Clinical trial NCT03885596
Conditions: Pain
Sponsor: Concentric Analgesics
Start date: 2019-03-25; Completion date: 2019-10-22
Enrollment: 36 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
A Phase 2, open-label study of CA-008 to evaluate post-surgical pain control with CA-008.

Detailed description:
This is a Phase 2, single-center, open-label study evaluating a single dose of CA-008 4.2 mg administered with different standard-of-care anesthetic regimens during an elective unilateral transpositional first metatarsal osteotomy for the correction of hallux valgus deformity (bunionectomy).

Arms: arm 1: CA-008 4.2 mg reconstituted in saline

All subjects received monitored anesthesia care (MAC) and a Mayo block followed by a sciatic (popliteal) nerve block. arm 2: CA-008 4.2 mg reconstituted in saline

All subjects received monitored anesthesia care (MAC) and a Mayo block. arm 3: CA-008 4.2 mg reconstituted in saline

All subjects received monitored anesthesia care (MAC) and a Mayo block. arm 4: 106 mg \[8 mL of the 133 mg/10 mL suspension\] only

All subjects received monitored anesthesia care (MAC) and a Mayo block.
Interventions: intervention 1: CA-008 intervention 2: Ketorolac intervention 3: Acetaminophen IV intervention 4: Fentanyl intervention 5: Bupivacaine Hydrochloride intervention 6: Lidocaine HCl intervention 7: Celecoxib intervention 8: Acetaminophen Oral intervention 9: Lidocaine Hydrochloride intervention 10: Exparel
Intervention descriptions: intervention 1: Drug: CA-008 4.2 mg reconstituted in saline intervention 2: 30 mg IV at the onset of anesthesia intervention 3: 1 g at the onset of anesthesia intervention 4: 100 mcg IV fentanyl administered at the onset of anesthesia and additional 50 mcg near the end of surgery intervention 5: 0.25% 30 mL (75 mg) prior to surgery intervention 6: 1.5% 12 mL at the end of surgery intervention 7: 200 mg PO bid each day postoperative intervention 8: 1 g postoperative intervention 9: 2% 15 mL at the end of surgery intervention 10: Bupivacaine liposome injection suspension

Protocol documents:
Prot_000.pdf: 
 
 
 
 
 
OFFICIAL TITLE: 
An Open-Label Study of Intraoperative CA-008 Administration in Subjects Undergoing 
Bunionectomy 
 
 
NCT NUMBER: 
03885596 
 
DOCUMENT DATE: 
02May2019 


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Clinical Trial Protocol                                                          
Version 4.0 
02 May 2019 
 
Version 3.0: 03 April 2019 
Version 2.0: 13 March 2019 
Version 1.0: 08 March 2019 
 
An Open-Label Study of Intraoperative CA-008 Administration in 
Subjects Undergoing Bunionectomy 
Investigational Product: CA-008 by Injection/Instillation 
IND: 129-114 
 
 
 
Concentric Analgesics, Inc. 
 
 
 
 
 
 
CONFIDENTIAL 
This protocol is the property of Concentric Analgesics, Inc. 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 Analgesics, 
Inc. 
 




Version: 02 May 2019 
 
Page 2 of 73 
SIGNATURE PAGE
Approved by: 
_____________________________________          
_______________________
Nancy Wu, MBA 
Date 
Head of Clinical Operations 
Concentric Analgesics, Inc. 
_____________________________________          
_______________________ 
Mike A Royal, MD JD MBA 
Date 
Chief Medical Officer 
Concentric Analgesics, Inc. 


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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 
Caitlyn Avila 
 
Project Manager 
cavila@locuscr.com 
530-902-3070 
CRO Medical 
Monitors 
Primary: Jon L. Ruckle, MD, CPI MedicalMonitorCA-PS-
205@Lotuscr.com 
808-349-9812 
Secondary: Royce Morrison, MD 
MedicalMonitorCA-PS-
205@Lotuscr.com 
206-799-7386 
 
 
 
 


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TABLE OF CHANGES 
 
Changes from Protocol version 3.0 to 4.0 
Rationale 
Addition of two more cohorts of 9 subjects each 
To explore CA-008 dosing in different standard of care 
settings and to evaluate Exparel in a similar setting 
Numerous text changes to accommodate the addition 
of the two cohorts and to provide Exparel instructions 
To provide clarity in protocol instructions with the 
addition of two cohorts, remove redundant text and 
improve clarity of language 
 
 
Changes from Protocol version 2.0 to 3.0 
Rationale 
Addition of stopping rules per Memo to File (MTF) 
dated 20 March 2019 
Per FDA request to continue use of stopping rule. 
Modification of Mayo block instructions prior to start 
of cohort 2 per MTF 26 March:  
• 
Previous instructions: A Mayo block using 
bupivacaine HCl 0.25% 30 mL prior to surgery 
and lidocaine HCl 1.5% 12 mL at the end of 
surgery 
• 
New instructions: A Mayo block prior to 
surgery 30 mL of a mixture of bupivacaine 
HCL 0.5% 15 mL combined with lidocaine HCl 
2% 15 mL resulting in bupivacaine 0.25% (75 
mg) and lidocaine 1% (300 mg). 
To provide adequate time for the Mayo block to set up 
and avoid a second infiltration post-surgery, lidocaine 
was added to the block at the outset and not used 
later on after CA-008 dosing. 
Use of monitored anesthesia care (as defined by ASA) 
rather than the term “sedation”. 
To avoid confusion over anesthesia conduct. 
Minor changes were made to remove confusing 
language or make text more readable. 
Reduce confusion or the potential for 
misinterpretation 
 
 
 
 
 
 


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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-205 
IND#: 
129-114 
Study Title: 
An Open-Label Study of Intraoperative CA-008 Administration in Subjects Undergoing 
Bunionectomy 
Investigational 
Product: 
CA-008  
Planned Study 
Center(s): 
1 US site 
Indication: 
Acute postsurgical pain 
Sample Size: 
N = 36 (9 per treatment cohort)  
Population: 
Adults ages 18 to 65 years, inclusive, who are planning to undergo an elective unilateral 
Bunionectomy (BUNX) and otherwise meet eligibility criteria may be considered for 
enrollment into the study. 
Study Duration: 
Up to 76 days: Screening period from 45 days prior to surgery (D-45) to D29±2 Study 
Completion Visit.  Unscheduled visits or visits after D29 may be necessary to assess 
ongoing safety issues or to follow an event to resolution or to establishment of a new 
baseline.   
Note that D0 is the day of surgery and T0hNRS is the time of admission to the post-
anesthesia care unit (PACU). 
Study Design: 
 
This is a Phase 2, single-center, open-label study of 3 cohorts of 9 subjects each 
evaluating a single dose of CA-008 4.2 mg administered during an elective unilateral 
transpositional first metatarsal osteotomy for the correction of hallux valgus deformity 
(bunionectomy or BUNX) under monitored anesthesia care (MAC) and Mayo field block 
with or without a supplemental popliteal block with bupivacaine hydrochloride (HCl) and 
lidocaine HCl.   
Additionally, a 4th cohort of 9 subjects will receive Exparel® (bupivacaine liposome 
injectable suspension; Pacira Pharmaceuticals, Inc.) under monitored anesthesia care 
(MAC) and Mayo field block with bupivacaine HCl and lidocaine HCl. 


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The study will be conducted in two parts: 
• 
Inpatient period which continues to T72hNRS  
• 
Outpatient period which begins on discharge from the inpatient unit through 
follow up visits to D29±2 after surgery (cohorts 1-3) or to D8±1 (cohort 4) 
Study 
Objectives: 
Primary Objective: 
To evaluate different standard of care anesthetic regimens on CA-008 administration in 
subjects undergoing an elective BUNX.  
 
Secondary Objective 
To confirm the safety and efficacy of CA-008 with different standard of care anesthetic 
regimens in subjects undergoing an elective BUNX. 
Exploratory Objective 
To evaluate Exparel’s performance in subjects undergoing an elective BUNX under a 
standard of care anesthetic regimen. 
CA-008 Dosing 
Schedule and 
Administration 
(Cohorts 1-3): 
CA-008 (4.2 mg in 14 mL) will be injected/instilled intraoperatively into the soft tissues 
and osteotomy surgical site as follows: 
• 
Instill 2 mL at cut bone sites 
• 
Prior to capsule closure, infiltrate the deep soft tissue and area proximal to the 
capsule with a total of 9 mL (approximately 2.25 mL into each quadrant 
circumferentially) 
• 
Close the capsule, but using a small gauge catheter (or needle) infiltrate 2 mL into 
the closed capsule space    
• 
Prior to closure of the subcutaneous tissues and skin, instill 1 mL to coat all 
exposed surfaces 
Exparel Dosing 
(Cohort 4) 
Exparel 106 mg (8 mL of the 133 mg/10 mL suspension) will be infiltrated 
intraoperatively into the soft tissues and osteotomy surgical site prior to closure as 
follows: 
• 
Infiltrate 7 mL into the tissues surrounding the osteotomy  
• 
Infiltrate 1 mL into the subcutaneous tissues 
See Exparel full prescribing information for detailed administration instructions:  
https://www.exparel.com/hcp/prescriptioninformation.pdf (as revised 11/2018; Pacira 
Pharmaceuticals, Inc.). 
Anesthesia and 
Intraoperative 
Analgesia: 
The surgery is to be performed under MAC anesthesia (Appendix 17.H) supplemented 
with one of two different standard of care regimens to produce surgical anesthesia.  In 
both regimens, intraoperative analgesia will include IV ketorolac 30 mg and IV 
acetaminophen 1 g at the onset of anesthesia. 
At least 100 mcg of IV fentanyl should be administered onset of anesthesia and an 
additional 50 mcg near the end of surgery if not contraindicated for any safety issue.  The 
anesthesiologist is free to administer additional IV fentanyl doses per anesthesia 
discretion. 
The systemic anesthesia medication doses detailed in the current protocol (including but 
not limited to fentanyl, ketorolac and acetaminophen) are suggested guidelines to be 


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followed by the anesthesiologist caring for the subject. The actual doses given are at the 
discretion of the anesthesiologist based on the clinical status of the subject.  With respect 
to non-analgesic medications, the anesthesiologist is free to use clinical discretion on the 
choice and dose. 
Popliteal and 
Mayo Block 
Instructions 
For the Mayo block, inject just distal to the base of the 1st metatarsal to provide coverage 
of each quadrant paying particular attention to the space between the 1st and 2nd 
metatarsals). 
In the 1st cohort of 9 subjects, prior to surgical incision (except as noted), perform the 
following local anesthetic nerve blocks: 
• 
A popliteal block performed under ultrasound guidance using bupivacaine HCl 
0.25% 30 mL (75 mg) 
• 
A Mayo block using bupivacaine HCl 0.25% 30 mL (75 mg) also prior to surgery 
and lidocaine HCl 1.5% 12 mL at the end of surgery 
In the 2nd cohort of 9 subjects perform the following: 
• 
A Mayo block alone using bupivacaine HCl 0.5% 15 mL combined with 
lidocaine HCl 2% 15 mL prior to surgery  
In the 3rd and 4th cohorts of 9 subjects in each perform the following: 
• 
A Mayo block alone using bupivacaine HCl 0.5% 10 mL combined with 
lidocaine HCl 2% 20 mL prior to surgery  
• 
CA-008 or Exparel must be injected no sooner than 20 minutes after the Mayo 
block 
• 
Total bupivacaine HCl equivalent dose 176.8 mg: 121.8 mg from Exparel and 55 
mg from bupivacaine HCl 
Postsurgical 
Care: 
Subjects will be monitored after surgery (through T72hNRS hour) at the trial site as an 
inpatient.  Safety and efficacy evaluations will be performed.  Subjects will be required to 
meet standard pre-specified criteria for discharge from the unit.  Subjects will continue to 
be monitored as an outpatient after discharge for safety and efficacy assessments. 
Inpatient 
Multimodal 
Analgesia: 
After recovery from surgery, subjects in cohorts 1 and 2 will be given:  
• 
celecoxib (Celebrex®) 200 mg PO bid each day while an inpatient, and  
• 
acetaminophen 1 g PO (2 doses on the day of surgery starting at 6±2h after 
surgery and again at 12±2h after surgery) and t.i.d. each day thereafter while an 
inpatient 
After recovery from surgery, subjects in cohorts 3 and 4 will be given no additional non-
opioid analgesics.   
After discharge from the inpatient unit, non-opioid analgesics may be recommended by 
the Principal Investigator for subject use as needed. 
Rescue 
Medication 
during the 
Inpatient 
The following rescue medication is available to subjects and may be administered for any 
moderate to severe breakthrough pain at any time during the inpatient period: 
• 
During the PACU stay (90 minutes, if possible, to ensure that pain is well 
controlled), administer IV fentanyl 25-50 mcg q5-10 min prn moderate (≥ 4) or 
severe pain (≥ 7) as reported by subjects using the 0 to 10 numerical rating scale 


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Period: 
of current pain intensity (NRS) 
• 
After PACU discharge to T24h, administer PO oxycodone 5 mg for moderate or 
10 mg for severe pain prn q2h 
• 
After 24h, administer PO oxycodone 5 mg for moderate or 10 mg for severe pain 
prn q4h 
Subjects will be encouraged to rescue only for moderate-to-severe pain scores, however 
rescue may be requested at any time and medication will be provided when requested per 
protocol timing. 
Documentation of time of rescue medication request or administration should be based on 
T0hNRS (defined as the time of PACU admission). 
Analgesia 
during 
Outpatient 
Period: 
 
Once discharged from the inpatient unit, all study participants will be instructed to take a 
combination of OTC analgesics (NSAID and acetaminophen) at an appropriate dose per 
Investigator medical judgment to manage any residual or breakthrough postsurgical pain 
(note that these medications will not be provided by the sponsor): 
• 
NSAID (e.g., ibuprofen 400 - 600 mg prn up to qid [Advil® or Motrin®] or 
naproxen 220 mg prn up to tid [Aleve®]) or other options per Investigator 
discretion and 
• 
Acetaminophen 1-2 tablets (325 mg or 500 mg) prn but no more than 1g for a 
single dose and doses may not be taken more frequently than q4h with a daily 
maximum acetaminophen dose of 3g. 
If a subject is still requiring opioid rescue in the 6h prior to discharge from the inpatient 
unit, then at discharge prescribe no more than 9 tablets (1 PO tid prn) of oxycodone 5 mg 
for the initial outpatient period.   Document this prescription and number of tablets 
prescribed, and if any repeat prescription is required per investigator discretion, 
document the date of such prescription and number of tablets prescribed. 
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. 
Stopping Rules: 
Enrollment in the study will be paused for evaluation of specific TEAEs after CA-008 
dosing (stopping rules will not be enforced during cohort 4): 
• 
If one or more subjects experience any grade 4 (or higher) related TEAE (see 
table below) or 
• 
If 2 or more subjects experience the same grade 3 related TEAE (see table below) 


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Inclusion 
Criteria: 
In order to participate, subjects must meet all inclusion criteria: 
1. 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, 2 or 3 (Appendix17.A). 
2. Plan to undergo an elective primary unilateral first metatarsal Bunionectomy 
repair, without collateral procedure or additional surgeries, to be performed under 
monitored anesthesia care (MAC) with a local block. 
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 of child-bearing potential (FCBP), must meet all of the following: 
a. Not be pregnant (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. 
5. Have a body mass index ≤ 36 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 


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communicate meaningfully in English 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, other than bunion-related pain, 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 HCl, Exparel, fentanyl, ketorolac, lidocaine 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 an existing arrhythmia, left 
bundle branch block, myocardial infarction within the prior 6 months, clinically 
significant abnormal ECG or clinical laboratory test value, 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 4) per day for greater than 4 out of 7 days per week over a 
one-month period within 6 months screening. 
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 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. If the subject is taking centrally- and/or peripherally-acting analgesic 
medications, such as acetaminophen, NSAIDs, tramadol or opioids, 
FOR bunion-related pain, the subject may participate in the study if 
4(a) above is not applicable and the subject is willing to discontinue 
these medications 3 days prior to surgery. 


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iii. 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). (Use of warfarin or other agents is allowed, at the 
investigator’s discretion, for DVT prophylaxis after the surgery is 
completed). 
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 test (breath or saliva) 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. 
a. 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.  Additionally, it may be permissible for 
the subject to participate if the results can be explained by a current 
prescription or acceptable over-the-counter medication as determined by the 
investigator at screening, and/or prior to surgery. 
7. Have previously participated in a clinical study with CA-008. 
8. 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 bunionectomy 
surgery or is scheduled to receive an investigational product other than CA-008 while 
participating in the study. 
Visit Schedule: 
 
1. 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.  If screening occurs prior to D-30, it may be necessary to 
reverify eligibility and ICF agreement, but only if the facility SOP requires such 
reverification be performed. 
2. Site Unit Admission D0: Day of surgery, perform baseline evaluations prior to 
surgery. 
3. Surgery D0: BUNX procedure is performed under MAC anesthesia with the 


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supplemental blocks and other treatments as described. 
4. Post-surgery to T72hNRS: Subject remains at the Site Unit for study assessments.  At 
discharge provide follow up instructions, particularly on diary completion. 
5. Follow Up D8±1: clinic visit for study assessments (cohorts 1-3) and study 
completion visit (cohort 4). 
6. Follow Up D15±2: clinic visit for study assessments (cohorts 1-3 only) 
7. Follow Up D29±2: clinic visit for study assessments and study completion visit 
(cohorts 1-3 only) unless a pending safety event is ongoing and requires follow up 
8. Early Termination (ET): For subjects who terminate early, an ET visit will be 
required. Safety and subject-reported outcome assessments will be performed. 
9. Unscheduled visits: may occur at any time to assess any safety event 
Safety 
Parameters: 
• 
Incidence of spontaneous reported TEAEs or SAEs: 
o TEAEs are defined as AEs occurring after start of CA-008 or Exparel dosing 
o AEs/SAEs recorded from the time the informed consent form (ICF) is signed 
up to D0/T0 will be recorded in medical history.  The Investigator must 
determine whether any such AE/SAE merits a delay in study participation. 
• 
Surgical site assessments and neurosensory testing near the incision as an outpatient 
on D8, D15 and D29 (CA-008) or D8 only (Exparel).   
o 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.  If 
the local reactions are typical of this type of surgery, it should not be 
captured as an AE. 
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 proximal to the incision at time of discharge, such as allodynia or 
hyperalgesia atypical of this type of surgery, 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. 
• 
D15 and D29 visits: assess for presence of rebound pain at the surgical site (cohorts 
1-3 only) 
• 
Physical examination (PE): complete at screening; interim assessments on D-1 (or D0 
prior to surgery if not done on D-1) and during each outpatient visit (D8, D15 and 
D29) for cohorts 1-3 only; for cohort 4, at screening, interim assessments on D-1 (or 
D0 prior to surgery if not done on D-1) and D8. 
• 
Vital signs (heart rate [HR], blood pressure [BP], respiratory rate [RR]) and 
temperature at screening, entrance and discharge from the PACU, and during the 
inpatient period (per site SOP but generally once per shift or every 8h) and during 


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each outpatient visit (D8, D15 and D29) for cohorts 1-3 only; and for cohort 4, 
through D8 only.    
• 
X-rays should be obtained during screening, if not already performed in the 6 months 
prior to screening, and at the D29 visit (cohorts 1-3 only). 
• 
Screening clinical laboratory tests 
o CBC 
o Blood Chemistry: sodium, potassium, calcium, chloride, creatinine 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. 
• 
Drug screen 
Efficacy 
Parameters: 
1. NRS scores will be assessed as follows: 
• 
At T0h (entry to PACU), T1hNRS, 2hNRS, 3hNRS, 4hNRS, 6hNRS, 8hNRS and 12hNRS 
and every 6h thereafter while an inpatient. 
• 
Pain scores may be skipped between the hours of midnight and 6 a.m., but the 
subject may not miss two consecutive assessments due to sleeping. 
• 
The T24hNRS and T48hNRS hour assessments must be completed even if the 
subject is asleep at these times.   
• 
An additional NRS assessment must be obtained within 15 min of the time of 
rescue medication request but prior to administration of rescue.  Note that failure 
to obtain this assessment will be considered a major protocol deviation. 
• 
Starting in the evening of the 1st postoperative day through the D8 visit, NRS 
assessments twice daily at approximately 0800h (±2h) and each evening prior to 
bedtime at approximately 2000h (±2h) at rest and with ambulation of 
approximately 10 yards.  Note that the actual time of these assessments must be 
documented in the diary. 
2. Daily and total opioid consumption (OC) in oral morphine dose equivalents (MEDs) 
will be recorded during the inpatient and outpatient periods. 
Safety 
Endpoints: 
The following safety endpoints will be evaluated: 
• 
Incidence of TEAEs or treatment-emergent SAEs  
• 
Clinically significant changes in surgical site assessments and neurosensory testing 
• 
X-ray healing (CA-008 only) 
• 
Absence of rebound pain at the surgical site (CA-008 only) 
Efficacy 
Endpoints: 
Using NRS scores (at rest and with ambulation), pain intensity over the 72h inpatient stay 
will be assessed.  NRS scores at various time points: T24hNRS, T48hNRS and T72hNRS. 
Sample Size 
Justification: 
The currently planned study is a follow-on exploratory study to a prior phase 2 study 
(CA-PS-201) which showed CA-008 4.2 mg was statistically significantly superior to 
placebo.  This study is being performed to evaluate optimal anesthesia conduct, therefore 
no sample size estimation was performed.   
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 
CA-008 or Exparel.   


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• 
Study completers (Study Completers) will include all subjects who receive a full dose 
of CA-008 or Exparel and complete the entire applicable study period. 
Subjects who elect to discontinue study participation during the inpatient phase of the 
study, will be asked to continue with assessments through T72hNRS if they have not 
elected to withdraw from all aspects of study participation.   
Subjects who elect to discontinue participation prior to D8 will be considered to have 
terminated as of the date of their election, however they will be asked to return to the site 
one time, if willing and at their convenience, to ensure wound healing. 
All assessments and baseline characteristics will be summarized using the Safety 
Population.   


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Table 1. 
Schedule of Assessments  
Assessment  
Screening 
In Patient 
Follow-Up 
Note: The D15 and 29 visits 
apply only to cohorts 1-3 
Unscheduled 
Visit 
Early 
Termination 
Prior to 
Surgery 
Surgery 
Post-
Surgery 
PACU Stay 
Assessments 
during Inpatient 
stay to 72h 
Study Day 
-45 to -1 
0 
0 
0 
1 
8±1 
day 
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 
 
X 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
Subject Pain Assessment Training 
X 
X 
 
 
 
 
 
 
 
 
Surgery 
 
 
X 
 
 
 
 
 
 
 
CA-008 administration 
 
 
X 
 
 
 
 
 
 
 
Pregnancy Test  
X (serum) 
X1 (urine) 
 
 
 
 
 
 
 
 
Vital Signs 
X 
X 
 
X2 
X2 
X2 
X2 
X2 
 
X 
Physical Examination3 
X3 
X3 
 
 
X3 
X3 
 
X3 
 
X 
ECG 
X 
 
 
 
 
 
 
 
 
 
Surgical Site assessment4 
X 
 
 
 
X4 
X 
X 
X 
X 
X 
Neurosensory Exam4 
X 
 
 
 
X4 
X 
X 
X 
X 
X 
Clinical laboratory tests5 
X 
 
 
 
 
 
 
 
 
 
X-ray of surgical site (cohorts 1-3 only) 
X 
 
 
 
 
 
 
X 
 
X 
Concomitant Medication Assessment 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Adverse Event Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Rebound pain assessment 
 
 
 
 
 
X 
X 
X 
X 
X 
NRS pain assessments (inpatient and 
outpatient) 
 
 
 
X6 
X6 
X 
 
 
 
X 
Subject home diary record (NRS)  
 
 
 
 
 
X6,7 
 
 
 
X 
Paper Diary (review, distribution 
and/or collection) 
 
 
 
 
X8,9 
X8,9,10 
 
 
 
X10 
Dispense outpatient rescue if needed 
 
 
 
 
X11 
 
 
 
 
 
1. 
Within 24 hours of scheduled surgery 


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2. 
Vital signs: (HR, BP, RR and temperature) at screening, entrance and discharge from the PACU, and during the inpatient period (per site SOP but generally at least once 
per shift or every 8h) and during each outpatient visit (D8, D15 and D29 for CA-008 and D8 for Exparel).   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 will be a ±15-minute window allowed. 
3. 
A complete medical history and physical examination including all major body systems will be performed at Screening.  In addition, at the following times, a targeted 
reassessment will be performed prior to surgery, at discharge from the inpatient unit to capture changes after Surgery, and on the D29 visit for CA-008 or D8 visit for 
Exparel.  If the subject terminates early, a targeted reassessment should be performed at that time if allowed by the subject.  Body weight (kg), in indoor clothing, but 
without shoes, will be measured at Screening.  Height (in cm) will be measured and BMI will be calculated at Screening. 
4. 
Surgical Site assessment and neurosensory testing: only at 72 hours (±2 hours) but prior to discharge from the inpatient unit, and on D8, D15 and D29 for CA-008 or D8 
for Exparel, and, if necessary, at any unscheduled or early termination visit. 
5. 
Clinical Laboratory tests at screening  
6. 
NRS pain assessments at T0h (entry to PACU), T1hNRS, 2hNRS, 3hNRS, 4hNRS, 6hNRS, 8hNRS and 12hNRS and every 6h thereafter while an inpatient (if awake at time of 
assessment especially between the hours of 00:00 and 06:00) until discharge from the inpatient unit (may not miss two consecutive assessments). The T24hNRS and T48hNRS 
assessments must be completed even if the subject is asleep at these times. During the inpatient stay, NRS must be obtained at the time of or within 15 min of rescue 
medication request, regardless of the time of other protocol-specified pain assessments and even if the subject is asleep. There will be a ±5-minute window allowed for the 
collection of each assessment in the first 4 hours after the end of surgery, after which will be a ±15-minute window allowed.  
7. 
Starting in the evening of the 1st postoperative day through the D8 visit, NRS assessments twice daily at approximately 0800h (±2h) and each evening prior to bedtime at 
approximately 2000h (±2h) at rest and with ambulation of approximately 10 yards.  Note that the actual time of these assessments must be documented in the diary. 
8. 
Review Subject Diary instructions with subject 
9. 
Dispense Subject Diary 
10. Collect Subject Diary 
11. Dispense no more than 9 tablets per investigator discretion of oxycodone 5 mg tablets.  Document prescription and # of tablets prescribed. 
 


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3. 
TABLE OF CONTENTS 
2. 
Protocol Synopsis .................................................................................................................. 5 
3. 
Table of Contents ................................................................................................................ 17 
4. 
List of Abbreviations and Definition of Terms ................................................................ 19 
5. 
Introduction ......................................................................................................................... 22 
5.1. 
Background .............................................................................................................................. 22 
5.2. 
CA-008 Product Introduction ................................................................................................. 22 
5.3. 
Previous Human experience ................................................................................................... 23 
5.4. 
Study and Dose Rationale ....................................................................................................... 24 
6. 
Study Objectives.................................................................................................................. 25 
6.1. 
Primary Objective ................................................................................................................... 25 
6.2. 
Secondary Objective ................................................................................................................ 25 
6.3. 
Exploratory Objective ............................................................................................................. 25 
7. 
Investigational Plan ............................................................................................................ 26 
7.1. 
Overall Study Design and Plan ............................................................................................... 26 
7.2. 
Screening Phase (Day -45 [D-45] to D-1 or D0): ................................................................... 26 
7.3. 
D-1 or D0: Prior to surgery (baseline) up to the end of surgery ......................................... 27 
7.4. 
Postoperative Multimodal Analgesia ..................................................................................... 29 
7.5. 
Postoperative Rescue Medication ........................................................................................... 29 
7.6. 
Postoperative Care While an Inpatient ................................................................................. 29 
7.7. 
Outpatient Phase: D8±1 Visit ................................................................................................. 31 
7.8. 
Outpatient Phase: D15±2 Visit ............................................................................................... 31 
7.9. 
Outpatient Phase: D29±2 Visit / Early Termination ............................................................ 32 
7.10. 
Outpatient Phase: Unscheduled Visits ................................................................................... 32 
8. 
Selection of Study Population ............................................................................................ 33 
8.1. 
Inclusion Criteria ..................................................................................................................... 33 
8.2. 
Exclusion Criteria .................................................................................................................... 34 
8.3. 
Study Stopping Rules .............................................................................................................. 36 
8.4. 
Removal of Subjects from Therapy or Assessment .............................................................. 36 
8.5. 
Study Restrictions .................................................................................................................... 37 
9. 
Study Treatment ................................................................................................................. 39 
9.1. 
CA-008 ...................................................................................................................................... 39 
9.2. 
Exparel...................................................................................................................................... 40 
9.3. 
Method of Assigning Subjects to Treatment Groups ........................................................... 40 
9.4. 
Blinding .................................................................................................................................... 40 
9.5. 
Prior and Concomitant Therapy ............................................................................................ 41 
9.6. 
Treatment Compliance............................................................................................................ 41 
10. 
Study Procedures and Assessments ............................................................................... 42 
10.1. 
Demographics and Other Baseline Characteristics .............................................................. 42 
10.2. 
Eligibility Review ..................................................................................................................... 43 
10.3. 
Subject Pain Assessment Training ......................................................................................... 43 
10.4. 
Efficacy Assessments ............................................................................................................... 43 
10.5. 
Safety Assessments .................................................................................................................. 44 


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10.6. 
Efficacy and Safety Endpoints ................................................................................................ 46 
11. 
ADVERSE EVENTS ...................................................................................................... 47 
11.1. 
Adverse Events and Serious Adverse Events ........................................................................ 47 
11.2. 
Pregnancy ................................................................................................................................. 51 
12. 
Data Quality Assurance .................................................................................................. 52 
12.1. 
Data Collection ......................................................................................................................... 52 
12.2. 
Study Auditing and Monitoring ............................................................................................. 52 
13. 
Statistical Methods .......................................................................................................... 54 
13.1. 
Statistical and Analytical Plans .............................................................................................. 54 
13.2. 
Sample Size Justification......................................................................................................... 54 
13.3. 
Analysis Populations ............................................................................................................... 54 
13.4. 
Planned Analyses ..................................................................................................................... 54 
13.5. 
Study Subjects and Demographics ......................................................................................... 55 
13.6. 
Analysis of Efficacy Measures ................................................................................................ 56 
13.7. 
Analysis of Safety ..................................................................................................................... 58 
14. 
Site and Investigator Responsibilities ........................................................................... 59 
14.1. 
Regulatory and Ethical Considerations ................................................................................. 59 
14.2. 
Privacy and Confidentiality .................................................................................................... 60 
14.3. 
Study and Site Closure ............................................................................................................ 61 
14.4. 
Regulatory Documents and Records Retention .................................................................... 61 
14.5. 
Delegation of Responsibilities and Adequate Resources ...................................................... 62 
14.6. 
Protocol Amendments ............................................................................................................. 62 
14.7. 
Financial Disclosure ................................................................................................................ 62 
15. 
Investigator Protocol Agreement Page ......................................................................... 63 
16. 
References ........................................................................................................................ 64 
17. 
APPENDICES ................................................................................................................. 65 
A. 
Appendix A: American Society of Anesthesiologists Physical Status Classification System 
(ASA Class) ........................................................................................................................................... 65 
B. 
Appendix B:  0-10 Numerical Rating Scale for Pain Intensity (NRS) ..................................... 66 
C. 
Appendix C: Assessment of Increased Pain at the Surgical Site (Rebound Pain) ................. 67 
D. 
Appendix D: Surgical Site Assessment....................................................................................... 68 
E. 
Appendix E: Wound Status Assessment Guide ......................................................................... 69 
F. 
Appendix F: Neurosensory Testing Form .................................................................................. 70 
G. 
Appendix G: Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled 
in Preventive Vaccine Clinical Trials .................................................................................................. 71 
H. 
Appendix H:  Monitored Anesthesia Care ................................................................................ 72 
LIST OF TABLES 
Table 1. 
Schedule of Assessments ......................................................................................... 15 
Table 2. 
Stopping Rule Triggers........................................................................................... 36 
Table 3. 
CA-008 ..................................................................................................................... 39 
Table 4. 
Equianalgesic Conversion Table ........................................................................... 44 
 


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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 
BUNX 
Bunionectomy 
CA-008 
Investigational product 
CA-101 
Cyclic urea 
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 
DIP 
Distal interphalangeal 
DMC 
Data Monitoring Committee 
DVT 
Deep Venous Thrombosis 
ECG 
Electrocardiogram 
EDC 
Electronic data capture 
ET 
Early Termination 
FCBP 
Female of child bearing potential 
FDA 
Food and Drug Administration 
FIH 
First-In-Human 
FSH 
Follicle Stimulating Hormone 
G 
Gram 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transferase 


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Abbreviation 
Term 
GLP 
Good Laboratory Practice 
h, H or HRS 
Hours 
HCl 
Hydrochloride 
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 
MAC 
Monitored anesthesia care 
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 
PO 
Per oram (oral) 
PRN 
Pro re nata (as needed) 
PT 
Prothrombin time 
QID 
Quater in die (four times daily) 
RBC 
Red blood cell 


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Abbreviation 
Term 
SAE 
Serious adverse event  
SAP 
Statistical analysis plan 
SBP 
Systolic blood pressure 
SC 
Subcutaneous 
SD 
Standard deviation 
SOC 
System Organ Class 
SNRIs 
Serotonin-norepinephrine reuptake inhibitors 
SSRIs 
Selective serotonin reuptake inhibitors 
T# 
Time in hours after 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.  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 in a polyethylene glycol solution for chronic knee osteoarthritis (currently 
in Phase 3) and Morton’s neuroma (see http://centrexion.com/our-pipeline/).    
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 


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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 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 and a Phase 2 parallel design 
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).   
Additionally, a first-in-human study (Study CA-PS-2017-101) evaluated the safety and 
tolerability of CA-008 (dose ranges 0.5 mg to 4.2 mg) in 40 subjects (6 at each CA-008 dose for 
a total of 30 and 10 receiving placebo) undergoing a unilateral transpositional first metatarsal 
osteotomy for correction of hallux valgus deformity, more commonly known as a bunionectomy.  
A follow-on Phase 2 bunionectomy study (CA-PS-201) was completed with 147 subjects 
enrolled and randomized to one of 3 active doses: 0.7 mg (N=36), 2.1 mg (N=36) and 4.2 mg 
(N=38) vs. placebo (N=37).  The highest dose of 4.2 mg was well tolerated and 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 


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(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).  There was a single SAE (delayed cellulitis) in the placebo group. 
5.4. 
Study and Dose Rationale 
5.4.1. 
 Study Rationale 
CA-008 is being investigated as a potential therapy for treatment of pain following surgery.   
5.4.2. 
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) as well as the first dosing cohorts (CA-
008 5 mg dose) in complete abdominoplasty and total knee arthroplasty.  These studies are 
considered sufficient to support the intended use of CA-008 in this study. 
5.4.3. 
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 to the potential areas where noxious pain is being 
generated. 


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6. 
STUDY OBJECTIVES 
6.1. 
Primary Objective 
The primary objective of the study is to evaluate different standard of care anesthetic regimens 
on CA-008 administration in subjects undergoing an elective BUNX.  
6.2. 
Secondary Objective 
The secondary objective of the study is to confirm the safety and efficacy of CA-008 with 
different standard of care anesthetic regimens in subjects undergoing an elective BUNX. 
6.3. 
Exploratory Objective 
The exploratory objective of the study is to evaluate Exparel’s performance in subjects 
undergoing an elective BUNX under a standard of care anesthetic regimen. 
 


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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design and Plan 
This is a Phase 2, single-center, open-label study evaluating a single dose of CA-008 4.2 mg or 
Exparel administered during an elective unilateral transpositional first metatarsal osteotomy for 
the correction of hallux valgus deformity (bunionectomy or BUNX) under MAC and Mayo field 
block with or without a supplemental popliteal block with bupivacaine HCl. 
 The study will be conducted in two parts: 
• Inpatient period which continues to T72NRS hour  
• Outpatient period which begins on discharge from the inpatient unit through various 
follow up visits to D29±2 (cohorts 1-3) or D8±1 (cohort 4) after surgery 
7.2. 
Screening Phase (Day -45 [D-45] to D-1 or D0):   
Subjects requiring bunionectomy between the ages of 18 and 65 years, inclusive, will be 
screened for participation at the study site within 45 days of surgery. The following assessments 
will be completed: 
• 
Informed Consent 
• 
Eligibility for study participation (Inclusion / Exclusion criteria) 
• 
Demographics 
• 
Medical and surgical history 
• 
Prior/current medications 
• 
Complete physical examination (PE) including vital signs (resting blood pressure, 
resting pulse and respiration rate) (Appendix 17.G). Tests must be obtained after resting 
(seated/reclined) for ≥ 5 minutes. 
• 
ECG 
• 
Ensure that an x-ray of the bunion to be operated on has been obtained (cohorts 1-3 
only) 
• 
Screening clinical laboratory tests 
• 
Urine Drug Screening (UDS) and alcohol breath test (or other appropriate test) 
• 
Serum Pregnancy test (FCBP) 
• 
Subject pain assessment training 
• 
Adverse Event (AE) Assessment 


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7.3. 
D-1 or D0: Prior to surgery (baseline) up to the end of surgery   
7.3.1. 
Prior to Surgery 
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 site may 
elect to admit the subject to the inpatient unit the evening prior to surgery (D-1) or the day of 
surgery (D0).  The following assessments will be performed: 
• 
Confirm informed consent and eligibility for study participation 
• 
Interim medical and surgical history 
• 
Prior medications 
• 
Interim PE and vital signs as before (include temperature assessment) 
• 
Planned Surgical Site Assessment including neurosensory exam of the Foot / Great toe 
(bilateral)  
• 
Screening clinical laboratory tests 
• 
Urine Drug Screening (UDS) and alcohol breath test 
• 
Urine Pregnancy test (FCBP) 
• 
AE Assessment 
7.3.2. 
Planned Anesthesia and Regional Blocks 
The surgery is to be performed under MAC supplemented with one of two different standard of 
care regimens to produce surgical anesthesia: popliteal + Mayo block OR Mayo block alone.  For 
the Mayo block, the surgeon should inject just distal to the base of the 1st metatarsal to provide 
coverage of each quadrant paying particular attention to the space between the 1st and 2nd 
metatarsals).  In each cohort, intraoperative analgesia will include IV ketorolac 30 mg and IV 
acetaminophen 1 g at the onset of anesthesia.   
The systemic anesthesia medication doses (including but not limited to fentanyl, ketorolac and 
acetaminophen) are suggested guidelines to be followed by the anesthesiologist caring for the 
subject. The actual doses given are at the discretion of the anesthesiologist based on the clinical 
status of the subject.  With respect to non-analgesic medications, the anesthesiologist is free to 
use clinical discretion on the choice and dose. 
In the 1st cohort of 9 subjects, prior to surgical incision (except as noted), perform the following 
local anesthetic blocks: 
• A popliteal block performed under ultrasound guidance using bupivacaine HCl 0.25% 
(30 mL volume) with an assessment of the adequacy of the block 
• A Mayo block using bupivacaine HCl 0.25% 30 mL (75 mg) prior to surgery and 
lidocaine HCl 1.5% 12 mL at the end of surgery.   


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In the 2nd cohort of 9 subjects, prior to surgical incision, perform the following: 
• A Mayo block using a combination of bupivacaine HCl 0.5% 15 mL and lidocaine HCl 
2% 15 mL prior to surgery.   
In the 3rd and 4th cohorts of 9 subjects in each, prior to surgical incision, perform the following: 
• A Mayo block using a combination of bupivacaine HCl 0.5% 10 mL and lidocaine HCl 
2% 20 mL prior to surgery.   
• Note that CA-008 or Exparel administration should be no sooner than 20 minutes after 
the Mayo block. 
• In cohort 4, total bupivacaine HCl equivalent dose 176.8 mg: 121.8 mg from Exparel and 
55 mg from bupivacaine HCl 
After the surgery, patients will be monitored in the PACU to ensure recovery from the 
anesthesia.  Note that T0hNRS is the time of entry to the PACU.  Subjects will be monitored for 72 
hours in an inpatient unit during which time safety and efficacy evaluations will be performed.  
Subjects will be required to meet certain pre-specified criteria prior to discharge. 
7.3.3. 
Administration of CA-008 
Prior to wound closure, CA-008 will be injected/instilled into the soft tissues and osteotomy 
surgical site with a total volume of 14 mL of CA-008 as follows: 
• Instill 2 mL at cut bone sites  
• Prior to capsule closure, infiltrate the deep soft tissue and area proximal to the capsule with 
a total of 9 mL (approximately 2.25 mL into each quadrant circumferentially) 
• Close the capsule, but using a small gauge catheter infiltrate 2 mL into the closed capsule 
space 
• Prior to closure of the subcutaneous tissues and skin, instill 1 mL to coat all exposed 
surfaces of the wound 
7.3.4. 
Administration of Exparel 
Exparel 106 mg (8 mL of the 133 mg/10 mL suspension) will be infiltrated intraoperatively into 
the soft tissues and osteotomy surgical site prior to closure as follows: 
• Infiltrate 7 mL into the tissues surrounding the osteotomy  
• Infiltrate 1 mL into the subcutaneous tissues 
Note that Exparel administration should not begin until 20 minutes after the Mayo block.  See 
Exparel full prescribing information for detailed administration instructions:  
https://www.exparel.com/hcp/prescriptioninformation.pdf (as revised 11/2018; Pacira 
Pharmaceuticals, Inc.). 


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7.4. 
Postoperative Multimodal Analgesia  
For cohorts 1 and 2, after recovery from surgery, subjects will be given:  
• celecoxib (Celebrex®) 200 mg PO bid each day while an inpatient, and  
• acetaminophen 1 g PO (2 doses on the day of surgery starting at 6±2h after surgery and 
again at 12±2h after surgery) and t.i.d. thereafter each day while an inpatient 
For cohorts 3 and 4, other than the non-opioids administered during surgery, no additional non-
opioids are to be given to subjects until discharged to outpatient status at which time the 
Investigator is free to recommend the appropriate non-opioid analgesic combination for prn use.  
No other non-opioid analgesics are to be administered during the inpatient phase except as 
specified in the protocol. 
7.5. 
Postoperative Rescue Medication 
Additionally, the following rescue medication may be administered for any moderate to severe 
breakthrough pain during the inpatient period: 
• During the PACU stay (90 minutes, if possible, to ensure that pain is well controlled), 
administer IV fentanyl 25-50 mcg q5-10 min prn moderate (≥ 4) or severe pain (≥ 7) as 
reported by subjects using the 0 to 10 numerical rating scale of current pain intensity 
(NRS) 
• From time of PACU discharge to T24hNRS hours, PO oxycodone 5 mg for moderate or 10 
mg for severe pain prn q2h 
• After T24hNRS hour to discharge from the inpatient unit, PO oxycodone 5 mg for 
moderate or 10 mg for severe pain prn q4h 
Subjects will be encouraged to rescue only for moderate pain scores (≥ 4), however rescue may 
be requested at any time and medication will be provided when requested per protocol timing. 
7.6. 
Postoperative Care While an Inpatient 
After surgery, subjects will be monitored as an inpatient until discharged.  Safety and efficacy 
evaluations will be performed.  Subjects will be required to meet standard pre-specified criteria 
for discharge from the unit.   
The schedule of assessments are as follows:  
• 
Perform NRS assessments of current pain intensity (Appendix 17.B):  
o 
During the inpatient stay, at T0hNRS (entrance to PACU), 1hNRS, 2hNRS, 3hNRS, 4hNRS, 
6hNRS, 8hNRS and 12hNRS and every 6 hours (if awake at time of assessment) until 
discharge from the inpatient unit (may not miss two consecutive assessments.   
o 
Pain scores may be skipped between the hours of midnight and 6 a.m., but the subject 
may not miss two consecutive assessments due to sleeping. 


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o 
The T24hNRS and T48hNRS assessments must be completed even if the subject is asleep at 
these times.  
o 
NRS must be completed within 15 minutes after rescue request but prior to use of pain 
rescue medication.   
o 
Starting in the evening of the 1st postoperative day through the D8 visit, NRS assessments 
twice daily at approximately 0800h (±2h) and each evening prior to bedtime at 
approximately 2000h (±2h) at rest and with ambulation of approximately 10 yards.  Note 
that the actual time of these assessments must be documented in the diary. 
o 
There will be a ±5 minute window allowed for the collection of each assessment in the 
first 4 hours after the end of surgery after which will be a ±15 minute window allowed 
while an inpatient. 
• 
Vital signs: (HR, BP, RR and temperature) at screening, entrance and discharge from the 
PACU, and during the inpatient period (per site SOP but generally at least once per shift or 
every 8h).   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 will be a ±15-minute window allowed. 
• 
Perform interim PE: surgical site assessment (Appendix 17.D and Appendix 17.E) and 
neurosensory testing (Appendix 17.F) of the foot proximal to the surgical site with 
contralateral comparison: prior to discharge from the inpatient unit.  
• 
Document concomitant medication use including doses and times taken  
• 
Document AEs 
After completing the assessments through T72NRS hours after surgery and prior to discharge from 
the inpatient unit, review with the subject the use of a diary for at-home use to record pain 
assessments and medication use (including pain medication) at home.  Finally, instruct subjects 
to return to the study center on D8±1 for a follow-up assessment.  
Once discharged from the inpatient unit, all study participants will be instructed to take a 
combination of OTC analgesics (NSAID and acetaminophen) at an appropriate dose per medical 
judgment to manage any residual or breakthrough postsurgical pain through D29/W4. 
Outpatient period:   
• If needed for pain management, over-the-counter (OTC) analgesics administered PO, 
e.g.,  
o NSAID (e.g., ibuprofen 200 mg to 400 mg prn qid [Advil® or Motrin®] or 
naproxen 220 mg prn tid [Aleve®]) or other options per investigator discretion 
and  
o Acetaminophen 1-2 500 mg tablets (up to 1 g) tid or 650 mg qid (3g daily limit) 
• If a subject is still requiring opioid rescue in the 6h prior to discharge from the inpatient 
unit then at discharge prescribe no more than 9 tablets (1 PO tid prn) of oxycodone 5 mg 
for the initial outpatient period.   Document this prescription and number of tablets 


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prescribed, and if any repeat prescription is required per investigator discretion, 
document the date of such prescription and number of tablets prescribed 
7.7. 
Outpatient Phase: D8±1 Visit 
In their diary, subjects will assess their current pain intensity at rest and after ambulation each 
morning (08:00 ±2 hours), and each evening (20:00 ±2 hours) using the NRS.  The morning NRS 
assessment should be obtained prior to taking any pain medication.  Subjects will also record any 
medication they take (dose and time) whether to treat their pain or for any other reasons. 
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 to capture this event as an adverse 
event (AE) and document any required treatments. 
For cohort 4, the D8 visit is the study completion visit. 
Subjects will return to the study center on D8±1 for the following assessments:  
• 
Subject home diary review, then collect subject home diary 
• 
Document pain intensity (NRS) at rest and after ambulation each day since discharge from 
the inpatient unit 
• 
Perform surgical site assessment and neurosensory exam of the foot proximal to the surgical 
site with contralateral comparison  
• 
Document concomitant medication use including doses and times taken for analgesic 
medications 
• 
Document concomitant treatment use including topical ice pack or cooling treatments 
• 
Record AE Assessment 
• 
Query the subject as to the presence of any rebound pain (increased pain at the surgery site) 
(Appendix 17.C) 
7.8. 
Outpatient Phase: D15±2 Visit (Cohort 1-3 only) 
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 to capture this event as an adverse 
event (AE) and document any required treatments. 
Subjects will return to the study center on D15±1 for the following assessments:  
• 
Perform surgical site assessment and neurosensory exam of the foot proximal to the surgical 
site with contralateral comparison  
• 
Document concomitant medication use including doses and times taken for analgesic 
medications 


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• 
Document concomitant treatment use including topical ice pack or cooling treatments 
• 
Record AE Assessment 
• 
Query the subject as to the presence of any rebound pain (increased pain at the surgery site) 
7.9. 
Outpatient Phase: D29±2 Visit (Cohort 1-3 only) / Early Termination 
Subjects will return to the study center on D29±2, or if applicable at premature study 
discontinuation (early termination or ET), for the following assessments:  
• 
Subject home diary review (NRS scores at rest and after ambulation each day since 
the last visit and pain medication usage, if ET is ≤ Day 8) 
• 
Perform surgical site assessment and neurosensory exam of the foot proximal to the surgical 
site with contralateral comparison  
• 
Interim PE and vital signs (if early termination prior to Day 8 visit). 
• 
Document concomitant medication use including doses and times taken for analgesic 
medications 
• 
Document concomitant treatment use  
• 
Record AE Assessment 
• 
Query the subject as to the presence of any rebound pain (increased pain at the surgery site) 
7.10. 
Outpatient Phase: Unscheduled Visits 
Unscheduled visits may be scheduled at any time if warranted due to the subject’s complaints or 
condition per investigator discretion.  Assessments performed at Unscheduled Visits will be at 
the discretion of the investigator.  If these visits occur prior to D29±2, perform the following: 
• 
Perform surgical site assessment and neurosensory exam of the foot proximal to the surgical 
site with contralateral comparison  
• 
Document concomitant medication use including doses and times taken for analgesic 
medications 
• 
Document concomitant treatment use  
• 
Record AE Assessment 
• 
Query the subject as to the presence of any rebound pain (increased pain at the surgery site) 


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8. 
SELECTION OF STUDY POPULATION 
8.1. 
Inclusion Criteria 
Subjects must meet all of the following criteria to be considered eligible to participate in the 
study: 
1. 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, 2 or 3 
(Appendix 17A). 
2. Plan to undergo an elective primary unilateral first metatarsal bunionectomy repair, without 
collateral procedure or additional surgeries, to be performed under monitored anesthesia care 
(MAC) (Appendix 17.H) with a local block. 
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 of child-bearing potential (FCBP), must meet all of the following: 
a. Not be pregnant (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. 
5. Have a body mass index ≤ 36 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 with study personnel and return for outpatient follow up visits as 
required. 


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8.2. 
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, other than bunion-related pain, 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 HCl, Exparel, fentanyl, ketorolac, lidocaine 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 abnormal clinical 
laboratory test value, 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 4) 
per day for greater than 4 out of 7 days per week over a one-month period within 
6 months screening. 
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 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. 


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ii. If the subject is taking centrally- and/or peripherally-acting analgesic 
medications, such as acetaminophen, NSAIDs, tramadol or opioids, FOR 
bunion-related pain, the subject may participate in the study if 4(a) above 
is not applicable and the subject is willing to discontinue these 
medications 3 days prior to surgery. 
iii. 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). (Use of warfarin or other agents is allowed, at the investigator’s 
discretion, for DVT prophylaxis after the surgery is completed). 
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 test (breath or saliva) 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. 
a. 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.  Additionally, it may be permissible for the subject to participate if 
the results can be explained by a current prescription or acceptable over-the-
counter medication as determined by the investigator at screening, and/or prior to 
surgery. 
7. Have previously participated in a clinical study with CA-008. 


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8. 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 bunionectomy surgery or is 
scheduled to receive an investigational product other than CA-008 while participating in the 
study. 
8.3. 
Study Stopping Rules 
Enrollment in the study will be paused for evaluation of specific TEAEs (cohorts 1-3 only): 
• If one or more subjects experience any grade 4 (or higher) related TEAE (Table 2) or 
• If 2 or more subjects experience the same grade 3 related TEAE (Table 2) 
Table 2. Stopping Rule Triggers 
 
Should a trigger occur, the principal investigator, CRO medical monitor and the Sponsor medical 
monitor will meet to determine whether to unblind study treatment for the subject and determine 
whether to continue study enrollment. 
8.4. 
Removal of Subjects from Therapy or Assessment 
A subject is free to withdraw 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: 


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• 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 CA-008, or both 
• At the request of the Sponsor, regulatory agency, or Institutional Review Board (IRB) 
• Subject is lost to follow-up 
• 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.  If 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.  
If a subject is discontinued while at the clinical site, the early termination procedures should be 
performed prior to discharge from the clinical site.  The investigator should ask the subject to 
participate in follow-up procedures, provided that the subject has not withdrawn consent for such 
procedures.  If the subject refuses to complete early termination/follow-up procedures or 
continued data collection, this information will be recorded. 
8.5. 
Study Restrictions 
In addition to the criteria described in Section 8.1 and Section 8.2, 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 
Abstain from the following during the outpatient portion of the study: 


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▪ illicit drug use or non-medical use of therapeutic drugs not allowed by the protocol 
▪ prohibited medications described in Section 9.5 
 


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9. 
STUDY TREATMENT 
9.1. 
CA-008 
9.1.1. 
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. 
The active drug product will be provided as CA-008 Solution for Injection, 1.0 mL in a 5 mL 
clear sterile vial, with the dose per vial calculated as the freebase.  Inactive ingredients are 
mannitol, citrate buffer and water. 
At time of use, the concentrate will be completely constituted with sterile saline and only a 
portion of the solution will be used for treatment (see the Pharmacy Manual for details on 
reconstitution).  For clarity, CA-008 and treatment solution is shown in Table 3. 
Table 3. CA-008  
CA-008 
Solution for Injection, 1.0 
mL per vial 
Drug Product as provided 
15 mg 
 
Each cohort 
 
Concentration upon 
reconstitution with saline 
0.30 mg/mL 
 
Dose in 14 mL of solution 
4.2 mg 
 
9.1.2. 
Storage 
CA-008s will be shipped to sites and stored at -20°C (-15°C to -30°C) until the day of 
surgery.  All CA-008 should be stored in a secured area and in accordance with the product 
labeling and all applicable laws, regulations, and local/institutional requirements.  A description 
of storage conditions for all investigational products will be provided in the Pharmacy Manual. 
9.1.3. 
Accountability 
All CA-008 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 


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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 CA-008. Only authorized 
research site staff may supply, prepare or administer the CA-008s. Once dispensed, CA-008 may 
not be relabeled or reassigned for use by other subjects.  
9.1.4. 
Control of CA-008 and Rescue Medication 
Mishandling, potential theft, significant loss of clinical supplies, including CA-008s, multimodal 
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. 
Exparel 
The site has responsibility for procuring sufficient Exparel supplies for cohort 4 administration 
and will be reimbursed for this purchase. 
9.3. 
Method of Assigning Subjects to 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.  Once 
any subject number is assigned, it cannot be reassigned to any other subject.  There will be 4 
treatment cohorts exploring different anesthesia regimens.  For cohorts 1-3, the site will be 
provided with sufficient CA-008 supplies.  Subjects may be rescreened if the screening window 
is exceeded due to scheduling issues.  
9.4. 
Blinding 
This is an open-label study without blinding. 


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9.5. 
Prior and Concomitant Therapy 
All concomitant medications, including prescription, over-the-counter, or herbal therapies, used 
by the subject will be reviewed for eligibility and documented for the 30 days prior to Screening 
and throughout the study. Allowed rescue medication is described in Section 7.5. 
The Investigator is permitted to use clinical discretion for required concomitant medications to 
treat any AE.  
9.6. 
Treatment Compliance  
Because all CA-008, Exparel or rescue 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. 
STUDY PROCEDURES AND ASSESSMENTS 
All study assessments will be performed at the visits and timepoints outlined in the Schedule of 
Assessments (Table 1); the following sections outline the details and procedures associated with 
the assessments.  
10.1. 
Demographics and Other Baseline Characteristics 
10.1.1. 
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. 
10.1.2. 
Demographics 
The following demographics will be recorded: age (birthdate), sex, race, and ethnicity.  
10.1.3. 
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. 
10.1.4. 
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.  
10.1.5. 
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).  


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Female subjects of non-childbearing potential are not required to use contraception or undergo 
pregnancy tests; however, they must be surgically sterile (hysterectomy and/or bilateral 
oophorectomy or salpingo-oophorectomy, as determined by subject medical history) or 
congenitally sterile or must be post-menopausal. Post-menopausal is defined as being 
amenorrheic for at least one year without another cause. 
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.   
10.2. 
Eligibility Review  
Subjects must meet all inclusion and not meet any exclusion criteria as outlined in Section 8.1 
and Section 8.2.  The Investigator or designee must document that the subjects met each 
individual criterion via a signed note or eligibility and inclusion/exclusion checklist during 
Screening and at D0 prior to surgery.  Signatures on these documents must be dated on or before 
the day of surgery.  
10.3. 
Subject Pain Assessment Training 
Subjects will undergo study participation education on pain assessments and written testing 
procedures according to the Schedule of Assessments. 
10.4. 
Efficacy Assessments 
10.4.1. 
Numerical Rating Scale (NRS) for Pain Intensity 
The NRS is an 11-point scale with anchors 0 (no pain) and 10 (worst possible pain).  Subjects will 
report or record the intensity of their current pain at designated times during the study after 
administration of CA-008.     
10.4.2. 
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 4 to calculate the morphine equivalent dose (MED) of various opioids. 
 
 


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Table 4. Equianalgesic Conversion Table 
Opioid (Doses in mg) 
Conversion Factor to 
IV morphine 
Conversion Factor to PO 
morphine 
IV Fentanyl 
100 
 
IV Hydromorphone 
6 
 
IV Morphine 
1 
6* 
PO Hydrocodone 
 
1 
PO Morphine 
 
1 
PO Oxycodone 
 
1.5 
PO Tramadol 
 
0.1 
For any IV opioid, we will use a 2-step process to calculate its oral (PO) morphine 
equivalent dose (MED).   
1. Convert its IV dose to IV morphine MED by multiplying by the conversion 
factor for IV equivalence.   
2. Once the IV morphine MED is calculated, convert to the PO morphine MED 
using the conversion factor for PO equivalence. 
For any PO opioid, use the conversion factor to calculate the PO MED. 
*Note that for non-tolerant patients, we are using the 6:1 conversion for IV to PO 
morphine, or in other words, 10 mg IV morphine = 60 mg PO morphine. 
10.5. 
Safety Assessments 
Safety monitoring will be performed throughout the study for all subjects.  All AEs, regardless of 
causality or severity, will be recorded on the AE CRF. 
10.5.1. 
Clinical Laboratory Assessments 
Appropriate screening labs will be performed at the site’s local laboratory.  It is the responsibility 
of the Investigator to review and sign all lab reports expeditiously, and 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, 
clinically significant laboratory values are expected to be associated with an item recorded in 
medical history or with an AE. 


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Blood samples will be collected, processed, and shipped according to instructions from the local 
lab. Additional 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 and to 
verify return to normal or to a new baseline. Suggested specific screening assessments are as 
follows:  
• CBC 
• Blood Chemistry: sodium, potassium, calcium, chloride, creatinine and glucose 
• Serum and urine pregnancy test for FCBP: βhCG test at screening and urine test 
usually to be done within 24 hours prior to surgery. 
• 
Urinalysis if indicated 
10.5.2. 
Urine Drug Screen and Alcohol Breath Test 
Urine drug screen and alcohol breath tests will be completed at screening and pre-procedure.  All 
subjects will be tested for drugs-of-abuse (i.e. amphetamines, barbiturates, benzodiazepines, 
cocaine, opiates, phencyclidine, tetrahydrocannabinol (THC), methadone, methamphetamine, 
tricyclic anti-depressants, and oxycodone). 
The drug and alcohol screens may be performed in-house at the Clinical Unit.  If any of these 
tests are positive (note exception for THC below), the subject will not be allowed further 
participation in the trial.  A positive test may be repeated at the discretion of the PI.  Note that for 
those subjects who test positive for THC, if they are willing to abstain from use (e.g., 
inhalational) or consumption of THC-containing products from 3 days prior to surgery to the D8 
visit, they may be allowed to participate in the study. 
10.5.3. 
X-Ray 
An X-ray of the surgical site will be performed during screening (or verified as previously done) 
and at D29/ET (cohorts 1-3 only). 
10.5.4. 
Physical Examination 
A complete physical examination (PE) including all major body systems (HEENT, neurologic, 
cardiovascular, respiratory, gastrointestinal, dermatologic and musculoskeletal systems) will be 
performed at Screening and an interim PEs prior to Surgery.  Evaluation of the surgical site and 
neurosensory testing of both lower extremities should be performed at specific times.   
Body weight (kg), in indoor clothing, but without shoes, and height in centimeters (cm) will be 
measured to calculate BMI at Screening.  BMI shall be calculated as kg/m2.  Use the NIH 
website BMI calculator http://www.nhlbi.nih.gov/health/educational/lose_wt/BMI/bmi-m.htm. 
10.5.5. 
Assessment of Adverse Events 
All SAEs will be documented and followed from the time the subject has signed the ICF until 
D29 (cohorts 1-3) or D8 (cohort 4), and, if necessary, later to follow an AE to resolution or 


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establishment of a new baseline.  All SAEs and non-serious AEs will be documented and 
followed from the time of administration of until D29 (cohorts 1-3) or D8 (cohort 4).  AEs/SAEs 
that occur between Screening and the study procedure should be considered medical history and 
be added to the subject’s medical record.  Serious AEs and AEs that have been designated as 
possibly related to CA-008 will be followed until resolution or stabilization.  Further details on 
AEs, including definitions, elicitation, and reporting are provided in Section 11. 
10.6. 
Efficacy and Safety Endpoints 
10.6.1. 
Efficacy Endpoints 
Using NRS scores (at rest and with ambulation), pain intensity over the 72h inpatient stay will be 
assessed.   
10.6.2. 
Safety Endpoints 
Safety endpoints include the following: 
• Incidence of TEAEs and SAEs 
• Surgical Site assessment findings 
• Neurosensory testing results 
• X-ray healing of the surgical site (cohorts 1-3 only) 
• Absence of rebound pain at the surgical site (cohorts 1-3 only) 


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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 CA-008 or Exparel 
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 CA-008 or Exparel.   
 
Causality 
Category 
Description 
Unlikely related 
A clinical event, including laboratory test abnormality, with a temporal 
relationship to CA-008 or Exparel 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 
CA-008 or Exparel, 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 
CA-008 or Exparel 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 CA-008 or Exparel. 
Possibly related 
A clinical event, including laboratory test abnormality, with a temporal 
relationship to CA-008 or Exparel 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 CA-008 or Exparel was partly responsible, 
then choose “possibly related.”  
For the purpose of this protocol, an event that has possible relationship 
to CA-008 or Exparel will be defined as a “Suspected Adverse Drug 
Reaction”.  
Probably related 
A clinical event, including laboratory test abnormality, with a temporal 
relationship to CA-008 or Exparel 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 CA-008 or Exparel 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  
▪ Action and outcome 
▪ Seriousness of event 
All SAEs will be documented and followed from the time the subject has signed the ICF until 
D29 visit (cohorts 1-3) or D8 visit (cohort 4) after the completion of surgery. All SAEs and non-


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serious AEs will be documented and followed from the time of administration of CA-008 or 
Exparel until D29 or D8, respectively, or later if necessary. AEs/SAEs 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 CA-008/Exparel 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. 
For cohorts 1-3, 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 CA-008-related by the 
Investigator.  For cohort 4, all AEs requiring hospitalization or prolongation of a pre-existing 
hospitalization should be reported as SAEs unless they occur after the Day 8 visit AND are not 
considered to be 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 CA-008 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 CA-008 or Exparel should be reported within 24 hours. 


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The procedure for reporting an SAE: 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-205@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 CA-008 or Exparel 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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11.1.4. 
Severity Grading for AEs 
Grading the severity of AEs is per investigator discretion (Section 17.G).   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.   
11.2. 
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, CA-
008 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  
13.1. 
Statistical and Analytical Plans 
This section describes the statistical methods to be used to analyze the efficacy and safety.  The 
final analysis plan will be documented in a formal Statistical Analysis Plan (SAP) that will 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 
The currently planned study is a follow-on exploratory study to a prior phase 2 study (CA-PS-
201) which showed CA-008 4.2 mg was statistically significantly superior to placebo.  This 
study is being performed to evaluate optimal anesthesia conduct, therefore no sample size 
estimation was performed.  It was felt that a comparison of 9 in each treatment cohort would be 
sufficient to demonstrate the effectiveness of any anesthesia combination.  
13.3. 
Analysis Populations 
The following analysis populations are planned for this study:  
• The Safety Population will include all subjects who received at least part of a dose of CA-
008 or Exparel.   
• The Study Completer Population will include all subjects who complete the D29 visit 
(cohorts 1-3) or D8 visit (cohort 4). 
Subjects who elect to discontinue study participation during the inpatient phase of the study, will 
be asked to continue with assessments through T72h if they have not elected to withdraw from 
all aspects of study participation.  Subjects who elect to discontinue participation after discharge 
from the inpatient unit but prior to D8 will be considered to have terminated as of the date of 
their election, however they will be asked to return to the site to reassess the surgical site for 
wound healing. 
All safety and efficacy assessments and baseline characteristics will be summarized using the 
Safety Population.  All summaries will be grouped by the actual treatment received.    
13.4. 
Planned Analyses 
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, 


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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 enrolling, 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 
All protocol deviations will be classified and documented before database lock and will be 
discussed in the CSR.  All protocol deviations, both minors and majors, 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 screening 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. 
13.5.4. 
Exposure  
Since this is a single dose study, CA-008 or Exparel administration will be summarized 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 


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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 T0hNRS is the time of entry to the PACU.  
• Day of surgery is defined as D0 
• Assessment visit times are defined by time T0NRS /D0. 
• Baseline value is defined as the last valid measurement prior to beginning CA-008 
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 
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). 
13.6. 
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.  Details may be found it the 
study statistical analysis plan (SAP) 
AUC calculations will be done using the standard trapezoidal rule  


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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 ambulation. 
In this study, subjects are permitted to take rescue medication for analgesia.  During both 
inpatient and outpatient portions of the study, the subjects will be instructed to record NRS 
immediately prior (within approximately 15 min) to taking rescue medication. 
Missing NRS will be handled as discussed in the Study’s SAP and as briefly outlined in Section 
13.6.1.   
13.6.1. 
Handling of Dropouts and 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 CA-008 or Exparel; 
• 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.   
For subjects who take rescue medication a windowed last pain score carried forward (LOCF) 
will be used. The pre-rescue pain score will be used to impute scheduled assessments for 30 min 
after IV fentanyl and 4 hours following PO oxycodone.  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 or replacing drop out with the 
median data from the remainder of subjects in that treatment group. 
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. 
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. 


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13.7. 
Analysis of Safety  
Safety analyses will be conducted using data from the Safety Population (as defined in 
Section 13.3).  
Safety will be assessed through TEAEs, surgical site and neurosensory assessments.  
No formal statistical comparisons will be performed for safety endpoints. 
13.7.1. 
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 through D29 (cohorts 1-3) or D8 (cohort 
4) or Early Termination, whichever occurs first;  
▪ Serious AEs with onset on the date of surgery through D29 (cohorts 1-3) or D8 (cohort 4) or 
Early Termination, whichever occurs first; 
▪ AEs that start before the start of treatment but increase in severity or relationship at the time 
of or following the start of treatment through D29 (cohorts 1-3) or D8 (cohort 4) 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 CA-008. A listing of SAEs will be provided if applicable. 
13.7.2. 
Surgical Site and Neurosensory Testing Findings 
Surgical site assessments and neurosensory testing data will be presented in the listings. 
Abnormal or clinically significant findings atypical for the surgery 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, if the site is required to use a local IRB as well as the central 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 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 CA-008s, 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 CA-008 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 CA-008 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 
Investigator’s portion) is completed, terminated, or discontinued or 2 years following withdrawal 


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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 
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 
An Open-Label Study of Intraoperative CA-008 Administration in Subjects 
Undergoing Bunionectomy  
Version: 4.0  
Date: 02 May 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 JF, Mouksassi MS et al. Pharmacokinetic analysis of capsaicin after topical 
administration of a high-concentration capsaicin patch to patients with peripheral neuropathic pain. Ther 
Drug Monit 2009; Aug;31(4):502-10. doi: 10.1097/FTD.0b013e3181a8b200. 
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 Dec 1;31(12):877-82. 
4. Suresh D and Srinivasan K. Tissue distribution & elimination of capsaicin, piperine & curcumin following 
oral intake in rats. Indian J Med Res 2010; 131:682– 691.  
5. Surh YJ, Ahn SH, Kim KC et al. Metabolism of capsaicinoids: evidence for aliphatic hydroxylation and its 
pharmacological implications. Life Sci 1995; 56:PL305–PL311. 
6. Tominaga M, Caterina MJ, Malmberg AB et al. The cloned capsaicin receptor integrates multiple pain-
producing stimuli. Neuron 1998; 21, 531–543. 


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17. APPENDICES 
A. 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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B. Appendix B:  0-10 Numerical Rating Scale for 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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D. Appendix D: Surgical Site Assessment 
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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E. Appendix E: Wound Status Assessment Guide 
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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F. Appendix F: Neurosensory Testing Form 
 
For all assessments, the foot should be warm.  
• 
Foot Inspection: The feet are inspected for evidence of excessively dry skin, callous formation, fissures, 
frank ulceration or deformities. Deformities include flat feet, hammer toes, overlapping toes, hallux valgus, 
joint subluxation, prominent metatarsal heads, medial convexity (Charcot foot) and amputation.  
• 
Monofilament Sensation Testing: For this examination, it is important that the patient’s foot be supported 
(i.e., allow the sole of the foot to rest on a flat, warm surface). The filament should initially be prestressed 
(4-6 perpendicular applications to the dorsum of the examiner’s first finger). The filament is then applied 
to the dorsum of the great toe midway between the nail fold and the DIP joint. Do not hold the toe directly. 
The filament is applied perpendicularly 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 bilaterally with the great toe unsupported. Allodynia 
will be tested using a foam brush applied to the dorsum of the great toe.  The foam brush will be lightly 
stroked 3 times across the skin over the dorsum of the great toe.  Subject will be asked to compare sensation 
of toe on the surgical side with the toe on the nonsurgical side.  If the sensation is described as painful or 
very unpleasant then allodynia will be reported as present.  If sensation is not felt at all then it will be 
reported as absent.   
 


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G. Appendix G: Toxicity Grading Scale for Healthy Adult and Adolescent 
Volunteers Enrolled in Preventive Vaccine Clinical Trials 
Table for Vital Sign Abnormalities 
Vital Signs * 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially Life 
Threatening 
(Grade 4) 
Fever (°C) ** 
           (°F) * 
38.0 – 38.4 
100.4 – 101.1 
38.5 – 38.9 
101.2 – 102.0 
39.0 – 40 
102.1 – 104 
> 40 
> 104 
Tachycardia - beats 
per minute 
101 – 115 
116 – 130 
> 130 
ER visit or 
hospitalization for 
arrhythmia 
Bradycardia - beats 
per minute*** 
50 – 54 
45 – 49 
< 45 
ER visit or 
hospitalization for 
arrhythmia 
Hypertension 
(systolic) - mm Hg 
141 – 150 
151 – 155 
> 155 
ER visit or 
hospitalization for 
malignant 
hypertension 
Hypertension 
(diastolic) - mm Hg 
91 – 95 
96 – 100 
> 100 
ER visit or 
hospitalization for 
malignant 
hypertension 
Hypotension 
(systolic) – mm Hg 
85 – 89 
80 – 84 
< 80 
ER visit or 
hospitalization for 
hypotensive shock 
Respiratory Rate – 
breaths per minute 
17 – 20 
21 – 25 
> 25 
Intubation 
* Subject should be at rest for all vital sign measurements. 
** Oral temperature; no recent hot or cold beverages or smoking. 
*** When resting heart rate is between 60 - 100 beats per minute. Use clinical judgement when 
characterizing bradycardia among some healthy subject populations, for example, conditioned athletes. 
 
 


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H. Appendix H:  Monitored Anesthesia Care 
 
 


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SAP_001.pdf: 
 
 
 
 
 
OFFICIAL TITLE: 
An Open-Label Study of Intraoperative CA-008 Administration in Subjects Undergoing 
Bunionectomy 
 
 
NCT NUMBER: 
03885596 
 
DOCUMENT DATE: 
05 Jun 2019 
 


Sponsor: Concentric Analgesics, Inc. 
 
Statistical Analysis Plan  
Protocol Number: CA-PS-205 
 
Date: 05JUN2019 
 
 
CONFIDENTIAL 
 
 
 
STATISTICAL ANALYSIS PLAN  
 
An Open-Label Study of Intraoperative CA-008 Administration in Subjects Undergoing 
Bunionectomy 
Protocol Number:  CA-PS-205 
Protocol Version 4.0 (02MAY2019) 
 
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. 
 
DocuSign Envelope ID: 912AFA3F-2BE7-4BBF-BE1E-3F20A1E209C6
SIGN


Sponsor: Concentric Analgesics, Inc. 
 
Statistical Analysis Plan  
Protocol Number: CA-PS-205 
 
Date: 05JUN2019 
 
CONFIDENTIAL 
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DOCUMENT VERSION CONTROL 
Version Number 
Date 
Comments/Changes 
V1.0 
05JUN2019 
SAP  
 
 
 
 
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Sponsor: Concentric Analgesics, Inc. 
 
Statistical Analysis Plan  
Protocol Number: CA-PS-205 
 
Date: 05JUN2019 
 
CONFIDENTIAL 
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APPROVALS 
Author: 
 
 
 
 
 
 
 
 
 
 
Song Liou 
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: 
 
 
 
DocuSign Envelope ID: 912AFA3F-2BE7-4BBF-BE1E-3F20A1E209C6
05-Jun-19
05-Jun-19
05-Jun-19


Sponsor: Concentric Analgesics, Inc. 
 
Statistical Analysis Plan  
Protocol Number: CA-PS-205 
 
Date: 05JUN2019 
 
CONFIDENTIAL 
 Page 4 of 34 
 
 
 
 
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 
2.1.3 
Exploratory Objective .......................................................................................... 9 
2.2 
Overall Study Design and Plan ............................................................................ 9 
2.2.1 
Study Population ............................................................................................... 12 
2.2.2 
Treatment Regimens ......................................................................................... 12 
2.2.3 
Treatment Group Assignments or Randomization ............................................. 13 
2.2.4 
Sample Size Determination ............................................................................... 14 
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............................................................................................ 16 
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 Analysis ............................................................................................ 20 
7.3 
Assessment Time Windows ............................................................................... 20 
7.4 
Efficacy Endpoints ............................................................................................. 21 
7.5 
Analysis Methods .............................................................................................. 21 
7.5.1 
NRS Measurements .......................................................................................... 21 
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Statistical Analysis Plan  
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CONFIDENTIAL 
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7.5.2 
Pain Intensity Scores at T24hNRS, T48hNRS and T72hNRS at Rest and with 
Ambulation ........................................................................................................ 22 
7.5.3 
AUC 0-72h at Rest ............................................................................................ 22 
7.5.4 
Daily and Total Opioid Consumption (OC) in Oral Morphine equivalents ........... 22 
8. 
SAFETY EVALUATION ..................................................................................... 23 
8.1 
Overview of Safety Analysis Methods ................................................................ 23 
8.2 
Adverse Events and SAEs ................................................................................. 24 
8.3 
Physical Examination ........................................................................................ 26 
8.4 
Vital Signs ......................................................................................................... 27 
8.5 
Surgical Site Assessments and Rebound Pain Assessments ............................ 27 
8.6 
Neurosensory Test ............................................................................................ 27 
8.7 
X-ray of  the Surgical Site .................................................................................. 27 
8.8 
Electrocardiogram (ECG) at Screening.............................................................. 27 
8.9 
Clinical Laboratory Test Results at Screening ................................................... 28 
8.10 
Drugs of Abuse and Alcohol Screens, Pregnancy Test ...................................... 28 
8.11 
Subject pain Assessment Training and Surgery Details ..................................... 28 
9. 
OTHER ANALYSES .......................................................................................... 28 
10. 
INTERIM ANALYSES ........................................................................................ 28 
11. 
REFERENCES .................................................................................................. 28 
12. 
APPENDICES ................................................................................................... 30 
12.1 
Planned Tables, Figures and Listings ................................................................ 30 
12.1.1 Tables ............................................................................................................... 30 
12.1.2 Figures .............................................................................................................. 32 
12.1.3 Listings .............................................................................................................. 33 
13. 
DOCUMENT HISTORY ..................................................................................... 34 
 
 
 
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Statistical Analysis Plan  
Protocol Number: CA-PS-205 
 
Date: 05JUN2019 
 
CONFIDENTIAL 
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LIST OF IN-TEXT TABLES AND FIGURES 
Table 2-1 
Protocol-Specified Visits and Visit Windows .................................. 12 
Table 3 
Equianalgesic Conversion Table ................................................... 23 
Table 4 
Table of Imputation Rules for Missing AE Start Dates ................... 26 
 
 
 
 
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Statistical Analysis Plan  
Protocol Number: CA-PS-205 
 
Date: 05JUN2019 
 
CONFIDENTIAL 
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LIST OF ABBREVIATIONS (COMMONLY USED) 
 
ADaM 
 
Analysis Data Model 
AE 
Adverse Event 
ATC 
Anatomical Therapeutic Chemical 
AUC 
Area Under the Curve 
BMI 
Body Mass Index 
BUNX 
Bunionectomy 
CDER 
Center for Drug Evaluation and Research 
CRF 
Case Report Form 
CSR 
Clinical Study Report  
ECG 
Electrocardiogram 
FDA 
Food and Drug Administration 
HCl 
Hydrochloride  
ICF 
Informed Consent Form 
ICH 
 
International Conference on Harmonization  
LOCF 
Last Observation Carried Forward 
MAC 
Monitored Anesthesia Care 
MedDRA 
Medical Dictionary for Regulatory Activities 
MED 
morphine equivalent dose 
NRS 
Numerical Rating Scale for Pain Intensity  
OC 
Opioid Consumption in morphine equivalent dose 
OTC 
Over-the-counter 
PACU 
Post-Anesthesia Care Unit 
PT 
Preferred Term 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
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Protocol Number: CA-PS-205 
 
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CONFIDENTIAL 
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SDTM  
Standard Data Table Model 
SOC 
System Organ Class 
SPI 
Sum of Pain Intensity 
TEAE 
Treatment Emergent Adverse Event 
WHO 
World Health Organization 
WOCF 
Worst Observation Carried Forward 
 
 
 
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Sponsor: Concentric Analgesics, Inc. 
 
Statistical Analysis Plan  
Protocol Number: CA-PS-205 
 
Date: 05JUN2019 
 
CONFIDENTIAL 
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1. PURPOSE OF THE ANALYSES 
This statistical analysis plan (SAP) is based on protocol number CA-PS-205 Version 4.0 
(02MAY2019) 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 different standard of care anesthetic regimens on CA-008 administration in 
subjects undergoing an elective bunionectomy (BUNX). 
2.1.2 Secondary Objective 
• 
To confirm the safety and efficacy of CA-008 with different standard of care anesthetic 
regimens in subjects undergoing an elective BUNX. 
2.1.3 Exploratory Objective 
• 
To evaluate Exparel’s performance in subjects undergoing an elective BUNX under a 
standard of care anesthetic regimen. 
2.2 
Overall Study Design and Plan 
This is a Phase 2, single-center, open-label study of 3 cohorts of 9 subjects each evaluating a 
single dose of CA-008 4.2 mg administered during an elective unilateral transpositional first 
metatarsal osteotomy for the correction of hallux valgus deformity (bunionectomy or BUNX) under 
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Date: 05JUN2019 
 
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monitored anesthesia care (MAC) and Mayo field block with or without a supplemental popliteal 
block with bupivacaine hydrochloride (HCl) and lidocaine HCI.  
Additionally, a 4th cohort of 9 subjects will receive Exparel® (bupivacaine liposome injectable 
suspension; Pacira Pharmaceuticals, Inc.) under MAC and Mayo field block with bupivacaine HCI 
and lidocaine HCI. 
 The study will be conducted in two parts:  
• 
Inpatient period which continues to T72hNRS (72 hours after entering Post-Anesthesia Care 
Unit (PACU)). 
• 
Outpatient period which begins on discharge from the inpatient unit through various follow 
up visits to D29±2 after surgery (cohorts 1-3) or to D8±1 (cohort 4).  
Subjects who elect to discontinue study participation during the inpatient phase of the study, will 
be asked to continue with assessments through T72hNRS if they have not elected to withdraw from 
all aspects of study participation.  Subjects who elect to discontinue participation after discharge 
from the inpatient unit but prior to D8 will be considered to have terminated as of the date of their 
election, however they will be asked to return to the site to reassess the surgical site for wound 
healing. 
The surgery is to be performed under MAC anesthesia (see Appendix 17.H of Protocol) 
supplemented with one of two different standard of care regimens to produce surgical anesthesia.  
In both regimens, intraoperative analgesia will include IV ketorolac 30 mg and IV acetaminophen 
1 g at the onset of anesthesia. The systemic anesthesia medication doses detailed in the current 
protocol (including but not limited to fentanyl, ketorolac and acetaminophen) are suggested 
guidelines to be followed by the anesthesiologist caring for the subject. The actual doses given 
are at the discretion of the anesthesiologist based on the clinical status of the subject.  With 
respect to non-analgesic medications, the anesthesiologist is free to use clinical discretion on the 
choice and dose. 
In the 1st cohort of 9 subjects, prior to surgical incision (except as noted), perform the following 
local anesthetic nerve blocks:  
• 
A popliteal block performed under ultrasound guidance using bupivacaine HCl 0.25% 30 
mL (75 mg)  
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Date: 05JUN2019 
 
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• 
A Mayo block using bupivacaine HCl 0.25% 30 mL (75 mg) also prior to surgery and 
lidocaine HCl 1.5% 12 mL at the end of surgery  
In the 2nd cohort of 9 subjects perform the following:  
• 
A Mayo block alone using bupivacaine HCl 0.5% 15 mL combined with lidocaine HCl and 
lidocaine HC1 2% 15 mL prior to surgery 
In the 3rd and 4th cohorts of 9 subjects in each perform the following: 
• 
A Mayo block alone using bupivacaine HCl 0.5% 10 mL combined with lidocaine HCl 2% 
20 mL prior to surgery 
• 
CA-008 or Exparel must be injected no sooner than 20 minutes after the Mayo block 
• 
Total bupivacaine HCl equivalent dose 176.8 mg: 121.8 mg from Exparel and 55 mg from 
bupivacaine HCl 
For the Mayo block, inject just distal to the base of the 1st metatarsal to provide coverage of each 
quadrant paying particular attention to the space between the 1st and 2nd metatarsals. 
After the surgery, patients will be monitored in the PACU to ensure recovery from the anesthesia.  
Subjects will be monitored for 72 hours (T72hNRS) in an inpatient unit during which time safety and 
efficacy evaluations will be performed. After recovery from surgery, subjects in cohorts 1 and 2 
will be given: celecoxib (Celebrex®) 200 mg PO bid each day while an inpatient, and 
acetaminophen 1 g PO (2 doses on the day of surgery starting at 6±2h after surgery and again at 
12±2h after surgery) and t.i.d. each day thereafter while an inpatient. After recovery from surgery, 
subjects in cohorts 3 and 4 will be given no additional non-opioid analgesics. After discharge from 
the inpatient unit, non-opioid analgesics may be recommended by the Principal Investigator for 
subject use as needed. 
After completing the assessments through T72hNRS hours after CA-008 administration and prior to 
discharge from the inpatient unit, review with the subject the use of a diary for at-home use to 
record pain assessments and medication use (including pain medication) at home.  Subjects are 
instructed to return to the study center on D8±1 for a follow-up assessment.  Once discharged 
from the inpatient unit, all study participants will be instructed to take a combination of over-the-
counter (OTC) analgesics (NSAID and acetaminophen) at an appropriate dose per medical 
judgment to manage any residual or breakthrough postsurgical pain through D29.  
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In their diary, subjects will assess their current pain intensity at rest and after ambulation each 
morning (08:00 ±2 hours), and each evening (20:00 ±2 hours) using the NRS.  The morning NRS 
assessment should be obtained prior to taking any pain medication.  Subjects will also record any 
medication they take (dose and time) whether it was taken to treat their pain or for any other 
reasons.  
Persistent pain or pain exacerbations during 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. 
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 PACU stay) to 72  
Follow-up 
Cohorts 1 - 3: Days 8(±1 day), 15(±2 days), 29(±2 days) 
Cohort 4       : Days 8(±1 day) 
 
All study assessments are outlined in Table 1 of the Protocol. 
2.2.1 Study Population 
Adults ages 18 to 65 years, inclusive, who are planning to undergo an elective unilateral BUNX 
and otherwise meet eligibility criteria (as described in the protocol Sections 8.1 and 8.2) may be 
considered for enrollment into the study.  
2.2.2 Treatment Regimens 
Cohorts 1, 2, and 3: 
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CA-008 (4.2 mg in 14 mL) will be injected/instilled intraoperatively into the soft tissues and 
osteotomy surgical site as follows:  
• 
Instill 2 mL at cut bone sites prior to fixation  
• 
Prior to capsule closure, infiltrate the deep soft tissue and area proximal to the capsule 
with a total of 9 mL (approximately 2.25 mL into each quadrant circumferentially)  
• 
Close the capsule, but using a small gauge catheter (or needle) infiltrate 2 mL into the 
closed capsule space     
• 
Prior to closure of the subcutaneous tissues and skin, instill 1 mL to coat all exposed 
surfaces   
Cohort 4: 
Exparel 106 mg (8 mL of the 133 mg/10 mL suspension) will be infiltrated intraoperatively into the 
soft tissues and osteotomy surgical site prior to closure as follows:  
• 
Infiltrate 7 mL into the tissues surrounding the osteotomy  
• 
Infiltrate 1 mL into the subcutaneous tissues  
See Exparel full prescribing information for detailed administration instructions: 
https://www.exparel.com/hcp/prescriptioninformation.pdf (as revised 11/2018; Pacira 
Pharmaceuticals, Inc.). 
2.2.3 Treatment Group Assignments or Randomization 
No randomization will be performed for this open label study. 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 is assigned, it cannot 
be reassigned to any other subject.  There will be 4 treatment cohorts exploring different 
anesthesia regimens and subjects will be assigned to cohorts prior to dosing.  Dose (CA-008 for 
cohorts 1-3 or Exparel for cohort 4) and treatment will be the same for all treated subjects within a 
cohort.   
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2.2.4 Sample Size Determination 
This study is a follow-on exploratory study to a prior phase 2 study (CA-PS-201) which showed 
CA-008 4.2 mg was statistically significantly superior to placebo.  This study is planned to 
evaluate optimal anesthesia conduct; therefore, no sample size estimation was performed.  It was 
felt that a comparison of 9 in each cohort would be sufficient to demonstrate the effectiveness of 
any anesthesia combination. 
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. 
Cohorts will be presented separately in summaries and analyses. A CA-008 overall column 
(cohorts 1-3) 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, standard deviation (SD), median, and range (minimum, 
and maximum). All of the categorical study assessments will be summarized by cohort 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, 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. 
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 
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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: 
• 
Day of surgery is defined as Day 0 (D0). 
• 
Time 0 (T0) is the time the first dose of study medication (CA-008 or Exparel) was 
completed. 
• 
Time 0 (T0hNRS) for efficacy measurements is the time of entry to the PACU.  
• 
Assessment visit times are defined by D0, T0 and/or T0hNRS. 
• 
Baseline value is defined as the last valid measurement prior to the dosing of study 
treatment (T0 of CA-008 or Exparel). 
• 
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 for to the site for 
assessment. 
• 
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 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). 
4. SUBJECT POPULATIONS 
4.1 
Analysis Populations 
The following analysis populations are planned for this study: 
• 
Safety Population will include all subjects who received any amount of study drug.  
• 
Completer Population will include all subjects who receive a full dose of study drug  and 
complete the Day 29 visit (D29 ± 2) for cohorts 1 – 3 or the Day 8 (D8± 1) for cohort 4.  
All analyses will be performed using Safety population using actual treatment received.  
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 enrollment or are enrolled but not treated will 
be listed and summarized in the disposition summary table. Subjects who are enrolled, 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 withdrawal will be 
summarized by cohort and for CA-008 groups 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 before database lock and will be discussed in the clinical study report (CSR). The 
number of subjects with protocol deviations, both minor and major, will be presented in a data 
listing. 
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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), body mass index (BMI; kg/m2) and target foot (left or right). 
Demographics and baseline characteristics will be summarized overall and by cohort using safety 
population.  
5.2 
Medical/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. Subject’s medical history will be evaluated by an Investigator for clinical significance.  
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 on going is considered concomitant 
medication/therapy. Prior and concomitant medications are collected for the 30 days prior to 
screening and throughout the study. Prior and concomitant medications will be coded using World 
Health Organization Drug Dictionary Anatomical Therapeutic Chemical (WHO/ATC) classification 
index version March 1, 2018. The number and percentage of subjects who take concomitant 
medications will be summarized by drug class and preferred term, overall and by study cohort, for 
the safety population. All medications and non-medical therapies captured in CRFs will appear in 
data listings. 
 
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6. MEASUREMENTS OF TREATMENT EXPOSURE AND COMPLIANCE 
Because study medication is administered as a single dose at the study center by trained study 
personnel, 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 72 hours after discharge to PACU, the diary for at-
home use will be distributed to the subject to collect pain intensity (twice daily on NRS) through 
Day 8 visit and pain medication through Day 15 visit for cohorts 1-3 or Day 8 for cohort 4. 
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 between the date subject discharged to PACU and date of Day 8 visit (or the date 
of the last study visit (whichever is earlier)).  The number of days of participation will be calculated 
as the date of the Day 8 visit or the date of the last study visit (whichever is earlier) minus the date 
of discharge. If subject is discharged after 10:00 (morning NRS that supposed to be collected at 
0800h (±2h)) then subtract 1 from the obtained value, assuming that morning NRS assessed on 
the date of discharge was collected while subject was still inpatient. Also subtract 1 for Day 8 visit 
evening NRS record (since it was not supposed to be collected). NRS recorded prior to a rescue 
use will not be included in this calculation of compliance. For example, Subject A in cohort 1 was 
discharged on Day 3, 7AM, if this subject discontinues the study on Day 8, then the expected N of 
NRS records on diary will be 11 (2 * (8-3+1) -1). Assuming Subject A had 5 NRS available from 
his/her diary, then compliance for this subject would be 45% ((5/11) *100). However, if subject A 
had discontinued the study on Day 6 (prior to Day 8), then the expected N of NRS for this subject 
would be 7 (2 * (6-3+1)-1) and compliance would be 71.4% ((5/7) *100).  Compliance will be 
calculated for both NRS at rest and after ambulation. A summary of compliance will be provided 
overall and by cohort.  
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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. 
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. 
• 
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: 
First, when rescue medication is used, any NRS measured at rest within following window is 
considered invalid:  
• 
30 minutes for IV fentanyl 
• 
4 hours for PO oxycodone or other PO opioids.  
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 schedule 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. If 
the NRS time is the same as the end of time window 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 (IV morphine) is taken at 1pm, all protocol-
scheduled NRS will be imputed with the appropriate NRS value up to and including through 5pm 
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(a 4-hour window). 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 
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 early, 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 efficacy endpoints derived from NRS (e.g., NRS at rest or with ambulation at 
Hours 24NRS, 48NRS or 72NRS).   
7.2 
Sensitivity Analysis 
The following imputation methods will be performed and analyzed as sensitivity analyses for NRS 
at Hours 24NRS, 48NRS, and 72NRS efficacy endpoints: 
1. Last observation carried forward (LOCF) will be imputed for missing assessment(s) after 
drop out. 
2. Median score (from the remainder of subjects in the group continuing in the study)  will be 
imputed for missing assessment(s) after dropping out.   
7.3 
Assessment Time Windows 
For calculations of 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, 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 
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. 
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Other efficacy and safety assessment summaries will be based on the nominal protocol-specified 
assessment times.  
7.4 
Efficacy Endpoints  
Pain intensity over the 72 hours inpatient stay (at 24NRS, 48NRS and 72NRS hours) will be assessed 
using NRS score at rest and with ambulation. 
In addition,  
• 
NRS scores at scheduled timepoints other than Hours 24NRS, 48NRS or 72NRS.  
• 
Area Under the Curve (AUC) of the NRS at rest from T0hNRS to T72hNRS (AUC0 to 72h).  
• 
Daily and total opioid consumption (OC) in oral morphine dose equivalents (MEDs) as 
recorded during the inpatient and outpatient period.  
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: 
• 
At T0hNRS (entry to PACU), 1NRS, 2NRS, 3NRS, 4NRS, 6NRS, 8NRS and 12NRS hours and every 6 
hours thereafter while an inpatient. 
• 
Pain scores may be skipped between the hours of midnight and 6 a.m., but the subject 
may not miss two consecutive assessments due to sleeping. 
• 
The 24NRS - and 48NRS -hour assessments must be completed even if the subject is asleep 
at these times. 
• 
An additional NRS assessment must be obtained within 15 min of the time of rescue 
medication request but prior to administration of rescue. 
• 
Starting in the evening of the 1st postoperative day through the D8 visit, NRS 
assessments twice daily at approximately 0800h (±2h) and each evening prior to bedtime 
at approximately 2000h (±2h) at rest and with ambulation of approximately 10 yards.  Note 
that the actual time of these assessments must be documented in the diary. 
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7.5.2 Pain Intensity Scores at T24hNRS, T48hNRS and T72hNRS at Rest and with Ambulation 
Missing NRS at Hours 24, 48 or 72 scheduled hours after T0hNRS will be handled as discussed in 
Sections 7.1 and 7.2.  
Descriptive summaries will be presented overall and for each cohort of the mean NRS at the 24, 
48 and 72 hour timepoints.  Similar summaries will also be displayed at each time point without 
imputation for early drop out. In addition, Mean NRS value by Cohort and Individual NRS values 
over time will be displayed graphically. 
7.5.3 AUC 0-72h at Rest 
AUC calculations will be done using the standard trapezoidal rule  
AUC =     ∑
(
𝑁𝑃𝑅𝑆𝑖+𝑁𝑃𝑅𝑆𝑖+1
2
)
𝑥
𝑖=0
∗ (𝑇𝑖+1 − 𝑇𝑖) 
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 1-
factor (treatment) analysis of variance (ANOVA) model with treatment as the main effect.    
The AUC analyses will be presented in a summary table with standard summary statistics for 
each cohort. 
The individual NRS and the computed AUC variables will be listed for all individual subjects. 
7.5.4 Daily and Total Opioid Consumption (OC) in Oral Morphine equivalents  
Opioid use is recorded on the rescue medication eCRF from the end of surgery through 14 days 
for cohorts 1-3 (or 7 days for cohort 4) after the end of surgery (D15/D8 visit) or to  Early 
termination (ET) visit if applicable. 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 of the 
medications taken on that day. For example, if a 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. 
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Date: 05JUN2019 
 
CONFIDENTIAL 
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Table 3 
Equianalgesic Conversion Table 
Opioid (Doses in mg) 
Conversion Factor to IV morphine 
Conversion Factor to PO morphine 
IV Fentanyl 
100 
 
IV Hydromorphone 
6 
 
IV Morphine 
1 
6* 
PO Hydrocodone 
 
1 
PO Morphine 
 
1 
PO Oxycodone 
 
1.5 
PO Tramadol 
 
0.1 
For any IV opioid, we will use a 2-step process to calculate its oral (PO) morphine equivalent dose (MED): 
1. Convert its IV dose to IV morphine MED by multiplying by the conversion factor for IV equivalence. 
2. Once the IV morphine MED is calculated, convert to the PO morphine MED using the conversion 
factor for PO equivalence. 
For any PO opioid, use the conversion factor to calculate the PO MED. 
*Note that for non-tolerant patients, we are using the 6:1 conversion for IV to PO morphine, or in other 
word, 10 mg IV morphine = 60 mg PO morphine. 
 
Total opioid consumption will be calculated for 0-72 hours (OC0 to 72h) and 24-72 hours (OC24 to 72h). 
A 1-way will be performed. A separate summary containing only subjects that have taken at least 
one dose of rescue will be performed if warranted.  
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 treatment-emergent adverse events (TEAEs) or treatment-emergent serious 
adverse events (SAEs) 
• 
Clinically significant changes in surgical site assessments and neurosensory testing 
• 
X-ray healing (cohorts 1-3 only) 
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• 
Absence of rebound pain at the surgical site (cohorts 1-3 only) 
• 
Physical examination 
• 
Vital signs 
• 
Drug screen 
8.2 
Adverse Events and SAEs 
All AEs and SAEs are documented and followed from the time the subject have signed the 
informed consent form (ICF) until D29 (for cohorts 1-3) or D8 (for cohort 4), and, if necessary, 
later. All events will be documented and followed from the time of administration of CA-008 until 
D29 or Exparel until D8. AEs will be coded by system organ class (SOC) and preferred term (PT) 
using the Medical Dictionary for Regulatory Activities (MedDRA Version 21.0) reporting system. 
All coding will be reviewed prior to database lock. All recorded AEs will be listed, but only TEAEs 
will be summarized. 
Treatment-emergent AEs are defined as any of the following:  
• 
Non-serious AEs with onset on the date of treatment with the study drug through D29 
(cohorts 1-3) or D8 (cohort 4) or Early Termination, whichever occurs first. 
• 
Serious AEs with onset on the date of treatment with the study drug through D29 (cohorts 
1-3) or Day8 (cohort 4) or Early Termination, whichever occurs first. 
• 
AEs that start before the start of treatment but increase in severity or relationship at the 
time of or following the start of treatment through D29 (cohorts 1-3) or D8 (cohort 4)  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 to be related. 
For the evaluation of event severity terms, the criteria are mild, moderate or severe. 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. 
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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 by SOC and PT 
sorted in alphabetically by SOC, and then by PT within SOC. These summaries will be given by 
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 
 
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., attribution to study material). 
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. 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. 
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 targeted reassessment will be performed prior to surgery, 
at discharge from the inpatient unit, and at the last visit (D29 for cohorts 1-3 or D8 for cohort 4) or 
if the subject terminates early, at that time if allowed.  
Abnormal or clinically significant physical exam will be recorded as AEs. Physical examination 
results will be listed for individual subjects.  
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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 cohort and time point. 
8.5 
Surgical Site Assessments and Rebound Pain Assessments 
Surgical sites will be assessed at 72 hours (prior to discharge from the unit) and then as an 
outpatient on Days 8, 15 and 29 (for cohorts 1-3 only). 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 rebound pain (rebound 
pain; Y/N) at the surgical site since the prior visit at Days 8, 15 and/or 29 (for cohorts 1-3 only).  
All data will be presented in data listings.  
8.6 
Neurosensory Test 
Neurosensory testing near the incision (compared to a similar site on the opposite leg) will be 
performed at screening, T72h (prior to discharge from the unit) and then as an outpatient on Days 
8, 15 and 29 (for cohorts 1-3 only). 
The neurosensory assessment results will be listed in data listing. 
8.7 
X-ray of  the Surgical Site 
X-ray of the  surgical site will be performed for subjects in cohorts 1-3 during screening (or verified 
as previously done) and at D29/ET.  
Results of x-ray of the surgical site will not be entered in database. Date and time of x-ray 
performed will be listed.  
8.8 
Electrocardiogram (ECG) at Screening 
ECG examination will be assessed at screening only. Findings at screening (normal, abnormal – 
not clinically significant or abnormal – clinically significant) will be provided in a data listing. 
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8.9 
Clinical Laboratory Test Results at Screening 
Appropriate screening labs will be performed at the site’s local laboratory.  It is the responsibility 
of the Investigator to review and sign all lab reports expeditiously, and to document appropriate 
safety monitoring of study subjects.  
Laboratory test results and sample collection information will be listed.  
8.10 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”. 
8.11 Subject pain Assessment Training and Surgery Details 
Subjects will undergo study participation education on pain assessments and written testing 
procedures during screening and prior to surgery.  
Patient pain assessment training and surgery Details will be documented in CRFs and will be 
listed for each subject. 
9. OTHER ANALYSES 
Any additional analyses not included in this SAP conducted after database lock will be considered 
exploratory and identified as Post Hoc in the CSR.  
10. INTERIM ANALYSES  
There are no planned interim analyses for this study. 
11. 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. 
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Statistical Analysis Plan  
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Date: 05JUN2019 
 
CONFIDENTIAL 
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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. 
 
 
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12. APPENDICES 
12.1 Planned Tables, Figures and Listings 
12.1.1 Tables 
Table 14.1.1 
All Subjects 
Summary of Subject Disposition 
Table 14.1.2 
Safety Population 
Summary of Demographics and Baseline 
Characteristics 
Table 14.1.3 
Safety Population 
Summary of Concomitant Medications by ATC Class 
and Preferred Term 
Table 14.1.4 
Safety Population 
Summary of Subject NRS and NRS at Rescue Diary 
Compliance 
Table 14.2.1.1 
Safety Population 
Summary of Hours 24, 48 or 72 NRS at Rest – 
WOCF (Primary Analysis) 
Table 14.2.1.2 
Safety Population 
Summary of Hours 24, 48 or 72 NRS at Rest – LOCF 
Table 14.2.1.3 
Safety Population 
Summary of Hours 24, 48 or 72 NRS at Rest – 
Median 
Table 14.2.2 
Safety Population 
Summary of NRS at Rest by Hour – Observed Data  
Table 14.2.3 
Safety Population 
Summary of NRS at Rest by Morning/Night – 
Observed Data 
Table 14.2.4.1 
Safety Population 
Summary of NRS with Walking by Morning/Night 
through Hour 72– WOCF  
Table 14.2.4.2 
Safety Population 
Summary of NRS with Walking by Morning/Evening 
through Hour 72– LOCF 
Table 14.2.4.3 
Safety Population 
Summary of Inpatient NRS with Walking by 
Morning/Evening through Hours 72 – Median 
Table 14.2.5 
Safety Population 
Summary of NRS with Walking by Morning/Night – 
Observed Data  
Table 14.2.6 
Safety Population 
Summary of AUC (0-72) NRS at Rest - WOCF 
Table 14.2.7 
Safety Population 
Summary of Opioid Consumption (in Morphine 
Equivalents) 
Table 14.2.8 
Safety Population 
 Summary of Opioid Consumption (in Morphine 
Equivalents) by Day 
Table 14.3.1.1 
Safety Population 
Overall Summary of Treatment-Emergent Adverse 
Events (TEAEs) 
Table 14.3.1.2 
Safety Population 
Summary of Treatment-Emergent Adverse Events 
(TEAEs) by System organ Class and Preferred Term 
Table 14.3.1.3 
Safety Population 
Summary of Treatment Related Treatment-Emergent 
Adverse Events (TEAEs) by System organ Class and 
Preferred Term 
Table 14.3.1.4 
Safety Population 
Summary of Serious Adverse Events by System 
organ Class and Preferred Term 
Table 14.3.1.5 
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 14.3.1.6 
Safety Population 
Summary of Treatment-Emergent Adverse Events 
(TEAEs) by System organ Class, Preferred Term and 
Severity 
Table 14.3.1.7 
Safety Population 
Summary of Treatment-Emergent Adverse Events 
(TEAEs) by System organ Class, Preferred Term and 
Relationship to Study Drug 
Table 14.3.2 
Safety Population 
Summary of Vital Signs: Results and Change from 
Baseline 
 
 
 
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12.1.2 Figures 
Figure 14.2.1.1 Safety Population 
Mean NRS over Time by Cohort – WOCF at Hours 24, 48 
and 72 
Figure 14.2.1.2 Safety Population 
Mean NRS over Time by Cohort - LOCF at Hours 24, 48 
and 72 
Figure 14.2.1.3 Safety Population 
Mean NRS over Time by Cohort - Median at Hours 24, 48 
and 72 
Figure 14.2.2 
Safety Population  Spaghetti Plot of NRS for each Subject by Cohort 
 
 
 
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12.1.3 Listings 
Listing 16.2.1 
All Subjects 
Screening 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 Subjects 
Demographics and Baseline Characteristics 
Listing 16.2.7 
All Subjects 
Medical/ Surgical History 
Listing 16.2.8.1 
All Subjects 
Prior and Concomitant Medications 
Listing 16.2.8.2 
All Subjects 
Rescue Medication Administration 
Listing 16.2.8.3 
All Subjects 
Non-Medication Therapies 
Listing 16.2.9 
All Subjects 
Surgery  
Listing 16.2.10 
All Subjects 
Study Drug Administration and Pain Assessment Training  
Listing 16.2.11 
All Subjects  
Discharge 
Listing 16.2.12 
All Subjects 
Subject NRS and NRS at Rescue Diary Compliance 
Listing 16.2.13 
All Subjects 
Pain Intensity Assessment (NRS at Rest) 
Listing 16.2.14 
All Subjects 
Pain Intensity Assessment (NRS with Walking) 
Listing 16.2.15 
All Subjects 
List of NRS Efficacy Endpoints  
Listing 16.2.16.1 
All Subjects 
Adverse Events 
Listing 16.2.16.2 
All Subjects 
Serious Adverse Events 
Listing 16.2.16.3 
All Subjects 
Treatment Related Adverse Events 
Listing 16.2.16.4 
All Subjects 
Adverse Events Leading to Study Discontinuation 
Listing 16.2.17.1 
All Subjects 
Chemistry Laboratory Test Results 
Listing 16.2.17.2 
All Subjects 
Hematology Laboratory Test Results 
Listing 16.2.17.3 
All Subjects 
Urinalysis Laboratory Test Results 
Listing 16.2.18 
All Subjects 
Vital Signs 
Listing 16.2.19 
All Subjects 
Alcohol and Urine Drug Screen Tests 
Listing 16.2.20 
All Subjects 
Pregnancy Tests 
Listing 16.2.21 
All Subjects 
Physical Examination and Targeted Physical Exam 
Assessment 
Listing 16.2.22 
All Subjects 
X-Ray of Surgical Site 
Listing 16.2.23 
All Subjects 
Surgical Site Assessment and Rebound Pain Assessment 
Listing 16.2.24 
All Subjects 
Neurosensory Exam 
Listing 16.2.25 
All Subjects 
12-Lead Electrocardiogram 
 
 
 
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13. DOCUMENT HISTORY 
 
Version 
# 
Summary of Changes 
Section Changed 
Date 
1.0 
Initial document released 
NA 
05JUN2019 
 
 
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disclosures electronically from us. 
How to contact Lotus Clinical Research, LLC:
You may contact us to let us know of your changes as to how we may contact you electronically,
to request paper copies of certain information from us, and to withdraw your prior consent to
receive notices and disclosures electronically:
 
To advise Lotus Clinical Research, LLC of your new e-mail address 
To let us know of a change in your e-mail address, you must send an email message to your
Lotus Lead Project Manager and in the body of such request you must state: your previous
e-mail address, your new e-mail address. We do not require any other information from you to
change your email address. 
In addition, you must notify DocuSign, Inc. to arrange for your new email address to be reflected
Electronic Record and Signature Disclosure created on: 8/14/2017 10:16:15 AM
Parties agreed to: Jennifer Nezzer, Mike Royal, Song Liou, Kelly Miller


in your DocuSign account by following the process for changing e-mail in the DocuSign system. 
To request paper copies from Lotus Clinical Research, LLC 
To request delivery from us of paper copies of the documents previously provided by us to you
electronically, you must send an e-mail to your Lotus Lead Project Manager and in the body of
such request you must state your e-mail address, full name, US Postal address, and telephone
number. 
To withdraw your consent
To inform us that you no longer want to receive future documents in electronic format via
DocuSign you may:
i. decline to sign a document from within your DocuSign session, and on the subsequent
page, select the check-box indicating you wish to withdraw your consent, or you may;
ii. send an email to your Lotus Lead Project Manager withdrawing consent, and in the
body of such request you must state your e-mail, full name, US Postal Address, and
telephone number. 
Required hardware and software
Operating Systems: 
Windows® 2000, Windows® XP, Windows
Vista® Mac OS® X 
Browsers: 
Final release versions of Internet Explorer® 6.0
or above (Windows only); Mozilla Firefox 2.0
or above (Windows and Mac); Safari™ 3.0 or
above (Mac only) 
PDF Reader: 
Acrobat® or similar software may be required
to view and print PDF files 
Screen Resolution: 
800 x 600 minimum 
Enabled Security Settings: 
Allow per session cookies
 
** These minimum requirements are subject to change. If these requirements change, you will be
asked to re-accept the disclosure. Pre-release (e.g. beta) versions of operating systems and
browsers are not supported. 
Acknowledging your access and consent to receive materials electronically
By checking the “I agree to use Electronic Records and Signatures” box in the DocuSign system,
you are confirming to us that: 
•
You can access and read this Electronic CONSENT TO ELECTRONIC RECEIPT OF
ELECTRONIC CONSUMER DISCLOSURES document; and
 
•
You can print on paper the disclosure or save or send the disclosure to a place where you can
print it, for future reference and access; and
 
•
Until or unless you notify Lotus Clinical Research, LLC, as described above, you consent to
receive through electronic means documents that require your signature