Clinical trial NCT03789318
Conditions: Postsurgical Pain
Sponsor: Concentric Analgesics
Start date: 2018-12-03; Completion date: 2019-06-12
Enrollment: 54 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Phase 2, single center, randomized, double-blind, placebo-controlled, parallel design study of CA-008 vs. placebo in subjects undergoing an elective C-ABD under general anesthesia supplemented with a bupivacaine hydrochloride (HCl)transverse abdominis plane (TAP) block.

Detailed description:
This is a Phase 2, single-center, randomized, double-blind, placebo-controlled, parallel design study evaluating up to 4 ascending dose level cohorts, each evaluating a single dose of CA-008 vs. placebo injected/instilled during an elective C-ABD. Up to 72 subjects may be randomized in 4 cohorts.

For each subject, postsurgical assessments will be conducted in two parts:

* Inpatient period: starts with completion of study treatment injection (T0) and continues through 96 hours (T96h).
* Outpatient period: begins on discharge from the inpatient unit through various follow up visits to day 29 (D29)/week 4 (W4) after surgery. Note that additional follow up visits may occur at any time or even after D29/W4 to follow adverse events (AEs) to resolution or establishment of a new baseline.

Arms: arm 1: Cohort 1 (CA-008 5 mg): the surgery for each subject is to be performed under general anesthesia supplemented by a transverse abdominis plane (TAP) block and local surgical site infiltration. Prior to the surgery, perform the TAP block as a single injection of 0.25% bupivacaine hydrochloride (HCl) 60 mL (150 mg). arm 2: Cohort 1:

Placebo comparator is identical in appearance to the investigational product, containing the same excipients as the active comparator.

The surgery for each subject is to be performed under general anesthesia supplemented by a transverse abdominis plane (TAP) block and local surgical site infiltration. Prior to the surgery, perform the TAP block as a single injection of 0.25% bupivacaine hydrochloride (HCl) 60 mL (150 mg). arm 3: Cohort 2 (CA-008 10 mg): the surgery is to be performed under general anesthesia supplemented by a transverse abdominis plane (TAP) block and local surgical site infiltration. Prior to the surgery, perform the TAP block as a single injection of 0.25% bupivacaine hydrochloride (HCl) 60 mL (150 mg). arm 4: Cohort 3 (CA-008 15 mg): the surgery is to be performed under general anesthesia supplemented by a transverse abdominis plane (TAP) block and local surgical site infiltration. Prior to the surgery, perform the TAP block as a single injection of 0.25% bupivacaine hydrochloride (HCl) 60 mL (150 mg). arm 5: Cohorts 2 \& 3:

Placebo comparator in each cohort is identical in appearance to the investigational product, containing the same excipients as the active comparator.

The surgery for each subject is to be performed under general anesthesia supplemented by a transverse abdominis plane (TAP) block and local surgical site infiltration. Prior to the surgery, perform the TAP block as a single injection of 0.25% bupivacaine hydrochloride (HCl) 60 mL (150 mg).
Interventions: intervention 1: CA-008 5 mg intervention 2: Placebo intervention 3: Bupivacaine Hydrochloride intervention 4: Hydromorphone intervention 5: Fentanyl intervention 6: Acetaminophen intervention 7: Oxycodone intervention 8: CA-008 10 mg intervention 9: CA-008 15 mg
Intervention descriptions: intervention 1: 5 mg CA-008 reconstituted in saline. intervention 2: Each cohort will use placebo reconstituted in saline. intervention 3: 0.25% administered pre-surgery intervention 4: 0.02 mg/kg IV administered intraoperatively intervention 5: 100 mcg IV administered intraoperatively intervention 6: 1000 mg IV administered intraoperatively intervention 7: 5-10 mg PO administered post-surgery intervention 8: 10 mg CA-008 reconstituted in saline. intervention 9: 15 mg CA-008 reconstituted in saline.

Protocol documents:
Prot_000.pdf: 
 
 
 
 
 
OFFICIAL TITLE: 
A Phase 2, Randomized, Double-blind, Placebo-Controlled Efficacy, 
Pharmacokinetics and Safety Study of CA-008 in Subjects Undergoing Complete 
Abdominoplasty 
 
NCT NUMBER: 
03789318 
DOCUMENT DATE: 
28 Jan 2019 
 


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Clinical Trial Protocol 
Version 2.0 
28JAN2019 
Version 1.3 05NOV2018 
Version 1.2 25OCT2018 
Version 1.1 24OCT2018 
Version 1.0 10OCT2018 
 
A Phase 2, Randomized, Double-blind, Placebo-Controlled Efficacy, 
Pharmacokinetics and Safety Study of CA-008 in Subjects Undergoing 
Complete Abdominoplasty 
 
Investigational Product: CA-008 by Injection/Instillation 
IND: 129114 
 
 
Concentric Analgesics, Inc. 
 
 
 
 
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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1. 
KEY PERSONNEL CONTACT INFORMATION 
Sponsor 
Concentric Analgesics, Inc. (Concentric) 
Carole Hodge, PhD 
Clinical Operations Director 
Carole@concentricanalgesics.com 
858-442-9884 
Mike A. Royal, MD 
Chief Medical Officer 
Sponsor Medical Monitor 
Mike@concentricanalgesics.com  
858-204-1112 
 
CRO 
Lotus Clinical Research, LLC (Lotus) 
Primary 
Contact 
Sunny Summers 
 
Project Manager 
ssummers@lotuscr.com  
512-212-3997 
CRO Medical 
Monitors 
Primary: Jon L. Ruckle, MD, CPI MedicalMonitorCA-PS-
204@Lotuscr.com 
808-349-9812 
Secondary: Royce Morrison, MD 
MedicalMonitorCA-PS-
204@Lotuscr.com 
206-799-7386 
 
 
 
 


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TABLE OF CHANGES: Protocol V 1.3 (05 NOV 2018) to V2.0 (17 JAN 2019) 
After a review of the 1st cohort results, it was decided that an additional two cohorts be added and to 
remove references to the second stage (parallel design portion) of the study.  The parallel design study 
will be conducted under a new protocol with new numbering identifier with the design features to be 
determined after the results from all three cohorts are evaluated.  Additional changes were made to 
reduce confusion and augment the standard of care treatment for all subjects. 
Location of material changes 
V 1.3 
V 2.0 
Synopsis, Sponsor p 8 
 
Address change 
Synopsis: Sample Size p 7/Overall Study 
Design p 7/ Study Objectives p 8/Dose 
Groups p 8 
§6.1 Study Objectives p 43 
§7.1 Overall Study Design and Plan p 44 
§8.1.1 Number of Participants p46 
§9.1.2 Study Treatment Description p 50  
§10.1.3 Surgery Day 0 p 55 
Universal changes throughout to reflect 
these changes. 
Only one cohort 
was anticipated 
prior to a parallel 
design stage. 
Added cohorts #2 and #3 including 18 subjects each with 2:1 randomization 
to active or standard of care alone, respectively (100 mL of study treatment), 
and possible a 4th cohort with the dose TBD (but between 5 and 15 mg). 
Removed stage 2 from this protocol. 
Study treatment administration instructions remain the same as in cohort #1. 
Synopsis: Anesthesia p13 
§10.1.2.2 Surgery Day 0 p 55 
Ropivacaine 0.5% 
30 mL for the TAP 
block with no 
additional local 
anesthetic. 
Prior to the surgery, perform the TAP block as a single injection of 0.25% 
bupivacaine hydrochloride (HCl) 60 mL (150 mg).   
Replaced ropivacaine dosage guidance with Marcaine’s. 
Synopsis: Intraoperative Analgesia 
p8/Inpatient Analgesia p 8/Rescue 
Medication During the Inpatient Stay 
p9/Analgesia during the Outpatien 
Period p 9/Primary Efficacy Endpoint p 
16/Key Secondary Efficacy Endpoints p 
16 
§9.2.1 Intraoperative and Early 
Postoperative Analgesia p 51 
§9.2.2 Inpatient Rescue Medications p 
51 
 
IV hydromorphone 
2mg during surgery 
(modified to weight 
based dosing). 
IV fentanyl 100 – 
300 mcg 
intraoperatively per 
anesthesia 
discretion 
Confusion as to PO 
or IV choice during 
the early 
postoperative 
period 
Modified intraoperative and immediate postoperative analgesia regimen to 
remove potential confusion and improve pain control. 
Within 30 min of anesthesia induction give the subject IV hydromorphone 
0.02 mg/kg. 
During the surgery, ensure that each subject has received at least 100 mcg of 
IV fentanyl with adjustments above this dose per anesthesiologist discretion. 
Within 15 min of the end of surgery, give the subject IV hydromorphone 0.007 
mg/kg. 
Within 15 min of the end of surgery, administer IV acetaminophen 1 g 
After surgery and during the PACU stay use only IV fentanyl 25-50 mcg q5 min 
prn moderate-to-severe pain (≥ 4 NRS), then from PACU discharge through 
T12h, use IV hydromorphone 0.2 to 0.5 mg q10-15 min prn, from T12-T24h, 
PO oxycodone 5 or 10 mg for pain q2h prn, and after T24h, PO oxycodone 5 
or 10 mg for pain q4h prn. 
After discharge from the inpatient unit recommend PO acetaminophen and 
ibuprofen as directed. 
PK endpoints p17/footnote 15 to Table 1 
Schedule of Assessments 
§10.1.4 Inpatient Phase p 57 
PK sampling 
stopped at T24h 
Added 3 additional PK sampling times at T30, T36 and T48h to cover increased 
study treatment doses. 
Synopsis: Inclusion Criteria p 10; 
Exclusion Criteria p 11 
§8.2.1 Inclusion Criteria p 47 
§8.2.2 Exclusion Criteria p 48 
English only 
Added Spanish to inclusion criteria (note this will not apply until the IRB 
approves the Spanish language ICF and related documents) 
Added bupivacaine and hydromorphone to exclusion criteria and removed 
ropivacaine 
§5.3 Previous Human Experience p29-41 
 
Added safety results from Phase 2 bunionectomy study (CA-pS-201) and the 
preliminary unblinded 1st cohort data from the current abdominoplasty study 
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TABLE OF CHANGES V. 1.2 TO 1.3 
After a review of the top line results from the bunionectomy study (CA-PS-201), it was decided 
that the concentration used in this study should be 0.05 mg/mL for a total dose of 5.0 mg which 
is slightly higher than the 4.2 mg dose, the highest dose used in the Phase 2 bunionectomy study 
(CA-PS-201) and the Phase 1b study (CA-PS-2017-101).  Note that the safety profile in these 
two bunionectomy studies were similar in that all active doses were well tolerated without an 
apparent dose response to adverse events. 
Location of change 
Change 
New text 
• 
Synopsis, Study Objectives 
• 
Synopsis, Dose Groups 
• 
Synopsis, Primary Efficacy 
Endpoint for the Pilot Stage 
• 
Section 6, Study Objectives 
• 
Section 7.1, Overall Study 
Design and Plan 
• 
Section 9.1.2, Study Treatment 
Description 
• 
Section 10.1.3, Surgery Phase: 
Administration of Study 
Medication into the Surgery Site 
Increase in CA-008 
concentration and dose:  
concentration will be 
increased from 0.025 mg/mL 
to 0.05 mg/mL or a total dose 
from 2.5 mg to 5.0 mg 
Universal change of CA-008 dose 
from 2.5 mg (100 mL of a 0.025 
mg/mL concentration) to 5.0 mg 
(100 mL of a 0.05 mg/mL 
concentration). 
 
TABLE OF CHANGES V. 1.1 TO 1.2 
After a meeting with the reconstructive surgeons participating in the study which could not be 
scheduled until after the site initiation visit, the request to increase the volume of study treatment 
to 100 mL was made to ensure sufficient volume for the full abdominoplasty particularly in 
subjects with larger body habitus. 
Location of change 
Change 
New text 
• 
Synopsis, Study Objectives 
• 
Synopsis, Dose Groups 
• 
Synopsis, Primary Efficacy 
Endpoint for the Pilot Stage 
• 
Section 6, Study Objectives 
• 
Section 7.1, Overall Study 
Design and Plan 
• 
Section 9.1.2, Study Treatment 
Description 
• 
Section 10.1.3, Surgery Phase: 
Administration of Study 
Medication into the Surgery Site 
Increase in study treatment 
volume to 100 mL (2.5 mg 
CA-008 for active) 
Universal change of CA-008 dose 
from 1.875 mg (75 mL) to 2.5 mg 
(100 mL).   
Note that the concentration will 
remain the same: 0.025 mg/mL. 
Additionally, note that this dose and 
concentration is below that used in 
both bunionectomy studies (CA-
PS-2017-101 and CA-PS-201) 
 
 
 


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TABLE OF CHANGES V. 1.0 TO 1.1 
Minor administrative changes were requested at the site kick-off meeting to remove 
inconsistencies, provide clarity or reduce the chance for confusion. 
Location of change 
Change 
New text 
P8: Synopsis: Analgesa 
during the Outpatient Period 
p41: Section 9.2.3 Outpatient 
Analgesic Medications 
Modified instructions for acetaminophen dosing 
during outpatient period per site request 
If needed for pain 
management, acetaminophen 
up to 1000 mg prn tid/qid (3g 
daily maximum limit)… 
P40: Section 9.2.2 Inpatient 
Rescue Medications 
Corrected mistake in frequency of oxycodone 
rescue after 24h  
PO oxycodone 5 mg q4h prn 
moderate pain (NRS ≥ 4 and 
≤ 6) or 10 mg q4h prn severe 
pain (NRS ≥ 7) for T24 to 
T96h 
P55: Section 10.3.14 Urine 
Drug Screen and Alcohol 
Test 
Removed the second paragraph which is 
inconsistent with the eligibility criteria: The 
drug and alcohol screens will be performed in-
house at the Clinical Unit. If any of these tests 
are positive, the subject will not be allowed 
further participation in the trial. However, a 
positive test may be repeated at the discretion of 
the investigator.  
n/a 


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2. 
PROTOCOL SYNOPSIS 
Sponsor:  
Concentric Analgesics, Inc. (Concentric) 
101 California St., Suite 1210 
San Francisco, CA 94111 
CRO: 
Lotus Clinical Research (Lotus) 
100 W. California Blvd., Unit 25 
Pasadena CA  91105 
Protocol Number: 
CA-PS-204 
IND# 
129114 
Study Title: 
A Phase 2, Randomized, Double-blind, Placebo-Controlled Efficacy, 
Pharmacokinetics and Safety Study of CA-008 in Subjects Undergoing 
Complete Abdominoplasty 
Study Treatment 
• 
CA-008, the investigational product  
• 
Placebo to match 
Planned Study 
Center(s): 
1 US site 
Indication: 
Acute postsurgical pain 
Sample Size: 
• 
Cohort #1: total N=18 (randomized 1:1 active or placebo)  
• 
Cohort #2: total N=18 (randomized 2:1 active or placebo) 
• 
Cohort #3: total N=18 (randomized 2:1 active or placebo)  
• 
Optional 4th cohort with a total N=24 randomized 1:1 to CA-008 or 
placebo 
Population: 
Adults ages 18 to 65 years, inclusive, who are planning to undergo an 
elective complete (full) abdominoplasty (C-ABD) and otherwise meet 
eligibility criteria may be considered for enrollment into the study. 
Study Duration: 
Approximately 76 days per subject from screening to the day 29 (D29) visit 
(however this could be longer to follow any AE to resolution or 
establishment of a new baseline) 
Overall Study Design: 
 
This is a Phase 2, single-center, randomized, double-blind, placebo-
controlled, parallel design study evaluating up to 4 exploratory cohorts, each 
with a single dose of CA-008 or placebo. 
For each subject, the study will be conducted in two parts: 
• 
Inpatient period starts with admission to Post-anesthesia care unit 
(PACU) and continues to 96h (T96h) after completion of study 
treatment injection (T0).   
• 
Outpatient period begins on discharge from the inpatient unit through 
various follow visits to D29±2 (W4) after surgery.  Note that additional 


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follow up visits may occur at any time or even after D29/W4 to follow 
adverse events (AEs) to resolution or establishment of a new baseline. 
Study Objectives: 
Primary Objective:  To evaluate the efficacy of a single intraoperative 
administration of CA-008 vs. placebo in subjects undergoing an elective C-
ABD.  
Secondary Objectives: 
• 
To evaluate the safety and tolerability of a single intraoperative 
administration of CA-008 vs. vehicle placebo in subjects undergoing an 
elective C-ABD.  
• 
To evaluate the PK profile of a single intraoperative administration of 
CA-008 vs. vehicle placebo in subjects undergoing an elective C-ABD.  
• 
To evaluate the opioid-sparing effect of CA-008 vs. placebo in terms of 
consumption and time to cessation. 
Study Treatment 
Dosing Schedule: 
Study treatment is to be administered intraoperatively as a single 
administration via “surgical site” infiltration prior to wound closure.   
“Surgical site” is defined as the area extending approximately 2-3 cm in all 
directions (lateral/medial/proximal/distal/deep) from the incision site and 
surrounding tissues. 
Anesthesia:  
The surgery is to be performed under general anesthesia supplemented by a 
transverse abdominis plane (TAP) block and local surgical site infiltration.  
Prior to the surgery, perform the TAP block as a single injection of 0.25% 
bupivacaine hydrochloride (HCl) 60 mL (150 mg).  
Dose Groups: 
• 
Cohort #1: total N=18 randomized 1:1 CA-008 5 mg or placebo 
• 
Cohort #2: total N=18 randomized 2:1 CA-008 10 mg or placebo 
• 
Cohort #3: total N=18 randomized 2:1 CA-008 15 mg or placebo 
• 
Optional 4th cohort with a total N=24 randomized 1:1 to CA-008 or 
placebo at a dose between 5 mg and 15 mg as determined based upon 
results from cohorts #1-3 
The volume for each cohort is 100 mL of CA-008 or placebo vehicle.  
Injection of Study 
Treatment: 
Prior to wound closure, study treatment will be infiltrated uniformly 
throughout the soft tissues around surgical sites with particular attention to 
the rectus fascia.   
A 25 g (or larger) 3.5” spinal needle may be useful for the infiltration 
process. 
Note that T0 is the time that the study treatment injection is completed. 
Allowed 
Substitutions: 
Note that if any standard of care drugs are unavailable, for example due to 
stock outages, available clinically equivalent alternatives may be substituted, 
particularly for the protocol-specified analgesic drugs for intraoperative or 


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postoperative inpatient analgesia, after approval of the medical monitor who 
should notify Sponsor of said substitution. 
Intraoperative 
Analgesia: 
Within 30 min of anesthesia induction give the subject IV hydromorphone 
0.02 mg/kg. 
During the surgery, ensure that each subject has received at least 100 mcg of 
IV fentanyl with adjustments above this dose per anesthesiologist discretion. 
Within 15 min of the end of surgery, administer IV acetaminophen 1g 
(Ofirmev® full prescribing information at http://ofirmev.com/) and IV 
hydromorphone 0.007 mg/kg. 
Inpatient Analgesia: 
 
No non-opioid analgesics are to be administered after transfer to the PACU 
during the inpatient phase (through T96h). 
Postsurgical Care: 
After surgery, subjects will be monitored in the post-anesthesia care unit 
(PACU) during which time efficacy asssessments can begin once the subject 
is awake.  Document PACU entrance and discharge times. 
After discharge from the PACU, subjects are followed through T96h as an 
inpatient.  Safety and efficacy evaluations will be performed and blood 
drawn and urine collected for pharmacokinetic (PK) assessments.  Subjects 
will be required to meet standard criteria for discharge to outpatient status.  
Subjects will continue to be monitored as an outpatient after discharge 
through D29/W4 for various safety and efficacy assessments, and later if 
necessary for safety follow up. 
Rescue Medication 
During the Inpatient 
Stay: 
During the PACU stay, the subject may be administered IV fentanyl 25-50 
mcg q5 min prn for moderate-to-severe pain (≥ 4) as reported by subjects 
using the 0 to 10 numerical rating scale of current pain intensity (NRS).   
From the time of PACU discharge through T12h administer IV 
hydromorphone 0.2 to 0.5 mg q10-15 min prn for NRS ≥ 4 as reported by 
subjects. 
After T12h, administer PO oxycodone 5 mg q2h prn moderate pain (NRS ≥ 
4 and ≤ 6) or 10 mg q2h prn severe pain (NRS ≥ 7).   
After T24, administer PO oxycodone 5 mg q4h prn moderate pain (NRS ≥ 4 
and ≤ 6) or 10 mg q4h prn severe pain (NRS ≥ 7) 
Subjects will be encouraged to rescue only for moderate-to-severe pain 
scores (NRS ≥ 4), however rescue may be requested at any time and 
medication will be provided when requested. 
Analgesia during the 
Outpatient Period: 
 
Once discharged from the inpatient unit, all study participants will be 
instructed to take a combination of over-the-counter (OTC) analgesics at an 
appropriate dose per medical judgment to manage any residual or 
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If a subject is still requiring opioid rescue in the 12h prior to discharge from 
the inpatient unit (i.e., from T84h on regardless of whether discharge is 
delayed), then prescribe no more than 9 tablets of oxycodone 5 mg (1 PO tid 
prn) per investigator discretion for the initial outpatient period. 
If needed for pain management, acetaminophen up to 1000 mg prn tid/qid 
(3g daily maximum limit) and ibuprofen 400-600 mg prn tid/qid will be 
recommended for subjects to self-administer (note that these medications 
will not be provided by the Sponsor). 
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 situation occurs, the Investigator should use clinical discretion 
on adequacy of analgesic treatment, but to capture this event as an adverse 
event (AE) and document any required treatments. 
Inclusion Criteria: 
In order to participate, subjects must meet all inclusion criteria:  
1. Plan to undergo an elective complete abdominoplasty (C-ABD), 
without collateral procedure or additional surgeries. 
2. In the medical judgment of the investigator, be a reasonably healthy 
adult aged 18 - 65 years old, inclusive, and American Society of 
Anesthesiology (ASA) physical Class 1 or 2 at the time of 
randomization (Section 17.1 Appendix A). 
3. If a male, unless he has a same sex partner, 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. 
4. If a female, must meet all of the following: 
a. Females 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, 
have a monogamous partner who is surgically sterile, have a 
same sex partner 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. 


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5. Have a body mass index ≤ 35 kg/m2. 
6. Be willing and able to sign the informed consent form (ICF) 
approved by an Institutional Review Board (IRB). 
7. Be willing and able to complete study procedures and pain scales 
and to communicate meaningfully in English or Spanish with study 
personnel and return for outpatient follow up visits as required. 
Exclusion Criteria: 
If any of the following exclusion criteria apply, subjects may not 
participate in the study:  
1. In the opinion of the Investigator,  
a. have a concurrent painful condition that may require analgesic 
treatment during the study period or may confound post-surgical 
pain assessments. 
b. have active skin disease or other clinically significant 
abnormality at the anticipated site of surgery that could interfere 
with the planned surgery. 
2. Have a known allergy to chili peppers, capsaicin or the components of 
CA-008, acetaminophen, bupivacaine, fentanyl, hydromorphone or 
oxycodone. 
3. As determined by the investigator (with input from the study’s Medical 
Monitor if requested by the investigator), have 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. 
4. The following are considered disallowed medications: 
a. Be tolerant to opioids defined as those who have been receiving 
or have received chronic opioid therapy greater than 15 mg of 
oral morphine equivalents (Table 9) per day for greater than 3 
out of 7 days per week over a one-month period within 6 months 
of screening. 
b. Within 1 day prior to surgery and throughout the inpatient 
period, be taking or using any capsaicin-containing products, 
such as dietary supplements or over-the-counter (OTC) 
preparations, including topical formulations, and prescription 
medications. 
c. Within the 7 days prior to surgery, be taking any central nervous 
system (CNS) active agent as an analgesic adjunct medication, 
such as anticonvulsants, antidepressants (such as SNRIs, SSRIs, 


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and tricyclic antidepressants), benzodiazepines, sedative-
hypnotics, clonidine and other central alpha-2 agents (e.g., 
tizanidine), ketamine or muscle relaxants.   [Note that SNRIs = 
Serotonin and norepinephrine reuptake inhibitors and SSRI = 
Selective serotonin reuptake inhibitors.] 
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. The use of benzodiazepines and the non-
benzodiazepines (eszopiclone, ramelteon, zaleplon and 
zolpidem) are permitted to treat insomnia during the 
postoperative period.   
d. Within the 7 days prior to the planned surgery and throughout 
the study, be taking antiarrhythmics except beta-blockers, 
digoxin, warfarin (see exception below), lithium, or 
aminoglycosides or other antibiotics for an infection (except for 
ophthalmic use or for treatment or prophylaxis of postoperative 
surgical site infections).  
e. Within the 14 days prior to surgery, be 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). 
f. Be on 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. 
5. In the opinion of the Investigator, within the past year have 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).   
6. Have positive results on the alcohol breath/saliva test indicative of 
alcohol abuse or urine drug screen indicative of illicit drug use (unless 
results can be explained by a current prescription or acceptable over-the-
counter medication at screening as determined by the investigator) at 
screening, and/or prior to surgery.  Note that for those subjects who test 
positive for tetrahydrocannabinol (THC), if they are willing to abstain 
from use or consumption of THC-containing products from 3 days prior 
to surgery to the day 8 visit, they may be allowed to participate in the 
study.   


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7. Willing and able to avoid foods containing capsaicin for 24 hours prior 
to surgery/ PK blood draws. 
8. Have previously participated in a clinical study with CA-008. 
9. Have participated in another clinical trial or used an investigational 
product within 30 days or five 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 D-1: Subjects undergo screening during this 
period. All screening assessments (including informed consent form 
[ICF]) must be completed at least 1 day prior to surgery.   
• 
Site Unit Admission D0: Day of surgery, subjects will be 
randomized and baseline evaluations will be performed prior to 
surgery.   
• 
Surgery D0: C-ABD procedure is performed; study treatment is 
injected prior to wound closure with T0 defined as the time of study 
treatment completion of administration.  PK assessments are to be 
done per protocol-specified time points through T24h. 
• 
Post-surgery T0 to T96h: Subject remains at the Site Facility for 
study assessments and PK blood draws.  Discharge after T96±4h 
assessments with follow up instructions, particularly on diary 
completion. 
• 
Follow Up D8±1 (W1): clinic visit for study assessments 
• 
Follow Up D15±2 (W2): clinic visit for study assessments 
• 
Follow Up D29±2 (W4): clinic visit for study assessments and 
study completion visit, unless follow up for wound healing is needed 
• 
If needed, Unscheduled visits or Follow Up after D29±2: Clinic 
visit as needed for any ongoing safety issue occurring between 
scheduled visits or continuing after the D29 visit 
• 
Early Termination (ET): For subjects who terminate early, an ET 
visit will be required if the subject is agreeable. Safety and subject-
reported outcome assessments will be performed.  If the subject does 
not wish to participate in these assessments, he/she should be asked 
to at least return for a wound check. 
Monitored 
Parameters: 
• 
Treatment-emergent AEs (TEAEs) 
• 
Medical history (MHx) 
• 
Physical examination (PE) findings, particularly neurosensory findings 
at the site of incision and the skin proximal and distal to the incision  
• 
Surgical site assessment for wound healing  
• 
Neurosensory testing near the surgical site 
• 
Clinical laboratory testing (standard chemistry, CBC, coagulation, 
urinalysis), drug and alcohol testing, pregnancy testing 
• 
Electrocardiograms (ECGs) 


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• 
Blood draws for pharmacokinetics (PK)  
• 
NRS scores at rest and on rising from a recumbent to sitting position 
(arising) using a 0 to 10 numeric rating scale for pain intensity 
• 
Presence of rebound pain at the surgical site 
• 
Total postsurgical opioid consumption converted to an oral morphine 
equivalent dose (MED) 
• 
Patient global evaluation (PGE) of satisfaction with study treatment  
• 
Investigator global evaluation (IGE) satisfaction with study treatment 
(performed by any qualified investigator) 
Safety 
Parameter 
Assessment Times:  
• 
Incidence of spontaneous reported TEAEs or SAEs from T0 through 
D29/W4 or later if necessary:  
o TEAEs are defined as AEs occurring post T0 
o AEs recorded from the time the informed consent form (ICF) is 
signed up to D0/T0 will be recorded in medical history.   
• 
PE: full PE at screening (without a breast, genital or rectal examination). 
Interim targeted PE on D-1 or D0 prior to surgery (to be conducted on 
D0 if not done on D-1), T96h, and as an outpatient on D8/W1, D15/W2, 
and D29/W4 (later if necessary). 
• 
Vital signs (heart rate [HR], blood pressure [BP], respiratory rate [RR]) 
at screening, D0 prior to surgery, post-surgery T1, T2, T4, T6, T12, and 
T24h, and every 8 hours thereafter until T96h, and as an outpatient on 
D8/W1, D15/W2, and D29/W4 or later if necessary.  Assess temperature 
on D-1 or D0 prior to surgery. Daily temps can be recorded along with 
vital signs per site SOPs at 1, 2, 4, 6, 12, 24, and every 8 hours thereafter 
until discharge from the inpatient facility (if awake at the time of 
assessment between hours of midnight and 6 a.m.). 
• 
Surgical site assessments at T96h (prior to discharge from the unit) and 
then as an outpatient on D8/W1, D15/W2, and D29/W4 (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 (compared to a control site just 
distal to the costal margin) will be performed at Screening visit, T96h 
(prior to discharge from the unit) and then as an outpatient on D8/W1, 
D15/W2, and D29/W4. 
o 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. 
o Sensory deficits or clinically significant persistent sensory 
change beyond the area immediately proximal/distal to the 
incision at time of discharge, such as allodynia or hyperalgesia, 


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must be designated as a neurologic AE. Subjects will be 
followed until there is a return to baseline or establishment of a 
new baseline. 
• 
Query subjects as to whether they have experienced any rebound or 
worsening pain at the surgical site at D8, 15 and 29. 
• 
ECGs, standard clinical labs 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.   
o ECG at screening and T24±2 h 
o Hematology/Coagulation at screening and T96±4h: 
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).    
o Blood Chemistry at screening and T96±4h to include at 
least the following: Alanine aminotransferase (ALT; 
SGPT) and Aspartate aminotransferase (AST; SGOT), 
total bilirubin (TBili), 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 Urinalysis at screening and T96±4h: including macroscopic 
analysis and, if indicated, microscopic analysis.  
Efficacy 
Parameter 
Assessment Times: 
 
 
 
 
 
 
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 subject is awake.  If the subject 
is able to provide responses, obtain NRS scores at 0.5, 1, 2, 4, 6, 8, 
12, 16, 20, 24, and every 4 hours (if awake at time of assessment) 
until discharge from the inpatient unit.  Time windows: for T0.5 to 
T2 (±5 min) and from T4 onward (±15 min). 
• 
Pain scores may be skipped between the hours of midnight and 6 
a.m., but the subject may not miss two consecutive assessments. 
• 
An additional NRS assessment must be obtained prior to rescue 
medication request (±15 min).  The T12, T24, T48, T72 and T96h 
assessments must be completed even if the subject is asleep at these 
times. 


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• 
During the inpatient stay, starting on postoperative day 1 perform 
the following each morning: on arising at 0800h (±2h) and each 
evening at 2000h (±2h) document the NRS on arising from a 
recumbent position to a sitting or standing position.  Actual 
assessment times must be documented.  If however these twice daily 
assessments coincide with timed assessments of NRS at rest, then 
the time assessment at rest is used in place of the twice daily 
assessments.  Resting pain scores are performed on the schedule 
noted above in the first bullet. 
• 
During the outpatient period, instruct the patient to document, if 
possible, their NRS scores twice daily at 0800h (±4h) and 2000h 
(±4h) at rest and on arising from a recumbent position to a sitting or 
standing position at T96. W1. W2. Amd W4.  Note that the actual 
time of these assessments must be documented in the diary 
whenever possible.  Instruct the patient to: 
o Obtain the morning NRS assessment prior to taking any pain 
medication or 2 (±15min) hours after taking any pain 
medication 
o 
Obtain the evening NRS assessment 2 (±15min) hours after 
taking any pain medication 
2. Total opioid consumption (OC) and daily opioid (rescue medication) 
consumption in MEDs will be recorded during the inpatient period.   
• 
Document subject days in which no rescue medication or analgesic 
consumption is required (opioid free, OF) during the inpatient and 
outpatient period.   
• 
Document daily use of OTC analgesics (and oxycodone if 
prescribed) during the outpatient period.   
• 
Document the fraction of subjects who rescue at T6, T12, T24, T48, 
T72 and T96h 
• 
Document any prescriptions for opioids provided to the subject prior 
to discharge to outpatient status and the number of tablets 
prescribed.  Also document any new such prescriptions. 
3. Patient Global Evaluation (PGE) at T96±4h prior to discharge, D8/W1, 
D15/W2 and D29/W4 clinic visits. 
4. Investigator Global Evaluation (IGE) at T96±4h prior to discharge, 
D8/W1, D15/W2 and D29/W4 clinic visits. 
Primary Efficacy 
Endpoint: 
Time-specific mean NRS pain intensity scores at T96h for CA-008 (100 mL 
volume) 0.05 mg/mL (5.0 mg) vs. vehicle placebo (100 mL volume). 
Key Secondary 
Efficacy Endpoints: 
For the CA-008 vs. vehicle placebo comparison: 


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• 
Weighted sum of pain intensity (SPI) assessments = Area Under the 
Curve (AUC) of the NRS current pain intensity scores from T0 to 96h at 
rest (AUC0 to 96h).    
• 
Time to opioid cessation or freedom (TOF) 
• 
Percentage of subjects who do not require opioids (i.e., opioid free; OF) 
from T24 to T96: OF24 to 96h   
Other Endpoints: 
 
For each CA-008 dose vs. placebo comparison: 
• 
Using NRS at rest: AUC 0 to 120h, AUC24 to 96h, AUC0 to W1  
• 
AUC 0 to 96h (arising), AUC 0 to W1 (arising),  
• 
Time-specific mean NRS at T48, T72, T96, T120, T144 and T168h 
• 
OC24 to 96h 
• 
OF24 to 96h, OF96h to W1 and OF96h to W2 
• 
The fraction of subjects who rescue at T48, T72 and T96h 
• 
Analgesic consumption from T96h to W1 (AC96h to W1) and AC96h to W2 
• 
PGE comparing the %age of subjects reporting “poor” + “fair” vs. 
“good” + “excellent” responses, and the %age reporting each category of 
response at T96h, D8/W1, D15/W2 and D29/W4 
• 
IGE comparing the %age of those reporting “poor” + “fair” vs. “good” + 
“excellent” responses, and the %age reporting each category at T96h, 
D8/W1, D15/W2 and D29/W4.  Note that the IGE may be performed by 
any investigator or sub-investigator. 
PK Endpoints: 
The time points for whole blood collection will be at baseline (from checkin 
and up to 30 min before the start of surgery), and T5min, T10 min, T15min, 
T30min, T45min, and T1, T1.5, T2, T2.5, T3, T4, T6, T8, T12, T16, T24, 
T30, T36 and T48h for a total of 20 samples) with T0 = end of study 
treatment administration.  Actual sampling times will be used to calculate 
plasma-derived PK parameters.  The PK will be documented in the PK 
Analysis Plan document. 
Additionally, immediately post surgery begin a 24h urine collection to assess 
urinary CA-101 excretion to be collected in two aliquots: after surgery to 
T6h and T6h to T24h.   
Stopping Rules: 
Study enrollment will be paused if subjects experience intolerable at least 
possibly related TEAEs, as defined: 
• 
1 or more subjects with any grade 4 “related” TEAE in any of the 
categories shown in the table below 
• 
2 or more subjects with the same grade 3 “related” TEAE in any of 
the categories shown in the table below 
Refer to the in-text table below for descriptions of AE grading. 


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Should a stopping rule be triggered, an external independent Safety Review 
Committee (SRC) will review the data to determine whether or not it is 
appropriate to continue with enrollment.  The SRC Charter details the 
membership, roles and responsibilities of the SRC. 
Sample Size 
Justification: 
Given the uncertainty in estimating a sample size for C-ABD surgery, the 
data from the current study will be used to determine the sample size for a 
subsequent parallel design study selecting one or more optimal doses of CA-
008 vs. placebo in the setting of standard of care for abdominoplasty. 
Study Populations: 
The following three analysis populations are planned for this study:  
• 
The Safety Population will include all subjects who received any part of 
a dose of study treatment.   
• 
The PK Population will include all subjects who receive a full dose of 
study treatment and complete all PK assessments. 
• 
The intent-to-treat (ITT) population will include all subjects as 
randomized to study treatment.  The modified intent-to-treat (mITT) 
Population will include all subjects who receive a full dose of study 
treatment and complete the first 3 pain assessments (through T2h).   
• 
Study completers (Study Completers) will include all subjects who 
receive a full dose of study treatment and complete the entire study 
period through D29±2/W4. 
Subjects who elect to discontinue study participation (early termination or 
ET) after randomization but prior to receiving study treatment will be 
replaced.   


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Subjects who elect to ET after receiving study treatment will not be 
replaced, however those who ET during the inpatient phase of the study, will 
be asked to continue with assessments through T96h if they have not elected 
to withdraw from all aspects of study participation.  Subjects who elect to 
discontinue participation prior to D8 (W1) 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, if willing and at their convenience, to ensure 
wound healing. 
Statistical 
Considerations: 
 
All safety assessments and baseline characteristics will be summarized using 
the Safety Population.  Efficacy analyses will be performed using the mITT 
population.  PK analyses will be performed using the PK population.  All 
summaries will be grouped by the actual treatment received.  Subjects 
receiving vehicle placebo will be combined for summaries.  
Safety and tolerability will be evaluated by examining the occurrence of 
AEs, including Treatment-Emergent AEs.  AEs leading to discontinuation 
from the study, AEs related to study treatment and AE severity will be 
summarized by treatment group.   
Actual 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 including n, mean, SD, 
SEM (if appropriate), median, minimum and maximum.  Abnormal values 
will be determined and flagged in the listings.  Laboratory shift tables 
displaying the change (number of subjects) 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.  
While the study is not specifically designed to detect a significant difference 
in efficacy between CA-008 and placebo, efficacy analyses will be 
performed as secondary endpoints.  


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Table 1. Schedule of Assessments  
Assessment  
Screening 
In Patient 
Follow-Up 
Unscheduled 
Visit1 
Early 
Termination19 
Prior to 
Surgery 
Surgery 
Post-
Surgery 
24h 
48h 
72h 
96h 
Study Day 
-45 to -1 
0 
0 
0 
1 
2 
3 
4 
8±1 
days 
15±2 
days 
29±2 
days 
Informed Consent 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Screening Medical and 
Surgical History 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Screens for alcohol/drugs of 
abuse 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Enroll/Randomize 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Subject Pain Assessment 
Training 
X2 
X2 
 
 
 
 
 
 
 
 
 
 
 
Surgery 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Study treatment 
Infiltration/instillation 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test  
X3 
(serum) 
X3 
(urine) 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs 
X 
X 
 
X4 
X4 
X4 
X4 
X4 
X 
X 
X 
X 
X 
Temperature 
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 
 
 
 
 
 
 
 
 
Surgical Site assessment 
 
 
 
 
 
X7 
 
X7 
X7 
X7 
X7 
X7 
X7 
Neurosensory Exam 
X 
 
 
 
 
X8 
 
X8 
X8 
X8 
X8 
X8 
X8 
Blood draw for laboratory 
tests 
X9 
 
 
 
 
 
X9 
 
 
 
 
 
Urine sample for urinalysis 
X9 
 
 
 
 
 
 
X9 
 
 
 
 
 
Rescue Medication 
consumption 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
Concomitant Medication 
Assessment 
X 
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 
Rebound Pain Assesmment 
 
 
 
 
 
 
 
 
X18 
X18 
X18 
X18 
X18 
NRS pain assessments 
 
 
 
X10 
X10 
X10 
X10 
X10 
X10 
X10 
 
X10 
X10 


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Assessment  
Screening 
In Patient 
Follow-Up 
Unscheduled 
Visit1 
Early 
Termination19 
Prior to 
Surgery 
Surgery 
Post-
Surgery 
24h 
48h 
72h 
96h 
Study Day 
-45 to -1 
0 
0 
0 
1 
2 
3 
4 
8±1 
days 
15±2 
days 
29±2 
days 
Subject home diary record 
(NRS) 
 
 
 
 
 
 
 
X11 
X11 
X11 
 
X11 
X11 
Paper Diary (review, 
distribution and/or 
collection) 
 
 
 
 
 
 
 
X12 
X12,13 
X12,13 
 
X12,13 
X13 
Subject home diary 
(analgesic consumption) 
 
 
 
 
 
 
 
X 
X 
X 
 
X 
X 
Prescription for outpatient 
opioid rescue if needed 
 
 
 
 
 
 
 
X14 
 
 
 
 
 
PGE assessment 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
IGE assessment 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
Blood draw for PK analysis 
 
X16 
 
X15, 16 
X15, 16 
 
 
 
 
 
 
 
 
24h Urine Collection 
 
 
 
X16, 17 
X16, 17 
 
 
 
 
 
 
 
 
Rebound pain 
 
 
 
 
 
 
 
 
X18 
X18 
X18 
X18 
X18 
1 
Unscheduled visit after Day 29 may occur if insufficient wound healing is assessed by the Investigator at the Day 29 visit or to follow up any ongoing AE to resolution or establishment of a new 
baseline.  For unscheduled visits prior to Day 15, collect efficacy assessments, including NRS scores and diary logs. 
2 
Pain assessment training with test during screening; rewatch 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 and temperature assessed together at 1, 2, 4, 6, 12, 24 and every 8 hours thereafter (if awake at time of assessment between the hours of 00:00 and 06:00) 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 (if not done on D-1), and to capture changes after Surgery, at 96 hours (± 4 hours) after the administration of study medication, but prior to 
discharge, and Day 8, Day 15 and Day 29 after the administration of study medication or if the subject terminates early, at that time if allowed.  Body weight (kg), in indoor clothing, but without 
shoes, will be measured at Screening and at 96 hours.  Height (in 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 study medication administration. 
7 
Surgical Site assessment: 48 hours (±2 hours) and 96 hours (±4 hours after study medication administration but prior to discharge from the inpatient unit) and Day 8, 15 and 29. 
8 
Neurosensory Exam of the area proximal to the surgical incision approximately 3 cm from the incision at Screening visit, 48 hours (±2 hours), 96 hours (±4 hours, but prior to discharge) and Day 
8, Day 15 and Day 29 after the administration of study medication or if the subject terminates early, at that time if allowed. 
9 
Clinical Laboratory tests (chemistry, hematology, coagulation and urinalysis) should be performed at screening and prior to discharge from the inpatient unit (Lab collection window for 96h is 
±4h hours). 
10 
NRS pain assessments during the inpatient stay, NRS at rest assessments start in the PACU once the subject is awake at 0.5, 1, 2, 4, 6, 8, 12, 16, 20, 24, and every 4 hours (if awake at time of 
assessment) until discharge from the inpatient unit. Pain scores may be skipped between the hours of midnight and 6 a.m., but the subject may not miss two consecutive assessments.  Also assess 


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NRS at the time of rescue request (±15 min). The T12, T24, T48, T72 and T96h assessments must be completed even if the subject is asleep at these times. There will be a ±5-minute window 
allowed for the collection of each assessment in the first 2 hours after PACU admission, after which will be a ±15-minute window allowed.  During the inpatient period document the NRS at rest 
and on arising from a recumbent position twice daily at 0800h (±2h) and 2000h (±2h) with the actual time of these assessments documented. These twice daily scores are performed 
independently of pain scores at rest during the inpatient period. If however these twice daily assessments coincide with timed assessments of NRS at rest, then the time assessment at rest is used 
in place of the twice daily assessments.  During the outpatient period, instruct the subject to document, if possible, their NRS scores twice daily at 0800h (±4h) and 2000h (±4h) at rest and on 
arising from T96 through D15 (not through D29).  Note that the actual time of these assessments must be documented in the diary.  Instruct the subject to: 
• 
Obtain the morning NRS assessment prior to taking any pain medication or 2 (±15-min) hours after taking any pain medication. 
• 
Obtain the evening NRS assessment 2 (±15-min) hours after taking any pain medication. 
If an early termination is elected before Day 15, collect efficacy assessments, including NRS scores and diary logs. 
11 
The subject is expected to document NRS pain scores at rest and on arising from recumbency to sitting or standing 2x/day through Day 15 (at the times and qualifications noted above).   
12 
The diary and instructions are provided to the subject prior to discharge (T96h).  At each subsequent visit, review Subject Diary instructions with subject and collect their NRS scores and other 
study-related assessments. 
13 
Collect Subject Diary Data  
14 
If the subject is continuing to require opioids during the 12 hours prior to discharge (any time from T84h onward), then write a prescription for no more than 9 tablets of oxycodone 5 mg tablets 
for use tid prn per investigator discretion.   
15 
Collect blood samples for PK. The time points for whole blood collection will be at baseline (from Check-in and up to 30 min prior to surgery), and T5min, T10 min, T15min, T30min, T45min, 
and T1, T1.5, T2, T2.5, T3, T4, T6, T8, T12, T16, T24, T30, T36 and T48h for a total of 20 samples) where T0 = end of study treatment administration. There will be a ±2-minute window 
allowed for the 5 to 15-minute collections, a ±5-minute window allowed for collections T30 min through T4h, and a ±15-minute window for collections after T4 hours. 
16 
Subjects must abstain from foods containing capsaicin for 24 hours prior to all PK blood draws. 
17 
Collect the subject’s urine for 24 hours after surgery in two aliquots: post surgery to T6h and T6h to T24h.   
18 
Assess for presence of rebound pain at the surgical site (yes/no response). 
19 
If the subject terminates early and is willing to come in to complete all safety and efficacy assessments then complete all procedures listed. If unwilling to come in for all such assessments, at 
least attempt to bring the subject in for a surgical site assessment,


 
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3. 
TABLE OF CONTENTS 
1. 
Key Personnel Contact Information ................................................................................... 3 
2. 
Protocol Synopsis .................................................................................................................. 7 
3. 
Table of Contents ................................................................................................................ 23 
4. 
List of Abbreviations and Definition of Terms .................................................................... 25 
5. 
Introduction ......................................................................................................................... 28 
5.1. 
Background .............................................................................................................................. 28 
5.2. 
CA-008 Product Introduction ................................................................................................. 29 
5.3. 
Previous Human experience ................................................................................................... 29 
5.4. 
Study Rationale ........................................................................................................................ 41 
5.5. 
Dose Rationale ......................................................................................................................... 42 
6. 
Study Objectives.................................................................................................................. 43 
6.1. 
Pilot Stage of the Study ........................................................................................................... 43 
7. 
Investigational Plan ............................................................................................................ 44 
7.1. 
Overall Study Design and Plan ............................................................................................... 44 
7.2. 
Study Stopping Rules .............................................................................................................. 44 
7.3. 
Duration of Participation ........................................................................................................ 45 
8. 
Selection of Study Population ............................................................................................ 46 
8.1. 
Study Population ..................................................................................................................... 46 
8.2. 
Eligibility Criteria ................................................................................................................... 46 
9. 
Study Treatments ................................................................................................................ 50 
9.1. 
Study Treatment ...................................................................................................................... 50 
9.2. 
Other Interventions ................................................................................................................. 51 
9.3. 
Method of Assigning Subjects to Treatment Groups ........................................................... 52 
9.4. 
Blinding .................................................................................................................................... 53 
9.5. 
Prior and Concomitant Therapy ............................................................................................ 53 
9.6. 
Study Restrictions .................................................................................................................... 54 
9.7. 
Treatment Compliance............................................................................................................ 54 
10. 
Conduct of the study ....................................................................................................... 55 
10.1. 
Study Visits ............................................................................................................................... 55 
10.2. 
Subject Completion and Withdrawal .................................................................................... 62 
10.3. 
Study Procedures and Assessments ....................................................................................... 63 
10.4. 
Safety, PK and Efficacy Endpoints ........................................................................................ 68 
11. 
ADVERSE EVENTS ...................................................................................................... 70 
11.1. 
Adverse Events and Serious Adverse Events ........................................................................ 70 
12. 
Data Quality Assurance .................................................................................................. 75 
12.1. 
Data Collection ......................................................................................................................... 75 
12.2. 
Study Auditing and Monitoring ............................................................................................. 75 


 
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13. 
Statistical Methods and Determination of Sample Size............................................... 77 
13.1. 
Statistical and Analytical Plans .............................................................................................. 77 
13.2. 
Sample Size Justification......................................................................................................... 77 
13.3. 
Analysis Populations ............................................................................................................... 77 
13.4. 
Planned Analyses ..................................................................................................................... 78 
13.5. 
Study Subjects and Demographics ......................................................................................... 78 
14. 
Site and Investigator Responsibilities ........................................................................... 84 
14.1. 
Regulatory and Ethical Considerations ................................................................................. 84 
14.2. 
Privacy and Confidentiality .................................................................................................... 85 
14.3. 
Study and Site Closure ............................................................................................................ 86 
14.4. 
Regulatory Documents and Records Retention .................................................................... 86 
14.5. 
Delegation of Responsibilities and Adequate Resources ...................................................... 87 
14.6. 
Protocol Amendments ............................................................................................................. 87 
14.7. 
Financial Disclosure ................................................................................................................ 87 
15. 
Investigator Protocol Agreement Page ......................................................................... 89 
16. 
References ........................................................................................................................ 90 
17. 
Appendices ....................................................................................................................... 91 
17.1. 
Appendix A: American Society of Anesthesiologists Physical Status Classification System 
(ASA Class) ........................................................................................................................................... 91 
17.2. 
Appendix B: 0 to 10 Numerical Rating Scale of Pain Intensity (NRS) ............................... 92 
17.3. 
Appendix C: Assessment of Rebound Pain at the Surgical Site (Rebound Pain) .............. 93 
17.4. 
Appendix D: Patient Global Evaluation (PGE) .................................................................... 94 
17.5. 
Appendix E: Investigator Global Evaluation of Study Treatment] (IGE) ......................... 95 
17.6. 
Appendix F: Surgical Site Assessment ................................................................................... 96 
17.7. 
Appendix G: Surgical Wound Adverse Event Grading Guide............................................ 97 
17.8. 
Appendix H: Neurosensory Examination Form ................................................................... 98 
17.9. 
Appendix I: Toxicity Grading Scale for Clinical Laboratory Abnormalities .................. 100 
17.10. 
Appendix J: Toxicity Grading Scale for Clinical Vital Sign Abnormalities ................ 103 
17.11. 
Appendix K: Toxicity Grading Scale for Systemic (General) Adverse Events ........... 104 
17.12. 
Appendix L: Bupivacaine (Marcaine) Dosage Recommendations ............................... 105 
LIST OF TABLES 
Table 1. 
Schedule of Assessments ......................................................................................... 20 
Table 2. 
Summary of Adverse Events (CA-PS-201) ........................................................... 31 
Table 3. 
Summary of TEAEs by MedDRA SOC/PT (CA-PS-201) ................................... 32 
Table 4. 
Summary of Related TEAEs by MedDRA SOC/PT ............................................ 37 
Table 5.  
Summary of Related TEAEs by Frequency ......................................................... 39 
Table 6. 
Summary of Related Local TEAEs by Frequency ............................................... 40 
Table 7. 
Summary of Severe TEAEs by Frequency ........................................................... 41 
Table 8:  
Study Stopping Rules .............................................................................................. 45 
Table 9. 
Equianalgesic Conversion Table ........................................................................... 65 
Table 10: Clinical Laboratory Assessments .......................................................................... 66 
 


 
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4. 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Term 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of Covariance 
aPTT 
Activated partial thromboplastin time 
ASA 
American Society of Anesthesiologists 
AST 
Aspartate aminotransferase 
AUC 
Area Under the Curve 
BID 
Bis in die (twice daily) 
BLQ 
Below limit of quantitation 
BP 
Blood Pressure 
BupiHCl 
Bupivacaine hydrochloride 
CA-008 
Investigational product 
CA-101 
Cyclic urea 
C-ABD 
Complete abdominoplasty 
CFR 
Code of Federal Regulations 
CK 
Creatine kinase 
CL 
Clearance 
Cmax 
Maximum plasma concentration 
CNS 
Central nervous system 
CRF 
Case Report Form (may include electronic data capture systems or paper forms) 
CRO 
Contract research organization 
CS 
Clinically significant 
CSA 
Clinical Study Agreement 
D# or D-# 
Day # (study days after surgery), Day # prior to surgery 
DBP 
Diastolic Blood Pressure 
ECG 
Electrocardiogram 
EDC 
Electronic data capture 
ET 
Early Termination 
FCBP 
Female of child bearing potential 
FDA 
Food and Drug Administration 
FIH 
First-In-Human 
FCBP 
Female of child-bearing potential 
G 
Gram 
GCP 
Good Clinical Practice 


 
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Abbreviation 
Term 
GGT 
Gamma-glutamyl transferase 
GLP 
Good Laboratory Practice 
H or HRS 
Hours 
HCl 
Hydrochloride 
HCU 
Health care utilization 
HED 
Human Equivalent Dose 
HEENT 
Head, Eye, Ear, Nose and Throat 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Institutional Ethics Committee 
IGE 
Investigator Global Evaluation 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
ITT 
Intent-to-treat 
LDH 
Lactate dehydrogenase 
LLOQ 
Lower limit of quantitation 
LOE 
Lack of efficacy 
mcg or µ 
Microgram 
MED 
Morphine equivalent dose 
MedDRA 
Medical Dictionary for Regulatory Activities 
Mg 
Milligram 
min 
Minutes 
mL 
Milliliter 
NCS 
Not clinically significant 
NOAEL 
No Observed Adverse Effect Level 
NRS 
Numeric Rating Scale of Pain Intensity 
NSAID 
Nonsteroidal anti-inflammatory drug 
OC 
Opioid consumption in morphine equivalent dose 
OF 
Opioid-free days 
OTC 
Over-the-counter 
PACU 
Post-anesthesia care unit 
PE 
Physical examination 
PGE 
Patient Global Evaluation 
PHN 
Postherpetic neuralgia 
PI 
Principal Investigator 
PK 
Pharmacokinetic[s] 


 
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Abbreviation 
Term 
PO 
Per oram (oral) 
PRN 
Pro re nata (as needed) 
PT 
Prothrombin time 
QID 
Quater in die (four times daily) 
RBC 
Red blood cell 
SAE 
Serious adverse event  
SAP 
Statistical analysis plan 
SBP 
Systolic blood pressure 
SC 
Subcutaneous 
SD 
Standard deviation 
SE 
Standard error 
SOC 
System Organ Class 
SNRIs 
Serotonin-norepinephrine reuptake inhibitors 
SRC 
Safety Review Committee 
SSRIs 
Selective serotonin reuptake inhibitors 
T# 
Time in hours after completion of study medication dosing (T0) 
t½  
Elimination half-life 
TEAEs 
Treatment emergent adverse event[s] 
TID 
Ter in die (three times daily) 
Tmax 
Time to maximum plasma concentration 
TRPV1 
Transient receptor potential vanilloid-1 
TTFR 
Time to first rescue  
UDS 
Urine drug screen[ing] 
US 
United States 
V 
Volume of distribution 
W# 
Week # visit after surgery 
WHO 
World Health Organization 
 


 
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5. 
INTRODUCTION 
5.1. 
Background 
Concentric Analgesics, Inc. (Concentric) is developing CA-008 to provide long-lasting pain 
relief of post-surgical pain following a single local administration (for 96h and beyond).  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 post-surgical 
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 route of administration while simple and perhaps convenient, 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. 
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 post-surgical 
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 


 
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http://centrexion.com/our-pipeline/).  Note that Centrexion is using the Anesiva highly viscous 
polyethylene glycol formulation for its intraarticular knee joint injections.  
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 either topically, 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 GLP safety studies and the PK profile for various 
doses were determined in a Phase 1 ascending dose safety study in patients undergoing 
bunionectomy. 
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 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).  


 
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5.3.1. 
Study CA-PS-201 (Bunionectomy) 
A first-in-human study (Study CA-PS-2017-101) evaluated the safety and tolerability of CA-008 
in subjects undergoing a unilateral transpositional first metatarsal osteotomy for correction of 
hallux valgus deformity, more commonly known as a bunionectomy.  This study also evaluated 
pharmacokinetic (PK) and preliminary efficacy assessment of CA-008 to inform future studies in 
our clinical development plan.  This study was originally designed to look at 4 different doses of 
CA-008 (0.5 mg, 1 mg, 2 mg, and 3 mg), however based upon the relatively benign adverse 
event (AE) profile, the Data Management Committee gave the go-ahead for a 5th cohort (4.2 mg) 
to be added.  The safety, efficacy and PK results for the Phase 1 bunionectomy study are shown 
in the current Investigators’ Brochure.   
Additionally, a follow-on Phase 2 bunionectomy study (CA-PS-201) was completed with 147 
subjects enrolled and randomized to one of 3 active doses: 0.05 mg/mL (0.7 mg), 0.15 mg/mL 
(2.1 mg) and 0.3 mg/mL (4.2 mg) vs. placebo in a 1:1:1:1 randomization, respectively.  The 
results are still being compiled at the time of this protocol amendment.  Based upon topline 
results, the highest dose of 4.2 mg was statistically significantly superior to placebo for the 
primary efficacy endpoint of AUC 0-96h (p=0.005) and key secondary efficacy endpoints: AUC 
0 to week 1 (p=0.036); mean opioid consumption (reduced by 50%, p<0.002); and percent of 
subjects who were opioid free from 0 to 96h (26% vs. 5% for placebo; p=0.039).  The following 
Tables 2-7 show the summary of safety for the study based upon summary tables and subject 
listings.  Note that in Table 3, the Summary of TEAEs by MedDRA SOC/PT, there were a 
number of preferred terms that were somewhat vague, so these are accompanied by footnotes 
detailing the verbatim terms to provide background context. 


 
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Table 2. Summary of Adverse Events (CA-PS-201) 
 


 
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Table 3. Summary of TEAEs by MedDRA SOC/PT (CA-PS-201) 
 
 
 
 


 
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Table 3 (Cont.). 
Summary of TEAEs by MedDRA SOC/PT (CA-PS-201) 
 
 
 
 


 
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Table 3 (Cont.). 
Summary of TEAEs by MedDRA SOC/PT (CA-PS-201) 
 
 
 
 


 
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Table 3 (Cont.). 
Summary of TEAEs by MedDRA SOC/PT (CA-PS-201) 
 
 
 
 
 


 
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Table 3 (Cont.). 
Summary of TEAEs by MedDRA SOC/PT (CA-PS-201) 
 
 
 
 


 
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Table 4. Summary of Related TEAEs by MedDRA SOC/PT 
 
 
 
 


 
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Table 4 (Cont.). 
Summary of Related TEAEs by MedDRA SOC/PT 
 
 
 


 
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Table 5.  Summary of Related TEAEs by Frequency 
 
 


 
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Table 6. Summary of Related Local TEAEs by Frequency 
 
 
 


 
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Table 7. Summary of Severe TEAEs by Frequency 
 
5.3.2. 
Study CA-PS-204 (Abdominoplasty) 
Preliminary unblinded safety data was made available with an interim data snapshot after the 
first cohort (5 mg) was completed.  For this cohort, 18 subjects were randomized 1:1 to receive 
100 mL infiltration of either 5 mg CA-008 or placebo vehicle in the setting of standard of care 
treatments including a a general anesthetic supplemented with a transverse abdominis plane 
(TAP) block, intraoperative IV opioids and intraoperative IV acetaminophen. 
There were 8/9 subjects in each treatment group who experienced TEAEs: 28 in the placebo 
group and 26 in the CA-008 group.  There was one SAE of a deep venous thrombosis in the 
active group which occurred on day 10 after surgery and was deemed unrelated and moderate in 
severity.  There were no severe events.  Most TEAEs were moderate in severity: 20/28 in the 
placebo group and 20/26 in the active group.  Most TEAEs were deemed unrelated.  There were 
5/28 possibly related events in the placebo group (all nausea events) and 2/26 possible related in 
the active group (one each of pruritus – mild and nausea – moderate).  The most frequent TEAEs 
in descending order were: 
• 
Placebo: nausea – 14; low back pain – 5; vomiting, constipation and hypoxia at 2 each and 
the rest single events 
• 
CA-008: nausea – 9; headache – 5; low back pain – 3; constipation – 3; and the rest were 
single events 
5.4. 
Study Rationale 
CA-008 is being investigated as a potential therapy for treatment of pain following surgery.   


 
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5.5. 
Dose Rationale 
5.5.1. 
 Selection of Doses 
The safety of CA-008 was established in relevant animal models and supported by two studies 
after bunionectomy (CA-PS-2017-101 and CA-PS-201) and knowledge from prior human 
studies with an injectable formulation of capsaicin.  Taken together, the characterization of the 
pharmacology, pharmacokinetics, and toxicology profiles are considered sufficient to support the 
intended use of CA-008 in this study. 
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 
of 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 
addresses the pain that results from TRPV1 agonism.  Administration of CA-008 during the 
closure process is ideal for delivering therapy to the surgical site, thus optimizing target 
engagement.  During closure, the 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 being generated. 


 
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6. 
STUDY OBJECTIVES 
6.1. 
Pilot Stage of the Study 
6.1.1. 
Primary Objective 
• To evaluate the efficacy of a single intraoperative administration of CA-008 vs. vehicle 
placebo (100 mL volume) in subjects undergoing an elective C-ABD.   
6.1.2. 
Secondary Objectives 
• To evaluate the safety and tolerability of a single intraoperative administration of CA-008 
vs. vehicle placebo in subjects undergoing an elective C-ABD.  
• To evaluate the PK profile of a single intraoperative administration of CA-008 vs. vehicle 
placebo in subjects undergoing an elective C-ABD.  
• To evaluate the opioid-sparing effect of CA-08 vs. placebo in subjects undergoing an 
elective C-ABD in terms of consumption and time to cessation. 


 
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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design and Plan 
This is a Phase 2, single-center, randomized, double-blind, placebo-controlled, parallel design 
study consisting of three  exploratory cohorts of 18 subjects each: a single dose of CA-008 at 5.0 
mg, 10 mg or 15 mg vs. placebo each in 100 mL of vehicle, randomized 1:1 in the first cohort 
and 2:1, respectively, in cohorts 2 and 3, and an optional 4th cohort may be enrolled with a total 
N=24 randomized 1:1 to CA-008 or placebo at a dose between 5 mg and 15 mg as determined 
based upon results from cohorts #1-3. 
For each subject, the postoperative assessments will be conducted in two parts: 
• Inpatient period which starts with completion of study treatment injection (T0) and continues 
through 96h (T96h).    
• Outpatient period which begins on discharge from the inpatient unit through various follow 
up visits to day 29 (D29) or week 4 (W4) after surgery, or later if necessary for ongoing 
safety assessments.  Note that additional follow up visits could occur after D29/W4 to follow 
adverse events (AEs) to resolution or establishment of a new baseline. 
7.2. 
Study Stopping Rules 
Study enrollment will be paused if subjects experience intolerable at least possibly related 
TEAEs, as defined: 
• 1 or more subjects with any grade 4 “related” TEAE in any of the categories shown in the 
table below 
• 2 or more subjects with the same grade 3 “related” TEAE in any of the categories shown 
in the table below 
Refer to Table 8 below for descriptions/definitions of AE severity grading.  Additional guidance 
on descriptions of AE grading may be found in Appendices I-K (Sections 17.9, 17.10 and 0). 
An external independent Safety Review Committee (SRC) will be consulted should a stopping 
rule be triggered to determine whether or not it is appropriate to continue with dosing in the 
study.  This committee will be independent of the Sponsor or CRO and will in no way be 
involved with study conduct.  The SRC Charter details the membership, roles and 
responsibilities of the SRC. 


 
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Table 8:  
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 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 
7.3. 
Duration of Participation 
Each subject is expected to be in the study up to 76 days (screening through end-of-study visit). 


 
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8. 
SELECTION OF STUDY POPULATION 
8.1. 
Study Population 
The study population consists of reasonably healthy men and women, aged 18-65 years old 
inclusive, who are undergoing elective C-ABD. 
8.1.1. 
Number of Participants 
• Cohort #1: N=18 randomized 1:1, CA-008 vs. placebo 
• Cohort #2: N=18 randomized 2:1, CA-008 vs. placebo, respectively 
• Cohort #3: N=18 randomized 2:1, CA-008 vs. placebo, respectively 
• Optional 4th cohort with a total N=24 randomized 1:1 to CA-008 or placebo at a dose 
between 5 mg and 15 mg as determined based upon results from cohorts #1-3 
8.2. 
Eligibility Criteria 
8.2.1. 
Inclusion Criteria 
Subjects must meet all of the following criteria to be considered eligible to participate in the study: 
1. Plan to undergo an elective complete abdominoplasty (C-ABD) without collateral procedure 
or additional surgeries. 
2. In the medical judgment of the investigator, be a reasonably healthy adult aged 18 - 65 years 
old, inclusive, and American Society of Anesthesiology (ASA) physical Class 1 or 2 at the 
time of randomization (Section 17.1 Appendix A). 
3. If a male, unless he has a same sex partner, 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. 
4. 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, have a monogamous 
partner who is surgically sterile, have a same sex partner 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 


 
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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. 
5. Have a body mass index ≤ 35 kg/m2. 
6. Be willing and able to sign the informed consent form (ICF) approved by an Institutional 
Review Board (IRB). 
7. Be willing and able to complete study procedures and pain scales and to communicate 
meaningfully in English or Spanish with study personnel and return for outpatient follow up 
visits as required. 
8.2.2. 
Exclusion Criteria 
Subjects will not be eligible to participate in this study if any one of the following exclusion criteria 
is met: 
1. In the opinion of the Investigator,  
a. have a concurrent painful condition that may require analgesic treatment during the 
study period or may confound post-surgical pain assessments. 
b. have active skin disease or other clinically significant abnormality at the anticipated 
site of surgery that could interfere with the planned surgery. 
2. Have a known allergy to chili peppers, capsaicin or the components of CA-008, 
acetaminophen, bupivacaine, fentanyl, hydromorphone or oxycodone. 
3. As determined by the investigator (with input from the study’s medical monitor if requested 
by the investigator), have 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. 
4. The following are considered disallowed medications: 
a. Be tolerant to opioids defined as those who have been receiving or have received 
chronic opioid therapy greater than 15 mg of oral morphine equivalents (Table 9) per 
day for greater than 3 out of 7 days per week over a one-month period within 6 
months of screening. 


 
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b. Within 1 day prior to surgery and throughout the inpatient period, be taking any 
capsaicin-containing products, such as dietary supplements or over-the-counter 
(OTC) preparations, including topical formulations, and prescription medications. 
c. Within the 7 days prior to surgery, be taking any central nervous system (CNS) active 
agent as an analgesic adjunct medication, such as anticonvulsants, 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.   [Note that SNRIs = Serotonin and norepinephrine reuptake 
inhibitors and SSRI = Selective serotonin reuptake inhibitors.] 
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. The use of benzodiazepines and the non-benzodiazepines (eszopiclone, 
ramelteon, zaleplon and zolpidem) are permitted to treat insomnia during the 
postoperative period.   
d. Within the 7 days prior to the planned surgery and throughout the study, be taking 
antiarrhythmics except beta-blockers, digoxin, warfarin (see exception below), 
lithium, or aminoglycosides or other antibiotics for an infection (except for 
ophthalmic use or for treatment or prophylaxis of postoperative surgical site 
infections).  
e. Within the 14 days prior to surgery, be 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). 
f. Be on 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. 
5. In the opinion of the Investigator, within the past year have 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).   
6. Have positive results on the alcohol breath test indicative of alcohol abuse or urine drug 
screen indicative of illicit drug use (unless results can be explained by a current prescription 
or acceptable over-the-counter medication at screening as determined by the investigator) at 
screening, and/or prior to surgery.  Note that for those subjects who test positive for 
tetrahydrocannabinol (THC), if they are willing to abstain from use or consumption of THC-
containing products from 3 days prior to surgery to the day 8 visit, they may be allowed to 
participate in the study.   


 
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7. Willing and able to avoid foods containing capsaicin for 24 hours prior to surgery and PK blood 
draws. 
8. Have previously participated in a clinical study with CA-008. 
9. Have participated in another clinical trial or used an investigational product within 30 days or 
five 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 
The active drug product will be provided as CA-008 frozen concentrate solution for injection in a 
1.0 mL vial with doses calculated as the freebase.   
The placebo comparator is identical in appearance. 
The proposed dose of CA-008 to be evaluated in the study are: 
• Cohort #1: CA-008 5 mg vs. placebo in 100 mL of vehicle 
• Cohort #2: CA-008 10 mg vs. placebo in 100 mL of vehicle 
• Cohort #3: CA-008 15 mg  vs. placebo in 100 mL of vehicle  
• Optional 4th cohort with a total N=24 randomized 1:1 to CA-008 or placebo at a dose 
between 5 mg and 15 mg as determined based upon results from cohorts #1-3 
At time of use, the concentrate will be completely reconstituted in saline and used for treatment 
(see the Pharmacy Manual).  All study treatment vials are unblinded and the dose (for CA-008) 
or placebo will be identified on the vial label.  The pharmacist reconstituting the study treatment 
for administration is unblinded, however the surgeon and other site participants are blinded. 
9.1.3. 
Study Treatment Storage 
Study treatments will be shipped to sites and stored at -20°C (-15°C to -30°C) until the day of 
surgery.  All study treatment 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. 


 
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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.  The unused quantities will be returned to the Sponsor’s drug supply vendor at the end 
of the trial. All unused supplies will be checked against the drug accountability records during 
the study and/or at the end of the study. The Investigator or designee must maintain an inventory 
record of all dispensed rescue medications to subjects. Additional details are provided in the 
Pharmacy Manual. 
Only eligible subjects 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 subjects.  
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. If 
diversion is confirmed or suspected (e.g., excessive use of rescue medications), the study staff 
will be required to complete a clinical supply documentation form, including information related 
to situations in which a subject sold drug or gave drug to a friend or relative, there is a 
discrepancy in drug accountability and suspected diversion, or a subject had drug stolen, or if 
there was diversion or theft by site staff or others. 
9.2. 
Other Interventions 
Note that if any standard of care drugs are unavailable, for example due to stock outages, 
available clinically equivalent alternatives may be substituted, particularly for the protocol-
specified drugs in Section 9.2.1 and 9.2.2, after approval of the medical monitor who should 
notify Sponsor of said substitution. 
9.2.1. 
Intraoperative and Early Postoperative Analgesia  
Within 30 min of anesthesia induction give the subject IV hydromorphone 0.02 mg/kg and IV 
acetaminophen 1 g (Ofirmev®, Mallinckrodt Pharmaceuticals 2018) full prescribing information 
at http://ofirmev.com/.  
During the surgery, ensure that each subject has received at least 100 mcg of IV fentanyl with 
adjustments above this dose per anesthesiologist discretion. 
Within 15 min of the end of surgery, give the subject IV hydromorphone 0.007 mg/kg. 


 
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9.2.1. 
Inpatient Rescue Medications 
After surgery, subjects will be monitored in the post-anesthesia care unit (PACU) during which 
time efficacy asssessments can begin once the subject is awake.  During the PACU stay 
administer the subject IV fentanyl 25-50 mcg q5 min prn for moderate-to-severe pain (≥ 4) as 
reported by subjects using the 0 to 10 numerical rating scale of current pain intensity (NRS).  
After discharge from the PACU, subjects are followed through T96h as an inpatient.  
From the time of discharge from the PACU through T12h administer IV hydromorphone 0.2 to 
0.5 mg q10-15 min prn for NRS ≥ 4 as reported by subjects. 
After T12h, administer PO oxycodone 5 mg q2h prn moderate pain (NRS ≥ 4 and ≤ 6) or 10 mg 
q2h prn severe pain (NRS ≥ 7).   
Subjects will be encouraged to rescue only for moderate pain scores (NRS ≥ 4), however rescue 
may be requested at any time and medication will be provided when requested. 
9.2.2. 
Outpatient Analgesic Medications 
Once discharged from the inpatient unit, all study participants will be instructed to take a 
combination of over-the-counter (OTC) analgesics at an appropriate dose per medical judgment 
to manage any residual or breakthrough postsurgical pain. 
If needed for pain management, acetaminophen up to 1000 mg prn tid /qid (3g daily maximum 
limit) will be recommended for subjects to self-administer (note that this medications will not be 
provided by the Sponsor). 
If a subject is still requiring opioid rescue in the 12h prior to discharge from the inpatient unit 
(i.e., from T84h on regardless of whether discharge is delayed), then prescribe no more than 9 
tablets of oxycodone 5 mg (1 PO tid prn) per investigator discretion for the initial outpatient 
period. 
Persistent pain or pain exacerbations during this period may suggest the need for an unscheduled 
in-person visit to assess the surgical site.  If such a situation occurs, the Investigator should use 
clinical discretion on adequacy of analgesic treatment, but capture this event as an AE and 
document any required treatments. 
9.3. 
Method of Assigning Subjects to Treatment Groups 
Randomization will be used to avoid bias in the assignment of subjects to treatments, to increase 
the likelihood that known and unknown subject attributes (e.g., demographics, baseline 
characteristics) are evenly balanced across treatment groups, and to enhance the validity of 
statistical comparisons across treatment groups.  
Subjects who have provided written informed consent will be assigned a unique number in the 
screening process. This number will be used to identify the subject throughout the study. 


 
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In the Pilot Stage, 18 subjects will be randomized to either the active medication or placebo in a 
1:1 ratio.  Subsequently, the number of active treatment groups and sample size will be 
determined after the interim unblinded analysis of topline data from the Pilot Stage. 
Once any subject number or randomization number is assigned, it cannot be reassigned to any 
other subject. This study will use manual randomization. 
Subjects 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 will be double-
blinded during the study. Aside from the unblinded pharmacist who reconstitutes the study 
treatment for administration by the surgeon, the subject, surgeon and all other study participants, 
including the Sponsor, directly involved in the conduct and/or monitoring of this study will not 
be aware of the treatment group assignments.  Note that the placebo is identical in appearance to 
CA-008. 
Under normal circumstances, 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 subject’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 sequence is prematurely unblinded, the 
reason, date and time of the unblinding, and the individual who broke the blind must be 
documented. Individual code breaks will result in withdrawal of the participant from the study. 
It is assumed that the need to unblind a study subject’s treatment assignment will occur in the 
setting of an 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, over-the-counter, or herbal therapies, used by 
the subject will be documented for the 30 days prior to Screening and throughout the study. The 
Investigator will determine if the prior/concomitant medication(s) affect the subject’s eligibility 
to participate or continue to participate in the study.  
On a case-by-case basis, the Investigator is permitted to allow the use of some concomitant 
medications, for example, to treat an AE, as long as the Investigator determines that the 
medication will not affect the subject’s safety or study integrity. Wherever possible, the 
Investigator should obtain approval from the Medical Monitor prior to administering the 
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9.6. 
Study Restrictions 
In addition to the criteria described in Sections 8.2, 9.5, and 10.1.2 the subject 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: 
▪ Subjects will be asked to abstain from consuming more than 1 (women) or 2 drinks (men) per 
day of alcohol  
▪ Subjects will be asked to abstain from illicit drug use or non-medical use of therapeutic drugs  
▪ Subjects will be asked to abstain from taking prohibited medications  
9.7. 
Treatment Compliance  
Because all study medication is being administered by study personnel, no compliance 
procedures are necessary. Diversion 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 -1):   
Subjects will be screened for participation at the study within 45 days of surgery/study drug 
administration. The following assessments will be completed: 
• 
Informed Consent 
• 
Inclusion / Exclusion evaluation 
• 
Demographics 
• 
Medical and surgical history 
• 
Prior/current medications 
• 
Complete Physical Exam (PE), including height and weight 
• 
Vital signs including temperature (Section 17.10 Appendix J) 
• 
Baseline neurosensory exam 
• 
Clinical laboratory tests (chemistry/coagulation, hematology, and urinalysis) (Section 
17.9 Appendix I) 
• 
Urine Drug Screening (UDS)  
• 
Alcohol breath/saliva test 
• 
Serum Pregnancy test (FCBP), if applicable 
• 
12-Lead Electrocardiograms (ECG)  
• 
Subject pain assessment training 
• 
Adverse Event (AE) assessment (record any current conditions as medical history) 
10.1.2. 
Surgery Phase: Day -1 Prior to surgery (baseline) up to the end of surgery Day 0  
10.1.2.1. Prior to Surgery (D-1 to D0) 
Subjects 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 within 45 days of screening. The following 
assessments will be performed: 
• 
Confirm informed consent 
• 
Review of Inclusion / Exclusion 


 
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• 
Review of medical and surgical history since screening (any changes to health should be 
added to medical history) 
• 
Review of prior and current concomitant medications 
• 
Interim targeted PE with inspection of the planned area of surgery (if not done at Screening 
visit) 
• 
Urine Pregnancy test (FCBP) if applicable 
• 
UDS  
• 
Alcohol breath/saliva test 
• 
Blood draw for PK analysis 
• 
Vital signs and temperature  
• 
Subject pain training review (watch video) 
• 
AE assessment 
• 
Randomize to treatment after confirmation of continued eligibility 
10.1.2.2. Surgery Day 0 
The surgery is to be performed under general anesthesia supplemented by a transverse abdominis 
plane (TAP) block with bupivacaine hydrochloride (BupiHCl).  Note that the regimen for the 
general anesthetic is left to the anesthesiologists’ discretion.  Prior to the surgery, perform the 
TAP block as a single injection of 0.25% bupivacaine hydrochloride (HCl) 60 mL (150 mg).  
Refer to Section 17.12 Appendix L for bupivacaine dosage recommendations.  The volume 
windows for the bupivacaine injection is ± 2 mL. 
During the surgery, ensure that each subject has received at least 100 mcg of IV fentanyl with 
adjustments above this dose per anesthesiologist discretion. 
Upon completion of surgery, subjects will be observed for 96-hours in the clinic. AEs will be 
assessed during the surgery. 
10.1.3. 
Surgery Phase: Administration of Study Medication Into the Surgical Site 
The “surgical site” is defined as the area extending approximately 2-3 cm in all directions 
(lateral/medial/proximal/distal/deep) from the incision  and surrounding tissues which may be 
affected by the infiltration of the study drug.  Study treatment is to be administered 
intraoperatively as a single administration via “surgical site” infiltration prior to wound closure.  
A total of 100 mL of study treatment will be infiltrated into the deep peri-incisional 
subcutaneous tissues and rectus fascia within the exposed incision surfaces.   
10.1.4. 
Inpatient Phase: Time 0 (Post-Surgery) to Day 4 (Discharge) 
Time 0 is defined as the time of completion of study drug administration. Following surgery, 
subjects will be transferred to the appropriate recovery unit where they will undergo an 


 
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assessment of safety and efficacy over the next 96 hours. The schedule of assessments are as 
follows:  
• 
Subjects with inadequately controlled pain may request rescue at any time; however, subjects 
will be encouraged to receive rescue medication only with an NRS ≥ 4.        
• 
Pain intensity (assessed with NRS):  
o 
During the inpatient stay, beginning with the PACU admission and after the subject is 
awake: assess the NRS at rest at 0.5, 1, 2, 4, 6, 8, 12, 16, 20, and 24 hours, and every 4 
hours (if awake at time of assessment) until discharge from the inpatient unit.  Time 
windows: for T0.5 to T2 (±5 min) and from T4 onward (±15 min). 
o 
Pain scores may be skipped between the hours of midnight and 6 a.m., but the subject 
may not miss two consecutive assessments.  The T12, T24, T48, T72 and T96h 
assessments must be completed even if the subject is asleep at these times. 
o 
Pain intensity (NRS) will be completed at the time of rescue medication request (±15 
minutes).     
o 
During the inpatient stay, starting on postoperative day 1: each morning on arising at 
0800h (±2h) and each evening at 2000h (±2h) document the NRS at rest and on arising 
from a recumbent position to a sitting or standing position.  Actual assessment times 
must be documented.  These assessments are in addition to the time-specific NRS 
assessments at rest.  If however these twice daily assessments coincide with timed 
assessments of NRS at rest, then the time assessment at rest is used in place of the twice 
daily assessments. 
• 
Vital signs (heart rate [HR], blood pressure [BP], respiratory rate [RR]) and temperature are 
assessed together at screening, D0 prior to surgery, post-surgery at T1, T2, T4, T6, T12, and 
T24h, and every 8 hours thereafter until T96h, and as an outpatient on D8/W1, D15/W2, and 
D29/W4 or later if necessary.  Assessments between the hours of 00:00 and 06:00 may be 
skipped if the subject is sleeping; however, two consecutive assessments may not be skipped.  
The allowable window is ±5 minutes for the first 4 hours post-surgery, and ±15 minutes for 
all other times. 
• 
Targeted Physical exam: 96 (±4) hours after the administration of study medication (prior to 
discharge from the unit).  Weight is included at the 96 hour assessment. 
• 
ECG: 24 (±2) hours after the administration of study medication.  
• 
Surgical Site assessment: 48 (±2) and 96 (±4) hours after the administration of study 
medication. If the investigator determines there are atypical wound healing or visible 
abnormal findings, a digital picture of the wound site should be performed (if subject has 
consented to digital photography). 
• 
Neurosensory testing of the surgical area: 48 (±2) and 96 (±4) hours after the administration 
of study medication.  
• Clinical laboratory tests: T96h (±4h) prior to discharge from the unit. 


 
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• 
Blood draw for PK analysis: The time points for whole blood collection will be at check-in/ 
baseline (up to 30 min prior to surgery), and T5min, T10 min, T15min, T30min, T45min, and 
T1, T1.5, T2, T2.5, T3, T4, T6, T8, T12, T16, T24, T30, T36 and T48h for a total of 20 
samples).   
• 
24h urine collection in two aliquots: end of surgery to T6h and T6h to T24h.   
• 
Subject completes Patient Global Evaluation (PGE) assessment at T96h (±4) prior to 
discharge 
• 
Investigator completes Investigator Global Evaluation (IGE) assessment at T96 (±4) prior to 
discharge.  Note that the IGE may be performed by any investigator or sub-investigator. 
• 
Record rescue medication consumption and concomitant medications throughout the 
inpatient period and record any prescriptions for opioids on discharge from the inpatient 
facility including the opioid prescribed and number of tablets.  Also document any additional 
prescriptions if needed. 
• 
Record AEs throughout the inpatient period (Section 17.11 Appendix K may be useful to the 
investigator for assessing systemic [general] AEs)  
After completing the assessments through T96h, the diary for at-home use will be reviewed and 
subjects will be discharged from the study center with diary to record pain assessments and pain 
medication at home.  Subjects will be provided routine standard of care for pain management 
after discharge from the study center.  Subjects will be instructed to return to the study center on 
Day 8 [±1 day] for follow-up assessments.  
10.1.5. 
Outpatient Phase: Days 4 (after discharge) through 8: 
In their diary, subjects will assess their pain intensity (at rest and after arising from recumbency) 
once in the morning (08:00 ±4 hours), and once in the evening (20:00 ±4 hours) using the NRS 
(these are two separate scores “at rest” and “on arising” obtained twice daily). Subjects will also 
record any medication they take to treat their pain. 
Subjects will return to the study center on Day 8 [±1 day] for the following assessments:  
• 
Subject home diary review (pain intensity and pain medication) 
• 
Pain Intensity assessment (NRS) 
• 
Vital signs including temperature 
• 
Targeted PE 
• 
Surgical Site assessment (If the investigator determines there are atypical wound healing or 
visible abnormal findings, a digital picture of the wound site should be performed if the subject 
has consented to such a photo) 
• 
Neurosensory testing of the surgical area 
• 
Query the subject as to any rebound pain 
• 
Concomitant Medication Use/Concomitant Treatments 


 
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• 
Document any prescriptions for opioids provided to the subject and the number of tablets 
prescribed.   
• 
AE Assessment 
• 
PGE 
• 
IGE 
10.1.6. 
Outpatient Phase: Days 9 through 15: 
In their diary, subjects will assess their pain intensity (at rest and after arising from recumbency) 
once in the morning (08:00 ±4 hours), and once in the evening (20:00 ±4 hours) using the NRS 
(these are two separate scores “at rest” and “on arising” obtained twice daily). Subjects will also 
record any medication they take to treat their pain.  
Subjects will return to the study center on Day 15 [±2 days] for the following assessments:  
• 
Subject home diary review (pain intensity and pain medication) 
• 
Pain Intensity assessment (NRS) 
• 
Vital signs including temperature 
• 
Targeted PE 
• 
Surgical Site assessment (If the investigator determines there are atypical wound healing or 
visible abnormal findings, a digital picture of the wound site should be performed if the subject 
has consented to such a photo) 
• 
Neurosensory testing of the surgical area 
• 
Query the subject as to any rebound pain 
• 
Concomitant Medication Use/Concomitant Treatments 
• 
Document any prescriptions for opioids provided to the subject and the number of tablets 
prescribed.   
• 
AE Assessment 
• 
PGE 
• 
IGE 
10.1.7. 
Outpatient Phase: Day 29 
Subjects will record any medication they take to treat their pain.  Subjects will return to the study 
center on Day 29 [±2 days], or at the time of discontinuation, for the following assessments:  
• 
Subject home diary review (pain medication) 
• 
Vital signs including temperature 
• 
Targeted PE 
• 
Surgical Site assessment (If the investigator determines there are atypical wound healing or 
visible abnormal findings, a digital picture of the wound site should be performed if the subject 
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• 
Neurosensory testing of the surgical area 
• 
Concomitant Medication Use/Concomitant Treatments 
• 
Document any prescriptions for opioids provided to the subject and the number of tablets 
prescribed.   
• 
Query the subject as to any rebound pain 
• 
AE Assessment 
• 
PGE 
• 
IGE 
10.1.8. 
Outpatient Phase: Early Termination 
Subjects who elect to ET and are willing to perform study completion assessments will return to 
the study center at a convenient time after discontinuation, for the following assessments:  
• 
Subject home diary review (pain intensity and pain medication) 
• 
Pain Intensity assessment (NRS) 
• 
Vital signs including temperature 
• 
Targeted PE 
• 
Surgical Site assessment (If the investigator determines there are atypical wound healing or 
visible abnormal findings, a digital picture of the wound site should be performed if the subject 
has consented to such a photo) 
• 
Neurosensory testing of the surgical area 
• 
Concomitant Medication Use/Concomitant Treatments 
• 
Document any prescriptions for opioids provided to the subject and the number of tablets 
prescribed.   
• 
Query the subject as to any rebound pain 
• 
AE Assessment 
• 
PGE 
• 
IGE  
If the subject has elected an early termination prior to Day 15, collect the information in their 
take-home Diary: where subjects should have assessed their pain intensity once in the morning 
(08:00 ±4 hours) at rest and on arising, and once in the evening (20:00 ±4 hours) at rest and on 
arising using the NRS.  Subjects should have also recorded any medication they take to treat 
their pain.  If the subject is unwilling to provide such assessments or perform any of the protocol-
specified assessments or even to come in for a face-to-face visit, at least try to have them come 
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10.1.9. 
Outpatient Phase: Unscheduled Visit 
Note that unscheduled visits will be at the discretion of the Investigator but should include the 
following if performed prior to D15 visit:  
• 
Subject home diary review (pain intensity and pain medication) 
• 
Pain Intensity assessment (NRS) 
• 
Vital signs including temperature 
• 
Surgical Site assessment (If the investigator determines there are atypical wound healing or 
visible abnormal findings, a digital picture of the wound site should be performed if the 
subject has consented to such a photo) 
• 
Targeted Physical Exam 
• 
Neurosensory testing of the surgical area 
• 
Concomitant Medication Use/Concomitant Treatments 
• 
Document any prescriptions for opioids provided to the subject and the number of tablets 
prescribed.   
• 
Query the subject as to any rebound pain 
• 
AE Assessment 
If after D15 visit, subjects will return for the following assessments:  
• 
Surgical Site assessment (If the investigator determines there are atypical wound healing or 
visible abnormal findings, a digital picture of the wound site should be performed if the subject 
has consented to such a photo ) 
• 
Neurosensory testing of the surgical area 
• 
Concomitant Medication Use/Concomitant Treatments 
• 
Document any prescriptions for opioids provided to the subject and the number of tablets 
prescribed.   
• 
Query the subject as to any rebound pain 
• 
AE Assessment 
If after D29 visit, the investigator has clinical discretion on when subjects should return for follow 
up and what is performed 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 picture of the wound site should be performed) 
• 
Neurosensory testing of the surgical area 
• 
Concomitant Medication Use/Concomitant Treatments 
• 
Query the subject as to any rebound pain 
• 
AE Assessment 


 
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10.2. 
Subject Completion and Withdrawal 
10.2.1. 
Subject Completion 
A subject is considered to have completed the study once all end-of-study assessments are 
completed at D29 (or later if necessary), or at the last visit upon early termination of the study. 
10.2.2. 
Subject Withdrawal 
A subject is free to withdraw his/her consent and discontinue participation in the study at any time 
for any reason. A subject’s participation must therefore be terminated immediately upon his/her 
request, and the reason(s) for discontinuation appropriately documented. 
A subject 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) 
▪ Subject is lost to follow-up 
▪ Subject treatment allocation is unblinded (i.e., individual code break; Section 9.4) 
▪ Death of subject 
A subject may also be discontinued from the study, at the discretion of the Investigator and/or 
Sponsor, for any of the following reasons:  
▪ Subject 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 subject to continue 
▪ Administrative reasons (e.g., termination of enrollment or study) 
The Investigator must maintain a record of all subjects who discontinue from the study prior to 
completion; the reason(s) for study discontinuation will be documented. In the event that a 
subject 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 subject 
is not obligated to provide such a reason.  
Subjects who elect to discontinue participation prior to D8 (W1) 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, if willing and at their convenience, to ensure wound healing.  If a subject refuses to 
complete early termination/Follow-up procedures or continued data collection, this information 


 
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will be recorded. 
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 subject by the 
Investigator or designated study personnel. The subject must voluntarily provide written 
informed consent on an ethics-approved informed consent form (ICF), prior to performing any 
study-related procedures. The subject’s source records must document that the consent process 
has been completed and that written informed consent has been obtained from the subject prior 
to the initiation of any study-specific procedures. Documentation that the subject 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 subject should also be included 
in the medical records or clinical chart. 
10.3.2. 
Demographics 
The following demographics 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 clinical 
significance. 
10.3.4. 
Medication History  
All medications (prescription and non-prescription, herbal medications/natural health products, 
or investigational drugs) taken by the subjects during the 30 days prior to Screening will be 
recorded in the source documentation as medication history.  
10.3.5. 
Contraceptive Requirements 
Female subjects of childbearing potential must be using and willing to continue using medically 
acceptable contraception during the study unless they have a same sex partner.  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 subjects 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 subject medical history) or 


 
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congenitally sterile, or must be post-menopausal. Post-menopausal is defined as being 
amenorrheic for at least one year without another cause. 
Male subjects, unless in a relationship with a same sex partner or 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 the study.   
10.3.6. 
Subject Pain Assessment Training 
Subjects 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, subjects 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.  
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 possible pain) (Section 17.2 
Appendix B).   
Subjects will report or record the intensity of their current pain at designated times during the 
study after administration of study treatment.  Subjects should be at rest for at least 5-10 minutes 
prior to completing NRS resting assessment and have sat or stood up from a recumbent position 
within the 5-10 minutes prior to completing NRS assessment after this change in position.   
10.3.9. 
Rebound Pain at the Surgical Site 
Subjects will be queried at each outpatient follow up visit as to whether they have noted any 
worsening pain (rebound pain) at the surgical site since the prior visit report (Section 17.3 
Appendix C). 
10.3.10. 
Patient Global Evaluation (PGE) 
Each subject will be asked to report their satisfaction with the study treatment for pain using a 4-
point categorical scale.  Each subject will be asked the following question:  
“How would you rate the study treatment that you have received for pain? Poor (0), Fair (1), 
Good (2), or Excellent (3)” (see Section 17.4 Appendix D). 


 
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10.3.11. 
Investigator Global Evaluation (IGE) 
The investigator will report their satisfaction with the subject’s study treatment for pain using a 
4-point scale at designated times during the study after administration of study treatment.  A 
study Investigator will be asked the following question:  
“How would you rate the study treatment that the patient received for pain? Poor (0), Fair (1), 
Good (2), or Excellent (3)” (see Section 17.5 Appendix E). 
10.3.12. 
Rescue Medications 
The details of rescue medication (doses and times) will be recorded beginning from the end of 
surgery through 14 days after the end of surgery (D15 visit) or to Early Termination Visit if 
applicable.  Subjects will be instructed on the proper use and timing of rescue medication.  Use 
Table 9 to calculate the morphine equivalent dose (MED) of various opioids. 
Table 9. Equianalgesic Conversion Table 
Opioid (Doses in mg) 
Conversion Factor 
IV Fentanyl 
0.3 
PO Hydrocodone 
1 
PO Hydromorphone 
4 
PO Morphine 
1 
PO Oxycodone 
1.5 
PO Tramadol 
0.1 
Multiply the opioid dose by the conversion factor = oral morphine equivalent dose 
(MED):  
e.g., PO oxycodone 5 mg X 1.5 = 7.5 mg MED 
or 
IV fentanyl 25 mcg X 0.3 = 7.5 mg MED 
10.3.13. 
Clinical Laboratory Assessments  
All protocol-specified laboratory tests on blood and urine samples will be collected, processed, 
shipped and analyzed according to instructions from a selected central laboratory. The lab 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 lab reports expeditiously, in order to 
document appropriate safety monitoring of study subjects. The Investigator should sign and date 
each lab report concurrent with her or his review, and should indicate the clinical significance of 
each abnormal/flagged value by noting “NCS” (not clinically significant) or “CS” (clinically 
significant), for example. 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, 


 
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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, biochemistry, and urinalysis assessments are listed in Table 
10. 
Table 10: Clinical Laboratory Assessments 
Hematology 
Biochemistry 
Urinalysis 
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 
Tot Bili 
ALT 
AST 
GGT 
LDH 
ALK  
Color 
Turbidity 
pH 
Specific gravity 
Ketones 
Protein 
Glucose 
Bilirubin 
Occult blood / Nitrite 
Urobilinogen 
Leukocyte esterase 
Microscopic 
examination 
of 
sediment, only if urinalysis 
dipstick results are abnormal 
Coagulation 
Activated partial thromboplastin 
time (aPTT) 
Prothrombin time (PT) / 
International normalized ratio 
(INR) 
 
The clinical laboratory tests will be completed per the Schedule of Assessments.  In addition to 
the clinical laboratory tests, a serum pregnancy test will be performed at the Screening Visit and 
a urine pregnancy test will be performed prior to surgery for women of childbearing potential. 
ALT or AST > 3x ULN / Tot. Bili > 2 X ULN/ ALK >2X ULN will be considered an adverse 
event, as well as any other changes deemed clinically significant by the Investigator.  
10.3.14. 
Urine Drug Screen and Alcohol Test 
Urine drug screen and alcohol breath/saliva tests will be completed at screening and pre-
procedure. All subjects will be tested for drugs-of-abuse (e.g., amphetamines, barbiturates, 
benzodiazepines, cocaine, opiates, phencyclidine, tetrahydrocannabinol, methadone, 
methamphetamine, tricyclic anti-depressants, oxycodone and others). 


 
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10.3.15. 
Vital Signs 
Vital signs will consist of BP, HR, and RR and temperature following a rest period. Vital signs 
will be assessed per the Schedule Assessments.   
10.3.16. 
12-Lead Electrocardiogram (ECG) 
12-Lead ECGs will be performed per the Schedule of Assessments after the subject 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 QTc, clinically significant changes in 
ECG (using QTCf, should be <450 msec for male subjects / < 470 msec for female subjects.  
Clinically significant changes in ECG are: an increase of QTcF of 30msec or greater, as well as 
any other changes deemed by the Investigator as significant will be considered an AE. 
10.3.17. 
Physical Examination 
A complete PE including all major body systems (HEENT, neurologic, cardiovascular, respiratory, 
gastrointestinal, dermatologic and musculoskeletal systems) 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 as per Table 1.  
Body weight (kg), in indoor clothing, but without shoes, will be measured at Screening and 96 
hours.  Height in centimeters (cm) will be measured, and BMI will be calculated at Screening 
only. BMI shall be calculated as kg/m2.  The site should use NIH website BMI calculator 
(available at: http://www.nhlbi.nih.gov/health/educational/lose_wt/BMI/bmi-m.htm. 
10.3.18. 
Surgical Site Assessment  
The surgical site should be assessed per the Schedule of Assessments 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 (0-10) where a score of 0 
is “Completely unsatisfied,” and a score of 10 is “Completely satisfied.” (Section 17.6 Appendix 
F).  Assessments will also be performed at each of the Follow-up visits or at the time of early 
discontinuation. When assessed on Day 29, if the Investigator observes insufficient wound or bone 
healing or to ensure an ongoing AE has resolved, the subject will be scheduled for a follow-up 
visit.  
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 


 
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of a new baseline (the grading guide for atypical wound findings may be useful to the 
investigator: Section 17.7 Appendix G). 
10.3.19. 
Neurosensory Testing 
A Neurosensory testing of the skin surrounding the incision will be conducted per the Schedule 
of Events.  This evaluation will include the details described in Section 17.8 Appendix H.  
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.  Subjects 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 
10.3.20. 
Assessment of Adverse Events 
All SAEs and non-serious AEs will be documented and followed from the time of administration 
of study treatment until Day 29 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 subject’s medical record, unless related to a study procedure. Serious AEs 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. 
10.3.21. 
Pharmacokinetic Assessments and Samples 
Details for the collection and processing of blood samples for measurement of PK (CA-008, 
Capsaicin, and CA-101) and urine collections are outlined in the Lab Manual. 
10.4. 
Safety, PK and Efficacy Endpoints 
10.4.1. 
Safety Endpoints 
Safety endpoints include the following: 
• Incidence of spontaneously reported TEAEs or SAEs 
• Clinical laboratory test results  
• Vital sign measurements 
• ECG results 
• PE findings  
• Surgical Site wound assessment findings 


 
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• Neurosensory testing results 
• Presence of rebound pain 
• Concomitant Medication Use/Concomitant Treatments 
10.4.2. 
Pharmacokinetic Endpoints 
Full details of pharmacokinetic endpoints will be described in a separate PK Analysis Plan. The 
time points for whole blood collection are outlined in the Schedule of Assessments.  Actual 
sampling times will be used to calculate plasma-derived PK parameters.  
10.4.3. 
Efficacy Endpoints 
10.4.3.1. Primary Efficacy Endpoint 
Time-specific mean NRS pain intensity scores at T96h for CA-008 vs. placebo. 
10.4.3.2. Key Secondary Efficacy Endpoints 
For the CA-008 vs. placebo comparison: 
• Weighted sum of pain intensity (SPI) assessments = Area Under the Curve (AUC) of the 
NRS current pain intensity scores from T0 to 96h at rest (AUC0 to 96h).  
• Time to opioid cessation or freedom (TOF) 
• Percentage of subjects who do not require opioids (i.e., opioid free; OF) from T24 to T96: 
OF24 to 96h 
• Total opioid consumption (in daily oral morphine equivalents) = OC from T0 to T96h: OC0 
to 96h    
10.4.3.3. Other Endpoints 
For the CA-008 vs. placebo comparison: 
• Using NRS at rest: AUC 0 to 120h, AUC24 to 96h, AUC0 to W1 
• AUC 0 to 96h (arising), AUC 0 to W1 (arising) 
• Time-specific mean NRS scores at T48, T72, T96, T120, T144 and T168h 
• OC24 to 96h 
• OF24 to 96h, OF96h to W1 and OF96h to W2 
• The fraction of subjects who rescue at T48, T72 and T96h 
• Analgesic consumption from T96h to W1 (AC96h to W1) and AC96h to W2 
• PGE comparing the %age of subjects reporting “poor” + “fair” vs. “good” + “excellent” 
responses, and the %age reporting each category of response at T96h, D8/W1, D15/W2 
and D29/W4 
• IGE comparing the %age of those reporting “poor” + “fair” vs. “good” + “excellent” 
responses, and the %age reporting each category at T96h, D8/W1, D15/W2 and D29/W4 


 
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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 Harmonization (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 subject administered a pharmaceutical product 
that does not necessarily have a causal relationship with this treatment.  An AE can therefore be 
any unfavorable and unintended sign (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. 
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 adverse event.   
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 
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.”   


 
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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 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, severe or potentially life-threatening) 
▪ Relationship to study treatment 
▪ Action and outcome 
▪ Seriousness of event 
All SAEs will be documented and followed from the time the subject has signed the ICF until 
D29±2 after the completion of surgery. All SAEs and non-serious AEs will be documented and 


 
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followed from the time of administration of study treatment until Day 29 or later if necessary. 
AEs that occur between Screening and the administration of study medication should be 
considered medical history and added to the subject’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.  Serious AEs and AEs that have been designated as possibly related to 
study treatment will be followed until resolution or stabilization. 
11.1.3. 
Serious Adverse Event (SAE) 
An 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 subject 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 an SAE when, based upon appropriate medical judgment, 
the event may jeopardize the subject 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 Day 29 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 an 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 an 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 subject is receiving study treatment and within 14 days 
following the study completion visit (or 21 days following an 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 an SAE is as follows: 


 
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▪ 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.  
o CRO Medical Monitor: Jon Ruckle, MD 
o 24/7 Emergency contact: 808-349-9812 / (253) 448-8690 
o SAE Reporting email: MedicalMonitorCA-PS-204@Lotuscr.com  
▪ The Sponsor’s Medical Monitor is available for questions about safety-related issues:  
Mike A. Royal, MD JD MBA; 858-204-1112 or mike@concentricanalgesics.com. 
▪ 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 in order to 
obtain resolution or follow-up information. 
▪ The site will enter into the electronic database (or fax, if the database cannot be accessed for 
any reason) an SAE report, or similar form, that includes the following information, as 
available: 
o Subject ID 
o Basic demographic information (age, gender, weight) 
o Outcomes attributed to the event (death, life-threatening hospitalization [new or 
prolonged], disability, congenital anomaly, required medical intervention to prevent 
permanent impairment/damage, etc.) 
o Onset date and severity of the event 
o Brief description of the event including frequency and severity of symptoms leading 
to diagnosis 
o List of relevant test results and laboratory data 
o Any other relevant history 
o Whether the study treatment was discontinued 
o 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. 


 
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11.2. 
Severity Grading for AEs 
Grading the severity of AEs is per investigator discretion (the guidance reflected in Sections 
17.9, 17.10 and 17.11; Appendices I, J and K 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.   
11.3. 
Pregnancy 
If a female subject 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 subject 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 an 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 an 
SAE. 


 
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12. 
DATA QUALITY ASSURANCE 
This study will be conducted under Good Clinical Practice (GCP) and all applicable regulatory 
requirements. 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, lab results, 
participant diaries, data recorded in automated instruments, microfilm or magnetic media, and 
pharmacy records, etc. This study will use electronic data capture (EDC). At a minimum, all data 
required by the protocol should have supporting source documentation for entries in the EDC 
system. 
All CRFs 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 collected on the CRF.  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 
electronic data capture system maintains a full audit trail.  
12.2. 
Study Auditing and Monitoring 
Monitoring of the study site (including, but not limited to, reviewing CRFs 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 


 
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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, 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 AND DETERMINATION OF 
SAMPLE SIZE 
13.1. 
Statistical and Analytical Plans 
The sections of the Statistical Considerations describe the statistical methods to be used to 
analyze the efficacy and safety.  These methods may be revised and updated due to reasons such 
as regulatory requirements or need for further clarifications.  The final analysis will be 
documented in a formal Statistical Analysis Plan (SAP) that must be finalized before database 
lock.  The SAP will include details on how variables will be derived, how missing data will be 
handled, and how data will be presented as well as the details on statistical methods to be used 
for safety and efficacy analyses.  The final clinical study report will discuss deviations from the 
SAP, if any. 
13.2. 
Sample Size Justification 
Given the uncertainty in estimating a sample size for C-ABD surgery, the data from the current 
study will be used to determine the sample size for a subsequent parallel design study selecting 
one or more optimal doses of CA-008 vs. placebo in the setting of standard of care for 
abdominoplasty. 
13.3. 
Analysis Populations 
The following analysis populations are planned for this study:  
• The Safety Population will include all subjects who received any part of a dose of study 
treatment.   
• The PK Population will include all subjects who receive a full dose of study treatment and 
complete all PK assessments. 
• The intent-to-treat (ITT) population will include all subjects as randomized to study 
treatment.   
Membership in analysis populations will be determined before unblinding. 
Subjects who elect to discontinue study participation (early termination or ET) after 
randomization but prior to receiving study treatment will be replaced.   
Subjects who elect to ET after receiving study treatment will not be replaced, however those who 
ET during the inpatient phase of the study, will be asked to continue with assessments through 
T96h if they have not elected to withdraw from all aspects of study participation.   


 
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13.4. 
Planned Analyses 
Unless otherwise indicated, all testing of statistical significance will be 2-sided, and a difference 
resulting in a P value of less than or equal to 0.05 will be considered statistically significant.  
Furthermore, the baseline will be the last assessment before the dosing of study medication.  
All inferential assessments will be 2-sided tests performed at the 0.05 alpha level unadjusted for 
multiple comparisons.  A hierarchical alpha testing strategy will be utilized to control for the 
overall experiment-wise alpha.  First the primary analysis will be performed at the 0.05 alpha 
level.  If the primary analysis is statistically significant, then a limited number of key secondary 
analyses will be analyzed in a pre-specified order and analyses will be considered as statistically 
significant only if the preceding test is statistically significant.  The order of the secondary 
analyses will be specified in the SAP and signed off prior to unblinding. 
Summary statistics will be provided for the variables described in the following sections. For 
continuous variables, these statistics will typically include the number of subjects, mean, 
standard deviation (SD), median, minimum, and maximum. For categorical variables, these 
statistics will typically include the number and percentage of subjects in each category. 
13.5. 
Study Subjects and Demographics 
13.5.1. 
Disposition and Withdrawals 
The numbers of subjects randomized, completing, and withdrawing, along with reasons for 
withdrawal, will be tabulated overall and by treatment group. The number of subjects in each 
analysis population will be reported. 
13.5.2. 
Protocol Deviations 
Major protocol deviations will be classified and documented before database lock and will be 
discussed in the CSR.  All protocol deviations, whether minor or major, will be presented in a 
data listing. 
13.5.3. 
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 subjects taking each medication, classified using World Health Organization Drug 
Dictionary Anatomical Therapeutic Chemical classes and preferred terms. 


 
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13.5.4. 
Exposure  
Since this is a single dose study, study drug administration will be summarized in terms of total 
exposure by cohort and treatment group. 
13.5.5. 
General Considerations 
All continuous study assessments will be summarized by treatment and time point (as applicable) 
using the descriptive statistics n, mean, SD, median, and range (minimum, and maximum).  
Categorical assessments will be summarized by treatment and time point (as applicable) using 
frequency counts and rates of occurrence (%).  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, subject and time point.  
No preliminary rounding will be performed; rounding will only occur after the analysis.  Means 
and medians will be presented with one more decimal place than the precision of the data.  
Standard deviations will be presented with two more decimal places than the precision of the 
data.  Percentages will be presented with one decimal place.  A percentage of 0% or 100% will 
be reported as 0% or 100%, respectively.  Minimums and maximums will be presented with the 
same precision as the original data. 
All analyses will be performed using the SAS System® version 9.3 or higher. The domain 
(Study data tabulation Model [SDTM]) and analysis (Analysis Data Model [ADaM]) data sets 
will be taken as input to the SAS programs that generate the report-ready tables, figures and 
listings. The submission ready SDTM and ADaM data sets will be provided to the sponsor along 
with display deliveries. 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 is the time of completion of study treatment administration.  
• Day of surgery is defined as D0 
• Assessment visit times are defined by time T0/D0. 
• Baseline value is defined as the last valid measurement prior to beginning study treatment 
administration. 
• Change from baseline is defined as post-baseline value minus 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.  Duration in hours will be calculated as the stop 
date/time of the event minus the start date/time.  Duration in days will be calculated by using 
stop date minus the start date +1 if AE occur on or after taking study medication.  If AE 
occur prior to the study medication, then the duration will be calculated by using stop date 
minus the start date.  If reported as ongoing at the time of database lock, the duration will be 
calculated using the date of the last visit or the last date of any AE for the subject in the 


 
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database, whichever is later.  Missing dates will be imputed as described in the Study’s 
Statistical Analysis Plan (SAP). 
• The number of days in the study is computed as: [Date of study completion or withdrawal 
minus the date of study drug administration (Day 1)] + 1.  
• If duplicate values are obtained at a given visit (e.g., repeated vital sign measurements), the 
last value will be used unless it is noted that the measurement was in error for that value. 
Values that compromise interpretation will not be used in summaries (e.g., values that were 
obtained post-dose will not be summarized as pre-dose values). 
13.5.6. 
Analysis of Efficacy Measures 
All efficacy endpoints (e.g., NRS scores), will be summarized over time by treatment using 
descriptive statistics including confidence intervals as appropriate. 
AUC calculations will be done using the standard trapezoidal rule  
AUC  =     ∑
(
𝑁𝑅𝑆𝑖+𝑁𝑅𝑆𝑖+1
2
)
𝑥
𝑖=0
∗ (𝑇𝑖+1 − 𝑇𝑖) 
Where:  NRSi = NRS at time i, and (Ti+1 – Ti) 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 will be handled as discussed in the Study’s 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. 
The AUC analyses will be presented in a summary table with standard summary statistics for 
each treatment group mean differences standard errors, confidence intervals and comparison p-
values as appropriate.   
Mean NRS scores over time (in-clinic and diary) will be graphed over time by treatment group.  
NRS over time by each subject may also be displayed graphically as warranted.  The individual 
NRS and the computed AUC variables will be listed for all individual subjects.   
In this study, subjects are permitted to take rescue medication for analgesia.  It is expected 
subjects randomized to placebo arm will take rescue medication more often.  During both 
inpatient and outpatient portions of the studies, the subjects will be instructed to record NRS 
immediately prior to taking rescue medication. 
For subjects who take rescue, the pre-rescue pain score will be used to impute scheduled 
assessments.  Intermittent missing pain scores (due to subject sleeping, etc.) will not be imputed, 


 
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and AUC will be calculated based on non-missing values. For subjects who drop out of the study 
prior to Day 15 due to Lack of Efficacy or Adverse Events, scheduled assessments may be 
imputed using worst prior pain score carried forward.  All other subjects who drop out will have 
their last pain score carried forward. 
Sensitivity analysis of the primary efficacy variable using different methods of imputation for 
rescue medication may also be performed.    
Additional sensitivity analysis with different missing value imputation methods for subjects who 
drop out of the study may also be performed.    
All imputation methods for pain intensity will be documented in the SAP. 
13.5.6.1. Handling of Dropouts or Missing Data 
All efforts will be made to minimize missing data.  These efforts will include the following: 
• Subjects are required to consent continuous data collection even after subjects 
discontinue the study medication; 
• Continue data collection after subjects taking rescue medication; 
• Establish robust efficacy data collection procedures. 
With the procedures above, it is expected that the missing would be minimal.  Missing at random 
is expected to be a reasonable assumption and the primary analyses are expected to be sufficient 
for this dose escalation study. Additional sensitivity analyses will be performed to support robust 
conclusions, if warranted and details are presented in a detailed SAP prior to database lock.  
For subjects who take rescue medication a windowed last pain score carried forward (wLOCF) 
will be used. 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 subject 
sleeping, etc.) will not be imputed, and AUC will be calculated based on non-missing values. For 
subjects who drop out of the study prior to Day 15, scheduled assessments will first be imputed 
using the worst prior pain score carried forward (WOCF). As sensitivity analyses, the AUC will 
also be calculated where assessments after drop out will be imputed using LOCF, using the last 
scheduled non missing pain score prior to drop out, and the median scores for the remainder of 
the group continuing in the study, without imputation using actual data. 
For secondary continuous efficacy endpoints, similar methods as the primary analysis will be 
used.  For categorical endpoints, when assessments are imputed for data after a subject 
discontinues from the study, a WOCF method will be used. 


 
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Sensitivity analysis of the primary efficacy variable using different methods of imputation for 
rescue medication may also be performed.  Additional sensitivity analysis with different missing 
value imputation methods for subjects who drop out of the study may also be performed.  All 
imputation methods for pain intensity will be documented in the SAP. 
13.5.7. 
Analysis of Safety  
Safety analyses will be conducted using data from the Safety Population (as defined in 
Section 13.2).  
Safety will be assessed through treatment-emergent AEs (TEAEs); hematologic, biochemical, 
and urinalysis laboratory parameters; vital signs measurements; ECGs; physical exam, surgical 
site and neurosensory assessments.  
No formal statistical comparisons will be performed for safety endpoints. 
13.5.7.1. 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 Day 29 or 
Early Termination, whichever occurs first;  
▪ Serious AEs with onset on the date of treatment with the study drug through 30 days after 
Day 29 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 Day 29 or Early Termination, whichever occurs 
first. 
The number and percentage of subjects 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. 
13.5.8. 
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 and the number and percentage of subjects in each 
category will be presented in shift tables. 


 
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Laboratory values that are outside the normal range will also be flagged in the data listings, 
along with corresponding normal ranges. 
13.5.9. 
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 ECG.  Detailed description of the 
analysis will be included in the Study SAP. 
The incidence of abnormal ECG findings will be summarized for each visit.  
13.5.10. 
Physical Examination Findings 
Physical and Surgical Site examination data will be presented in the listings. Abnormal or 
clinically significant physical exam and surgical site 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. 
Subject 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 subject 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.  


 
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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. 
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 United States 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 subject’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 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. 


 
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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 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 subject 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 subject 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 


 
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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. 
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 principal investigator 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 


 
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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 Phase 2, Randomized, Double-blind, Placebo-Controlled Efficacy, 
Pharmacokinetics and Safety Study of CA-008 in Subjects Undergoing 
Complete Abdominoplasty 
 
Version: 2.0 
Date:  28 January 2019 
 
 
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 guidances. 
 
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 J, Mouksassi M 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(4):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 postoperative 
pain following total knee arthroplasty: a preliminary report of a randomized, double-
blind, parallel-group, placebo-controlled, multicentre trial.  Clin Drug Investig 2011; 
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. Surh YJ, Lee SS. Capsaicin, a double-edged sword: toxicity, metabolism, and 
cheopreventive potential.  Life Sci 1995; 56: 1845-55. 
7. Tominaga, M., Caterina, M.J., Malmberg, A.B., Rosen, T.A., Gilbert, H., Skinner, K., 
Raumann, B.E., Basbaum, A.I., Julius, D., 1998. The cloned capsaicin receptor integrates 
multiple pain-producing stimuli. Neuron 21, 531–543. 
 
 
 
 
 
 
 
 
 
 


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17. 
APPENDICES 
17.1. 
Appendix A: 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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17.2. 
Appendix B: 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 
 
Subject Initials: __________ 
 
 
 


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17.4. 
Appendix D: Patient Global Evaluation (PGE) 
Patient Global Evaluation (PGE) 
Instructions to Subject:  Please respond to the question below. When completed, please initial 
at the bottom of the page. 
How would you rate your satisfaction with the study treatment that you received during 
surgery for postop pain? 
(Mark one box) 
 
 Excellent (3) 
 
 Good (2) 
 
 Fair (1) 
 
 Poor (0) 
Subject Initials: __________ 
 
 
 


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17.5. 
Appendix E: Investigator Global Evaluation of Study Treatment] 
(IGE) 
Investigator Global Evaluation (IGE) 
Instructions to Investigator: Please respond to the question below. When completed, please 
initial at the bottom of the page. 
How would you rate the study treatment that this patient received during surgery for pain? 
(Mark one box) 
 
 Excellent (3) 
 
 Good (2) 
 
 Fair (1) 
 
 Poor (0) 
Investigator Initials: __________ 
 
 
 


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17.6. 
Appendix F: 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: __________ 
 
 
 


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17.7. 
Appendix G: 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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17.8. 
Appendix H: Neurosensory Examination Form 
 
Neurosensory testing should be performed in an area approximately 3 to 5 cm above and 
below the surgical incision site in three locations lateral on each side and in the midline.  The 
instructions below may assist the investigator or designee in performing neurosensory 
testing. 
• 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 subject, 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: testing should be performed at the location to be assessed using a 
foam brush but allodynia may also be a finding during the monofilament testing.   


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For allodynia assessment the foam brush will be lightly stroked 3 times across the skin in the 
location to be assessed.  Subject will be asked to compare 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 subject 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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17.9. 
Appendix I: 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 adverse events, 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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17.10. 
Appendix J: Toxicity Grading Scale for Clinical Vital Sign 
Abnormalities 
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 adverse events, 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. 
 
 
 


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17.11. 
Appendix K: 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 adverse events, 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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17.12. 
Appendix L: Bupivacaine (Marcaine) Dosage Recommendations 
 
 

SAP_001.pdf: 
 
 
 
 
 
OFFICIAL TITLE: 
A Phase 2, Randomized, Double-blind, Placebo-Controlled Efficacy, 
Pharmacokinetics and Safety Study of CA-008 in Subjects Undergoing Complete 
Abdominoplasty 
 
NCT NUMBER: 
03789318 
 
DOCUMENT DATE: 
24 April 2019 
 


Sponsor: Concentric Analgesics, Inc. 
 
Statistical Analysis Plan 
Protocol Number: CA-PS-204 
 
Date: 24APR2019 
 
 
CONFIDENTIAL 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
A Phase 2, Randomized, Double-blind, Placebo-Controlled Efficacy, Pharmacokinetics and 
Safety Study of CA-008 in Subjects Undergoing Complete Abdominoplasty 
Protocol Number:  CA-PS-204 
Protocol Version 2.0 (28JAN2019) 
 
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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Date: 24APR2019 
 
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DOCUMENT VERSION CONTROL 
Version Number 
Date 
Comments/Changes 
V1.0 
24Apr2019 
SAP 
 
 
 
 
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APPROVALS 
Author: 
 
 
 
 
 
 
 
 
 
 
Napoleon Oleka 
Senior Biostatistician 
Lotus Clinical Research®, LLC  
 
Date: 
 
 
Reviewed:  
 
 
 
 
 
 
 
 
 
Jennifer Nezzer 
Director, Biometrics 
Lotus Clinical Research®, LLC  
 
Date: 
 
 
Approved: 
 
 
 
 
 
 
 
 
Mike A. Royal, MD, JD, MBA 
Chief Medical Officer 
Concentric Analgesics Inc. 
 
Date: 
 
 
 
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26-Apr-19
27-Apr-19
28-Apr-19


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TABLE OF CONTENTS 
 
1. 
PURPOSE OF THE ANALYSES ......................................................................... 9 
2. 
PROTOCOL SUMMARY ..................................................................................... 9 
2.1 
Study Objectives ................................................................................................. 9 
2.1.1 
Primary Objective ................................................................................................ 9 
2.1.2 
Secondary Objective ........................................................................................... 9 
2.2 
Overall Study Design and Plan ............................................................................ 9 
2.2.1 
Study Stopping Rules ........................................................................................ 11 
2.2.2 
Study Population ............................................................................................... 13 
2.2.3 
Treatment Regimens ......................................................................................... 13 
2.2.4 
Treatment Group Assignments or Randomization ............................................. 13 
2.2.5 
Sample Size Determination ............................................................................... 13 
3. 
GENERAL ANALYSIS AND REPORTING CONVENTIONS .............................. 14 
4. 
SUBJECT POPULATIONS ................................................................................ 16 
4.1 
Analysis Populations ......................................................................................... 16 
4.2 
Disposition of Subjects ...................................................................................... 16 
4.3 
Protocol Deviations............................................................................................ 17 
5. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ..................... 17 
5.1 
Demographics and Baseline Characteristics...................................................... 17 
5.2 
Medical/Surgical History .................................................................................... 17 
5.3 
Prior and Concomitant Medications ................................................................... 17 
6. 
MEASUREMENTS OF TREATMENT EXPOSURE AND COMPLIANCE .......... 18 
7. 
EFFICACY EVALUATION ................................................................................. 19 
7.1 
Handling of Dropouts or Missing Data ............................................................... 19 
7.2 
Sensitivity Analyses ........................................................................................... 20 
7.3 
Assessment Time Windows ............................................................................... 20 
7.4 
Efficacy Endpoints ............................................................................................. 21 
7.4.1 
Primary Efficacy Endpoint .................................................................................. 21 
7.4.2 
Key Secondary Efficacy Endpoints .................................................................... 21 
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7.4.3 
Other Endpoints ................................................................................................ 21 
7.5 
Analysis Methods .............................................................................................. 22 
7.5.1 
NRS Measurements .......................................................................................... 22 
7.5.2 
Time-specific mean NRS pain intensity scores at T96h (Primary Efficacy 
Endpoint) and other time points ......................................................................... 23 
7.5.3 
AUC 0-96h at Rest (Key Secondary Efficacy Endpoint) and other AUC endpoints23 
7.5.4 
Time to opioid cessation or freedom (TOF) (Key Secondary Efficacy Endpoint) .. 23 
7.5.5 
Opioid Free (OF) 24-96h (Key Secondary Efficacy Endpoint) and other 
timepoints. ......................................................................................................... 24 
7.5.6 
Total Opioid Consumption (OC) in Daily Oral Morphine equivalents 0-96h (Key 
Secondary Efficacy Endpoint) and other timepoints ........................................... 24 
7.5.7 
Percentage of Subjects who Rescue at T48 and other timepoints ..................... 25 
7.5.8 
PGE and IGE ..................................................................................................... 25 
8. 
SAFETY EVALUATION ..................................................................................... 26 
8.1 
Overview of Safety Analysis Methods ................................................................ 26 
8.2 
Adverse Events and SAEs ................................................................................. 26 
8.3 
Physical Examination ........................................................................................ 29 
8.4 
Vital Signs ......................................................................................................... 30 
8.5 
Surgical Site Assessments and Rebound (or Worsening) Pain Assessments .... 30 
8.6 
Neurosensory Test ............................................................................................ 30 
8.7 
ECG .................................................................................................................. 31 
8.8 
Clinical Laboratory Test Results ........................................................................ 31 
8.9 
Drugs of Abuse and Alcohol Screens, Pregnancy Test ...................................... 31 
8.10 
Subject Pain Assessment Training and Surgery Details .................................... 31 
9. 
PHARMACOKINETIC EVALUATION ................................................................ 31 
10. 
OTHER ANALYSES .......................................................................................... 32 
11. 
INTERIM ANALYSES ........................................................................................ 32 
12. 
REFERENCES .................................................................................................. 32 
13. 
APPENDICES ................................................................................................... 32 
13.1 
Planned Tables, Figures and Listings ................................................................ 32 
13.1.1 Tables ............................................................................................................... 32 
13.1.2 Figures .............................................................................................................. 35 
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13.1.3 Listings .............................................................................................................. 36 
14. 
DOCUMENT HISTORY ..................................................................................... 37 
 
LIST OF IN-TEXT TABLES AND FIGURES 
Table 2-1 
Protocol-Specified Visits and Visit Windows .................................. 10 
Table 2-2 
Study Stopping Rules .................................................................... 12 
Table 3 
Equianalgesic Conversion Table ................................................... 25 
Table 4 
Table of Imputation Rules for Missing AE Start Dates ................... 29 
 
 
 
 
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LIST OF ABBREVIATIONS (COMMONLY USED) 
 
ADaM 
 
Analysis Data Model 
ADLs 
Actives of Daily Living 
AE 
Adverse Event 
ANOVA 
Analysis of variance 
ATC 
Anatomical Therapeutic Chemical 
AUC 
Area Under the Curve 
BMI 
Body Mass Index 
CDER 
Center for Drug Evaluation and Research 
CP 
Completer 
CRF 
Case Report Form 
CRO 
Clinical Research Organization 
CSR 
Clinical Study Report  
ECG 
Electrocardiogram 
EOS 
End of Study 
ET 
Early Termination 
FDA 
Food and Drug Administration 
ICF 
Informed Consent Form 
ICH 
 
International Conference on Harmonization  
IGE 
Investigator Global Evaluation 
ITT 
Intent-to-treat 
LOCF 
Last Observation Carried Forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
MED 
morphine equivalent dose 
NRS 
Numerical Rating Scale for Pain Intensity  
OC 
Opioid Consumption in morphine equivalent dose 
OF 
Opioid-Free days 
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PACU 
Post Anesthesia Care Unit 
PE 
Physical Examination 
PGE 
Patient Global Evaluation 
PK 
Pharmacokinetic 
PT 
Preferred Term 
QOL 
Quality of Life 
SAE 
Serious Adverse Event/Experience 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SDTM  
Standard Data Tabulation Model 
SOC 
System Organ Class 
SRC 
Safety Review Committee 
TEAE 
Treatment Emergent Adverse Event 
WHO 
World Health Organization 
WOCF 
Worst Observation Carried Forward 
 
 
 
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1. PURPOSE OF THE ANALYSES 
This statistical analysis plan (SAP) is based on protocol number CA-PS-204 Version 2.0 
(28JAN2019) from Concentric Analgesics, Inc. This SAP provides details of the specific statistical 
methods that will be performed on data collected in this study and will be finalized and signed off 
before database lock.  
This SAP is being written with due consideration of the recommendations outlined in the most 
recent International Conference on Harmonization (ICH) E9 Guideline entitled Guidance for 
Industry:  Statistical Principles for Clinical Trials, the most recent ICH E3 Guideline and the 
Guidance for Industry:  Structure and Content of Clinical Study and the most recent FDA draft 
Guidance for Industry - Analgesic Indications:  Developing Drug and Biological Products, dated 
February 2014. 
2. PROTOCOL SUMMARY 
2.1 
Study Objectives 
2.1.1 Primary Objective 
• 
To evaluate the efficacy of a single intraoperative administration of CA-008 vs. vehicle 
placebo (100 mL volume) in subjects undergoing an elective C-ABD. 
2.1.2 Secondary Objective 
• 
To evaluate the safety and tolerability of a single intraoperative administration of CA-008 
vs. vehicle placebo in subjects undergoing an elective C-ABD.  
• 
To evaluate the PK profile of a single intraoperative administration of CA-008 vs. vehicle 
placebo in subjects undergoing an elective C-ABD.  
• 
To evaluate the opioid-sparing effect of CA-008 vs. placebo in subjects undergoing an 
elective C-ABD in terms of consumption and time to cessation. 
2.2 
Overall Study Design and Plan 
This is a Phase 2, single-center, randomized, double-blind, placebo-controlled, parallel design 
study evaluating up to 4 exploratory cohorts, each with a single dose of CA-008 or placebo. 
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For each subject, the study will be conducted in two parts: 
• 
Inpatient period starts with admission to Post-anesthesia care unit (PACU) and continues 
to 96h (T96h) after completion of study treatment injection (T0).   
• 
Outpatient period begins on discharge from the inpatient unit through various follow up 
visits to D29±2 (W4) after surgery, or later if necessary, for ongoing safety assessments.  
Note that additional follow up visits may occur at any time or even after D29/W4 to follow 
adverse events (AEs) to resolution or establishment of a new baseline.  
The protocol-defined visits are presented in Table 2-1: 
Table 2-1 
Protocol-Specified Visits and Visit Windows 
 
Study Phase 
Visit Time 
Screening 
From days -45 to -1 
Prior to Surgery/ Surgery 
Day 0 
In-Patient (Post Surgery) 
Hours 0 (post-surgery), 24, 48, 72 and 96  
Follow-up 
If needed, unscheduled visits or Follow Up after 
D29±2 
Early Termination (ET) visit (for subjects who 
terminate early, and are agreeable to a return 
visit) 
Days 8(±1 day), 15(±2 days), 29(±2 days) 
 
 
All study assessments are outlined in Table 1 of the Protocol. 
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2.2.1 Study Stopping Rules 
Study enrollment will be paused if subjects experience intolerable possibly related TEAEs, as 
defined: 
• 
1 or more subjects with any grade 4 “related” TEAE in any of the categories shown in 
Table 2-2.  
• 
2 or more subjects with the same grade 3 “related” TEAE in any of the categories shown in 
Table 2-2.  
More details are described in Section 7.2 of the Protocol. 
An external independent safety review committee (SRC) will be consulted should a stopping rule 
be triggered to determine whether it is appropriate to continue with dosing in the study. This 
committee will be independent of the Sponsor or clinical research organization (CRO) and will in 
no way be involved with study conduct. The SRC Charter details the membership, roles and 
responsibilities of the SRC.  
 
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Table 2-2 
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 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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2.2.2 Study Population 
Adults ages 18 to 65 years, inclusive, who are planning to undergo an elective complete (full) 
abdominoplasty (C-ABD) and otherwise meet eligibility criteria may be considered for enrollment 
into the study.  
2.2.3 Treatment Regimens 
Cohort #1: CA-008 5 mg vs. placebo in 100 mL of vehicle  
Cohort #2: CA-008 10 mg vs. placebo in 100 mL of vehicle  
Cohort #3: CA-008 15 mg vs. placebo in 100 mL of vehicle 
Cohort #4 (optional): CA-008 (5mg to 15 mg) vs. placebo in 100 mL of vehicle 
2.2.4 Treatment Group Assignments or Randomization 
Subjects who meet the enrollment criteria will be randomly allocated to receive either an active 
drug or placebo in a 1:1 (for Cohorts #1 or #4) or a 2 active:1 placebo ratio (for Cohorts #2 or #3).  
This study will use manual randomization.  
Subjects who have provided written informed consent will be assigned a unique number in the 
screening process. This number will be used to identify the subject throughout the study. Once 
any subject number or randomization number is assigned, it cannot be reassigned to any other 
subject. Subjects may be rescreened if the screening window is exceeded due to scheduling 
issues.  
2.2.5 Sample Size Determination 
There is no formal sample size estimation for this study. Given the uncertainty in estimating a 
sample size for C-ABD surgery, data from the current study will be used to determine the sample 
size for a subsequent parallel design study selecting one or more optimal doses of CA-008 vs. 
placebo in the setting of standard of care for abdominoplasty. The sample size is considered 
sufficient for that purpose. 
Subjects will be randomized to either the active medication or placebo as follows: 
• 
Cohort #1: total N=18 randomized 1:1. CA-008 5 mg or placebo 
• 
Cohort #2: total N=18 randomized 2:1. CA-008 10 mg or placebo 
• 
Cohort #3: total N=18 randomized 2:1. CA-008 15 mg or placebo 
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• 
Cohort #4 (optional): total N=24 randomized 1:1 to CA-008 (5mg to 15mg) or placebo  
After the 3rd cohort was enrolled, the decision was made not to enroll the optional 4th cohort, 
therefore the final sample size will be 54 subjects.  
3. GENERAL ANALYSIS AND REPORTING CONVENTIONS 
This section discusses general policies to be employed in the analysis and reporting of the data 
from the study. Departures from these general policies may be provided in the specific detailed 
sections of this SAP. When this situation occurs, the rules set forth in the specific section take 
precedence over the general policies. 
Summaries and analyses will be presented separately for Cohort 1, then the other cohorts: active 
and placebo groups associated with Cohort 1 will be presented alone, then active arms and 
pooled placebo group associated with Cohorts 2, 3 and 4 (if performed) will be presented 
together). An overall column will be provided where appropriate.  
All continuous study assessments will be summarized by treatment and time point (as applicable) 
using the descriptive statistics n, mean, SD, median, and range (minimum, and maximum). All 
categorical study assessments will be summarized by treatment and time point (as applicable) 
using frequency counts and rates of occurrence (%). Changes from baseline for continuous 
outcomes will be presented as their corresponding continuous measures for post-baseline visits if 
applicable. All study data will be listed by cohort, treatment, subject, and time point (as 
applicable).  
No preliminary rounding will be performed; rounding will only occur after the analysis. To round, 
consider the digit to the right of the last significant digit:  if <5, then round down; if ≥5, then round 
up. Means and medians will be presented with one more decimal place than the precision of the 
data. Standard deviations will be presented with two more decimal places than the precision of 
the data. Percentages will be presented with one decimal place. A percentage of 100% will be 
reported as 100%. Minimums and maximums will be presented with the same precision as the 
original data. 
Unless otherwise indicated, all testing of statistical significance will be 2-sided, and a difference 
resulting in a p-value of less than or equal to 0.05 will be considered statistically significant.  
Furthermore, the baseline will be the last assessment before the dosing of study medication.  
No adjustment will be made for multiple comparisons in this exploratory study. 
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All analyses will be performed using the SAS System® version 9.3 or higher. For final TLFs, the 
domain (Study data tabulation Model [SDTM]) and analysis (Analysis Data Model [ADaM]) data 
sets will be taken as input to the SAS programs that generate the report-ready tables, figures and 
listings. The submission ready SDTM and ADaM data sets will be provided to the sponsor along 
with display deliveries.   
The following conventions will be used in the study analysis as needed for intermediate 
calculations: 
• 
Time 0 (T0) is the time of completion of study drug administration. 
• 
Time P (TP) is the time of discharge from the Post anesthesia care unit (PACU) 
• 
Day of surgery is defined as Day 0 (D0). 
• 
Assessment visit times are defined by D0 and/or T0. 
• 
Baseline value is defined as the last valid measurement prior to the dosing of study 
treatment. 
• 
Change from baseline is defined as post-baseline value minus baseline value. 
• 
The date/time of early termination will be the date/time that the subject confirms they no 
longer want to participate in the study, regardless of whether they decide to withdraw from 
all or only some study procedures and regardless of if they return to the site for 
assessment of wound healing.  
• 
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.  Duration in hours will be calculated as the stop 
date/time of the event minus the start date/time.  Duration in days will be calculated by 
using stop date minus the start date +1 if AE occurs on or after taking study medication.  If 
AE occurs prior to the study medication, then the duration will be calculated by using stop 
date minus the start date.  If reported as ongoing at the time of database lock, the duration 
will be calculated using the date of the last visit or the last date of any AE for the subject in 
the database, whichever is later.   
• 
The number of days in the study is computed as: [Date of study completion or withdrawal 
minus the date of study drug administration] + 1. 
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• 
If duplicate values are obtained at a given visit (e.g., repeated vital sign measurements), 
the last value will be used unless it is noted that the measurement was in error for that 
value. Values that compromise interpretation will not be used in summaries (e.g., values 
that were obtained post-dose will not be summarized as pre-dose values). 
• 
Values that compromise interpretation will not be used in summaries (e.g., values that 
were obtained post-dose will not be summarized as pre-dose values). 
4. SUBJECT POPULATIONS 
4.1 
Analysis Populations 
The following analysis populations are planned for this study:  
• 
The Safety Population will include all subjects who received any part of a dose of study 
treatment.   
• 
The PK Population will include all subjects who receive a full dose of study treatment and 
complete all PK assessments. 
• 
The intent-to-treat (ITT) population will include all subjects who are randomized to study 
treatment. 
Membership in analysis populations will be determined before unblinding. 
Subjects who elect to ET after receiving study treatment and during the inpatient phase of the 
study will be asked to continue with assessments through T96h if they have not elected to 
withdraw from all aspects of study participation.  
All efficacy and safety analyses will be performed using Safety population. PK analyses will be 
performed using PK population.  
4.2 
Disposition of Subjects 
All subjects and the populations for which they qualify will be listed. Subjects who are screened 
and who fail screening or withdraw consent prior to randomization or are randomized but not 
treated will be listed and summarized in the disposition summary table. Subjects who are 
randomized, subject inclusion into each study population, subjects who are treated, subjects who 
complete follow-up as well as subjects who withdraw early from the study and the reason for 
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withdrawal will be summarized by treatment group and overall in the subject disposition summary 
table. 
4.3 
Protocol Deviations 
Deviations are categorized as informed consent procedures, inclusion/exclusion criteria, study 
medication, prohibited medications, study procedures, study drug assignment/treatment, visit or 
assessment time window, missed visit or assessment and/or other. All protocol deviations will be 
captured on case report forms (CRFs) and/or documented in site specific logs throughout the 
study. Deviations will be categorized and classified as major or minor by the project team and the 
medical monitor after database lock but before unbinding and will be discussed in the CSR. 
Subjects with protocol deviations, both minor and major, will be presented in a data listing and will 
be summarized by type of deviation and major/minor classification for all randomized subjects. 
5. DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
5.1 
Demographics and Baseline Characteristics 
Demographic variables include age, sex, race, and ethnicity. Baseline characteristics include 
height (cm), weight (kg), and body mass index (BMI; kg/m2). Demographics and baseline 
characteristics will be summarized overall and by treatment group using the safety population.  
5.2 
Medical/Surgical History 
Medical and Surgical history, as collected at screening, will be coded using the Medical Dictionary 
for Regulatory Activities (MedDRA) version 21.0 to determine system organ class (SOC) and 
preferred term (PT). Medical histories will be presented in a by-subject listing. Any events that 
occur prior to the study procedure will be categorized as medical history. 
5.3 
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 after this time or is ongoing at the time of 
discontinuation/completion is considered concomitant medication/therapy. Prior and concomitant 
medications will be 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 1, 2018. The 
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number and percentage of subjects who take concomitant medications will be summarized by 
drug class and preferred term, overall and by cohort and treatment group, for the safety 
population. All medications and non-medical therapies captured in CRFs will appear in data 
listings. 
6. MEASUREMENTS OF TREATMENT EXPOSURE AND COMPLIANCE 
Because study medication is administered as a single dose at the study center by trained study 
personnel, compliance with respect to study medication will not be calculated. A listing of study 
drug administration and exposure data will be provided. 
After completing the assessments through 96 hours after study medication administration, the 
diary for at-home use will be distributed to the subject to collect pain intensity (twice daily on NRS) 
and pain medication through Day 15. Compliance with home diary use will be evaluated based on 
post-discharge home diary records. Compliance for each subject will be based on the number of 
days the subject participated in the outpatient study period, defined as:  
Compliance (%) =   
(N of non-missing NRS recorded on Diary) 
 
X 100 
(N of Expected NRS from diary) 
 
Where the N of expected NRS records in the diary for each subject is calculated as 2 times the 
number of days the subject participated in the outpatient portion of the study.  The number of days 
of participation will be calculated as the date of the Day 15 visit or the date of the last study visit 
(whichever is earlier) minus the date of discharge. NRS recorded prior to a rescue use will not be 
included in this calculation of compliance. For example, Subject A was discharged on Day 4, if 
this subject discontinues the study on Day 13, then the expected N of NRS records on diary will 
be 18 (2 * (13-4)). Assuming Subject A had 10 NRS available from his/her diary, then compliance 
for this subject would be 55.6% ((10/18) *100). However, if subject A had discontinued the study 
on Day 10 (prior to Day 13), then the expected N of NRS for this subject would be 12 (2 * (10-4)) 
and compliance would be 83.3% ((10/12) *100).  A summary of compliance will be provided 
overall, and by cohort and treatment group. Compliance with recording an NRS prior to rescue in 
the diary will be calculated as the number of NRS recorded prior to taking rescue medications 
divided by the number of rescue medication uses recorded. 
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7. EFFICACY EVALUATION 
7.1 
Handling of Dropouts or Missing Data 
All efforts will be made to minimize missing data. These efforts will include the following: 
• 
Subjects are required to consent to continuous data collection even after discontinuation of 
study medication; 
• 
Data collection will continue after subjects take rescue medication. 
With the procedures above, it is expected that missing data will be minimal. Missing at random is 
expected to be a reasonable assumption for this study.  
For the endpoints of NRS (at rest and/or after ambulation) in this study, NRS values will be 
imputed in the following manner: 
For subjects who take rescue medication, a windowed last pain score carried forward (wLOCF) 
will be used. 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 or other oral opioid is used. 
The last NRS prior to the use of any rescue medication will be used to impute subsequent NRS at 
rest scores for the subsequent protocol-specified time points for measurement of pain intensity 
through an appropriated time window (as specified above) after the time of the dosing of the 
rescue medication. Note: if a pre-rescue NRS assessment occurs at the same time as a 
scheduled assessment, the scheduled NRS will be assumed to happen first, and then the pre-
rescue NRS will be assumed to occur. If an NRS assessment occurs at the same time as the time 
of taking a rescue medication, the NRS will be assumed to be a Pre-rescue medication result. As 
an example, using PO oxycodone, if the NRS time is the same as 4 hours after taking the rescue 
medication (end of imputation period), then NRS will be considered as occurring before the 4 
hours assessment and will be imputed. For example, if a rescue dose is taken at 1pm, all 
protocol-scheduled NRS will be imputed with the appropriate NRS value up to and including 
through 5pm. If multiple doses of rescue medication are taken within a 4-hour period, the pre-
rescue NRS for the first rescue use will be carried forward continuously until 4 hours past the last 
use of rescue falling within the continuous window. For example, if rescue is used at Hour 2.3 and 
Hour 5.1, the pre-rescue NRS at Hour 2.3 will be carried forward till Hour 9.1 (5.1 +4). NRS 
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scores taken after ambulation will be based on reported values and the pre-rescue 4-hour 
imputation rule will not be used.  The scores after ambulation are collected every 12 hours and no 
ambulation NRS score is collected prior to taking rescue medication. Intermittent missing pain 
scores at rest or after ambulation (due to subject sleeping, etc.) will not be imputed, and AUC will 
be calculated based on non-missing values. For subjects who drop out of the study, scheduled 
assessments will first be imputed using the worst prior pain score carried forward (WOCF). Data 
resulting from imputation method described above will be used in the analysis of all endpoints 
derived from NRS, e.g, primary endpoint (Hour 96 NRS at Rest) and key secondary efficacy 
endpoint (AUC(0-96) of NRS at Rest).  
For categorical endpoints of PGE and IGE, assessments imputed for data after a subject 
discontinues from the study will be handled using a WOCF method (worst category available). 
7.2 
Sensitivity Analyses  
The following imputation methods will be performed and analyzed as sensitivity analyses of the 
primary analysis of mean NRS scores at 96 hours: 
• 
For: subjects who drop out of the study prior to Day 15 due to Lack of Efficacy or Adverse 
Events, scheduled assessments to be imputed using worst prior pain score carried 
forward.  All other subjects who drop out will have their last pain score carried forward. 
• 
Regardless ET reasons, pain assessments after dropout to be imputed using LOCF (last 
scheduled non missing pain score prior to dropout 
• 
Replace missing values after discontinuation with the within treatment median of the 
subjects continuing in the study. 
For each of the above, values imputed after use of rescue medication will remain the same as the 
primary analysis.  
7.3 
Assessment Time Windows 
For calculations of all AUC endpoints and use of opioid endpoints, the actual dates/times of the 
assessments will be used in calculations. Thus, while the NRS are intended to be collected at the 
pre-defined protocol scheduled time points (e.g., Hour 0.5, 1, 2, etc.), it is recognized that 
operationally the scores are collected as close to the target times as possible but there is some 
flexibility in terms of the actual times the scores are collected. Thus, to account for this inherent 
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aspect of data collection, the ACTUAL TIMES will be used for the calculation of the AUC. The 
actual times will be based relative to the time of completion of study drug administration. 
Safety assessment summaries will be based on the nominal protocol-specified assessment times.  
7.4 
Efficacy Endpoints 
7.4.1 Primary Efficacy Endpoint 
• 
Time-specific mean NRS pain intensity scores at T96h for CA-008 vs. placebo.  
7.4.2 Key Secondary Efficacy Endpoints 
For the CA-008 vs. placebo comparison, the following are key secondary endpoints (in 
descending order of importance): 
• 
Weighted sum of pain intensity (SPI) assessments = Area Under the Curve (AUC) of the 
NRS current pain intensity scores from T0 to 96h at rest (AUC0 to 96h).  
• 
Time to opioid cessation or freedom (TOF) 
• 
Percentage of subjects who do not require opioids (i.e., opioid free; OF) from T24 to T96: 
OF24 to 96h 
• 
Total opioid consumption (in daily oral morphine equivalents) = OC from T0 to T96h: OC0 to 
96h  
7.4.3 Other Endpoints 
For the CA-008 vs. placebo comparison: 
• 
Using NRS at rest: AUC0 to 120h, AUC24 to 96h, AUC0 to W1 
• 
AUC 0 to 96h (arising), AUC0 to W1 (arising) 
• 
Time-specific mean NRS scores at T48, T72, T96, T120, T144 and T168h 
• 
OC24 to 96h 
• 
OF24 to 96h, OF96h to W1 and OF96h to W2 
• 
The fraction of subjects who rescue at T48, T72 and T96h 
• 
Analgesic consumption from T96h to W1 (AC96h to W1) and AC96h to W2 
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• 
PGE comparing the %age of subjects reporting “poor” + “fair” vs. “good” + “excellent” 
responses, and the %age reporting each category of response at T96h, D8/W1, D15/W2 
and D29/W4 
• 
IGE comparing the %age of those reporting “poor” + “fair” vs. “good” + “excellent” 
responses, and the %age reporting each category at T96h, D8/W1, D15/W2 and D29/W4 
7.5 
Analysis Methods 
7.5.1 NRS Measurements 
The NRS is an 11-point scale with anchors 0 (no pain) and 10 (worst possible pain). NRS will be 
assessed as follows: 
• 
During the inpatient stay, NRS at rest beginning with the PACU admission may be 
assessed once the subject is awake. If the subject is able to provide responses, obtain 
NRS scores at T0.5, 1, 2, 4, 6, 8, 12, 16, 20, 24, and every 4 hours (if awake at time of 
assessment) until discharge from the inpatient unit. Time windows: for T0.5 to T2 (±5 min) 
and from T4 onward (±15 min).  
• 
Pain scores may be skipped between the hours of midnight and 6 a.m., but the subject 
may not miss two consecutive assessments. The T12, T24, T48, T72 and T96h 
assessments must be completed even if the subject is asleep at these times. 
• 
An additional NRS assessment must be obtained prior to rescue medication request (±15 
min). 
• 
During the inpatient stay, starting on postoperative day 1 (after T24) perform the following 
each morning at 0800h (±2h) and each evening at 2000h (±2h): document the NRS at rest 
and on arising. Actual assessment times must be documented. If, however these twice 
daily assessments coincide with timed assessments of NRS at rest, then the time 
assessment at rest is used in place of the twice daily assessments. Resting pain scores 
are performed on the schedule noted above in the first bullet. 
• 
During the outpatient period (after T96h through W2), instruct the patient to document, if 
possible, their NRS scores twice daily at 0800h (±4h) and 2000h (±4h) at rest and on 
arising.  Note that the actual time of these assessments must be documented in the diary 
whenever possible.  Instruct the patient to:  
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• Obtain the morning NRS assessment prior to taking any pain medication or 2 
(±15min) hours after taking any pain medication. 
• Obtain the evening NRS assessment 2 (±15min) hours after taking any pain 
medication. 
7.5.2 Time-specific mean NRS pain intensity scores at T96h (Primary Efficacy Endpoint) and 
other time points 
Missing NRS will be handled as discussed in Section 7.1. 
Mean NRS scores at specific time points will be analyzed using a 1-factor (treatment) analysis of 
variance (ANOVA) model with treatment as the main effect.   Descriptive summaries will be 
presented for each treatment group. In addition, the pain intensity score at Hour 96 and at each 
time point will be analyzed using Wilcoxon sum-rank test for sensitivity.  
7.5.3 AUC 0-96h at Rest (Key Secondary Efficacy Endpoint) and other AUC endpoints  
AUC calculations will be done using the standard trapezoidal rule  
AUC =     ∑
ቀ
𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑖𝑖+𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑖𝑖+1
2
ቁ
𝑥𝑥
𝑖𝑖=0
∗ (𝑇𝑇𝑖𝑖+1 − 𝑇𝑇𝑖𝑖) 
Where:  NRSi = NRS at rest at time i, and (Ti+1 – Ti) is the Time difference in hours between time i 
and time i+1.  
Missing NRS will be handled as discussed in Section 7.1.  AUC values will be analyzed using a 
one factor analysis of variance (ANOVA) with treatment as the main effect.  Descriptive 
summaries (N, median, range) will be presented for each treatment group.  Exact Two-Sided p-
values from Wilcoxon Rank-Sum test comparing treatment group with Placebo (or Pooled 
Placebo) will also be presented.   
Mean NRS scores (in-clinic and diary) will be graphed over time by cohort and treatment group.  
NRS over time by each subject may also be displayed graphically as warranted.  The individual 
NRS and the computed AUC variables will be listed for all individual subjects. 
7.5.4 Time to opioid cessation or freedom (TOF) (Key Secondary Efficacy Endpoint) 
 
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Time to opioid cessation or freedom (TOF) will be defined as the time to the last use of opioid for a 
subject and will be analyzed using Kaplan-Meier techniques.  Number of subjects with event, 
number of subjects censored, median time to OF, and p-values from log-rank test will be 
displayed in a summary table. Subjects not ceasing opioid use before ET, or until End of Study 
(EOS) will be censored at ET or EOS days respectively. TOF starting after T24 and T48 and 
staying opioid free to D29 will also be derived and presented in the same table 
In addition, Kaplan-Meier curves will be presented by treatment group.  
7.5.5 Opioid Free (OF) 24-96h (Key Secondary Efficacy Endpoint) and other timepoints.  
Opioid use is recorded on the rescue medication eCRF from the end of surgery through the D15 
follow up/Early termination (ET). If additional opioids, other than the study rescue medications, 
appear on the concomitant medications page and can be identified, those opioids will also be 
considered.  
The percentage of subjects who do not require opioids (are Opioid Free or OF) during each time 
period will be analyzed using a logistic regression or Chi Square test if there are not enough data 
to support the logistic regression, with treatment group as the main effect. The analysis will 
compare the odds ratios of the proportions of OF subjects between each treatment group and the 
placebo group. A summary of frequencies as well as odds ratio, 95% confidence intervals and p-
values will be presented. 
In addition to other specified timepoints, the proportion of subjects who are Opioid Free after T24 
through D29, and the proportion of subjects who are OF after T48 through D29 will also be 
derived and presented. 
7.5.6 Total Opioid Consumption (OC) in Daily Oral Morphine equivalents 0-96h (Key Secondary 
Efficacy Endpoint) and other timepoints 
The amount of opioids taken as rescue will be calculated using the rescue medication page of the 
eCRF. If additional opioids, other than the study rescue medications, appear on the concomitant 
medications page and can be identified, those opioids will also be included (in terms of morphine 
equivalents) in the total consumed. Table 3 will be used to calculate the morphine equivalent dose 
(MED) for each medication. The total opioid consumption for each day for each subject will be 
calculated as the sum of the MEDs of all the medications taken on that day. For example, if a 
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subject takes 5 MED morphine on Day 1 and Day 2, and 10 MED of Oxycodone on Day 2, the 
total consumption for Day 1 is 5 MED, and the total consumption for Day 2 is 15 MED. Subjects 
that take no opioids on a day will have a total opioid consumption value of zero for that day. 
Table 3 
Equianalgesic Conversion Table 
 
Opioid (Doses in mg) 
Conversion Factor 
IV Fentanyl 
0.3 
PO Hydrocodone 
1 
PO Hydromorphone 
4 
PO Morphine 
1 
PO Oxycodone 
1.5 
PO Tramadol 
0.1 
Multiply the opioid dose by the conversion factor = oral morphine equivalent 
dose (MED):  
e.g., PO oxycodone 5 mg X 1.5 = 7.5 mg MED 
or 
IV fentanyl 25 mcg X 0.3 = 7.5 mg MED 
 
Total opioid consumption will be calculated for 0-96 hours (OC0 to 96h) and 24-96 hrs (OC24 to 96h). 
An ANOVA with treatment arm as the main effect will be performed. A separate summary 
containing only subjects that have taken at least one dose of rescue will be performed if 
warranted. 
7.5.7   Percentage of Subjects who Rescue at T48 and other timepoints 
The percentage of subjects who rescue at T48, T72 and T96 hours will be calculated as the 
number of subjects who have taken at least one dose of rescue prior to the specified timepoint.  
The percentage of subjects who rescue during each specific time period will be analyzed using a 
Chi Square test.  A summary of frequencies as well as odds ratio, 95% confidence intervals and 
p-values will be presented. (OC) 
7.5.8 PGE and IGE 
The proportions of subjects in each individual PGE or IGE category will be summarized by 
treatment group and analyzed using the Cochran-Mantel-Haenszel (CMH) mean score test (using 
equally spaced scores) at each time point they are collected to compare treatments across the 4 
levels of outcomes (poor, fair, good, or excellent). In addition, Fisher’s exact test will be performed 
to compare treatments across 2 levels of outcomes (Poor/Fair versus Good/excellent). 
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Individual PGE and IGE scores will be listed. 
8. SAFETY EVALUATION 
8.1 
Overview of Safety Analysis Methods 
All safety outcomes will be summarized using the safety population.  No formal statistical 
comparisons will be performed for safety outcomes. Safety outcomes include: 
• 
Incidence of spontaneous reported treatment-emergent adverse events (TEAEs) or 
serious adverse events (SAEs) 
• 
Physical examination (PE) 
• 
Vital signs 
• 
Surgical site assessments 
• 
Neurosensory testing near the incision 
• 
Rebound or worsening pain  
• 
ECG 
• 
Clinical laboratory test results 
8.2 
Adverse Events and SAEs 
All AEs will be listed, but only TEAEs will be summarized. 
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 Day 29 
or Early Termination, whichever occurs first. 
• 
Serious AEs with onset on the date of treatment with the study drug through 30 days after 
Day 29 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 Day 29 or Early Termination, whichever 
occurs first.  
For evaluation of causal relatedness to treatment, the categories are probably related, possibly 
related or unlikely related. For categorization in the summary tables, AEs designated as probably 
or possibly related will be considered related. 
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For the evaluation of event severity terms, the criteria are mild, moderate, severe or potentially 
life-threatening. In addition to a listing of all TEAEs, treatment related TEAEs, serious TEAEs, 
Deaths, and TEAEs leading to premature discontinuation from the study will be provided. 
An overall summary will be prepared giving for each treatment group and overall, both the number 
of TEAEs, and the number of subjects with at least one TEAEs, as well as SAEs, treatment 
related TEAEs and TEAEs leading to premature discontinuation from study.  
The number of subjects with AEs will be summarized for each  treatment group and overall by 
SOC and PT sorted in alphabetically by SOC, and then by PT within SOC. These summaries will 
be given by cohort and treatment in separate tables for each of the following TEAE event sets: 
• 
All events 
• 
Treatment related events 
• 
Serious events 
• 
Events leading to premature discontinuation from study 
• 
Events by maximum severity 
• 
Events by Relationship to Study Drug 
If a given subject experiences a TEAE that maps to the same PT/SOC more than once, the 
subject will be counted only once for the SOC/PT at the greatest severity (i.e., mild, moderate, or 
severe) and causality (i.e., related). 
Duration of a TEAE lasting more than 24 hours will be computed in days as the stop date of the 
event minus the start date plus 1 and will be reported in days. TEAEs lasting less than 24 hours 
will be computed as stop date/time minus start date/time and reported in hours. If reported as 
ongoing at the time of database lock, the stop date is defined as the date of the last visit or the 
last date of any event for the subject in the database, whichever is later. 
If a TEAE is considered resolved, but the stop date is missing, the last day of the month will be 
imputed if the month and year are available. If only the year is available, and the year is the same 
as the year of the last visit, the stop date will be the latest of the last visit date or latest event for 
the subject in the database. 
If the year of the event is prior to the year of the last treatment, the end day and month will be set 
to 31 December. 
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For missing or partial start and stop dates/times, the most conservative imputation will be used 
(AEs will be assumed to be temporally related to the study medication). Table 4 will be used to 
impute any missing dates/times: 
 
 
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Table 4 
Table of Imputation Rules for Missing AE Start Dates 
 
 
Missing Date 
Portion 
Prior to 
Treatment 
Same as Treatment 
Start Date 
After Treatment Start 
Date 
Day 
Month and Year < 
Month and Year of 
Study treatment: 
 
Start Day = 1 
Stop Day=last day of 
the month 
Month and Year = 
Month and Year of 
Study treatment: 
 
Start Day = Day of first 
treatment 
Stop Day= last day of 
the month 
Month and Year > 
Month and Year of 
Study Treatment: 
 
Start Day = 1 
Stop Day=last day of 
the month 
Day and Month 
Define Day as 
above, then: 
Year < Year of first 
treatment: 
 
Start Month = July 
Stop Month = Dec 
Year = Year of study 
treatment: 
Start Month = Month of 
study treatment 
Stop Month = Dec 
Year > Year of study 
treatment: 
 
Start Month = January 
Stop Month = Dec 
Day, Month, and 
Year 
 
To be conservative, completely missing start dates will be imputed using the 
date of study treatment, Missing end dates will be imputed using date of last 
study contact with the subject 
Time 
Missing start times will be imputed as 00:01 
Missing stop times will be imputed as 23:59 
 
After following these imputation rules, if the start date/time is imputed as a date after the end 
date/time, the start date/time will be set to the end date/time to provide a positive duration for the 
event incidence.   
Missing assessments for AE study medication relationship or severity will be analyzed as related 
or severe respectively. No other imputation is planned for safety data. 
8.3 
Physical Examination  
A complete medical history and physical examination including all major body systems will be 
performed at Screening.  In addition, a focused interim medical history and targeted physical 
examination will be performed prior to surgery (if not done on D-1), and to capture changes after 
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Surgery, at 96 hours (± 4 hours) after the administration of study medication, but prior to 
discharge, and Days 8, 15 and 29/ET after the administration of study medication.  
Abnormal or clinically significant physical exam will be recorded as AEs. Physical examination 
results will be listed for individual subjects.  
8.4 
Vital Signs 
Vital signs results including blood pressure (systolic and diastolic; mmHg), heart rate (beats per 
minute), respiration rate (breaths/min), and temperature will be listed for individual subjects.  
Baseline for vital signs measurements will be defined as the last evaluation before dosing with 
study medication. Summary statistics, including change from baseline, will be determined for each 
measure and will be summarized by treatment and time point. 
8.5 
Surgical Site Assessments and Rebound (or Worsening) Pain Assessments 
Surgical sites will be assessed at 48 hours (±2 hours) and 96 hours (±4 hours after study 
medication administration but prior to discharge from the inpatient unit) and then as an outpatient 
on Days 8, 15 and 29. The investigator will evaluate their satisfaction with the healing of the 
wound 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). In addition, subjects will report 
whether they have noted any worsening pain (rebound pain; Y/N) at the surgical site since the 
prior visit at Days 8, 15 and/or 29.  
All data will be presented in data listings. Results of surgical site assessments and the number of 
subjects with rebound pain will be summarized descriptively by treatment and time point. 
8.6 
Neurosensory Test 
Neurosensory testing of the area proximal to the surgical incision approximately 3 cm from the 
incision will be performed at Screening visit, 48 hours (±2 hours), 96 hours (±4 hours, but prior to 
discharge) and Day 8, Day 15 and Day 29 after the administration of study medication or if the 
subject terminates early, at that time if allowed. 
The neurosensory assessment results will be listed and the number of subjects in each response 
will be summarized descriptively by treatment group and time point for each wound (cephalad or 
caudad). 
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8.7 
ECG 
ECG examination will be assessed at screening and 24 hours (±2 hours) after study medication 
administration.  
Number of subjects with abnormal results will be summarized by treatment and time point.  All 
ECG data will be listed. 
8.8 
Clinical Laboratory Test Results 
Clinical laboratory tests (chemistry, hematology, coagulation and urinalysis) will be collected at 
screening and before discharge from the inpatient unit (T96h). All results will be listed. For each 
lab test, the raw value and change from screening will be summarized by treatment group. 
Each clinical laboratory test will be defined by the clinical laboratory to be “Low”, “Normal”, or 
“High”, according to the normal reference range from the clinical laboratory. 
The number and percentage of subjects who have a shift from within to outside the normal 
reference range from screening to T96h will be summarized for overall, and by cohort and 
treatment. 
8.9 
Drugs of Abuse and Alcohol Screens, Pregnancy Test 
Pregnancy (for female subjects of childbearing potential), urine drug screen and alcohol (breath or 
saliva) tests will be performed at screening and pre-surgery.  
Results will be listed for individual subjects. Each test result will be defined to be “negative” or 
“positive”. 
8.10 Subject Pain Assessment Training and Surgery Details 
Pain assessment training will be provided during screening. Subjects will re-watch video prior to 
surgery. Patient pain assessment training and surgery details will be documented in CRFs and 
will be listed for each subject. 
9. PHARMACOKINETIC EVALUATION 
The time points for PK whole blood collections will be at baseline (from Check-in and up to 30 min 
prior to surgery), 5, 10, 15, 30, 45 minutes, and at hours 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, 24, 30, 36 
and 48 (for a total of 20 samples) after the end of study treatment administration.  
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Actual sampling times will be used to calculate plasma-derived PK parameters. Full details of PK 
endpoints/analyses will be described in a separate PK Analysis plan.  
10. OTHER ANALYSES 
N/A 
11. INTERIM ANALYSES  
N/A 
12. REFERENCES 
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.  
Guidance for Industry (2014) Analgesic Indications:  Developing Drug and Biological Products -  
Draft Guidance.  Department of Health and Human Services:  Food and Drug Administration.  
Center for Drug Evaluation and Research (CDER) February 2014 Clinical/Medical. 
13. APPENDICES 
13.1 Planned Tables, Figures and Listings 
13.1.1 Tables 
Table 14.1.1 
All Subjects 
Summary of Subject Disposition 
Table 14.1.2 
Randomized 
Subjects 
Summary of Protocol Deviations 
Table 14.1.3 
Safety 
Population 
Summary of Demographics and Baseline Characteristics 
Table 14.1.4 
Safety 
Population 
Summary of Concomitant Medications by ATC Class and 
Preferred Term 
Table 14.1.5 
Safety 
Population 
Summary of Subject NRS and NRS at Rescue Diary Compliance 
Table 14.2.1.1 
Safety 
Population 
ANOVA Analysis of Hour 96 NRS at Rest – WOCF (Primary Analysis) 
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Table 14.2.1.2 
Safety 
Population 
Wilcoxon Analysis of Hour 96 NRS at Rest – WOCF (Sensitivity 
Analysis) 
Table 14.2.1.3 
Safety 
Population 
ANOVA Analysis of Hour 96 NRS at Rest – WOCF and LOCF 
(Sensitivity Analysis) 
Table 14.2.1.4 
Safety 
Population 
ANOVA Analysis of Hour 96 NRS at Rest – LOCF (Sensitivity 
Analysis) 
Table 14.2.1.5 
Safety 
Population 
ANOVA Analysis of Hour 96 NRS at Rest – Median (Sensitivity 
Analysis) 
Table 14.2.2.1 
Safety 
Population 
ANOVA Analysis of NRS at Rest by Hour  
Table 14.2.2.2 
Safety 
Population 
ANOVA Analysis of NRS at Rest by Morning/Night  
Table 14.2.2.3 
Safety 
Population 
Wilcoxon Analysis of NRS at Rest by Hour 
Table 14.2.2.4 
Safety 
Population  
Wilcoxon Analysis of NRS at Rest by Morning/Night 
Table 14.2.3.1 
Safety 
Population 
ANOVA Analysis of AUC (0-96) NRS at Rest – WOCF (Key 
Secondary Efficacy Analysis) 
Table 14.2.3.2 
Safety 
Population 
Wilcoxon Analysis of AUC (0-96) NRS at Rest – WOCF  
Table 14.2.3.3 
Safety 
Population 
ANOVA Analysis of AUC over Various Time Periods NRS at Rest – 
WOCF  
Table 14.2.3.4 
Safety 
Population 
ANOVA Analysis of AUC over Various Time Periods upon Arising - 
WOCF 
Table 14.2.4 
Safety 
Population 
Log-Rank Analysis of Time to opioid cessation or freedom (TOF) (Key 
Secondary Efficacy Analysis) 
Table 14.2.5 
Safety 
Population 
Logistic Analysis of Proportion of Subjects Who Are Opioid Free at 
Various Time Periods (Key and Exploratory Secondary Efficacy 
Analysis) 
Table 14.2.6 
Safety 
Population 
Logistic Analysis of Proportion of Subjects Who Rescue at Various 
Time Periods 
Table 14.2.7 
Safety 
Population 
ANOVA Analysis of Opioid Consumption (in Morphine Equivalents) 
(Key Secondary and Exploratory Efficacy Analysis) 
Table 14.2.8 
Safety 
Population 
CMH Analysis of Patient Global Evaluation at T96h and Other Time 
Periods 
Table 14.2.9 
Safety 
Population 
CMH Analysis of Investigator Global Evaluation at T96h and Other 
Time Periods 
Table 14.3.1 
Safety 
Population 
Overall Summary of Treatment-Emergent Adverse Events (TEAEs) 
Table 14.3.1.1 
Safety 
Population 
Summary of Treatment-Emergent Adverse Events (TEAEs) by System 
organ Class and Preferred Term 
Table 14.3.1.2 
Safety 
Population 
Summary of Treatment Related Treatment-Emergent Adverse Events 
(TEAEs) by System organ Class and Preferred Term 
Table 14.3.1.3 
Safety 
Population 
Summary of Serious Adverse Events by System organ Class and 
Preferred Term 
Table 14.3.1.4 
Safety 
Population 
Summary of Treatment-Emergent Adverse Events (TEAEs) Leading to 
Study Discontinuation by System organ Class and Preferred Term 
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Table 14.3.1.5 
Safety 
Population 
Summary of Treatment-Emergent Adverse Events (TEAEs) by System 
organ Class, Preferred Term and Severity 
Table 14.3.1.6 
Safety 
Population 
Summary of Treatment-Emergent Adverse Events (TEAEs) by System 
organ Class, Preferred Term and Relationship to Study Drug 
Table 14.3.2.1 
Safety 
Population 
Summary of Chemistry Laboratory Tests: Results and Change from 
Baseline 
Table 14.3.2.2 
Safety 
Population 
Summary of Chemistry Laboratory Tests: Shift from Baseline 
Table 14.3.3.1 
Safety 
Population 
Summary of Coagulation Laboratory Tests: Results and Change from 
Baseline 
Table 14.3.3.2 
Safety 
Population 
Summary of Coagulation Laboratory Tests: Shift from Baseline 
Table 14.3.4.1 
Safety 
Population 
Summary of Hematology Laboratory Tests: Results and Change from 
Baseline 
Table 14.3.4.2 
Safety 
Population 
Summary of Hematology Laboratory Tests: Shift from Baseline 
Table 14.3.5.1 
Safety 
Population 
Summary of Urinalysis Laboratory Tests: Results and Change from 
Baseline 
Table 14.3.5.2 
Safety 
Population 
Summary of Urinalysis Laboratory Tests: Shift from Baseline 
Table 14.3.6 
Safety 
Population 
Summary of Vital Signs: Results and Change from Baseline 
Table 14.3.7 
Safety 
Population 
Summary of Surgical Site Assessment 
Table 14.3.8 
Safety 
Population 
Summary of Rebound Pain Assessment 
Table 14.3.9.1 
Safety 
Population 
Summary of Neurosensory Exam – Cephalad to Wound 
Table 14.3.9.2 
Safety 
Population 
Summary of Neurosensory Exam – Caudad to Wound 
Table 14.3.10 
Safety 
Population 
Summary of ECG Exam Abnormal Findings 
 
 
 
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13.1.2 Figures 
Figure 14.2.1 
Safety Population 
Mean NRS scores over time (in-clinic and diary) by Treatment 
Group 
Figure 14.2.2 
Safety Population 
NRS over time for each subject by Cohort 
 
   
 
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13.1.3 Listings 
Listing 16.2.1 
All Subjects 
Randomization and Study Population 
Listing 16.2.2 
All Subjects 
Informed Consent and Re-Consent 
Listing 16.2.3 
All Subjects 
Eligibility 
Listing 16.2.4 
All Subjects 
Protocol Deviations 
Listing 16.2.5 
All Subjects 
Subject disposition/ Early Termination 
Listing 16.2.6 
All Randomized Subjects 
Demographics and Baseline Characteristics 
Listing 16.2.7 
All Randomized Subjects 
Medical/ Surgical History 
Listing 16.2.8.1 
All Randomized Subjects 
Prior and Concomitant Medications 
Listing 16.2.8.2 
All Randomized Subjects 
Rescue Medication Administration 
Listing 16.2.8.3 
All Randomized Subjects 
Non-Medication Therapies 
Listing 16.2.9 
All Randomized Subjects 
Surgery 
Listing 16.2.10 
All Randomized Subjects 
Study Drug Administration, Pain Assessment Training 
and Discharge 
Listing 16.2.11 
All Randomized Subjects 
Subject NRS and NRS at Rescue Diary Compliance 
Listing 16.2.12.1 
All Randomized Subjects 
Pain Intensity Assessment (NRS at Rest) 
Listing 16.2.12.2 
All Randomized Subjects 
Pain Intensity Assessment (NRS on Arising) 
Listing 16.2.13 
All Randomized Subjects 
List of Efficacy Endpoints 
Listing 16.2.14 
All Randomized Subjects 
Patient Global Evaluation (PGE) 
Listing 16.2.15 
All Randomized Subjects 
Investigator Global Evaluation (IGE) 
Listing 16.2.16.1 
All Randomized Subjects 
Adverse Events 
Listing 16.2.16.2 
All Randomized Subjects 
Serious Adverse Events 
Listing 16.2.16.3 
All Randomized Subjects 
Treatment Related Adverse Events 
Listing 16.2.16.4 
All Randomized Subjects 
Adverse Events Leading to Study Discontinuation 
Listing 16.2.17.1 
All Randomized Subjects 
Chemistry Laboratory Test Results 
Listing 16.2.17.2 
All Randomized Subjects 
Coagulation Laboratory Test Results  
Listing 16.2.17.3 
All Randomized Subjects 
Hematology Laboratory Test Results 
Listing 16.2.17.4 
All Randomized Subjects 
Urinalysis Laboratory Test Results 
Listing 16.2.18 
All Randomized Subjects 
Vital Signs 
Listing 16.2.19 
All Randomized Subjects 
Alcohol Breath and Urine Drug Screen Tests 
Listing 16.2.20 
All Randomized Subjects 
Pregnancy Test 
Listing 16.2.21 
All Randomized Subjects 
Physical Examination and Targeted Physical Exam 
Assessment 
Listing 16.2.22 
All Randomized Subjects 
Surgical Site Assessment and Rebound Pain 
Assessment 
Listing 16.2.23 
All Randomized Subjects 
Neurosensory Exam 
Listing 16.2.24 
All Randomized Subjects 
12-Lead Electrocardiogram 
Listing 16.2.25 
PK Population 
Pharmacokinetic (PK) Concentration Data 
 
 
 
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14. DOCUMENT HISTORY 
 
Version 
# 
Summary of Changes 
Section Changed 
Date 
1.0 
Initial document released 
NA 
24Apr2019 
 
 
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