
Summary of Study Drug Volume Administered for Part A 
Table 14.1.6.2  
Safety Population 
Summary of Study Drug Volume Administered for Part B 
Table 14.1.6.3  
Safety Population 
Summary of Study Drug Volume Administered for Part C 
Table 14.2.1.1.1  
mITT Population 
ANOVA Analysis of Rest NRS AUC0-96 (Primary Analysis) 
for Part C 
Table 14.2.1.1.2  
PP Population 
ANOVA Analysis of Rest NRS AUC0-96 (Primary Analysis) 
for Part C 
Table 14.2.1.2.1  
mITT Population 
ANOVA Analysis of Rest NRS  AUC0-96 – (Scheduled Rest 
NRS and Pre-rescue NRS Scores) (Sensitivity Analysis) for 
Part C 
Table 14.2.1.2.2 
PP Population 
ANOVA Analysis of Rest NRS  AUC0-96 – (Scheduled Rest 
NRS and Pre-rescue NRS Scores) (Sensitivity Analysis) for 
Part C 
Table 14.2.1.3.1  
mITT Population 
ANOVA Analysis of Rest NRS  AUC0-96 – Scheduled Rest 
NRS Scores (Sensitivity Analysis) for Part C 
Table 14.2.1.3.2  
PP Population 
ANOVA Analysis of Rest NRS  AUC0-96 – Scheduled Rest 
NRS Scores (Sensitivity Analysis) for Part C 
Table 14.2.1.4 
mITT Population 
Rest NRS AUC0-96 and Total Opioid Use, Silverman Rank 
Analysis (Exploratory Analysis) for Part C 
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Table 14.2.1.5  
mITT Population 
ANCOVA Analysis of Rest NRS  AUC0-96 (Exploratory 
Analysis) for Part C 
Table 14.2.2.1.1 
mITT Population 
ANOVA Analysis of Rest NRS AUC0-96 for Part B 
Table 14.2.2.1.2 
PP Population 
ANOVA Analysis of Rest NRS AUC0-96 for Part B 
Table 14.2.2.2.1 
mITT Population 
ANOVA Analysis of Rest NRS AUC for Part C 
Table 14.2.2.2.2 
PP Population 
ANOVA Analysis of Rest NRS AUC for Part C 
Table 14.2.2.3.1 
mITT Population 
ANOVA Analysis of Evoked NRS AUC0-96 for Part B 
Table 14.2.2.3.2 
PP Population 
ANOVA Analysis of Evoked NRS AUC0-96 for Part B 
Table 14.2.2.4.1 
mITT Population 
ANOVA Analysis of Evoked NRS AUC for Part C  
Table 14.2.2.4.2 
PP Population 
ANOVA Analysis of Evoked NRS AUC for Part C 
Table 14.2.3.1.1 
mITT Population 
ANOVA Analysis of Total Opioid Consumption in OME Dose 
from T0 to D8 for Part B 
Table 14.2.3.1.2 
PP Population 
ANOVA Analysis of Total Opioid Consumption in OME Dose 
from T0 to D8 for Part B 
Table 14.2.3.2.1 
mITT Population 
ANOVA Analysis of Total Opioid Consumption in OME Dose 
for Part C 
Table 14.2.3.2.2 
PP Population 
ANOVA Analysis of Total Opioid Consumption in OME Dose 
for Part C 
Table 14.2.4.1 
mITT Population 
ANOVA Analysis of Total Non-Opioid Analgesic 
Consumption in mg for Part C 
Table 14.2.4.2 
PP Population 
ANOVA Analysis of Total Non-Opioid Analgesic 
Consumption in mg for Part C 
Table 14.2.5.1 
mITT Population 
Time to Cessation of Opioid Use for Part C 
Table 14.2.5.2 
PP Population 
Time to Cessation of Opioid Use for Part C 
Table 14.2.6.1 
mITT Population 
Analysis of Percentage of Patients Who Are Opioid Free for 
Part C 
Table 14.2.6.2 
PP Population 
Analysis of Percentage of Patients Who Are Opioid Free for 
Part C 
Table 14.2.7.1 
mITT Population 
Repeated Measures Analysis of Rest NRS Scores, by Time 
Point for Part C 
Table 14.2.7.2 
PP Population 
Repeated Measures Analysis of Rest NRS Scores, by Time 
Point for Part C 
Table 14.2.8.1 
mITT Population 
Repeated Measures Analysis of Performance Based 
Outcome Measures (PBOM) for Part C 
Table 14.2.8.2 
PP Population 
Repeated Measures Analysis of Performance Based 
Outcome Measures (PBOM) for Part C 
Table 14.2.9.1.1 
mITT Population 
Repeated Measures Analysis of PROMIS Questionnaire for 
Part C 
Table 14.2.9.1.2 
PP Population 
Repeated Measures Analysis of PROMIS Questionnaire for 
Part C 
Table 14.2.9.2.1  
mITT Population 
Repeated Measures Analysis of PROMIS Questionnaire for 
Part C (sensitivity analysis) 
Table 14.2.9.2.2 
PP Population 
Repeated Measures Analysis of PROMIS Questionnaire for 
Part C (sensitivity analysis) 
Table 14.2.10.1 
mITT Population 
Summary of Activities Assessment Scale (AAS): Results and 
Change from Baseline for Part C 
Table 14.2.10.2 
PP Population 
Summary of Activities Assessment Scale (AAS): Results and 
Change from Baseline for Part C 
Table 14.2.11.1 
mITT Population 
Proportion of patients with NRS ≤ 3 for Part C 
Table 14.2.11.2 
PP Population 
Proportion of patients with NRS ≤ 3 for Part C 
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Table 14.2.12.1.1 
mITT Population 
Rest NRS Scores by Time Point (Primary Analysis—Post-
rescue Medication Censoring and Imputation and Post-
dropout Imputation) 
Table 14.2.12.1.2 
PP Population 
Rest NRS Scores by Time Point (Primary Analysis—Post-
rescue Medication Censoring and Imputation and Post-
dropout Imputation) 
Table 14.2.12.2.1 
mITT Population 
Rest NRS Scores by Time Point (Sensitivity Analysis of 
Primary Endpoint—Post-dropout Imputation and No Post-
rescue Medication Censoring and Imputation 
Table 14.2.12.2.2 
PP Population 
Rest NRS Scores by Time Point (Sensitivity Analysis of 
Primary Endpoint—Post-dropout Imputation and No Post-
rescue Medication Censoring and Imputation 
Table 14.2.12.3.1 
mITT Population 
Rest NRS Scores by Time Point (Sensitivity Analysis of 
Primary Endpoint—No Imputations, Observed Scores Only) 
Table 14.2.12.3.2 
PP Population 
Rest NRS Scores by Time Point (Sensitivity Analysis of 
Primary Endpoint—No Imputations, Observed Scores Only) 
Table 14.2.12.4.1 
mITT Population 
Evoked NRS Scores by Time Point (Post-dropout 
Imputation) 
Table 14.2.12.4.2 
PP Population 
Evoked NRS Scores by Time Point (Post-dropout 
Imputation) 
Table 14.2.12.5.1 
mITT Population 
Evoked NRS Scores by Time Point (No Imputations, 
Observed Scores Only 
Table 14.2.12.5.2 
PP Population 
Evoked NRS Scores by Time Point (No Imputations, 
Observed Scores Only 
Table 14.3.1.1.1 
Safety Population 
Overall Summary of Treatment Emergent Adverse Events 
(TEAEs) for Part A 
Table 14.3.1.1.2  
Safety Population 
Overall Summary of Treatment Emergent Adverse Events 
(TEAEs) for Part B 
Table 14.3.1.1.3 
Safety Population 
Overall Summary of Treatment Emergent Adverse Events 
(TEAEs) for Part C 
Table 14.3.1.2.1  
Safety Population 
Summary of Treatment Emergent Adverse Events, by 
System Organ Class and Preferred Term for Part A 
Table 14.3.1.2.2  
Safety Population 
Summary of Treatment Emergent Adverse Events, by 
System Organ Class and Preferred Term for Part B 
Table 14.3.1.2.3  
Safety Population 
Summary of Treatment Emergent Adverse Events, by 
System Organ Class and Preferred Term for Part C 
Table 14.3.1.3.1  
Safety Population 
Summary of Treatment Emergent Adverse Events, by 
System Organ Class, Preferred Term, and Severity for Part 
A 
Table 14.3.1.3.2  
Safety Population 
Summary of Treatment Emergent Adverse Events, by 
System Organ Class, Preferred Term, and Severity for Part 
B 
Table 14.3.1.3.3 
Safety Population 
Summary of Treatment Emergent Adverse Events, by 
System Organ Class, Preferred Term, and Severity for Part 
C 
Table 14.3.1.4.1  
Safety Population 
Summary of Treatment Emergent Adverse Events, by 
System Organ Class, Preferred Term and Toxicity grade for 
Part A 
Table 14.3.1.4.2  
Safety Population 
Summary of Treatment Emergent Adverse Events, by 
System Organ Class, Preferred Term and Toxicity grade for 
Part B 
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Table 14.3.1.4.3  
Safety Population 
Summary of Treatment Emergent Adverse Events, by 
System Organ Class, Preferred Term and Toxicity grade for 
Part C 
Table 14.3.1.5.1  
Safety Population 
Summary of Treatment Emergent Adverse Events, by 
System Organ Class, Preferred Term, and Relationship to 
Study Drug for Part A 
Table 14.3.1.5.2  
Safety Population 
Summary of Treatment Emergent Adverse Events, by 
System Organ Class, Preferred Term, and Relationship to 
Study Drug for Part B 
Table 14.3.1.5.3 
Safety Population 
Summary of Treatment Emergent Adverse Events, by 
System Organ Class, Preferred Term, and Relationship to 
Study Drug for Part C  
Table 14.3.1.6.1 
Safety Population 
Summary of Serious Treatment Emergent Adverse Events 
(TEAEs), by System Organ Class and Preferred Term for 
Part A 
Table 14.3.1.6.2 
Safety Population 
Summary of Serious Treatment Emergent Adverse Events 
(TEAEs), by System Organ Class and Preferred Term for 
Part B 
Table 14.3.1.6.3  
Safety Population 
Summary of Serious Treatment Emergent Adverse Events 
(TEAEs), by System Organ Class and Preferred Term for 
Part C 
Table 14.3.1.7.1  
Safety Population 
Summary of Serious Treatment Emergent Adverse Events, 
by System Organ Class, Preferred Term, and Relationship 
to Study Drug for Part A 
Table 14.3.1.7.2 
Safety Population 
Summary of Serious Treatment Emergent Adverse Events, 
by System Organ Class, Preferred Term, and Relationship 
to Study Drug for Part B 
Table 14.3.1.7.3  
Safety Population 
Summary of Serious Treatment Emergent Adverse Events, 
by System Organ Class, Preferred Term, and Relationship 
to Study Drug for Part C 
Table 14.3.1.8.1 
Safety Population 
Summary of Treatment Emergent Adverse Events (TEAEs) 
Leading to Study Discontinuation, by System Organ Class 
and Preferred Term for Part A 
Table 14.3.1.8.2  
Safety Population 
Summary of Treatment Emergent Adverse Events (TEAEs) 
Leading to Study Discontinuation, by System Organ Class 
and Preferred Term for Part B 
Table 14.3.1.8.3 
Safety Population 
Summary of Treatment Emergent Adverse Events (TEAEs) 
Leading to Study Discontinuation, by System Organ Class 
and Preferred Term for Part C 
Table 14.3.2.1.1  
Safety Population 
Summary of Serious Treatment Emergent Adverse Events 
(TEAEs) Leading to Death, by System Organ Class and 
Preferred Term for Part A 
Table 14.3.2.1.2  
Safety Population 
Summary of Serious Treatment Emergent Adverse Events 
(TEAEs) Leading to Death, by System Organ Class and 
Preferred Term for Part B 
Table 14.3.2.1.3  
Safety Population 
Summary of Serious Treatment Emergent Adverse Events 
(TEAEs) Leading to Death, by System Organ Class and 
Preferred Term for Part C 
Table 14.3.4.1.1  
Safety Population 
Summary of Hematology Laboratory Tests: Results and 
Change from Baseline for Part A 
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Table 14.3.4.1.2  
Safety Population 
Summary of Hematology Laboratory Tests: Results and 
Change from Baseline for Part B 
Table 14.3.4.1.3  
Safety Population 
Summary of Hematology Laboratory Tests: Results and 
Change from Baseline for Part C 
Table 14.3.4.1.4  
Safety Population 
Summary of Hematology Laboratory Tests: Shift from 
Baseline for Part A 
Table 14.3.4.1.5 
Safety Population 
Summary of Hematology Laboratory Tests: Shift from 
Baseline for Part B 
Table 14.3.4.1.6 
Safety Population 
Summary of Hematology Laboratory Tests: Shift from 
Baseline for Part C 
Table 14.3.4.2.1 
Safety Population 
Summary of Chemistry Laboratory Tests: Results and 
Change from Baseline for Part A 
Table 14.3.4.2.2 
Safety Population 
Summary of Chemistry Laboratory Tests: Results and 
Change from Baseline for Part B 
Table 14.3.4.2.3  
Safety Population 
Summary of Chemistry Laboratory Tests: Results and 
Change from Baseline for Part C 
Table 14.3.4.2.4  
Safety Population 
Summary of Chemistry Laboratory Tests: Shift from Baseline 
for Part A 
Table 14.3.4.2.5 
Safety Population 
Summary of Chemistry Laboratory Tests: Shift from Baseline 
for Part B 
Table 14.3.4.2.6 
Safety Population 
Summary of Chemistry Laboratory Tests: Shift from Baseline 
for Part C 
Table 14.3.4.3.1  
Safety Population 
Summary of Coagulation Laboratory Tests: Results and 
Change from Baseline for Part A 
Table 14.3.4.3.2 
Safety Population 
Summary of Coagulation Laboratory Tests: Results and 
Change from Baseline for Part B 
Table 14.3.4.3.3 
Safety Population 
Summary of Coagulation Laboratory Tests: Results and 
Change from Baseline for Part C 
Table 14.3.4.3.4  
Safety Population 
Summary of Coagulation Laboratory Tests: Shift from 
Baseline for Part A 
Table 14.3.4.3.5  
Safety Population 
Summary of Coagulation Laboratory Tests: Shift from 
Baseline for Part B 
Table 14.3.4.3.6 
Safety Population 
Summary of Coagulation Laboratory Tests: Shift from 
Baseline for Part C 
Table 14.3.4.5.1 
Safety Population 
Summary of Vital Signs: Results and Change from Baseline 
for Part A 
Table 14.3.4.5.2  
Safety Population 
Summary of Vital Signs: Results and Change from Baseline 
for Part B 
Table 14.3.4.5.3  
Safety Population 
Summary of Vital Signs: Results and Change from Baseline 
for Part C 
Table 14.3.4.6.1.1 
Safety Population 
Summary of ECG: Results and Change from Baseline for 
Part A 
Table 14.3.4.6.1.2  Safety Population 
Summary of ECG: Results and Change from Baseline for 
Part B 
Table 14.3.4.6.1.3 
Safety Population 
Summary of ECG: Results and Change from Baseline for 
Part C 
Table 14.3.4.6.2.1  Safety Population 
Summary of ECG: Overall Interpretation for Part A 
Table 14.3.4.6.2.2  Safety Population 
Summary of ECG: Overall Interpretation for Part B 
Table 14.3.4.6.2.3 
Safety Population 
Summary of ECG: Overall Interpretation for Part C 
Table 14.3.4.7.1 
Safety Population 
Summary of Surgical Site Assessment for Part A 
Table 14.3.4.7.2 
Safety Population 
Summary of Surgical Site Assessment for Part B 
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Table 14.3.4.7.3 
Safety Population 
Summary of Surgical Site Assessment for Part C 
Table 14.3.4.8.1 
Safety Population 
Summary of Neurosensory Examination for Part A 
Table 14.3.4.8.2 
Safety Population 
Summary of Neurosensory Examination for Part B 
Table 14.3.4.8.3  
Safety Population 
Summary of Neurosensory Examination for Part C 
 
15.7.2 Figures 
Figure 14.2.1.1.1 
mITT Population 
Mean Rest NRS Scores by Time Point (Primary Analysis—
Post-rescue Medication Censoring and Imputation and 
Post-dropout Imputation), by Treatment Group for Part C 
Figure 14.2.1.1.2 
PP Population 
Mean Rest NRS Scores by Time Point (Primary Analysis—
Post-rescue Medication Censoring and Imputation and 
Post-dropout Imputation), by Treatment Group for Part C 
Figure 14.2.1.2.1 
mITT Population 
Mean Rest NRS Scores by Time Point (Sensitivity Analysis 
of Primary Endpoint—Post-dropout Imputation and No Post-
rescue Medication Censoring and Imputation by Treatment 
Group for Part C  
Figure 14.2.1.2.2 
PP Population 
Mean Rest NRS Scores by Time Point (Sensitivity Analysis 
of Primary Endpoint—Post-dropout Imputation and No Post-
rescue Medication Censoring and Imputation, by Treatment 
Group for Part C 
Figure 14.2.1.3.1 
mITT Population 
Mean Rest NRS Scores by Time Point (Sensitivity Analysis 
of Primary Endpoint - No Imputation, Observed Scores 
Only), by Treatment Group for Part C 
Figure 14.2.1.3.2 
PP Population 
Mean Rest NRS Scores by Time Point (Sensitivity Analysis 
of Primary Endpoint - No Imputations, Observed Scores 
Only), by Treatment Group for Part C 
Figure 14.2.1.4.1 
mITT Population 
Mean Evoked NRS Scores by Time Point (Post-dropout 
Imputation), by Treatment Group for Part C 
Figure 14.2.1.4.2 
PP Population 
Mean Evoked NRS Scores by Time Point (Post-dropout 
Imputation), by Treatment Group for Part C 
Figure 14.2.1.5.1 
mITT Population 
Mean Evoked NRS Scores by Time Point (No Imputations, 
Observed Scores Only), by Treatment Group for Part C 
Figure 14.2.1.5.2 
PP Population 
Mean Evoked NRS Scores by Time Point (No Imputations, 
Observed Scores Only), by Treatment Group for Part C 
Figure 14.2.1.6 
mITT Population 
Silverman Rank Analysis Scores, by Treatment Group for 
Part C 
Figure 14.2.2.1.1.1 
mITT Population 
Mean Rest NRS AUC, by Treatment Group for Part B 
Figure 14.2.2.1.1.2 
mITT Population 
Mean Rest NRS AUC, by Treatment Group for Part C 
Figure 14.2.2.1.2.1 
PP Population 
Mean Rest NRS AUC, by Treatment Group for Part B 
Figure 14.2.2.1.2.2 
PP Population 
Mean Rest NRS AUC, by Treatment Group for Part C 
Figure 14.2.2.2.1.1 
mITT Population 
Mean Evoked NRS AUC, by Treatment Group for Part B 
Figure 14.2.2.2.1.2 
mITT Population 
Mean Evoked NRS AUC, by Treatment Group for Part C 
Figure 14.2.2.2.2.1 
PP Population 
Mean Evoked NRS AUC, by Treatment Group for Part B 
Figure 14.2.2.2.2.2 
PP Population 
Mean Evoked NRS AUC, by Treatment Group for Part C 
Figure 14.2.3.1.1.1 
mITT Population 
Total Opioid Consumption in OME Doses, by Treatment 
Group for Part B 
Figure 14.2.3.1.1.2 
mITT Population 
Total Opioid Consumption in OME Doses, by Treatment 
Group for Part C 
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Figure 14.2.3.1.2.1 
PP Population 
Total Opioid Consumption in OME Doses, by Treatment 
Group for Part B 
Figure 14.2.3.1.2.2 
PP Population 
Total Opioid Consumption in OME Doses, by Treatment 
Group for Part C 
Figure 14.2.3.2.1 
mITT Population 
Total Non-opioid Analgesic Consumption (mg), by 
Treatment Group for Part C 
Figure 14.2.3.2.2 
PP Population 
Total Non-opioid Analgesic Consumption (mg), by 
Treatment Group for Part C 
Figure 14.2.3.3.1 
mITT Population 
Time to Cessation of Opioid Use for Part C 
Figure 14.2.3.3.2 
PP Population 
Time to Cessation of Opioid Use for Part C 
Figure 14.2.3.4.1 
mITT Population 
Cumulative Opioid Use for Part C 
Figure 14.2.3.4.2 
PP Population 
Cumulative Opioid Use for Part C 
 
15.7.3 Listings 
Listing 16.2.1.1  
All Patients 
Randomization and Study Population  
Listing 16.2.1.2  
All Patients 
Informed Consent and Re-Consent 
Listing 16.2.1.3 
All Patients 
Eligibility 
Listing 16.2.2 
All Patients 
Protocol Deviations 
Listing 16.2.3  
All Patients 
Patient Disposition/Early Termination 
Listing 16.2.4.1  
All Randomized Patients 
Demographics and Baseline Characteristics 
Listing 16.2.4.2  
All Randomized Patients 
Medical / Surgical History 
Listing 16.2.4.3  
All Randomized Patients 
Prior and Concomitant Medications 
Listing 16.2.4.4  
All Randomized Patients 
Rescue Medication Administration 
Listing 16.2.4.5  
All Randomized Patients 
Non-Medication Therapies 
Listing 16.2.4.6  
All Randomized Patients 
Surgery 
Listing 16.2.5.1  
All Randomized Patients 
Study Drug Administration, Pain Assessment 
Training, and Discharge 
Listing 16.2.6.1 
All Randomized Patients 
Pain Intensity Assessment (Rest NRS)  
Listing 16.2.6.2  
All Randomized Patients 
Pain Intensity Assessment (Evoked NRS) 
Listing 16.2.6.3 
All Randomized Patients 
Primary Endpoint Rest NRS AUC 
Listing 16.2.6.4 
All Randomized Patients 
Secondary and Exploratory Rest NRS AUC Efficacy 
Endpoints (LOCF and WOCF) 
Listing 16.2.6.5 
All Randomized Patients 
Evoked NRS AUC Efficacy Endpoints (LOCF and 
WOCF) 
Listing 16.2.6.6   
All Randomized Patients 
Total Opioid Consumption (OME Dose) and Non-
opioid Analgesic Consumption (mg) Efficacy 
Endpoints 
Listing 16.2.6.7   
All Randomized Patients 
Opioid-free Efficacy Endpoints 
Listing 16.2.6.8  
All Randomized Patients 
Sit to Stand Test 
Listing 16.2.6.9  
All Randomized Patients 
Timed Up and Go Test 
Listing 16.2.6.10.1  
All Randomized Patients 
PROMIS Questionnaire Scales 
Listing 16.2.6.10.2  
All Randomized Patients 
PROMIS Questionnaire Details 
Listing 16.2.6.11.1  
All Randomized Patients 
Activities Assessment Scale (AAS) 
Listing 16.2.6.11.2 
All Randomized Patients 
Activities Assessment Scale (AAS) Details 
Listing 16.2.6.12   
All Randomized Patients 
Use of Rescue Medications Efficacy Endpoints 
Listing 16.2.7.1 
All Randomized Patients 
Adverse Events 
Listing 16.2.7.2 
All Randomized Patients 
Serious Adverse Events 
Listing 16.2.7.3  
All Randomized Patients 
Treatment Related Adverse Events 
Listing 16.2.7.4   
All Randomized Patients 
Adverse Events Leading to Study Discontinuation 
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Listing 16.2.7.5  
All Randomized Patients 
Adverse Events Leading to Death  
Listing 16.2.8.1 
All Randomized Patients 
Hematology Laboratory Test Results 
Listing 16.2.8.2  
All Randomized Patients 
Chemistry Laboratory Test Results 
Listing 16.2.8.3 
All Randomized Patients 
Coagulation Laboratory Test Results 
Listing 16.2.8.4 
All Randomized Patients 
Alcohol and Urine Drug Screen Tests 
Listing 16.2.8.5 
All Randomized Patients 
Pregnancy Test 
Listing 16.2.8.6 
All Randomized Patients 
FSH Test  
Listing 16.2.9.1 
All Randomized Patients 
Vital Signs  
Listing 16.2.9.2  
All Randomized Patients 
12-Lead Electrocardiogram 
Listing 16.2.9.3 
All Randomized Patients 
Physical Examination 
Listing 16.2.9.4   
All Randomized Patients 
Surgical Site Assessment  
Listing 16.2.9.5 
All Randomized Patients 
Neurosensory Examination  
 
 
 
 
DocuSign Envelope ID: E2444B36-966A-481D-A757-F35AC5C753CC


Sponsor: Concentric Analgesics, Inc.  
Statistical Analysis Plan 
Protocol Number: CA-PS-209 
Date: 14MAY2021 
 
CONFIDENTIAL 
Page 78 of 78 
16. DOCUMENT HISTORY 
Version 
# 
Summary of Changes 
Section Changed 
Date 
1.0 
Initial document released 
NA 
14MAY2021 
 
 
DocuSign Envelope ID: E2444B36-966A-481D-A757-F35AC5C753CC


Certificate Of Completion
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Subject: Please DocuSign: CA-PS-209_SAP_Final_V1.0_14May2021.pdf
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Isaac Briskin
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100 W California Blvd., Unit 25
Pasadena, CA  91105
ibriskin@lotuscr.com
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             5/17/2021 7:43:10 AM
Holder: Isaac Briskin
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HENRY FOEHL
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Henry Foehl
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Isaac Briskin
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Biostatistician
Lotus Clinical Research, LLC-Sub Account
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Sam Teichman
steichman@concentricanalgesics.com
VP, Clinical Development
Concentric Analgesics
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Swarupa Changan
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Electronic Record and Signature Disclosure


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Electronic Record and Signature Disclosure created on: 8/14/2017 10:16:15 AM
Parties agreed to: HENRY FOEHL, Sam Teichman, Swarupa Changan


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