Conditions: Post-surgical Pain
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 147
Healthy volunteers: no

Brief summary:
This is a Phase 2, multi-center, randomized, double-blind, placebo-controlled, parallel design study evaluating a single dose of one of three CA-008 dose levels vs. placebo injected during an elective bunionectomy Bunionectomy to assess post-surgical pain management and the need for rescue medication (oxycodone).

Detailed description:
Primary Objective:

To evaluate the efficacy of a single intraoperative administration of CA- 008 vs placebo in subjects undergoing an elective Bunionectomy .

Secondary Objectives

* To evaluate the safety and tolerability of a single intraoperative administration of CA-008 vs. placebo in subjects undergoing an elective Bunionectomy.
* To evaluate the PK profile of a single intraoperative administration of CA-008 vs. placebo in subjects undergoing an elective Bunionectomy .
* To explore the efficacy of various doses of CA-008 administered intraoperatively in subjects undergoing an elective Bunionectomy .

Arms:
arm 1: Each patient will receive a single dose of 0.7 mg CA-008 injected during an elective Bunionectomy with a multimodal analgesia regimen including a Nonsteroidal anti-inflammatory drug (NSAID) and regional Mayo block with bupivacaine. arm 2: Each patient will receive a single dose of 2.1 mg CA-008 injected during an elective Bunionectomy with a multimodal analgesia regimen including a Nonsteroidal anti-inflammatory drug (NSAID) and regional Mayo block with bupivacaine. arm 3: Each patient will receive a single dose of 4.2 mg CA-008 injected during an elective Bunionectomy with a multimodal analgesia regimen including a Nonsteroidal anti-inflammatory drug (NSAID) and regional Mayo block with bupivacaine. arm 4: Each patient will receive a single dose of CA-008 vehicle (identical to active treatment but without CA-008) injected during an elective Bunionectomy with a multimodal analgesia regimen including a Nonsteroidal anti-inflammatory drug (NSAID) and regional Mayo block with bupivacaine.

Interventions: intervention 1: CA-008 intervention 2: Placebo intervention 3: Ketorolac intervention 4: Acetaminophen intervention 5: Oxycodone intervention 6: Bupivacaine Hydrochloride
Intervention descriptions: intervention 1: single-dose wound infiltration prior to surgical incision closure intervention 2: single-dose wound infiltration prior to surgical incision closure intervention 3: 30mg IV administered intraoperatively intervention 4: 1000mg IV administered intraoperatively intervention 5: 5mg PO prn post-surgery intervention 6: 0.5% infiltration pre-surgery

Protocol document:
Prot_000.pdf: 
 
 
 
 
 
OFFICIAL TITLE: 
A Phase 2, Randomized, Double-blind, Placebo-controlled Safety, 
Pharmacokinetics and Efficacy Study of CA-008 in Subjects Undergoing 
Bunionectomy 
 
NCT NUMBER: 
03599089 
 
DOCUMENT DATE: 
06 Jun 2018 
 


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Clinical Trial Protocol                                                          
Version 1.2: 06 June 2018 
 
Version 1.1:  03 May 2018 
 
A Phase 2, Randomized, Double-blind, Placebo-controlled Safety, 
Pharmacokinetics and Efficacy Study of CA-008 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. 
 
 
 




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1. 
KEY PERSONNEL CONTACT INFORMATION 
Sponsor  
Concentric Analgesics, Inc. 
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@lotuscr.com  
530-902-3070 
Biostatistician Jennifer Nezzer, MS  
Director of Biometrics 
Director, Biometrics 
jnezzer@lotuscr.com  
512-775-5321 
CRO Medical 
Monitors 
Primary: Jon L. Ruckle, MD, CPI 
MedicalMonitorCA-PS-
201@Lotuscr.com 
808-349-9812 
 
Secondary: Royce Morrison, MD 
MedicalMonitorCA-PS-2018-
201@Lotuscr.com 
206-799-7386 
 
Institutional Review Board 
Aspire IRB 
 
Taylor Lazar, LVN, Paralegal 
 
taylor@aspire-irb.com  
619-469-0108 
 


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2. 
TABLE OF CHANGES PROTOCOL VERSION 1.1 TO VERSION 1.2 
In lieu of an Administrative Protocol Clarification Letter to respond to requests from the various 
participating sites’ additional questions, it was elected to proceed with this administrative 
amendment to provide improved readability and clarity to ensure proper conduct of the study. 
Material change made (page #s are for 
Protocol V1.1) 
Rationale 
P7, P40 (Section 8.1.3), P53 (Section 
10.2.1): Multimodal analgesia – reduced 
the number of doses of ketorolac and 
acetaminophen allowed by the protocol 
from 3 to 1 
Prior to receipt of the final data from the Phase 1 bunionectomy 
study, there was a concern that the Mayo block alone would not be 
sufficient to control pain sufficiently in the immediate hours after 
surgery before the onset of benefit from the active product.  
However, this turned out not to be the case, and to reduce any 
confounding from the use of additional doses of systemic analgesics 
on the primary endpoint after the Mayo block wore off, it was 
elected to make this change. 
Note that all other changes are administrative in nature and do not materially affect the conduct of the study. 
Administrative changes made 
Rationale/Clarification 
P3: added additional names and contact 
information for Lotus Project Mgr and 
Aspire IRB 
n/a 
P8 (Synopsis), P42 (Section 8.1.4): 
clarification on outpatient multimodal 
analgesia dosing and timing of the 12h 
period before discharge triggering the 
potential need for a 2-day oxycodone 
prescription for pain control 
Rescue analgesia as an outpatient should be p.r.n. whether for 
ibuprofen or acetaminophen. 
If the subject requires opioid rescue in the period after T84h 
regardless of the time of discharge this triggers the need for a 
prescription for oxycodone.  Refills are per investigator discretion. 
P11 (Synopsis), P49: clarification of 
Exclusion criterion 4d to allow antibiotics 
for treatment if necessary after surgery 
to treat an AE; 4e refers to steroid 
inhaler for allergy treatment 
If the investigator feels that antibiotics are appropriate treatment 
for an AE this should be done and should not automatically trigger 
an ET.  Antibiotic prophylaxis is allowed is routinely performed per 
site standard of care. 
Language was added to include the use of steroid inhaler for 
treatment of asthma as well. 
P11 (Exclusion 6.a), P49 (Exclusion 6.a), 
P61 (Section 11.5.2): clarification on 
positive drug screen 
There is the potential for confusion with Exclusion 6.a and language 
on P61: “If any of these tests are positive (note exception for THC 
below [referring to Exclusion criterion 6.a]), the subject will not be 
allowed further participation.”   
Added explanatory note to this exclusion criterion.  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. 
P13 (Synopsis), P58 (Section 11.4.1): 
clarification on guidelines for 
“ambulation” 
In the immediate postoperative period, partial weightbearing on 
transfers to/from bed/wheelchair may be all that is appropriate for 
“ambulation”.  Once closer to discharge from the inpatient facility 
and during the outpatient period, subjects should be instructed to 
walk about 10 yards to assess pain with “ambulation”. 
P14(Synopsis), P20 (Schedule of Events): 
clarification on timing of specific protocol 
assessments 
The physical examination, neurosensory examination and surgical 
site assessment need not be collected at 24h after study treatment 
injection.   
Clinical laboratory tests should be collected at screening and 96h.   


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Urinalysis is performed only at screening and 96h.   
No need for repeat screening labs on day 0 (surgery day) unless it 
was not performed during screening.   
Daily temps can be recorded along with vital signs per site SOPs at 
1, 2, 4, 6, 12, 24, and every 8 h thereafter until discharge from the 
inpatient facility (if awake at the time of assessment between hours 
of midnight and 6 a.m.) 
P14 (Synopsis): clarification on time 
windows 
Lab collection window for 24h and 96h are ±30 min.  Neurosensory 
examination at 96h is ±4 h, but prior to discharge from the inpatient 
facility. 
P14 (Synopsis): clarification on 
coagulation tests 
These tests are not required. 
P20 (Schedule of Events), P62 (Section 
11.5.6): clarification on subject weights 
Weight assessments are not needed on day 15 and 29, or day 36 if 
this visit is necessary. 
P38 (Section 8.1); regarding timing of 
enrollment of PK subjects 
Removed language regarding a “smooth startup” 
P39 (Section 8.1.2), 44 (Section 8.1.8): 
clarification on vital signs 
Site is to collect temperature, BP, HR and RR. 
P42 (Section 8.1.4): clarification on 
topical ice and cooling packs 
Use of topical cooling is not allowed during the inpatient stay but is 
allowed for treatment of areas remote from the surgery site.  It may 
be used as an outpatient on the surgical site but subjects should be 
instructed to report this as a concomitant treatment that may be in 
response to an AE. 
P52 (Section 10.1.2): clarification on IP 
preparation 
Any language on preparation has been removed and the 
investigator is referred to the Pharmacy Manual to avoid potential 
conflicting language. 
P57 (Section 11.4.1): clarification on 
medical history documentation 
Only medical history deemed pertinent to the study by the 
investigator need be assessed for clinical significance. 
P57 (Section 11.1.5): clarification on 
contraceptives to prevent pregnancy 
Under double-barrier methods, the protocol specifies that this is a 
“male condom in addition to a diaphragm of a contraceptive 
sponge.” 
Spermicidal contraceptives are acceptable as part of a double-
barrier contraceptive program (i.e., spermicidal jellies, foams or 
gels) in any combination per discretion of the investigator. 
When considering male inclusion, they should be qualified by 
Inclusion #3. 
P59 (Section 11.1.4): clarification on 
rescue usage documentation after 
discharge 
Rescue consumption should be recorded through the day 15 visit 
when diaries are collected. 
P59 (Section 11.1.3): clarification on who 
may perform the IGE 
The IGE assessment may be performed by any of the investigators 
listed on the 1572. 
P61 (Section 11.5.5): clarification on 
timing of ECGs 
ECGs are required only at screening and 24h. 
P62 (Section 11.5.7): clarification on 
frequency of follow up for AEs 
Regarding the sentence “…they will be evaluated and graded for 
severity regularly until resolution.” The word “regularly” in this 
context should be clarified to mean as deemed per standard of care 
by the investigator.  Contact the medical monitor for any questions 
and guidance for follow-up if this occurs. 
P63 (Section 11.5.9): clarification on 
serious AEs and AEs deemed possibly 
related 
P63, “Serious AEs and AEs that have been designated as possible 
related to study treatment will be followed until resolution or 
stabilization.” 


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To clarify, AEs that are either possibly or probably related should be 
followed. 
P64 (Section 11.6.3.1): clarification on PK 
draw instructions 
The language on handling of PK samples has been removed and the 
investigator is instructed to refer to the Clinical Laboratory Manual. 
P81 (Section 15.1.3): clarification on 
documentation of ICF process 
Protocol language: “the time that informed consent is obtained 
must be documented;” however the ICF time will not be required 
per the IRB-approved ICF template. 
P44 (Section 8.1.7), P45 (Section 8.1.9), 
Table 1 Schedule of Events 
Requirement for x-rays of the operated foot was inadvertently left 
off and should be included in the D29 visit (and if not done on D29, 
perform x-rays on D36 visit) and the Schedule of Events Table 
Throughout the Protocol, clarification on 
timing of NRS assessments and impact of 
subject sleeping and use of rescue. 
Rewritten for clarity 
 
P10, 48: clarification on exclusion 
criterion 3 regarding arrhythmia 
The word “significant” at the beginning of the exclusion criterion 
applies to arrhythmia and is subject to clinical discretion. 
P61 (Section 11.5.8): clarification on 
location and timing of neurosensory 
testing 
Language in the protocol states that “The exam will involve the 
dorsal aspect of the great toe, midway between the nail fold and 
the distal interphalangeal joint;” however, the assessment and of 
the foot should focus on the area proximal to the surgical site, i.e. 
the area over the dorsum of the foot near the great toe. 
Additional language removed regarding changes within 3 days of 
end of surgery (EOS). 
P71 (Section 12.1.3.1.)Serious Adverse 
Event Reporting:  Added CRO medical 
Monitor  information for Jon L. Ruckle, 
MD, CPI 
 
CRO Medical Monitor and 24/7 Emergency contact information 
needed 
 
 
 
 
 
 
 


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3. 
PROTOCOL SYNOPSIS 
Sponsor:  
Concentric Analgesics, Inc. (Concentric) 
One Ferry Building, Suite 255 
San Francisco, CA 94111 
CRO: 
Lotus Clinical Research (Lotus) 
100 W. California Blvd., Unit 25 
Pasadena CA  91105 
Protocol Number: 
CA-PS-201 
IND# 
129-114 
Study Title: 
A Phase 2, Randomized, Double-blind, Placebo-controlled Safety, 
Pharmacokinetics and Efficacy Study of CA-008 in Subjects Undergoing 
Bunionectomy 
Study Treatment: 
CA-008, the investigational product (IP), and matching placebo vehicle are 
collectively referred to as study treatment 
Planned Study 
Center(s): 
≈ 3 US sites 
Indication: 
Acute postsurgical pain 
Sample Size: 
N ≈ 144 (target ≈ 36 subjects per treatment arm) 
Population: 
Adults ages 18 to 75 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 83 days: Screening period from 45 days prior to surgery (D-45) to D29±2 
(week 4 or W4) Study Completion Visit, and if necessary to assess any ongoing 
safety issues, a D36±2 Safety Follow-Up Visit.  Note that D0 is the day of 
surgery and study treatment administration. 
Study Design: 
 
This is a Phase 2, multi-center, randomized, double-blind, placebo-controlled, 
parallel design study evaluating a single dose of one of three CA-008 dose 
groups vs. placebo injected during an elective BUNX under light to moderate 
sedation supplemented by a Mayo block with bupivacaine hydrochloride (HCl) 
and a multimodal analgesia regimen, including ketorolac and acetaminophen, 
and access to rescue medication (oxycodone).  
The study will be conducted in two parts: 
 
Inpatient period which continues to 96h after completion of study 
treatment injection (T0) or T96h. 
 
Outpatient period which begins on discharge from the inpatient unit 


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through various follow up visits to D29±2 (W4) after surgery, or if 
necessary for ongoing safety assessments, to D36±2 (W5). 
Study Objectives: 
Primary Objective: 
 
To evaluate the efficacy of a single intraoperative administration of CA-
008 vs placebo in subjects undergoing an elective BUNX.  
Secondary Objectives  
 
To evaluate the safety and tolerability of a single intraoperative 
administration of CA-008 vs. placebo in subjects undergoing an elective 
BUNX.  
 
To evaluate the PK profile of a single intraoperative administration of 
CA-008 vs. placebo in subjects undergoing an elective BUNX.  
 
To explore the efficacy of various doses of CA-008 administered 
intraoperatively in subjects undergoing an elective BUNX.  
Exploratory Objectives  
Pharmacoeconomic benefits from administration of CA-008 vs. placebo in 
subjects undergoing an elective BUNX. 
Study Treatment 
Dosing Schedule: 
Study treatment is to be administered intraoperatively as a single administration 
via “surgical site” infiltration / instillation prior to wound closure.   
“Surgical Site”: 
“Surgical site” is defined as the area extending approximately 2-3 cm in all 
directions (lateral/medial/proximal/distal) from the incision site and surrounding 
tissues which may be affected by the infiltration of the Investigational Product 
(IP). 
Anesthesia:  
The surgery will be performed under light to moderate sedation (what constitutes 
this level of sedation and the additional anesthetic medications used per 
discretion of the anesthesiologist) and a Mayo block to produce surgical 
anesthesia and postoperative analgesia.  After administering light to moderate 
sedation, but prior to surgery, perform a Mayo block by infiltrating 0.5% 
bupivacaine hydrochloride (up to 30 mL total volume, 150 mg) proximal to the 
planned surgical incision.  The Mayo block should be performed 15-30 minutes 
prior to study treatment dosing. 
Injection of Study 
Treatment: 
Prior to wound closure, study treatment will be injected/instilled into the soft 
tissues and osteotomy surgical sites with a total volume of 14 mL of study 
treatment as follows: 
 
CA-008: 3 doses: 0.7, 2.1 and 4.2 mg in 14 mL volume (concentrations: 
0.05, 0.15, 0.3 mg/mL) 
 
Placebo: CA-008 vehicle using the same 14 mL volume 


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Study treatment will be injected/instilled into the 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 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  
Note that T0 is the time that the study treatment injection/instillation is 
completed. 
Postoperative 
Multimodal Analgesia 
Regimen during the 
Inpatient Period: 
In addition to the Mayo block noted above, a multimodal analgesia regimen will 
include the following during the immediate postoperative period: 
 
Ketorolac 30 mg IV (a non-steroidal anti-inflammatory drug (NSAID) to 
be administered intraoperatively before end of surgery (EOS).  Per 
investigator discretion, adjust the ketorolac dose as necessary for subject 
age and medical condition. 
 
Acetaminophen 1000 mg IV to be administered intraoperatively before 
EOS. 
After the above have been administered, no additional NSAIDs or 
acetaminophen are to be administered during the inpatient phase of the study 
through T96h. 
Postsurgical Care: 
Subjects will be monitored for 96 hours after completion of study treatment 
(through T96h) at the trial site as an inpatient. Safety and efficacy evaluations 
will be performed, and blood drawn for pharmacokinetic (PK) assessments in a 
portion of enrolled subjects.  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 through 
D29/W4 for various safety and efficacy assessments, and if necessary for safety 
follow up, D36/W5 or longer if needed to establish a new baseline for an AE. 
Rescue Medication 
during the Inpatient 
Period: 
Additionally, the following rescue medication are available to subjects and may 
be administered for any moderate to severe breakthrough pain at any time during 
the inpatient period: 
 
PO oxycodone 5 mg prn q2h in the first 12 hours after surgery for 
moderate or severe pain (≥ 4) as reported by subjects using the 0 to 10 
numerical rating scale of current pain intensity (NRS)   
 
PO oxycodone 5 mg prn q4h from 12 to 96 hours after surgery for 


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moderate or severe pain (NRS ≥ 4)  
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. 
Multimodal Analgesia 
and Rescue 
Medication 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 medical judgment to manage any residual or breakthrough 
postsurgical pain through D29/W4.  Administration of rescue medication should 
be based on T0. 
Outpatient period: D4 through D29/W4, if needed for pain management, the 
following oral over-the-counter (OTC) analgesics will be recommended for 
subjects to self-administer (note that these medications will not be provided by 
the sponsor):  
 
NSAID (e.g., ibuprofen 200 – 400 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 1-2 500 mg tablets prn up to tid or 650 mg prn up to qid 
(3g daily maximum limit) 
If a subject is still requiring opioid rescue in the 12h prior to discharge from the 
inpatient unit (i.e., from T84h on regardless of whether discharge is delayed), 
then prescribe no more than 6 tablets (1 PO tid prn) of oxycodone 5 mg for the 
initial outpatient period with the number of tablets dispensed and refills as 
needed per investigator discretion. 
Persistent pain or pain exacerbations during the outpatient period may suggest 
the need for an unscheduled in-person visit to assess the surgical site.  If such a 
situation occurs, the Investigator should use clinical discretion on adequacy of 
analgesic treatment, but to capture this event as an adverse event (AE) and 
document any required treatments. 
Inclusion Criteria: 
In order to participate, subjects must meet all inclusion criteria:  
1. In the medical judgment of the investigator, be a reasonably healthy 
adult aged 18 - 75 years old, inclusive, and American Society of 
Anesthesiology (ASA) physical Class 1, 2 or 3 at the time of 
randomization (Appendix 1A). 
2. Plan to undergo an elective primary unilateral first metatarsal 
Bunionectomy repair, without collateral procedure or additional 
surgeries, to be performed under light to moderate sedation with regional 
anesthesia. 


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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 ≤ 40 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. 
8. For the portion of subjects who will participate in the PK analyses, be 
willing to undergo 17 blood draws for PK assessments at various time 
points during the surgery and the following 24 hours. 
Exclusion Criteria: 
If any of the following exclusion criteria apply, subjects may not participate 
in the study:  
1. In the opinion of the Investigator,  


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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, bupivacaine HCl, ketorolac, acetaminophen 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 5) 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, 


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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. 
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, subjects will be randomized and 
baseline evaluations will be performed prior to surgery.   
3. Surgery D0: BUNX procedure is performed under light to moderate 
sedation (what constitutes this level of sedation and the additional anesthetic 
medications used per discretion of the anesthesiologist) and Mayo block; 
study treatment is injected/instilled prior to wound closure with T0 defined 
as the time of study treatment completion of administration.  If a subject is to 
participate in the PK study, assessments are to be done per protocol-specified 
time points through T24h. 
4. Post-surgery T0 to T96h: Subject remains at the Site Unit for study 
assessments and PK blood draws.  Discharge after T96h assessments with 
follow up instructions, particularly on diary completion. 
5. Follow Up D8±1 (W1): clinic visit for study assessments 
6. Follow Up D15±2 (W2): clinic visit for study assessments 
7. Follow Up D29±2 (W4): clinic visit for study assessments and study 
completion visit, unless follow up for wound healing is needed 
8. If needed follow Up D36±2: Clinic visit as needed for any ongoing safety 
issue continuing after the D29 visit 
9. Early Termination (ET): For subjects who terminate early, an ET visit will 
be required. Safety and subject-reported outcome assessments will be 
performed. 
Monitored 
Parameters: 
 
Treatment-emergent AEs (TEAEs) 
 
Medical history 
 
Clinical laboratory testing, drug and alcohol testing, pregnancy testing 
 
ECGs 
 
X-rays of the surgical site  
 
Surgical wound healing assessments.   


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 
Physical examination findings 
 
Neurosensory testing of the lower extremity and foot proximal to the 
surgical incision with contralateral comparison for a control 
 
Blood draws for PK assessments for participating subjects  
 
Pain intensity scores to be assessed at rest and with “ambulation” (standing 
or walking on transfers to/from bathroom or frank ambulation (for 
approximately 10 yards) after discharge) 
 
Total postsurgical opioid consumption converted to an oral morphine 
equivalent dose (MED) 
 
Total OTC analgesic or prescription analgesic consumption 
 
Time to first rescue medication use  
 
Patient global assessment of satisfaction with study treatment  
 
Investigator global satisfaction with overall analgesia performance, and 
discharge readiness.  
 
Postsurgical health economic outcome assessments  
Efficacy Parameter 
Assessment Times: 
1. NRS scores will be assessed as follows: 
 
During the inpatient stay, at T0.5, 1, 2, 4, 6, 8, 12, 16, 20, 24, and every 
4 hours (if awake at time of assessment and if no rescue opioid had been 
administered in the past 4 hours) until discharge from the inpatient unit. 
 
Pain scores may be skipped between the hours of midnight and 6 a.m., 
but the subject may not miss two consecutive assessments. 
 
An additional NRS assessment must be obtained 4 hours (±15 min) after 
every rescue dose even if this time point occurs between midnight and 6 
a.m.  The T12, T24, T48, T72 and T96h assessments must be completed 
even if the subject is asleep at these times. 
 
During the inpatient stay, starting on postoperative day 1 (after T24): 
each morning on arising at approximately 0800h (±2h) and each evening 
prior to bedtime at approximately 2000h (±2h) document the NRS score 
with partial (e.g., transfers to or from bed or wheelchair) or full 
ambulation of approximately 10 yards (must document time of 
assessment).  Actual assessment times must be documented. 
 
During the outpatient period, twice daily at approximately 0800h (±3h) 
and 2000h (±3h) document the NRS score at rest and with ambulation of 
approximately 10 yards.  Note that the actual time of these assessments 
must be documented in the diary. 
2. Total opioid consumption (OC) and daily opioid (rescue medication) 
consumption in MEDs will be recorded during the inpatient period.   


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 
Document subject days in which no rescue medication or analgesic 
consumption is required (opioid free, OF) during the inpatient and 
outpatient period.   
 
Document daily use of OTC analgesics (and oxycodone if prescribed) 
during the outpatient period.   
 
Document time to first use of rescue medication (TTFR) after T0 
(TTFRafter T0) and first use after 24h (TTFRafter T24h). 
3. Patient Global Evaluation (PGE) at T96h prior to discharge, W1, W2 and W4 
clinic visits. 
4. Investigator Global Evaluation (IGE) at T96h prior to discharge, W1, W2 and 
W4 clinic visits. 
5.  Healthcare utilization (HCU) costs defined as an overall summary of costs 
related to prescription medications, additional visits related to post discharge 
treatments, particularly for pain crises, and other related outpatient or inpatient 
treatments D29/W4 or if necessary D36/W5 visits 
Safety Parameter 
Assessment Times:  
 
Incidence of spontaneous reported TEAEs or SAEs from T0 through 
D29/W4 or if necessary D36/W5:  
o TEAEs are defined as AEs occurring post T0 
o AEs recorded from the time the informed consent form (ICF) is 
signed up to D0/T0 will be recorded in medical history.   
 
Surgical site wound status assessments at T96h (prior to discharge from the 
unit) and then as an outpatient on D8/W1, D15/W2, and D29/W4 or if 
necessary D36/W5.  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. 
 
Physical examination (PE): complete at screening; interim assessments on 
D-1 (or D0 prior to surgery if not done on D-1), T96h, and as an outpatient 
on D8/W1, D15/W2, and D29/W4 or if necessary D36/W5 
 
Vital signs (heart rate [HR], blood pressure [BP], respiratory rate [RR]) at 
screening, and T24h, T96h, and as an outpatient on D8/W1, D15/W2, and 
D29/W4 or if necessary D36/W5.   Assess temperature on D-1 or D0 prior to 
surgery.  Daily temps can be recorded along with vital signs per site SOPs at 
1, 2, 4, 6, 12, 24, and every 8 h thereafter until discharge from the inpatient 
facility (if awake at the time of assessment between hours of midnight and 6 
a.m.).   
 
Neurosensory testing at site of incision and the skin surrounding the incision 
will be performed at T96h (prior to discharge from the unit) and then as an 
outpatient on D8/W1, D15/W2, and D29/W4. 
o Numbness at or near the incision need not be considered a 


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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, 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. 
 
ECGs, standard clinical labs at screening and T96h post-treatment [except as 
noted for pregnancy test].   The Investigator is responsible for determining if 
out of range laboratory values are clinically significant or not.  All clinically 
significant values will be recorded in the eCRF and followed until resolution.  
o ECG at screening and T24h ±2 hr 
o Hematology at screening and T96h: hemoglobin, hematocrit, white 
blood cell count with differential, red blood cell count, platelet 
count, 
o Blood Chemistry at screening and T96h: Alanine aminotransferase 
(ALT; SGPT) and Aspartate aminotransferase (AST; SGOT), total 
bilirubin (TBili), gamma-glutamyl transferase (GGT), blood urea 
nitrogen (BUN), creatinine, alkaline phosphatase (ALK), lactate 
dehydrogenase (LDH), sodium, potassium, calcium, chloride and 
glucose. 
o Serum and urine pregnancy test for FCBP: βhCG test at screening 
and urine test usually to be done within 24 hours prior to surgery.  
o Urinalysis at screening and T96h: including macroscopic analysis 
and, if indicated, microscopic analysis.   
Primary Endpoint: 
Weighted sum of pain intensity (SPI) assessments = Area Under the Curve 
(AUC) of the NRS current pain intensity scores from T0 to 96h at rest (AUC0 to 
96h).    
Key Secondary 
Endpoints: 
The key secondary endpoints are: 
 
Percentage of subjects who do not require opioids or are opioid free (OF) 
from T0 to T96: OF0 to 96h 
 
Total opioid consumption (in daily oral morphine equivalents) = OC from 
T0 to T96h: OC0 to 96h  
 
Using NRS at rest: AUC0 to W1 
Other Endpoints: 
 
 
AUC 0 to 24h, AUC 0 to 120h, AUC 0 to W1 (walking), AUC 0 to W2, AUC 0 to W2 (walking), 
AUC 12 to 24h, AUC24 to 48h, AUC24 to 72h, AUC24 to 96h, AUC96h to 120h, AUC96h to W1, 
AUC24h to W1(walking), AUC96h to W2, AUC96h to W2(walking) 
 
OC24 to 48h, OC24 to 72h, OC24 to 96h 


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 
OF24 to 96h, OF96h to W1 and OF96h to W2 
 
TTFRafter T0 and TTFRafter T24h  
 
Analgesic consumption from T96h to W1 (AC96h to W1) and AC96h to W2 
 
PGE comparing the %age of subjects reporting “poor” + “fair” vs. “good” + 
“excellent” responses, and the %age reporting each category of response at 
W1, W2 and W4 
 
IGE comparing the %age of those reporting “poor” + “fair” vs. “good” + 
“excellent” responses, and the %age reporting each category at W1, W2 and 
W4 
 
Number and %age subjects with an AE of lack of efficacy (LOE) during the 
inpatient period: LOE0 to 96h 
 
HCU96h to W2 and HCU96h to W4 
Safety Endpoints:  
The following safety endpoints will be evaluated: 
 
Incidence of TEAEs or treatment-emergent SAEs from D0/T0 through D29: 
Note that all AEs will be recorded from the time the informed consent form 
(ICF) is signed through D29 (or D36 as applicable).  TEAEs are defined as 
AEs occurring post T0 (end of study treatment infiltration). 
 
Surgical site assessment / wound evaluations to assess for atypical skin 
reactions, e.g., erythema, pain, pruritus, bruising, swelling, bruising or other 
skin changes, should be evaluated and graded for severity and followed 
regularly until resolution or a stable baseline is achieved. 
 
Physical examination (PE) of the lower extremities and vital signs, including 
neurosensory testing of both lower extremities   
o Note that any observed or reported sensory deficit or clinically 
significant persistent sensory change remote from the immediate 
surgical site, such as allodynia or hyperalgesia, must be designated 
as a neurologic AE.  Subjects should be followed until resolution or 
a stable baseline is achieved. 
o Numbness proximal to the incision need not be considered a 
neurologic AE since this could occur because of tissue trauma and 
inflammation from the surgery. 
 
ECG changes from screening to T24h post-treatment 
 
Clinically significant clinical labs changes from screening  
Pharmacokinetics: 
Approximately 1/3rd of enrolled subjects at each site will participate in the PK 
study (48 in total; 12 in each treatment group).  The PK population will include 
all subjects who have sufficient concentration-time profiles for estimation of PK 
parameters.   
Based upon the PK results from the Phase 1 bunionectomy ascending dose safety 
study, the time points for whole blood collection will be at baseline (within the 
30 min before the start of study treatment dosing), and T5min, T10 min, T15min, 


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T30min, T45min, and T1, T1.5, T2, T2.5, T3, T4, T6, T8, T12, T16, and T24h, 
for a total of 17 samples).  Actual sampling times will be used to calculate 
plasma bupivacaine-derived PK parameters.   
The following parameters will be estimated using noncompartmental analysis for 
CA-008, capsaicin and CA-101:  
 
Cmax: The maximum measured plasma concentration, obtained directly from 
the data without interpolation  
 
Clast: Last observed (quantifiable) concentration  
 
Tmax: Time of Cmax 
 
t½: The apparent first-order terminal elimination half-life, calculated as 
0.693/λz  
 
Tlag: Time delay between drug administration and first measurable (above 
lower limit of quantitation) concentration  
 
Tlast: Time of occurrence of Clast  
 
λz: Terminal first-order elimination rate constant  
 
AUC0–t: Area under the plasma concentration-time curve from time 0 to the 
last measurable concentration (where time is postdose), calculated by the 
linear trapezoidal method   
 
AUC0–∞: Area under the plasma concentration-time curve, from time of 
dosing to infinity.  
 
AUClast:  Area under the plasma concentration-time curve, from time of 
dosing to the time of the last measurable concentration 
Sample Size 
Justification: 
In the previously completed Phase 1 ascending dose safety study in 
bunionectomy (CA-008 vs. placebo), the mean difference between CA-008 (all 
dose groups combined) and placebo for the AUC24 to 96h was -120.  The standard 
deviation (SD) estimates for the six treatment arms in this study ranged from 70 
to 190 with a median SD of 108.  For the primary endpoint (AUC0 to 96h), the true 
treatment difference between the 4.2 mg CA-008 group and the placebo group is 
assumed to be equal to -100 and the assumed true SD is equal to 130.  For these 
assumptions, and based on the use of a two-sided, two-sample comparison of 
means at the alpha=0.05 level of significance, a sample size of 36 subjects per 
arm will provide 90% power.  Thus, the planned total sample size is 144 
subjects. 
Study Populations: 
The following three analysis populations are planned for this study:  
 
The Safety Population will include all subjects who received any part of a 
dose of study treatment.   
 
The PK Population will include all subjects who receive a full dose of study 
treatment and complete all PK assessments through the T6h timepoint.  


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Subjects who fail to complete these PK assessments will be replaced.   
 
The intent-to-treat (ITT) population will include all subjects as randomized 
to study treatment.  The modified intent-to-treat (mITT) Population will 
include all subjects who receive a full dose of study treatment and complete 
the first 3 pain assessments (through T2h).   
 
Inpatient study completers (Inpatient Completers) will include all subjects 
who receive a full dose of study treatment and complete the inpatient 
assessment period (through T96h).   
 
Study completers (Study Completers) will include all subjects who receive a 
full dose of study treatment and complete the entire study period through 
D29±2/W4. 
Subjects who elect to discontinue study participation during the inpatient phase 
of the study, will be asked to continue with assessments through T96h if they 
have not elected to withdraw from all aspects of study participation.  Subjects 
who elect to discontinue participation prior to D8 (W1) will be considered to 
have terminated as of the date of their election, however they will be asked to 
return to the site one time, if willing and at their convenience, to ensure wound 
healing. 
All safety assessments and baseline characteristics will be summarized using the 
Safety Population.  PK and efficacy analyses will be performed using the PK and 
mITT Populations, respectively.  Additional efficacy analyses will be performed 
on the ITT, Inpatient Completer and Study Completer Populations.  All 
summaries will be grouped by the actual treatment received.  Each active dose 
cohort will be presented separately, along with a combined active dose group.  


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4. 
TABLE 1. 
SCHEDULE OF ASSESSMENTS  
Assessment  
Screening 
In Patient 
Follow-Up 
Unscheduled 
Visit 
Early 
Termination 
Prior to 
Surgery 
Surgery 
Post-
Surgery 
24h 
48h 
72h 
96h 
Study Day 
-45 to -1 
0 
0 
0 
1 
2 
3 
4 
8±1 
days 
15±2 
days 
29±2 
days 
36±2 
days1 
Informed Consent 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Screening Medical and Surgical 
History 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Screens for alcohol/drugs of abuse 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Enroll/Randomize 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subject Pain Assessment Training 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Surgery 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Study treatment 
Infiltration/instillation 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test  
X2 (serum) 
X2 (urine) 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs 
X 
X 
 
X3 
X3 
X3 
X3 
X3 
X 
X 
X 
 
 
X 
Physical Examination4 
X4 
X4 
 
 
 
 
 
X4 
X4 
X4 
X4 
 
 
X 
12-Lead ECG 
X 
 
 
 
X5 
 
 
 
 
 
 
 
 
 
Surgical Site assessment 
 
 
 
 
 
 
 
X6 
X 
X 
X 
X 
X 
X 
Neurosensory Exam 
X 
 
 
 
 
 
 
X7 
X 
X 
X 
X 
X 
X 
Blood draw for hematology and 
serum chemistry 
X 
X8 
 
 
 
 
 
X8 
 
 
 
 
 
 
Urine sample for urinalysis 
X 
X 
 
 
 
 
 
X8 
 
 
 
 
 
 
X-ray of surgical site 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
Concomitant Medication 
Assessment 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Event Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
NRS pain assessments 
 
 
 
X9 
X9 
X9 
X9 
X9 
X 
X 
 
 
 
X 
Subject home diary record (NRS) 
 
 
 
 
 
 
 
X 
X10 
X10 
 
 
 
X 
Paper Diary (review, distribution 
and/or collection) 
 
 
 
 
 
 
 
X11,12 
X11,12 
X13 
 
 
 
X 


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Assessment  
Screening 
In Patient 
Follow-Up 
Unscheduled 
Visit 
Early 
Termination 
Prior to 
Surgery 
Surgery 
Post-
Surgery 
24h 
48h 
72h 
96h 
Study Day 
-45 to -1 
0 
0 
0 
1 
2 
3 
4 
8±1 
days 
15±2 
days 
29±2 
days 
36±2 
days1 
Subject home diary (analgesic 
consumption) 
 
 
 
 
 
 
 
X 
X13 
X13 
 
 
 
X 
Dispense outpatient opioid rescue if 
needed 
 
 
 
 
 
 
 
X14 
 
 
 
 
 
 
PGE assessment 
 
 
 
 
 
 
 
X 
X 
X 
X 
 
 
X 
IGE assessment 
 
 
 
 
 
 
 
X 
X 
X 
X 
 
 
X 
Blood draw for PK analysis 
 
X 
 
X15 
X15 
 
 
 
 
 
 
 
 
 
1. Day 36 visit will occur if insufficient wound healing is assessed by the Investigator at the Day 29 visit. 
2. Note pregnancy tests are for FCBP; urine pregnancy test is to be performed within 24 hours of scheduled surgery 
3. Vital signs: 1, 2, 4, 6, 12, 24 and every 8 hours thereafter (if awake at time of assessment between the hours of 00:00 and 06:00) until discharge from the inpatient unit (may not miss two consecutive assessments).  
There will be a ±5-minute window allowed for the collection of vital signs in the first 4 hours after the end of surgery, after which will be a ±15-minute window allowed. 
4. A complete medical history and physical examination including all major body systems will be performed at Screening.  In addition, at the following times, an interim medical history and targeted physical examination 
will be performed prior to surgery (if not done on D-1), and to capture changes after Surgery, at 96 hours (within 4 hours of discharge), and Day 8, Day 15 and Day 29 after the administration of study medication or if 
the subject terminates early, at that time if allowed.  Body weight (kg), in indoor clothing, but without shoes, will be measured at Screening, at 96 hours and Day 29, or at the time of discontinuation.  Height (in cm) 
will be measured and BMI will be calculated at Screening only. 
5. Post-Surgery ECG should be performed at 24 hours (±2 hours) after study medication administration 
6. Surgical Site assessment: 96 hours (±4 hours) after study medication administration but prior to discharge from the inpatient unit 
7. Neurosensory Exam of the Foot / Great toe (bilateral): 96 hours after study medication administration but within 4 hours of discharge from the inpatient unit   
8. 
Clinical Laboratory tests (chemistry, hematology, and urinalysis) should be performed at screening (note if not done during screening, then perform prior to surgery) and prior to discharge from the inpatient unit (Lab 
collection window for 96h is ±30 min) 
9. NRS pain assessments during the inpatient stay, at T0.5, 1, 2, 4, 6, 8, 12, 16, 20, 24, and every 4 hours (if awake at time of assessment and if no rescue opioid had been administered in the past 4 hours) until 
discharge from the inpatient unit. Pain scores may be skipped between the hours of midnight and 6 a.m., but the subject may not miss two consecutive assessments.  An additional NRS assessment must be obtained 
4 hours (±15 min) after every rescue dose even if this time point occurs between midnight and 6 a.m. The T12, T24, T48, T72 and T96h assessments must be completed even if the subject is asleep at these times. 
There will be a ±5-minute window allowed for the collection of each assessment in the first 4 hours after the end of surgery, after which will be a ±15-minute window allowed.  
10. 2x/day through Day 15 
11. Review Subject Diary instructions with subject 
12. Dispense Subject Diary 
13. Collect Subject Diary Data 
14. Dispense no more than 6 tablets of oxycodone 5 mg tablets for use tid prn (although # tablets and refills per investigator discretion). 
15. Collect blood samples if subject is participating in the PK study.  The time points for collection are at baseline (before dosing), and at T5min, T10 min, T15min, T30min, T45min, and T1, T1.5, T2, T2.5, T3, T4, T6, 
T8, T12, T16, and T24h (a total of 17 samples). There will be a ±2-minute window allowed for the 5 to 15-minute collections, a ±5-minute window allowed for collections T30 min through T4h, and a ±15-minute window 
for collections after T4 hours. 


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5. 
TABLE OF CONTENTS 
1. 
Key Personnel Contact Information ................................................................................... 3 
2. 
Table of changes protocol version 1.1 to version 1.2 ......................................................... 4 
3. 
Protocol Synopsis .................................................................................................................. 7 
4. 
Table of Contents ................................................................................................................ 23 
5. 
List of Abbreviations and Definition of Terms ................................................................ 25 
6. 
Introduction ......................................................................................................................... 28 
6.1. 
Background .............................................................................................................................. 28 
6.2. 
Study Rationale ........................................................................................................................ 38 
7. 
Study Objectives.................................................................................................................. 39 
7.1. 
Primary Objectives .................................................................................................................. 39 
7.2. 
Secondary Objectives .............................................................................................................. 39 
8. 
Investigational Plan ............................................................................................................ 40 
8.1. 
Overall Study Design and Plan ............................................................................................... 40 
8.2. 
Discussion of Study Design ..................................................................................................... 48 
9. 
Selection of Study Population ............................................................................................ 49 
9.1. 
Inclusion Criteria ..................................................................................................................... 49 
9.2. 
Exclusion Criteria .................................................................................................................... 50 
9.3. 
Removal of Subjects from Therapy or Assessment .............................................................. 52 
9.4. 
Study Restrictions .................................................................................................................... 53 
10. 
Study Treatments ............................................................................................................ 54 
10.1. 
Study Treatment ...................................................................................................................... 54 
10.2. 
Other Interventions ................................................................................................................. 55 
10.3. 
Method of Assigning Subjects to Treatment Groups ........................................................... 56 
10.4. 
Selection of Doses ..................................................................................................................... 57 
10.5. 
Blinding .................................................................................................................................... 57 
10.6. 
Prior and Concomitant Therapy ............................................................................................ 58 
10.7. 
Treatment Compliance............................................................................................................ 58 
11. 
Study Procedures and Assessments ............................................................................... 59 
11.1. 
Demographics and Other Baseline Characteristics .............................................................. 59 
11.2. 
Eligibility Review and Randomization .................................................................................. 60 
11.3. 
Subject Pain Assessment Training ......................................................................................... 60 
11.4. 
Efficacy Assessments ............................................................................................................... 60 
11.5. 
Safety Assessments .................................................................................................................. 62 
11.6. 
Efficacy, Safety and PK Endpoints ........................................................................................ 65 
12. 
ADVERSE EVENTS ...................................................................................................... 68 
12.1. 
Adverse Events and Serious Adverse Events ........................................................................ 68 
12.2. 
Pregnancy ................................................................................................................................. 72 


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13. 
Data Quality Assurance .................................................................................................. 73 
13.1. 
Data Collection ......................................................................................................................... 73 
13.2. 
Study Auditing and Monitoring ............................................................................................. 73 
14. 
Statistical Methods .......................................................................................................... 75 
14.1. 
Statistical and Analytical Plans .............................................................................................. 75 
14.2. 
Sample Size Justification......................................................................................................... 75 
14.3. 
Analysis Populations ............................................................................................................... 75 
14.4. 
Planned Analyses ..................................................................................................................... 76 
14.5. 
Study Subjects and Demographics ......................................................................................... 76 
14.6. 
Analysis of Efficacy Measures ................................................................................................ 78 
14.7. 
Analysis of Safety ..................................................................................................................... 80 
15. 
Site and Investigator Responsibilities ........................................................................... 82 
15.1. 
Regulatory and Ethical Considerations ................................................................................. 82 
15.2. 
Privacy and Confidentiality .................................................................................................... 83 
15.3. 
Study and Site Closure ............................................................................................................ 84 
15.4. 
Regulatory Documents and Records Retention .................................................................... 84 
15.5. 
Delegation of Responsibilities and Adequate Resources ...................................................... 85 
15.6. 
Protocol Amendments ............................................................................................................. 85 
15.7. 
Financial Disclosure ................................................................................................................ 85 
16. 
Investigator Protocol Agreement Page ......................................................................... 87 
17. 
References ........................................................................................................................ 88 
1. 
Appendices ........................................................................................................................... 90 
 
LIST OF TABLES 
Table 1. 
Schedule of Assessments ......................................................................................... 21 
Table 2. 
Preliminary Summary of Adverse Events (Study CA-PS-2017-101) ................. 34 
Table 3. 
Subject Listing of Adverse Events (Study CA-PS-2017-101) .............................. 35 
Table 4. 
Study Treatments .................................................................................................... 54 
Table 5. 
Equianalgesic Conversion Table ........................................................................... 61 
Table 6. 
Clinical Laboratory Assessments ..................................................................... 62 
 
 


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6. 
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 


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Abbreviation 
Term 
FIH 
First-In-Human 
FCBP 
Female of child-bearing potential 
FSH 
Follicle Stimulating Hormone 
G 
Gram 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transferase 
GLP 
Good Laboratory Practice 
H or HRS 
Hours 
HCl 
Hydrochloride 
HCU 
Health care utilization 
HED 
Human Equivalent Dose 
HEENT 
Head, Eye, Ear, Nose and Throat 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Institutional Ethics Committee 
IGE 
Investigator Global Evaluation 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
ITT 
Intent-to-treat 
LDH 
Lactate dehydrogenase 
LLOQ 
Lower limit of quantitation 
LOE 
Lack of efficacy 
mcg or µ 
Microgram 
MED 
Morphine equivalent dose 
MedDRA 
Medical Dictionary for Regulatory Activities 
Mg 
Milligram 
min 
Minutes 
mL 
Milliliter 
NCS 
Not clinically significant 
NOAEL 
No Observed Adverse Effect Level 
NRS 
Numeric Rating Scale of Pain Intensity 
NSAID 
Nonsteroidal anti-inflammatory drug 
OC 
Opioid consumption in morphine equivalent dose 
OF 
Opioid-free days 


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


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7. 
INTRODUCTION 
7.1. 
Background  
Concentric Analgesics, Inc. (Concentric) is developing CA-008 to provide up to 96-hour relief of 
post-surgical pain following a single local administration.  CA-008 is a prodrug of trans-
capsaicin (trans-8-methyl-N-vanillyl-6-nonenamide), the substance in chili peppers that produces 
the sensation of spiciness.  Capsaicin is a transient receptor potential cation channel, subfamily V 
(vanilloid), member 1 (TRPV1) agonist.  TRPV1 is a ligand-gated, nonselective, cation channel 
preferentially expressed most densely in C-fiber nociceptors and to a lesser extent on Aδ–fiber 
nociceptors (Babbar 2009, Caterina 2001). TRPV1 responds to noxious stimuli including 
capsaicin, heat, and extracellular acidification, and integrates simultaneous exposures to these 
stimuli (Suresh 2010, Surh 1995, Tominaga 1998).   
Capsaicin exposure to TRPV-1-expressing nociceptor peripheral terminals results in initial 
excitation of the nociceptor followed by a functional desensitization which continues for some 
time after removal of capsaicin from the site.  Based upon this mechanism of action, it is thought 
that the local infiltration of a TRPV1 agonist into a surgical site prior to wound closure will 
result in a meaningful reduction of post-surgical pain that lasts days to weeks.  This improved 
long-term pain relief, particularly in combination with infiltration of local anesthetics, may help 
reduce the need for supplemental opioid use after surgery. The capsaicin pro-drug CA-008 has 
been developed for local infiltration to improve upon the physicochemical properties of capsaicin 
while providing equivalent local analgesia.  
Capsaicin formulations in relatively low concentrations (0.025 to 0.25%) are marketed as over-
the-counter (OTC) products (e.g., Zostrix®) under a tentative final monograph for external 
analgesics (proposed in the Federal Register 8 Feb 1983; vol 48, No. 27; proposed for 21 CFR 
348.12).  These formulations include topical ointments, nasal sprays (Sinol-M®) and dermal 
patches to relieve pain.  For example, the Qutenza® (capsaicin) 8% dermal patch (Acorda 
Therapeutics) was approved in 2009 in the US for the management of neuropathic pain 
associated with postherpetic neuralgia (PHN).  Note that each Qutenza patch contains 179 mg of 
capsaicin (640 mcg/cm2) (Qutenza PI).   
While no capsaicin products have been approved for injection or instillation into a wound site in 
the US, several companies have or had clinical development programs for such products.  
Centrexion Therapeutics has an active development program (CTNX-4975) for intraarticular 
injection of capsaicin for chronic osteoarthritis and Morton’s neuroma (see 
http://centrexion.com/our-pipeline/).  Anesiva, Inc. previously had an early stage program for 
intraarticular injection for osteoarthritis as well as a late-stage program (Adlea™) evaluating 
capsaicin instillation during surgery for the management of post-surgical pain.  Capsaicin, 
however, is virtually insoluble in aqueous media or local anesthetic solutions.  Anesiva’s 


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formulation was solubilized capsaicin in polyethylene glycol (Hartrick 2011) and it was instilled 
in the open surgical site, and after waiting for 5 minutes, was removed via surgical suction.  This 
route of administration was inconvenient and limited exposure of capsaicin to the exposed 
surfaces of cut tissue and bone. 
7.1.1. 
CA-008 Product Introduction 
The active moiety of CA-008, capsaicin, has certain attractive properties for treatment of post-
operative pain from a pharmaceutical perspective.  CA-008 is water soluble and easy to inject 
through a 25 g needle or larger.  It readily penetrates surgical site tissues where it releases 
capsaicin through a non-enzymatic pH-driven process.  Local administration of CA-008 at or 
near the source of pain either topically, by infiltration or by instillation into a surgical site results 
in low systemic levels of capsaicin.   
Capsaicin, however, is virtually insoluble in aqueous media or local anesthetic solutions which 
means that capsaicin formulations tend to be quite hydrophobic making them hard to inject and 
less likely to permeate surgical site tissues resulting in poor target engagement.  Anesiva, which 
had been developing capsaicin for the management of post-surgical pain and osteoarthritis, 
solubilized capsaicin in polyethylene glycol (Hartrick 2011).  The product was instilled into the 
open surgical site and after waiting for 5 minutes, was removed via surgical suction.  This route 
of administration was inconvenient and limited exposure of capsaicin only to the exposed 
surfaces of cut tissue and bone. 
CA-008 was created to improve delivery of capsaicin without having to account for its poor 
solubility profile in tissues.  CA-008 provides an aqueous formulation that could be simply 
infiltrated in the wound site to achieve local capsaicin release to produce a maximal effect.  The 
free base form of CA-008 rapidly breaks down at physiological pH to yield capsaicin and a 
cyclic urea, as shown in the scheme below: 
 
CA-008 was specifically selected for development due to its short half-life (<5 min) at neutral 
pH.  In Tris buffer at pH 7.4 and 37°C, it completely breaks apart to capsaicin and CA-101 as the 
sole degradants. 
The cyclic urea (CA-101) formed has not been previously evaluated for biological activity and it 
was shown to be inactive.  While not a known compound in the clinical literature, its safety was 
evaluated in all nonclinical studies with CA-008.  The toxicokinetic profiles for CA-008, CA-
101, and capsaicin were determined in GLP safety studies and in a Phase 1 ascending dose safety 
study in patients undergoing bunionectomy. 


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7.1.2. 
Capsaicin Metabolism and Clearance 
The most common route of human capsaicin exposure is ingestion in spicy foods, like chili 
peppers.  Capsaicin is absorbed by a nonactive process from the stomach and whole intestine 
(Leelahuta 1983; Kawada 1984), where the total absorption capacity varies between 50 and 90% 
in different animal studies.  Maximum blood concentration is seen about an 1 h after ingestion 
(Suresh 2010). To a certain extent, capsaicin is absorbed in its intact form, and the amount in the 
portal blood is measurable by radiolabeling capsaicin (Kawada 1984).  A minor part of capsaicin 
metabolism occurs in the small intestine epithelial cells (Kawada 1984).  A study by Chaiyasit 
and colleagues investigated the human PK profile of 5 g of orally ingested C. frutescens, 
approximately 26.6 mg of capsaicin or the equivalent of eating 15 habanero peppers (Chaiyasit 
2009). Capsaicin could be detected in plasma after 10 min, and the Cmax was 2.47 ng/ml, Tmax 
was 47.1 min, t½ was 24.9 min, and after 90 min, capsaicin could not be detected. 
Capsaicin metabolism after oral administration is believed to be similar in the human, rat, and 
canine microsome. Once absorbed, capsaicin is heavily protein-bound and most is metabolized in 
the liver.  In vitro human investigation with hepatic microsomes to investigate involvement of 
phase 2 metabolisms, showed that capsaicin was rapidly metabolized, producing three major 
metabolites, 16-hydroxycapsaicin, 17-hydroxycapsaicin, and 16,17-hydroxycapsaicin, whereas 
vanillin was a minor metabolite (Chanda 2008).  This suggests that cytochrome P450 enzymes 
minimally participate in capsaicin biotransformation in skin compared with their key role in 
hepatic metabolism. 
Animal studies have shown that capsaicin metabolites are eliminated mainly by the kidneys, with 
a small untransformed proportion excreted in the feces and urine (Leelahuta 1983, Kawada 1984, 
Surh 1995).  It is excreted in both free form and capsaicin glucuronide form.  In vivo animal 
studies have shown that after 48 h, only a small amount (<10%) of an administered dose was 
found in feces (Leelahuta 1983, Kawada 1984). 
7.1.3. 
Capsaicin PK 
Other than by ingestion, most human exposure to capsaicin is from topical administration 
therapeutically with ointments or patches as noted above or for self-defense or noxious effects 
with pepper spray.  Topical capsaicin in humans is rapidly absorbed through the skin (Hayman 
2008).  Additionally, capsaicin is often used in basic science studies, such as in experimental 
pain studies (animal and human), where the main administration method is intradermal or 
intraplantar injections.   
Systemic PK data for topical capsaicin is somewhat limited.  In 173 patients with PHN, painful 
human immunodeficiency virus-associated neuropathy and painful diabetic neuropathy, the 
highest Cmax observed in any patient was 17.8 ng/mL (Babbar 2009).  Sparse sampling resulted 
in most patients not having quantifiable levels.  Plasma concentrations were fitted adequately 
using a 1-compartment model with first-order absorption and linear elimination. Capsaicin levels 


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declined very rapidly, with a mean population elimination half-life of 1.64 hours. Mean area 
under the curve and Cmax values after a 60-minute application were 7.42 ng*h/mL and 1.86 
ng/mL, respectively. Ninety-minute applications of Qutenza resulted in AUC and Cmax values 
approximated 1.78- and 2.15-fold higher than those observed after a 60-minute application.  Due 
to capsaicin’s TRPV1 mechanism of action of inducing a prolonged functional depolarization, 
the duration of pain relief extends well beyond the relatively limited time of its exposure to the 
target peripheral site. 
7.1.4. 
Background Information on the Use of Capsaicin in Analgesia  
While capsaicin is well understood to have long lasting analgesic benefits, it has shown a limited 
effect in the initial hours following administration in both nonclinical (Dudley-Cash 2012) and 
clinical studies (Pollak 2009, Savage 2009).  In Phase 3 clinical trials conducted by Anesiva, 
capsaicin instillation demonstrated statistically significant reductions in cumulative pain and 
opioid use over 48 hours, but failed to show a difference with shorter periods of observation (e.g. 
pain AUC 4-32 hours) (Hartrick 2011, Pollak 2009).  Based upon a post hoc review of these data 
that periods longer than 48 hours are necessary to demonstrate capsaicin’s benefit as the 
treatment difference increases during this period. 
Activation of TRPV1 receptor with an agonist such as capsaicin immediately results in transient 
hyperalgesia, erythema, and localized burning sensation followed by a functional desensitization 
that results in reduction in noxious pain stimuli without affecting evoked pain sensations or 
muscle control.  This desensitization can lead a sustained analgesia for a week or longer.  Given 
CA-008’s rapid conversion to capsaicin, a similar profile (PK and pharmacodynamic or PD) 
would be expected following the administration of CA-008 alone. 
It is anticipated that CA-008 will be used with standard of care or best practice multimodal 
analgesia (systemic medications +/- local anesthetic administered by regional block or local 
infiltration) appropriate for the surgery in question to manage pain for the first 24 hours after 
which the TRPV1 agonism will provide pain relief.  Concentric is planning to confirm the 
efficacy of CA-008 as monotherapy in combination with standard of care systemic analgesic 
therapy or proximal regional nerve blocks for treatment of post-surgical pain for periods of up to 
96 hours or longer.  
7.1.5. 
Acute Post-Operative Pain Management: the unmet need  
A clinical practice guideline on the management of post-surgical pain from the American Pain 
Society, the American Society of Regional Anesthesia and Pain Medicine, and the American 
Society of Anesthesiologists’ Committee on Regional Anesthesia, Executive Committee, and 
Administrative Council was published recently in the Journal of Pain (Chaiyasit 2009, Chanda 
2008, Chou 2016).  This publication presents evidenced-based recommendations for 
preoperative, intraoperative, and postoperative interventions and pain management strategies.  
As summarized in this guideline, more than 80% of patients who undergo surgical procedures 


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experience acute post-surgical pain and approximately 75% of those with post-surgical pain 
report the severity as moderate, severe, or extreme (Apfelbaum 2003; Gan 2014).  Evidence 
suggests that fewer than half of patients who undergo surgery report adequate post-surgical pain 
relief (Apfelbaum 2003).  Inadequately controlled pain negatively affects quality of life, 
function, and functional recovery, the risk of post-surgical complications, and the risk of 
persistent postsurgical pain (Kawada 1984, Kehlet 2006).  The publication recommends 
strategies for the management of post-surgical pain ranging from preoperative education and 
perioperative pain management planning, multimodal therapies, physical modalities, cognitive-
behavioral modalities, systemic pharmacologic therapies, local and/or topical pharmacologic 
therapies, use of peripheral regional anesthesia, and neuraxial therapies, all depending on the 
nature of the patient and surgical procedure.   
Despite these options, management of pain in patients after surgery remains insufficient 
(Pogatzki-Zahn 2012), and there is no ideal way to provide continuous, effective pain relief 
beyond the immediate hours after surgery.  Systemic pharmacological therapies remain the 
mainstay of post-surgical pain relief, with opioids a key component of the arsenal, especially for 
moderate-to-severe pain.  Systemic opioids are effective, but increase cost and morbidity due to 
known safety issues such as respiratory depression, gastrointestinal dysfunction, and abuse, and 
produce a heavy societal burden.  Non-opioid analgesics including acetaminophen, nonselective 
NSAIDs and selective COX-2 inhibitors are useful for the treatment of light-to-moderate pain 
and are part of a balanced multimodal pain treatment (Pogatzki-Zahn 2012).  These products also 
have known safety risks.  The use of peripheral regional anesthetic techniques has been shown to 
be effective as a component of multimodal analgesia for management of post-surgical pain 
associated with several surgical procedures, including thoracotomy, lower extremity joint 
surgery, shoulder surgery, cesarean section, hemorrhoid surgery, and circumcision.  This 
approach has limitations including the increased cost and intensively of care and the potential for 
increased incidence of patient falls. 
Site-specific infiltration techniques utilizing a novel mechanism of action are attractive as a 
component of multimodal analgesia due to the potential for prevention of post-surgical pain, with 
lower potential safety risks due to the local nature of administration.  Treating pain at its source 
with local anesthetic, e.g., liposomal bupivacaine (Exparel®), while highly effective, is limited 
due to its typically short duration of action and the potential for unwanted numbness or motor 
effects.  
7.1.6. 
Clinical burden  
Opioids are used to treat short and long-term pain or other indications, but have side effects and 
the risk of addiction or abuse.  Opioid overdose is a major public health problem in the United 
States (US) and other countries.  In the US, opioid overdose contributes to a significant number 
of accidental deaths among persons that either misuse or abuse illicit and prescription opioids.  It 
was estimated by the Center for Disease Control that in 2016 more than 40,000 deaths from 


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prescription opioid analgesics (https://www.cdc.gov/drugoverdose/data/index.html), not 
including illicit drug use, and this number is expected to continue to increase significantly over 
time unless something can be done.   
Common side effects of opioid administration include sedation, dizziness, nausea, vomiting, 
constipation, physical dependence, tolerance, and respiratory depression.  Physical dependence 
and addiction are clinical concerns that may prevent proper prescribing and in turn inadequate 
pain management. 
7.1.7. 
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 be ingested 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).  
A first-in-human study (Study CA-PS-2017-101) evaluated the safety and tolerability of CA-008 
in subjects undergoing a unilateral transpositional first metatarsal osteotomy for correction of 
hallux valgus deformity, more commonly known as a bunionectomy.  This study also evaluated 
PK and preliminary efficacy assessment of CA-008 to inform future studies in our clinical 
development plan.  This study was originally designed to look at 4 different doses of CA-008 
(0.5 mg, 1 mg, 2 mg, and 3 mg), however based upon the benign adverse event (AE) profile, a 5th 
cohort (4.2 mg) was added.  Based upon the results from this study we selected 3 doses for this 
phase 2 bunionectomy study.   
Of note, is that no dose limiting toxicity or severe or serious AEs were observed in the study.  
The maximum tolerated dose was not identified.  Table 2 shows the preliminary summary of 
AEs by CA-008 dose and placebo in the study.  Table 3 shows the preliminary by-subject listing 
of TEAEs by CA-008 dose and placebo in the study (note that the TEAEs designated as possibly 
related are bolded).  Due to the desire to complete this phase 2 protocol in a timely fashion, these 
results are based upon an assessment after the last patient completed the study but prior to 
database lock in the study by an external biostatistician who was not involved in study conduct.  
The clinical team at Concentric and the CRO site remained blinded until after database lock. 
 
 


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Table 2. Preliminary Summary of Adverse Events (Study CA-PS-2017-101) 
  
CA-008 
Placebo (8) 
Doses (n) 
0.5 mg (6) 
1.0 mg (5) 
2.0 mg (6) 
3.0 mg (6) 
4.2 mg (6) 
All Active (29) 
Subjects w/TEAEs  
N2 (%) 
4 (66.7%) 
3 (60.0%) 
2 (33.3%) 
3 (50.0%) 
4 (66.7%) 
16 (55.2%) 
4 (50.0%) 
TEAEs n 
8 
4 
2 
3 
5 
22 
6 
“Possibly” Related 
TEAEs n (%) 
2 (25.0%) 
0 (0.0%) 
2 (100%) 
2 (66.7%) 
2 (40.0%) 
8 (36.4%) 
1 (16.7%) 
Mild TEAEs n (%) 
6 (75.0%) 
2 (50.0%) 
0 (0.0%) 
2 (66.7%) 
3 (60.0%) 
13 (59.1%) 
6 (100%) 
Moderate TEAEs n 
(%) 
2 (25.0%) 
2 (50.0%) 
2 (100%) 
1 (33.3%) 
2 (40.0%) 
9 (40.9%) 
0 (0.0%) 
Severe TEAEs n (%)  
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
SAEs n (%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 


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Table 3. Subject Listing of Adverse Events (Study CA-PS-2017-101) 
TEAEs 
Cohort # 
Subject # 
Gender (M/F) 
Age (y) 
Group 
Inj Date Time 
Start Date 
Time 
End Date 
PT (if documented) 
Severity 
Relatedness 
Action Taken 
1 
101-001 
F 
34 
0.5 mg  
10/31/17 
~1009h 
11/1/17 
0055h 
11.1.17 
Nausea 
Mild 
Unlikely 
None 
11/3/17 
1530h 
11/4/17 
Headache 
Mild 
Unlikely 
ConMed 
11/5/17 
1300h 
11/10/17 
Back pain 
Mild 
Unlikely 
ConMed 
1 
101-004 
F 
42 
Pbo 
10/31/17 ~1148h 
11/2/17 
1300h 
11/2/17 
Headache 
Mild 
Unlikely 
ConMed 
11/3/17 
0900h 
12/4/17 
Blepharitis (eyelid dermatitis) 
Mild 
Unlikely 
None 
11/2/17 
1004h 
12/19/17 
Hyperesthesia (R great toe) 
Mild 
Possible 
None 
1 
110-007 
M 
51 
0.5 mg 
10/31/17 ~0815h 
11/13/17 
0914h 
12/6/17 
Muscle strain (lumbar strain) 
Mild 
Unlikely 
ConMed 
1 
101-011 
F 
49 
0.5 mg 
11/13/17 
~0821h 
11/14/17 
0840 
11/14/17 
Dizziness 
Mild 
Unlikely 
None 
11/20/17 
unk 
11/28/17 
Skin abrasion (wound foot 
abrasion) 
Mild 
Unlikely 
None 
1 
101-024 
F 
19 
0.5 mg 
11/15/17 
~1139h 
11/16/17 
0300h 
11/16/17 
Nausea 
Moderate 
Possible 
ConMed 
11/16/17 
0300h 
11/16/17 
Vomiting 
Moderate 
Possible 
ConMed 
 
2 
101-026 
F 
42 
Pbo 
11/27/17 
~1322h 
11/28/17 
0950h 
11/28/17 
Nausea 
Mild 
Unlikely 
ConMed 
2 
101-028 
F 
27 
1.0 mg 
11/28/17 
~0759h 
11/29/17 
0511h 
11/29/17 
Syncope (vasovagal) 
Mild 
Unlikely 
ConMed 
2 
101-033 
1.0 mg 
12/1/17 
12/1/17 
Nausea 
Moderate 
Unlikely 
ConMed 


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F 
33 
11/30/17 
~1040h 
0900h 
12/1/17 
1940h 
12/1/17 
Vomiting 
MIld 
Unlikely 
None 
2 
101-034 
F 
43 
1.0 mg 
11/30/17 
~1127h 
12/11/17 
0155h 
12/11/17 
Hypoxia 
Moderate 
Unlikely 
ConMed 
 
3 
101-036 
F 
63 
Pbo 
12/11/17 
~0853h 
12/1/17 
2035h 
12/1/17 
Headache 
Mild 
Unlikely 
None 
3 
101-040 
F 
36 
2.0 mg 
12/11/17 
~0943h 
12/18/17 
Unk 
1/8/18 
Rash (bilateral lower extremity) 
Moderate 
Possible 
ConMed 
3 
101-042 
F 
34 
2.0 mg 
12/12/17 
~0806h 
12/14/17 
0944h 
12/14/17 
Nausea 
Moderate 
Possible 
ConMed 
 
4 
101-054 
F 
26 
Pbo 
1/15/18 
~0847h 
1/15/18 
1800h 
1/15/18 
Dizziness 
Mild 
Unlikely 
None 
4 
101-055 
F 
29 
3.0 mg 
1/8/18 
~1142h 
1/9/18 
0640h 
1/9/18 
Nausea 
Moderate 
Possible 
ConMed 
4 
101-058 
F 
34 
3.0 mg 
1/8/18 
~1416h 
1/9/18 
1430h 
1/10/18 
Headache 
Mild 
Possible 
None 
4 
101-061 
F 
59 
3.0 mg 
1/15/18 
~1035h 
1/17/18 
0229h 
1/17/18 
Hypoxia 
Mild 
Unlikely 
ConMed 
 
5 
101-068 
F 
25 
4.2 mg 
2/12/18 
~1122h 
2/12/18 
1330h 
2/12/18 
Nausea 
Mild 
Unlikely 
ConMed 
5 
101-073 
F 
44 
4.2 mg 
2/19/18 
~0729h 
2/20/18 
0825h 
2/27/18 
(wound erythema) 
Mild 
Possibly 
None 
2/19/18 
0800h 
2/22/18 
(constipation) 
Moderate 
Unlikely 
ConMed 
5 
101-074 
F 
4.2 mg 
2/12/18 
2/13/18 
0251h 
2/13/18 
Hypoxia 
Moderate 
Possibly 
ConMed 


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50 
~1028h 
5 
101-077 
F 
30 
4.2 mg 
2/19/18 
~0904h 
2/24/18 
1730h 
2/24/18 
Headache 
Mild 
Unlikely 
ConMed 


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The PK profile was not available at the time of preparation of this protocol, however the 
preliminary time-concentration values were instructive as to Cmax and Tmax.  The following 
preliminary assessments could be made: 
 For CA-008, the highest Cmax value was 1.04 ng/mL and the median Tmax was 15 
minutes.  No measurable concentration was identified after 2.5h at the highest dose (4.2 
mg) and after 45 min at lower doses.  Given the paucity of measurable concentrations at 
various timepoints in the lower dose cohorts, no assessment of dose proportionality could 
be made.  Note the LLOQ was 0.025 ng/mL. 
 For CA-101, the Cmax value ranged from 3.81 to 19.7 ng/mL with the highest dose and 
the median Tmax was 1.5 hours.  No apparent dose proportionality was observed.  Note 
the LLOQ was 0.5 ng/mL. 
 For capsaicin, the Cmax value ranged from 0.713 to 5.34 ng/mL with the Cmax and median 
Tmax being highly variable.  No apparent dose proportionality was observed.  Note the 
LLOQ was 0.05 ng/mL. 
7.2. 
Study Rationale 
CA-008 is being investigated as a potential therapy for treatment of pain following surgery.  CA-
008 is administered (injected and instilled) directly into the postoperative wound during the 
surgery.  This study is a follow-on placebo-controlled efficacy and safety study which includes 
assessments of wound healing and a PK study in enrolled subjects.   
 


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8. 
STUDY OBJECTIVES 
8.1. 
Primary Objectives 
The primary objective of the study is:  
 To evaluate the efficacy of a single intraoperative administration of CA-008 vs. placebo 
in subjects undergoing an elective bunionectomy (BUNX) 
8.2. 
Secondary Objectives 
The secondary objectives of the study are: 
 To evaluate the safety and tolerability of a single intraoperative administration of CA-008 
vs. placebo in subjects undergoing an elective BUNX.  
 To evaluate the PK profile of a single intraoperative administration of CA-008 vs. 
placebo in subjects undergoing an elective BUNX.  
 To identify the minimally effective and optimal doses of CA-008 to be administered 
intraoperatively in subjects undergoing an elective BUNX. 


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9. 
INVESTIGATIONAL PLAN 
9.1. 
Overall Study Design and Plan 
This is a Phase 2, multi-center, randomized, double-blind, placebo-controlled, parallel design 
study evaluating a single dose of one of three CA-008 dose groups vs. placebo injected during an 
elective BUNX with a multimodal analgesia regimen including an NSAID and regional Mayo 
block with bupivacaine.  The study will be conducted in two parts: 
 Inpatient period which continues to 96h after completion of study treatment injection 
(T0) or T96h. 
 Outpatient period which begins on discharge from the inpatient unit through various 
follow visits to D29±2 (W4) after surgery, or if necessary for ongoing safety assessments, 
to D36±2 (W5). 
Subjects will be undergoing unilateral transpositional first metatarsal osteotomy for the 
correction of hallux valgus deformity (bunionectomy or BUNX).  The surgery is to be performed 
under light to moderate sedation anesthesia (what constitutes this level of sedation and the additional 
anesthetic medications used per discretion of the anesthesiologist).  In accordance with standard of 
care, light to moderate sedation will be supplemented with a Mayo block to produce surgical 
anesthesia and postoperative analgesia.  After administering light to moderate sedation, but prior 
to surgery, perform a Mayo block by infiltrating 0.5% bupivacaine hydrochloride (up to 30 mL 
total volume, 150 mg) at least 3 cm proximal to the “surgical site”.  The Mayo block should be 
performed at 15-30 minutes prior to study treatment dosing.  “Surgical site” is defined as the area 
extending approximately 2-3 cm in all directions (lateral/medial/proximal/distal) from the 
incision site and surrounding tissues which may be affected by the infiltration of study treatment. 
After the surgery, subjects will be monitored for 96 hours in an inpatient unit. Safety and 
efficacy evaluations will be performed.  After the first week of enrollment, subjects may be 
enrolled for the pharmacokinetic (PK) portion of the study and have samples drawn prior to CA-
008 injection and at various time points over 24h after surgery until the target of 48 PK subjects 
(12 per treatment group) are enrolled and complete PK assessments.  Subjects will be required to 
meet certain pre-specified criteria prior to discharge. 
9.1.1. 
Screening Phase (Day -45 [D-45] to D-1 or D0):   
Subjects requiring bunionectomy between the ages of 18 and 75 years, inclusive, will be 
screened for participation at the study site in the United States within 45 days of surgery/study 
treatment administration. The following assessments will be completed: 
 
Informed Consent 
 
Eligibility for study participation (Inclusion / Exclusion criteria) 


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 
Demographics 
 
Medical and surgical history 
 
Prior/current medications 
 
Complete physical examination (PE).  
 
Vital signs and temperature must be obtained after resting (seated/reclined) for ≥ 5 
minutes.  
 
Baseline neurosensory testing 
 
X-ray of the bunion to be operated on 
 
Clinical laboratory tests (chemistry and hematology) 
 
Urine Drug Screening (UDS) and alcohol test (breath or saliva) 
 
Serum Pregnancy test (FCBP) 
 
12-Lead Electrocardiograms (ECGs) will be performed after the subject has been resting 
in a recumbent/supine position for at least 5 minutes.  
 
Subject pain assessment training (video and post-test) 
 
Adverse Event (AE) Assessment 
9.1.2. 
D-1 or D0: Prior to surgery (baseline) up to the end of surgery   
9.1.2.1. 
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) 
 
Subject pain assessment training (video only) 
 
Urine Drug Screening (UDS) and alcohol test (breath or saliva) 
 
Urine Pregnancy test (FCBP) 
 
In those subjects participating in the PK study, baseline blood draw for PK analysis prior 
to surgery (may be done after light to moderate sedation) 
 
AE Assessment 
 
Randomize to study treatment 


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9.1.2.2. 
Administration of Study treatment 
Prior to wound closure, study treatment will be injected/instilled into the soft tissues and 
osteotomy surgical sites with a total volume of 14 mL of CA-008 or placebo as follows: 
 CA-008: 3 doses: 0.7, 2.1 and 4.2 mg in 14 mL volume (concentrations: 0.05, 0.15, 0.3 
mg/mL) 
 Placebo: CA-008 vehicle (identical to active treatment but without CA-008) 
Study treatment will be injected/instilled into the 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 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 
Note that T0 is the time that the study treatment injection/instillation is completed. 
9.1.3. 
Postoperative Multimodal Analgesia and Rescue Medication 
Following surgery, subjects will be transferred to the appropriate recovery unit where they will 
undergo various assessments over the next 96 hours (end of surgery [EOS] to T96h).  
In addition to the Mayo block noted above, a multimodal analgesia regimen will include the 
following during the immediate postoperative period: 
 Ketorolac 30 mg IV (a non-steroidal anti-inflammatory drug (NSAID) to be administered 
intraoperatively before the end of surgery.  Per investigator discretion, adjust the dose as 
necessary for subject age and medical condition. 
 Acetaminophen 1000 mg IV to be administered intraoperatively before the end of 
surgery. 
After the non-opioid analgesics noted above have been administered, no additional NSAIDs or 
acetaminophen are to be administered during the inpatient phase of the study (through T96h). 
Additionally, the following rescue medication may be administered for any moderate to severe 
breakthrough pain during the inpatient period: 
 PO oxycodone 5 mg prn q2h in the first 12 hours after surgery for moderate or severe 
pain (≥ 4) as reported by subjects using the 0 to 10 numerical rating scale of current pain 
intensity (NRS)  
 PO oxycodone 5 mg prn q4h from 12 to 96 hours after surgery for moderate or severe 


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pain (NRS ≥ 4)  
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. 
9.1.4. 
Postoperative Care Through 96 Hours (T96h) 
After surgery, subjects will be monitored for 96 hours (through T96h) at the trial site as an 
inpatient.  Safety and efficacy evaluations will be performed and blood drawn for PK 
assessments (for the PK study).  Subjects will be required to meet standard pre-specified criteria 
for discharge from the unit.  Note that topical ice packs or cooling treatments are prohibited 
during the inpatient period for use on the foot near the surgical site.  Such treatments are allowed 
to treat conditions remote from the surgical site.  After discharge, topical ice packs or cooling 
treatments may be used over the surgical site or elsewhere. 
The schedule of assessments are as follows:  
 
Perform NRS assessments of current pain intensity:  
o 
During the inpatient stay, at T0.5, 1, 2, 4, 6, 8, 12, 16, 20, 24, and every 4 hours (if 
awake at time of assessment and if no rescue opioid had been administered in the past 4 
hours) until discharge from the inpatient unit. 
o 
Pain scores may be skipped between the hours of midnight and 6 a.m., but the subject 
may not miss two consecutive assessments. 
o 
An additional NRS assessment must be obtained 4 hours (±15 min) after every rescue 
dose even if this time point occurs between midnight and 6 a.m. The subject must be 
awakened if asleep to assess this NRS.  
o 
The T12, T24, T48, T72 and T96h assessments must be completed even if the subject is 
asleep at these times. 
o 
During the inpatient stay, starting on postoperative day 1 (after T24): each morning on 
arising at approximately 0800h (±2h) and each evening prior to bedtime at 
approximately 2000h (±2h) document the NRS score with ambulation (partial or full; 
must document time of assessment).  Actual assessment times must be documented. 
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. 
 
Record vital signs: 1, 2, 4, 6, 12, 24 and every 8 hours thereafter (if awake at time of 
assessment between the hours of 00:00 and 06:00) until discharge from the inpatient unit 
(may not miss two consecutive assessments).  There will be a ±5 minute window allowed for 
the collection of vital signs in the first 4 hours after the end of surgery, after which will be a 
±15 minute window allowed.  Daily temps can be recorded along with vital signs per site 
SOPs at 1, 2, 4, 6, 12, 24, and every 8 h thereafter until discharge from the inpatient facility 
(if awake at the time of assessment between hours of midnight and 6 a.m.). 
 
Perform interim PE: surgical site assessment and neurosensory exam of the foot proximal to 
the surgical site with contralateral comparison prior to discharge from the inpatient unit.  


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 
Perform ECG: at 24 (±2) hours after surgery.  
 Clinical laboratory tests (chemistry, hematology and urinalysis): at 96 hours prior to 
discharge from the inpatient unit. 
 
If the subject is participating in the PK study, obtain whole blood for PK analyses: at baseline 
(within the 30 min before the start of study treatment dosing), and T5min, T10 min, T15min, 
T30min, T45min, and T1, T1.5, T2, T2.5, T3, T4, T6, T8, T12, T16, and T24h, for a total of 
17 samples).   
 
Subjects with inadequately controlled pain may request and receive rescue medication at any 
time; however, subjects will be encouraged to receive rescue only for an NRS ≥ 4. 
Additionally, subjects should be encouraged to wait at least 1 hour after completion of 
surgery (EOS) before utilizing pain rescue medication, if possible.  NRS must be completed 
within 15 minutes prior to use of pain rescue medication if the time between rescue request 
and consumption is prolonged.   
 
Document the time to first use of rescue medication after T0 (between T0 and T24h) and 
after T24 (between T24h and T96h). 
 
Document concomitant medication use including doses and times taken  
 
All AEs that occur from the time a subject's informed consent but prior to study treatment 
will be captured in the medical history.  All AEs and SAEs will be documented and followed 
from the time of administration of study treatment and will be considered treatment-emergent 
AEs (TEAEs).    
After completing the assessments through T96h hours after study treatment 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.  
Additionally, obtain the subject’s global assessment of satisfaction with study treatment (patient 
global evaluation or PGE) and the investigator’s global evaluation (IGE) prior to discharge.  
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: D4 through D29/W4:   
 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) prn tid or 650 mg prn qid (3g daily 
limit) 


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 If a subject is still requiring opioid rescue in the 12h prior to discharge (i.e., from T84h 
on regardless of whether discharge is delayed), prescribe oxycodone 5 mg PO tid prn 
(medical discretion on dosing and number of tablets dispensed per consideration of 
subject’s age/history and needs, but no more than six tablets should be prescribed and 
may be taken as needed over the next several days).  If additional oxycodone is required, 
refills are left to investigator discretion. 
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. 
9.1.5. 
Outpatient Phase: D8±1 (W1) Visit 
Subjects will return to the study center on D8±1 (W1) for the following assessments:  
 
Subject home diary review  
 
Document pain intensity (NRS) at rest and after ambulation (approximately 10 yards) each 
day since discharge from the inpatient unit 
 
Record vital signs (HR, BP and RR) 
 
Perform interim PE: 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 (only 
allowed during outpatient period) 
 
Record AE Assessment 
 
Obtain PGE assessment 
 
Obtain IGE assessment 
In their diary, subjects will assess their current pain intensity at rest and after ambulation each 
morning (08:00 ±3 hours), and each evening (20:00 ±3 hours) using the NRS.  The subject 
should be instructed to perform, if possible, the daily assessments as follows: 
 Obtain the morning NRS assessment prior to taking any pain medication or 
approximately 2 hours after taking any pain medication 
 Obtain the evening NRS assessment approximately 2 hours after taking any pain 
medication  
Subjects should be instructed to record any medication they take (dose and time) whether to treat 
their pain or for any other reasons. 


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9.1.6. 
Outpatient Phase: D15±2 (W2) Visit 
Subjects will return to the study center on D15±1 (W2) for the following assessments:  
 
Subject home diary review  
 
Document pain intensity (NRS) at rest and after ambulation (approximately 10 yards) each 
day since discharge from the inpatient unit 
 
Record vital signs (HR, BP and RR) 
 
Perform interim PE: 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 
 
Obtain PGE assessment 
 
Obtain IGE assessment 
In their diary, subjects will assess their current pain intensity at rest and after ambulation each 
morning (08:00 ±3 hours), and each evening (20:00 ±3 hours) using the NRS.  The subject 
should be instructed to perform, if possible, the daily assessments as follows: 
 Obtain the morning NRS assessment prior to taking any pain medication or 
approximately 2 hours after taking any pain medication 
 Obtain the evening NRS assessment approximately 2 hours after taking any pain 
medication  
Subjects should be instructed to record any medication they take (dose and time) whether to treat 
their pain or for any other reasons. 
9.1.7. 
Outpatient Phase: D29±2 (W4) Visit  
Subjects will return to the study center on D29±2 (W4) for the following assessments:  
 
X-ray of the surgical site  
 
Record vital signs (HR, BP and RR) 
 
Perform interim physical exam: 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 
 
Obtain PGE assessment 
 
Obtain IGE assessment 


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 
When assessed, if the Investigator observes insufficient wound healing or atypical findings 
on surgical site assessment or to follow up on any unresolved AE, the subject may be 
scheduled for a follow-up visit on D36±2.  If the wound is considered healed at D29, the D36 
visit is not required.)  
9.1.8. 
Outpatient Phase: Optional D36±2 (W5) Visit 
If required due to any ongoing safety issue, insufficient wound healing or atypical findings on 
surgical site assessment noted at Day 29 visit or to follow up on an unresolved AE, subjects will 
return to the study center on D36±2 (W5) for the following assessments:  
 
Record vital signs (HR, BP and RR) 
 
Interim PE focusing on the surgical site assessment and neurosensory exam of both feet 
(proximal to the surgical site) 
 
Concomitant Medication Use including doses and times taken for analgesic medications 
 
AE Assessment 
9.1.9. 
Early Termination Visit 
If willing, subjects who elect to prematurely discontinue from the study will be requested to 
come in at their convenience for the following assessments (if subjects are not willing to return 
for assessments, request that they at least come in to assess the surgical site to ensure adequate 
wound healing):  
 
Record vital signs (HR, BP and RR) 
 
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 
9.1.10. 
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 (W4), perform the 
following: 
 
Record vital signs (HR, BP and RR) 
 
Interim PE focusing on the surgical site assessment and neurosensory exam of both feet 
(proximal to the surgical site) 
 
Concomitant Medication Use including doses and times taken for analgesic medications 


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 
Concomitant Treatments including topical ice pack or cooling treatments 
 
AE Assessment 
9.2. 
Discussion of Study Design 
This trial is designed to determine the efficacy of study treatment (CA-008 vs. placebo) 
infiltrated/instilled during surgery in treating postoperative pain after a bunionectomy in the 
setting of multimodal analgesia in addition to a Mayo block with bupivacaine in the first 24h and 
to confirm the safety profile observed in the phase 1 study recently completed.  For the PK study, 
additional assessments will be done to further characterize the PK profiles of CA-008, CA-101 
and capsaicin. 
The current design, post-operative pain following elective primary unilateral first metatarsal 
bunionectomy surgery with osteotomy, has been used as a model of postoperative pain 
previously.  In this model, the pain is generated from the correction of hallux valgus deformity of 
the first metatarsal and is used as a model to evaluate the treatment effect on duration of acute 
pain (multiple-day efficacy) (Singla 2013; Wang 2010). 
Randomization will be used to avoid bias in the assignment of subjects to treatment, to increase 
the likelihood that known and unknown subject attributes (e.g., demographics and baseline 
characteristics) or other variables are evenly balanced across treatment groups, and to enhance 
the validity of statistical comparisons across treatment groups. 
A placebo control will be used to establish the frequency and magnitude of changes in clinical 
endpoints that may occur in the absence of active treatment as well as to minimize subject and 
investigator bias.  Double-blinded treatments will be used to reduce potential bias of subjects and 
investigators during data collection and evaluation of clinical endpoints.  


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10. 
SELECTION OF STUDY POPULATION 
10.1. 
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 - 75 years 
old, inclusive, and American Society of Anesthesiology (ASA) physical Class 1, 2 or 3 at the 
time of randomization (Appendix 1A). 
2. Plan to undergo an elective primary unilateral first metatarsal Bunionectomy repair, without 
collateral procedure or additional surgeries, to be performed under light to moderate sedation 
with regional anesthesia. 
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 ≤ 40 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 


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required. 
8. For the portion of subjects who will participate in the PK analyses, be willing to undergo 17 
blood draws for PK assessments at various time points during the surgery and the following 
24 hours. 
10.2. 
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, bupivacaine 
HCl, ketorolac, acetaminophen 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 5) 
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 


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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. 
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 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 


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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. 
10.3. 
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: 
 Safety reasons, including AEs or significant concomitant illness, injury, or urgent 
surgeries/procedures that would, in the judgment of the investigator, affect assessments of 
clinical status to a significant extent, require discontinuation of study treatment, or both 
 At the request of the Sponsor, regulatory agency, or Institutional Review Board (IRB) 
 Subject is lost to follow-up 
 Subject treatment allocation is unblinded (i.e., individual code break; Section 11.5) 
 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 


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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. 
10.4. 
Study Restrictions 
In addition to the criteria described in Section 10.1 and Section 10.2, 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: 
 illicit drug use or non-medical use of therapeutic drugs not allowed by the protocol 
 prohibited medications described in Section 11.6 
 


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11. 
STUDY TREATMENTS 
11.1. 
Study Treatment  
11.1.1. 
CA-008 HCl Description 
CA-008, provided as the hydrochloride salt is a white solid, highly soluble in water.  It degrades 
rapidly to capsaicin at neutral pH but is stable for several days at room temperature in aqueous 
solution at pH~3.  Capsaicin is known to be irritating to mucous membranes when aerosolized 
and is a skin irritant. 
11.1.2. 
Study Treatment Description 
The active drug product will be provided as CA-008 Solution for Injection 2.5 mg, 7.5 mg and 
15 mg/mL, 1.0 mL per vial, calculated as the freebase.  Inactive ingredients are mannitol, citrate 
buffer and water and solution is provided in a 5 mL clear sterile vial. 
Placebo comparator identical in appearance will be provided as 1.0 mL per vial. Inactive 
ingredients are mannitol, citrate buffer and water. 
At time of use, the concentrate will be completely constituted with 49 mL of sterile saline and 
only a portion of the solution will be used for treatment.  The Pharmacy Manual includes details 
on reconstitution and disposal of unneeded solution.  For clarity, the drug product and treatment 
solutions are shown in Table 4. 
Table 4. Study Treatments 
 
Solution for Injection, 1.0 mL per vial 
Drug Product as provided 
2.5 mg 
7.5 mg 
15 mg 
Concentration upon constitution with 49 mL 
saline 
0.05 mg/mL 
0.15 mg/mL 
0.30 mg/mL 
Dose in 14 mL of solution 
0.7 mg 
0.21 mg 
0.42 mg 
 
All study treatment vials are blinded and will be identified on the label by vial number. 
11.1.3. 
Study Treatment Storage 
Study treatments will be shipped to sites and stored at -20°C (-15°C to -30°C) until the day of 
surgery.  All study treatment should be stored in a secured area and in accordance with the 
product labeling and all applicable laws, regulations, and local/institutional requirements.  A 
description of storage conditions for all investigational products will be provided in the 
Pharmacy Manual. 


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11.1.4. 
Study Treatment Accountability 
All study treatment will be transported, received, stored, and handled strictly in accordance with 
the container or product label, the instructions provided to the research site, and applicable 
regulations.  Detailed drug accountability records must be maintained, including the dates 
shipments are received, the quantity of material received, the dates dispensed and the running 
inventory.  The unused quantities will be returned to the Sponsor’s drug supply vendor at the end 
of the trial. All unused supplies will be checked against the drug accountability records during 
the study and/or at the end of the study. The Investigator or designee must maintain an inventory 
record of all dispensed rescue medications to subjects. Additional details are provided in the 
Pharmacy Manual. 
Only eligible subjects participating in the study will receive the study treatment. Only authorized 
research site staff may supply, prepare or administer the study treatments. Once dispensed, study 
treatment may not be relabeled or reassigned for use by other subjects.  
11.1.5. 
Control of Study Treatment and Rescue Medication 
Mishandling, potential theft, significant loss of clinical supplies, including study treatments, 
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. 
11.2. 
Other Interventions 
11.2.1. 
Inpatient Multimodal Analgesia  
While in-clinic, subjects will be treated with a multimodal analgesic regimen to supplement the 
Mayo block in the immediate postoperative period.  The regimen will include IV ketorolac and 
IV/PO acetaminophen.  Administer the following:  
 Ketorolac 30 mg IV (a non-steroidal anti-inflammatory drug (NSAID) to be administered 
intraoperatively before the end of surgery.  Per investigator discretion, adjust the dose as 
necessary for subject age and medical condition. 
 Acetaminophen 1000 mg IV to be administered intraoperatively before the end of 
surgery. This administration should be based off of T0.  
After the above have been administered, no additional NSAIDs or acetaminophen are to be 
administered during the inpatient phase of the study through T96h. 


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11.2.2. 
Inpatient Rescue Medications 
Additionally, should the subject have breakthrough or poorly controlled pain at any time from 
EOS to T96h (the inpatient period), oxycodone rescue medication may be administered for any 
moderate to severe pain (NRS ≥ 4) (see Section 9.1.3). 
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. 
11.2.3. 
Outpatient Analgesic Medications 
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: T96h through D29/W4:   
 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®])  
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 period beyond the T84 hour timepoint, then 
prescribe no more than 6 tablet supply of oxycodone 5 mg (for use up to tid prn) to cover the 
initial outpatient period with actual number of tablets prescribed and refills per investigator 
discretion and based upon the subject’s needs. 
Persistent pain or pain exacerbations during this period may suggest the need for an unscheduled 
in-person visit to assess the surgical site.  If such a situation occurs, the Investigator should use 
clinical discretion on adequacy of analgesic treatment, but capture this event as an AE and 
document any required treatments. 
11.3. 
Method of Assigning Subjects to Treatment Groups 
Randomization will be used to avoid bias in the assignment of subjects to treatments, to increase 
the likelihood that known and unknown subject attributes (e.g., demographics, baseline 
characteristics) are evenly balanced across treatment groups, and to enhance the validity of 
statistical comparisons across treatment groups.  Subjects who have provided written informed 
consent will be assigned a unique number in the screening process. This number will be used to 
identify the subject throughout the study.  Once any subject number or randomization number is 
assigned, it cannot be reassigned to any other subject. The randomization plan is described in 
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There will be up to 4 treatment groups of subjects (3 active dose groups and placebo).  Each site 
will be provided with sufficient study treatment supplies for all treatment groups.   
Subjects may be rescreened if the screening window is exceeded due to scheduling issues.  For 
other out of screen window situations, Sponsor approval is needed prior to the rescreen visit. 
11.4. 
Selection of Doses 
The safety of CA-008 was established in relevant animal models and a prior phase 1 study after 
bunionectomy.  These results support the potential safety of CA-008 with no apparent abnormal 
findings.  Based on these nonclinical studies, a single instillation administration of CA-008 into 
the surgical site, at an initial dose of 0.7 mg/person and a maximum dose of 4.2 mg/person, has a 
minimal risk of causing adverse events.  This dose range is within the range used in the phase 1 
ascending dose safety study in a bunionectomy model and was found to be well tolerated.   
Taken together, the characterization of the pharmacology, pharmacokinetics, and toxicology 
profiles are considered sufficient to support the intended use of CA-008 in the Phase 2 efficacy 
and safety study for the treatment of acute post-surgical pain after bunionectomy. 
11.5. 
Blinding 
To reduce the potential for bias in the study, treatment group assignments will be double-blinded 
during the study.  The subject, investigational site personnel, Sponsor, and Sponsor designees 
directly involved in the conduct and/or monitoring of this study will not be aware of the 
treatment group assignments.  In the PK study all participating subjects whether randomized to 
active or placebo will have blood drawn at the specified time points and sent to the bioanalytical 
laboratory for subsequent processing.  As no one at the site is unblinded as to which treatment 
group any subject is assigned, blinding is preserved within the PK study. 
Under normal circumstances, the blind will not be broken until all participants have completed 
treatment. In case of emergency, and only if the information is required by the Investigator to 
ensure subject’s safety in managing a medical condition, the treatment may be unblinded at the 
site by using a code break module.  The code break module will be provided by the Sponsor’s 
designee.  If possible, the Investigator should contact the Sponsor prior to unblinding and after 
any actions have been taken.  Whenever a treatment sequence is prematurely unblinded, the 
reason, date and time of the unblinding, and the individual who broke the blind must be 
documented.  Individual code breaks will result in withdrawal of the participant from the study. 


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11.6. 
Prior and Concomitant Therapy 
All non-study treatments, 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 11.2.1. 
The Investigator is permitted to use clinical discretion for required concomitant medications to 
treat an AE.  
11.7. 
Treatment Compliance  
Because all study treatment 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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12. 
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.  
12.1. 
Demographics and Other Baseline Characteristics 
12.1.1. 
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. 
12.1.2. 
Demographics 
The following demographics will be recorded: age (birthdate), sex, race, and ethnicity.  
12.1.3. 
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. Subject’s medical history will be evaluated by an Investigator for clinical significance. 
12.1.4. 
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.  
12.1.5. 
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 (using investigator discretion, 
recommend provide guidance as to the appropriate combination of available methods).  


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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 (e.g., 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 (using investigator discretion, recommend the appropriate 
combination of methods, such as male condom, diaphragm, contraceptive sponge, spermicidal 
contraceptives and other similar methods) during the study.   
12.2. 
Eligibility Review and Randomization 
Prior to randomization, subjects must meet all inclusion and not meet any exclusion criteria as 
outlined in Section 10.1 and Section 10.2. 
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 date of randomization on 
the day of surgery.  
Randomization will be accomplished manually. 
12.3. 
Subject Pain Assessment Training 
Subjects will undergo study participation education on pain assessments and written testing 
procedures according to the Schedule of Study Procedures. 
12.4. 
Efficacy Assessments 
Details regarding primary and secondary endpoints are provided in Section 12.6 (Efficacy 
Variables); and discussed further in Section 15 (Statistical Analysis). The following sections 
provide an overview of the efficacy assessments included in the study.   
12.4.1. 
Numerical Rating Scale for Pain Intensity (NRS) 
The NRS is an 11-point scale with anchors 0 (no pain) and 10 (worst possible pain) (Ferreira-
Valente 2011, Hjermstad 2011) (see Appendix 1A).   
Subjects will report or record the intensity of their current pain at designated times during the study 
after administration of study treatment (see Section 9.1.4).  Subjects should be at rest for at least 


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10 minutes prior to completing NRS resting assessments and have ambulated approximately 10 
yards within 15 minutes prior to completing NRS ambulation assessments.   
12.4.2. 
Patient Global Evaluation (PGE) 
At T96h (prior to discharge), and on the D8, D15 and D29/ET visits, each subject will be asked 
to report their satisfaction with the study treatment for pain using a 4-point categorical scale.  
Each subject will be asked the following question:  
“How would you rate the study treatment that you have received for pain? Poor (0), Fair (1), 
Good (2), or Excellent (3)” (see Appendix 1C). 
12.4.3. 
Investigator Global Evaluation (IGE) 
At T96h (prior to discharge), and on the D8, D15 and D29/ET visits, the principal investigator or 
designee will report their satisfaction with the subject’s study treatment for pain using a 4-point 
scale.  A study Investigator (or authorized designee) will be asked the following question:  
“How would you rate the study treatment that the patient received for pain? Poor (0), Fair (1), 
Good (2), or Excellent (3)” (see Appendix 1D). 
12.4.4. 
Rescue Medications 
The details of rescue medication (doses and times) will be recorded beginning from the end of 
surgery through the D15 visit or to Early Termination Visit if applicable.  Subjects will be 
instructed on the proper use and timing of rescue medication.  Use Table 5 to calculate the 
morphine equivalent dose (MED) of various opioids. 
Table 5. Equianalgesic Conversion Table 
Opioid (Doses in 
mg) 
Conversion 
Factor 
Hydrocodone 
1 
Hydromorphone 
4 
Morphine 
1 
Oxycodone 
1.5 
Tramadol 
0.1 
Multiply the opioid dose by the 
conversion factor = morphine equivalent 
dose (MED):  
e.g., oxycodone 5 mgX1.5 = 7.5 mg MED 


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12.5. 
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. 
12.5.1. 
Clinical Laboratory Assessments 
All protocol-specified laboratory tests on blood and urine samples will be performed at a central 
laboratory.  Blood samples will be collected, processed, and shipped according to instructions 
from the central laboratory.  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. Required 
assessments for blood tests are listed in Table 6. 
Table 6. Clinical Laboratory Assessments 
Hematology 
Chemistry 
Hematocrit 
Hemoglobin 
Red blood cell (RBC) count  
Total and differential (absolute) 
white blood cell count 
Platelet count 
Sodium 
Potassium  
Calcium  
Chloride 
Glucose   
Creatinine 
Blood urea nitrogen 
Total bilirubin 
Alanine aminotransferase (ALT) 
Aspartate aminotransferase (AST) 
Lactic dehydrogenase (LDH) 
Gamma-glutamyl transferase (GGT) 
Alkaline phosphatase  
 
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 


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medical history or with an AE.  The investigator may use Appendix 1H (severity assessments of 
labs) to assist in the determination of clinical significance. 
The clinical laboratory tests will be completed at Screening and at T96h before discharge from 
the inpatient unit (see).  In addition to the clinical laboratory tests, a serum pregnancy test will be 
performed at the Screening Visit and a urine pregnancy test will be performed prior to surgery 
for women of childbearing potential.  ALT or AST > 3x upper limit normal range (ULN) / Tot. 
Bili > 3 X ULN/ Alk Phos. >2X ULN will be considered an adverse event, as well as any other 
changes deemed clinically significant by the Investigator.  
12.5.2. 
Urine Drug Screen and Alcohol Test 
Urine drug screen and alcohol (breath or saliva) tests will be completed at screening and pre-
procedure.  All subjects will be tested for drugs-of-abuse (e.g, amphetamines, barbiturates, 
benzodiazepines, cocaine, opiates, phencyclidine, tetrahydrocannabinol (THC), methadone, 
methamphetamine, tricyclic anti-depressants, oxycodone and others). 
The drug and alcohol screens may be performed in-house at the Clinical Unit, and the alcohol 
saliva test may be sent out to a local lab (e.g., LabCorp).  If any of these tests are positive, the 
subject will not be allowed further participation in the trial unless one of the previously noted 
exceptions is present.  A positive test may be repeated at the discretion of the PI.   
12.5.3. 
X-Ray 
An X-ray of the surgical site will be performed during screening and at D29/ET. 
12.5.4. 
Vital Signs 
Vital signs will consist of blood pressure (BP, mmHg), pulse rate (HR, beats per minute), and 
respiratory rate (RR, breaths/min) collected while sitting, following a rest period of at least 5 
minutes. Vital signs and temperatures will be assessed at various study time points (see Section 
9.1.4 through Section 9.1.8).   
Vital sign abnormalities are graded in Appendix 1I.  If in the opinion of the Investigator the 
perturbation is considered clinically significant, it will be considered an adverse event.  
12.5.5. 
12-Lead Electrocardiogram (ECG) 
12-Lead ECGs will be performed after the subject has been resting in a recumbent/supine 
position for at least 5 minutes.  The ECG variables will include ventricular heart rate and the PR, 
QRS, QT and QTcF intervals.  The ECGs will be signed and dated by a medically-qualified 
individual to confirm review of the ECG and verify whether any abnormalities are clinically 
significant.  In general, abnormal, clinically significant ECGs are expected to be associated with 
an item recorded in medical history or with an AE.  ECGs will be assessed at Screening and at 
T24h (± 2 hour).  Clinically significant changes in ECG (i.e., QTcF should be <450 msec / < 470 


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msec for female / male subjects, respectively; and an increase of QTcF of > 30 msec will be 
considered an AE. 
12.5.6. 
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 interim PEs prior to Surgery, and additional interim PEs focused on 
the surgical site and neurosensory testing of both lower extremities at T96h prior to discharge 
from the inpatient unit, D8, D15 and D29/ET.   
Body weight (kg), in indoor clothing, but without shoes, will be measured at Screening, at T96h 
prior to discharge from the inpatient unit and ET.  Height in centimeters (cm) will be measured, 
and BMI will be calculated at Screening only.  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. 
12.5.7. 
Surgical Site Assessment  
The surgical site should be assessed to determine if any related AEs have occurred.  Assessments 
will be conducted at T96h prior to discharge from the inpatient unit, and on the D8, D15 and 
D29/ET visits.    
At T96h prior to discharge, 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.” Appendix 1E 
Assessments will also be performed at each of the Follow-up visits on Days 8, 15 and 29, or at 
the time of discontinuation. When assessed on Day 29, if the Investigator observes insufficient 
wound healing, the subject will be scheduled for a follow-up visit on Day 36. Appendix 1F 
If there are atypical skin reactions, for example, erythema, pain, pruritus, bruising, swelling, 
bruising or other skin changes, they will be evaluated and graded for severity. 
12.5.8. 
Neurosensory Exam 
A neurosensory exam of the lower extremity (foot/great toe surgical site with contralateral 
comparison) will be conducted at screening, at T96h prior to discharge from the inpatient unit, 
on the D8, D15 and D29/ET (and D36 if necessary) visits.  The exam will involve the dorsal 
aspect of the foot proximal to the great toe.  
This evaluation will include the following (details described in Appendix 1G): 
 Visual exam of the foot 
 Deep Tendon Reflexes (normal, reduced or absent) 
 Vibratory sensation (normal, reduced or absent) 


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 Monofilament Sensation (normal, reduced or absent) 
 Allodynia to brush (pain (allodynia), hyperesthesia, normal, reduced or absent) 
A persistent atypical sensory change after EOS, such as allodynia or hyperalgesia proximal to the 
surgical site will be reported as an AE.  Numbness at or near the incision need not be considered 
an AE since this could occur due to tissue trauma and inflammation from surgery. 
12.5.9. 
Assessment of Adverse Events 
All SAEs will be documented and followed from the time the subject has signed the ICF until 
D29 or, if necessary, D36 after the completion of surgery.  All SAEs and non-serious AEs will 
be documented and followed from the time of administration of study treatment until D29 or, if 
necessary, D36 after the completion of surgery.  AEs that occur between Screening and the study 
procedure should be considered medical history and added to the subject’s medical record. AEs 
that have been designated as possibly or probably related to study treatment will be followed 
until resolution or stabilization. Further details on AEs, including definitions, elicitation, and 
reporting are provided in Section 13. 
12.6. 
Efficacy, Safety and PK Endpoints 
12.6.1. 
Efficacy Endpoints 
Using NRS scores (at rest and with ambulation) a variety of time-specific summed pain intensity 
assessments (area under the curve or AUC for pain intensity) will be calculated comparing each 
CA-008 dosing groups to placebo.   
12.6.1.1. Primary Efficacy Endpoint 
Weighted sum of pain intensity (SPI) assessments = Area Under the Curve (AUC) of the NRS 
scores from T0 to T96h at rest (AUC0 to 96h).  
12.6.1.2. Secondary Efficacy Endpoints 
The key secondary endpoints for the comparison of the 4.2 mg CA-008 dose vs. placebo (in 
descending order of importance): 
1. Percentage of subjects who do not require opioids or are opioid free (OF) from T0 to 
T96): OF0 to 96h 
2. Total opioid consumption (in daily oral morphine equivalents) = OC from T0 to T96h: 
OC0 to 96h  
3. Using NRS at rest: AUC0 to W1 
12.6.1.3. Other Efficacy Endpoints 
 AUC 0 to 24h, AUC 0 to 120h, AUC 0 to W1 (walking), AUC 12 to 24h, AUC24 to 48h, AUC24 to 72h, AUC24 to 
96h, AUC96h to 120h, AUC96h to W1, AUC24h to W1(walking), AUC96h to W2, AUC96h to W2(walking) 
 OC24 to 48h, OC24 to 72h, OC24 to 96h 


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 OF24 to 96h, OF96h to W1 and OF96h to W2 
 TTFRafter T0 and TTFRafter T24h  
 Analgesic consumption of OTC analgesics and if prescribed, oxycodone, from T96h to W1 
and T96h to W2 
 PGE comparing the %age of subjects reporting “poor” + “fair” vs. “good” + “excellent” 
responses, and the %age reporting each category of response at W1, W2 and W4 
 IGE comparing the %age of those reporting “poor” + “fair” vs. “good” + “excellent” 
responses, and the %age reporting each category at W1, W2 and W4 
 Number and %age Subjects with an AE of lack of efficacy (LOE) during the inpatient period: 
LOE24 to 96h, LOE0 to 96h 
 HCU96h to W2 and HCU96h to W4 
12.6.2. 
Safety Endpoints 
Safety endpoints include the following: 
 Incidence of TEAEs and SAEs 
 Vital sign measurements 
 Physical Exam findings  
 Surgical Site assessment findings 
 Neurosensory Exam results 
 Clinical laboratory test results 
 Electrocardiogram (ECG) results 
 Concomitant medications 
12.6.3. 
Pharmacokinetic Endpoints 
12.6.3.1. PK Sampling and Parameters 
Based upon the PK results from the Phase 1 bunionectomy ascending dose safety study, the time 
points for whole blood collection will be at baseline (within the 30 min before the end of study 
treatment dosing at T0), and at T5min, T10 min, T15min, T30min, T45min, and T1, 1.5, 2, 2.5, 
3, 4, 6, 8, 12, 16, and 24h, for a total of 17 samples or approximately 102 mL).  Actual sampling 
times will be used to calculate plasma bupivacaine-derived PK parameters.   
A selected number of subjects will participate in the PK study.   
The following parameters will be estimated using noncompartmental analysis for CA-008, 
capsaicin and CA-101:  
 Cmax: The maximum measured plasma concentration, obtained directly from the data without 
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 Clast: Last observed (quantifiable) concentration  
 Tmax: Time of Cmax 
 t½: The apparent first-order terminal elimination half-life, calculated as 0.693/λz  
 Tlag: Time delay between drug administration and first measurable (above lower limit of 
quantitation) concentration  
 Tlast: Time of occurrence of Clast  
 λz: Terminal first-order elimination rate constant  
 AUC0–t: Area under the plasma concentration-time curve from time 0 to the last measurable 
concentration (where time is postdose), calculated by the linear trapezoidal method   
 AUC0–∞: Area under the plasma concentration-time curve, from time of dosing to infinity. 
 AUClast: Percentage of the area extrapolated beyond the last quantifiable plasma 
concentration 
12.6.3.2. Sample Handling: 
Handling and labeling requirements after the collection of each PK sample are described in detail 
in the Clinical Laboratory Manual. 


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13. 
ADVERSE EVENTS  
13.1. 
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.   
13.1.1. 
Relationship to Study Treatment 
A qualified investigator must make the determination of relationship to the investigational 
product for each AE.  The Investigator should decide whether, in his or her medical judgment, 
there is a reasonable possibility that the event may have been caused by the study treatment.   
 
Causality 
Category 
Description 
Unlikely related 
A clinical event, including laboratory test abnormality, with a temporal 
relationship to study treatment administration which makes a causal 
relationship improbable or if other drugs, chemicals or underlying 
disease provide more plausible explanations.  
While temporal sequence may be an important factor in determining 
causality: i.e., whether the observed reaction or event began after the 
study treatment, it may well be that the surgery, anesthesia, a concurrent 
medical condition or concomitant medications administered during or 
after surgery were more likely than not to be responsible for the AE.  
The investigator should use clinical judgment to evaluate the evidence 
and determine whether there is a reasonable possibility that study 
treatment actually caused the AE or whether based upon the evidence it 
is more likely that something else is responsible.  If the former, choose 
“possibly related” and if the latter, “unlikely related.”   


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For the purpose of this protocol, the term “unlikely related” will be 
considered an AE not related to study treatment. 
Possibly related 
A clinical event, including laboratory test abnormality, with a temporal 
relationship to study treatment administration, which also may be 
explained by concurrent disease or other drugs or chemicals.  In such 
cases, if the investigator using clinical judgment is unable to rule out a 
reasonable possibility that study treatment was partly responsible, then 
choose “possibly related.”  
For the purpose of this protocol, an event that has possible relationship 
to study treatment will be defined as a “Suspected Adverse Drug 
Reaction”.  
Probably related 
A clinical event, including laboratory test abnormality, with a temporal 
relationship to study treatment administration, in which the investigator 
has determined that the event is unlikely to be attributed to other 
factors.   
For the purpose of this protocol, an event that has probable relationship 
to study treatment will be defined as an “Adverse Drug Reaction”. 
 
13.1.2. 
Adverse Event Reporting 
All AEs must be entered on the AE CRF, regardless of causality or severity. AEs include new 
AEs, worsening baseline conditions, clinically significant laboratory findings, disease-related 
signs and symptoms that were not present at baseline, and any events or findings that the 
Investigator feels are clinically significant. 
Disease-related signs and symptoms that are present at baseline should not be recorded as AEs 
unless they worsen in severity or increase in frequency. 
Information collected concerning AEs will include the following: 
 Name of the event 
 Onset date 
 Resolution date 
 Severity (i.e., mild, moderate, severe or potentially life-threatening) 
 Relationship to study treatment 
 Action and outcome 
 Seriousness of event 


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All SAEs will be documented and followed from the time the subject has signed the ICF until 29 
(+/- 3 days), or, if necessary, Day 36 after the completion of surgery. All SAEs and non-serious 
AEs will be documented and followed from the time of administration of study treatment until 
Day 29 or, if necessary, Day 36 after the completion of surgery. AEs that occur between 
Screening and the administration of study medication should be considered medical history and 
added to the subject’s medical record, unless the AE is due to a study-related procedure (such as 
phlebotomy), in which case it will be recorded as a non-treatment emergent AE.  AEs that have 
been designated as possibly related to study treatment will be followed until resolution or 
stabilization. 
13.1.3. 
Serious Adverse Event (SAE) 
An SAE or reaction is any adverse drug experience occurring at any dose that results in any of 
the following outcomes: 
 Death 
 Is life-threatening (at the time of the event) 
 Requires subject hospitalization or prolongation of existing hospitalization, 
 Results in persistent or significant disability/incapacity 
 Is a congenital anomaly/birth defect (in an offspring) 
 An Important medical event that may not result in death, be life-threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical judgment, 
the event may jeopardize the subject and/or may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition. 
All AEs requiring hospitalization or prolongation of a pre-existing hospitalization should be 
reported as SAEs unless they occur greater than 14 days after the Day 29 visit, or 21 days after 
early termination AND are not considered to be study treatment-related by the Investigator. 
Hospitalizations meeting the following criteria will not be reported as an SAE but must be 
recorded on the appropriate CRF: study specified hospitalization, short-term administrative 
hospitalization for procedures, tests or treatments of conditions that would not otherwise 
constitute an SAE, elective hospitalizations. 
13.1.3.1. Serious Adverse Event Reporting 
Serious AEs must be reported to the Sponsor or designee within 24 hours of knowledge of the 
event. All SAEs that occur while a subject is receiving study treatment and within 14 days 
following the study completion visit (or 21 days following an ET if applicable) are reportable 
within 24 hours. During this follow-up period beyond study completion or after an ET, only 


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those SAEs considered to be possibly related to study treatment should be reported within 24 
hours. 
The procedure for reporting an SAE is as follows: 
 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.  
CRO Medical Monitor: Jon L. Ruckle, MD, CPI 
24/7 Emergency contact: 808-349-9812 
SAE Reporting email: MedicalMonitorCA-PS-201@Lotuscr.com  
 The Sponsor’s Medical Monitor is available for questions about safety-related issues: Mike 
A. Royal, MD JD MBA; 858-204-1112 or mike@concentricanalgesics.com. 
 The initial report should include all information known at the time of the report (additional 
information can be reported as discovered). Do not delay the initial reporting in order to 
obtain resolution or follow-up information. 
 The site will enter into the electronic database (or fax, if the database cannot be accessed for 
any reason) an SAE report, or similar form, that includes the following information, as 
available: 
o Subject ID 
o Basic demographic information (age, gender, weight) 
o Outcomes attributed to the event (death, life-threatening hospitalization [new or 
prolonged], disability, congenital anomaly, required medical intervention to prevent 
permanent impairment/damage, etc.) 
o Onset date and severity of the event 
o Brief description of the event including frequency and severity of symptoms leading 
to diagnosis 
o List of relevant test results and laboratory data 
o Any other relevant history 
o Whether the study treatment was discontinued 
o Investigator’s assessment of causality 
The CRO Medical Monitor or another representative of the Sponsor may contact the Investigator 
to request additional information regarding the event or to confirm information. All SAEs will be 
entered on the AE CRF. The same nomenclature should be used on both the SAE report and the 
AE CRF.  The Investigator is responsible for the complete and timely reporting of all SAEs to 
the Sponsor (or designee), reporting pertinent follow-up information on the SAE, and notifying 
the appropriate IRB of the occurrence of and details surrounding the event. In the event there is a 
question as to whether the AE is serious, the event should be reported. 


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13.2. 
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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14. 
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 14.2.  
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. 
14.1. 
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.  
14.2. 
Study Auditing and Monitoring 
Monitoring of the study site (including, but not limited to, reviewing CRFs for accuracy and 
completeness) will be performed by the Sponsor’s designated monitor(s). The extent, nature, and 
frequency of on-site visits will be based on such considerations as the study objectives and/or 


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endpoints, the purpose of the study, study design complexity, and enrollment rate. By signing the 
protocol, the Investigator agrees that, within local regulatory restrictions and institutional and 
ethical considerations, authorized representatives of the Sponsor, a regulatory authority, and/or 
an IRB may visit the site to perform audits or inspections, including the drug storage area, study 
treatment 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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15. 
STATISTICAL METHODS  
15.1. 
Statistical and Analytical Plans 
This section describes the statistical methods to be used to analyze the efficacy and safety.  The 
final analysis 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. 
15.2. 
Sample Size Justification 
In the previously completed Phase 1 ascending dose safety study in bunionectomy (CA-008 vs. 
placebo), the mean difference between CA-008 (all dose groups combined) and placebo for the 
AUC24 to 96h was -120.  The standard deviation (SD) estimates for the six treatment arms in this 
study ranged from 70 to 190 with a median SD of 108.  For the primary endpoint (AUC0 to 96h), 
the true treatment difference between the 4.2 mg CA-008 group and the placebo group is 
assumed to be equal to -100 and the assumed true SD is equal to 130.  For these assumptions, 
and based on the use of a two-sided, two-sample comparison of means at the alpha=0.05 level of 
significance, a sample size of 36 subjects per arm will provide 90% power.  Thus, the planned 
total sample size is 144 subjects. 
15.3. 
Analysis Populations 
The following three analysis populations are planned for this study:  
 The Safety Population will include all subjects who received at least part of a dose of study 
treatment.   
 The PK Population will include all subjects who receive a full dose of study treatment and 
complete at least all PK assessments through the T6h timepoint.  Subjects who fail to 
complete these PK assessments will be replaced.   
 The modified ITT (mITT) Population will include all subjects who receive a full dose of 
study treatment and complete the first 3 pain assessments (through T2h).   
Subjects who elect to discontinue study participation during the inpatient phase of the study, will 
be asked to continue with assessments through T96h if they have not elected to withdraw from 
all aspects of study participation.  Subjects who elect to discontinue participation after discharge 
from the inpatient unit but prior to D8 (W1) will be considered to have terminated as of the date 
of their election, however they will be asked to return to the site to reassess the surgical site for 
wound healing. 


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All safety assessments and baseline characteristics will be summarized using the Safety 
Population.  PK and efficacy analyses will be performed using the PK and mITT Populations, 
respectively.  All summaries will be grouped by the actual treatment received.  Each active dose 
cohort will be presented separately, along with a combined active dose group.  
Inpatient Study Completer will be defined as those subjects who complete the assessments 
through T96h.  Outpatient Study Completer will be defined as those subjects who complete the 
assessments through D29±2 (W4). 
Membership in the analysis populations will be determined before unblinding. 
15.4. 
Planned Analyses 
Unless otherwise indicated, all testing of statistical significance will be 2-sided, and a difference 
resulting in a P value of less than or equal to 0.05 will be considered statistically significant.  
Furthermore, the baseline will be the last assessment before the dosing of study treatment. 
Summary statistics will be provided for the variables described in the following sections. For 
continuous variables, these statistics will typically include the number of subjects, mean, 
standard deviation (SD), median, minimum, and maximum. For categorical variables, these 
statistics will typically include the number and percentage of subjects in each category. 
15.5. 
Study Subjects and Demographics 
15.5.1. 
Disposition and Withdrawals 
The numbers of subjects randomized, completing, and withdrawing, along with reasons for 
withdrawal, will be tabulated overall and by treatment group.  The number of subjects in each 
analysis population will be reported. 
15.5.2. 
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. 
15.5.3. 
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. 


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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. 
15.5.4. 
Exposure  
Since this is a single dose study, study treatment administration will be summarized in terms of 
total exposure by cohort and treatment group. 
15.5.5. 
General Considerations 
All continuous study assessments will be summarized by treatment and time point (as applicable) 
using the descriptive statistics n, mean, SD, median, and range (minimum, and maximum).  
Categorical assessments will be summarized by treatment and time point (as applicable) using 
frequency counts and rates of occurrence (%).  Changes from baseline for continuous outcomes 
will be presented as their corresponding continuous measures for post-baseline visits.  All study 
data will be listed by treatment group, subject and time point.  
No preliminary rounding will be performed; rounding will only occur after the analysis.  Means 
and medians will be presented with one more decimal place than the precision of the data.  
Standard deviations will be presented with two more decimal places than the precision of the 
data.  Percentages will be presented with one decimal place.  A percentage of 0% or 100% will 
be reported as 0% or 100%, respectively.  Minimums and maximums will be presented with the 
same precision as the original data. 
All analyses will be performed using the SAS System® version 9.3 or higher. The domain 
(Study data tabulation Model [SDTM]) and analysis (Analysis Data Model [ADaM]) data sets 
will be taken as input to the SAS programs that generate the report-ready tables, figures and 
listings. The submission ready SDTM and ADaM data sets will be provided to the sponsor along 
with display deliveries. The specifications for the domain data sets and analysis data sets will be 
provided in a separate document. 
The following conventions will be used throughout the study analysis: 
 Time T0 is the time of completion of study treatment administration.  
 Day of surgery is defined as D0 
 Assessment visit times are defined by time T0/D0. 
 Baseline value is defined as the last valid measurement prior to beginning study treatment 
administration. 
 Change from baseline is defined as post-baseline value minus baseline value. 
 Duration of an AE will be computed in days for AEs lasting longer than 24 hours, and as 
hours for AEs lasting less than 24 hours.  Duration in hours will be calculated as the stop 
date/time of the event minus the start date/time.  Duration in days will be calculated by using 


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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). 
15.6. 
Analysis of Efficacy Measures 
All efficacy endpoints (e.g., NRS scores), will be summarized over time by treatment using 
descriptive statistics including confidence intervals as appropriate. 
AUC calculations will be done using the standard trapezoidal rule  
AUC  =     ∑
(
𝑁𝑅𝑆𝑖+𝑁𝑅𝑆𝑖+1
2
)
𝑥
𝑖=0
∗ (𝑇𝑖+1 − 𝑇𝑖) 
Where:  NRSi = NRS at time i, and (Ti+1 – Ti) is the Time difference in minutes between time i 
and time i+1.  A similar calculation and handling of missing data will be performed for the NRS 
scores with ambulation. 
In this study, subjects are permitted to take rescue medication for analgesia.  It is expected 
subjects randomized to placebo arm will take rescue medication more often.  During both 
inpatient and outpatient portions of the 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 
15.6.4.   
15.6.1. 
Primary Efficacy Analysis 
The primary efficacy analysis of the primary endpoint (AUC0 to 96h) will be conducted using an 
analysis of variance (ANOVA) model with treatment group (four levels) as the main effect.  The 
primary analysis will compare the 4.2 mg CA-008 group to the placebo group using a two-sided 
test at the alpha=0.05 level of significance. 


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15.6.2. 
Key Secondary Efficacy Analyses 
If the primary efficacy analysis is statistically significant (p<0.05), then comparisons between the 
4.2 mg CA-008 group and the placebo group will be made for the following endpoints: 
 Percentage of subjects who do not require opioids or are opioid free (OF) from T0 to T96): 
OF0 to 96h 
 Total opioid consumption (in daily oral morphine equivalents) = OC from T0 to T96h: OC0 to 
96h 
 Using NRS at rest: AUC0 to W1 
Each of the above comparisons will be made using a two-sided test at the alpha=0.05 level of 
significance.  However, once a nonsignificant result occurs, then all subsequent analyses in the 
hierarchy will be exploratory rather than confirmatory. 
The percentage of subjects who do not require opioids or are OF will be analyzed using a logistic 
regression model with treatment group (four levels) as a factor.  The other two key secondary 
endpoints will be analyzed using the same type of ANCOVA model as described for the primary 
efficacy analysis. 
15.6.3. 
Other Efficacy Analyses 
For the primary endpoint and the three key secondary endpoints, comparisons between the 0.7 
mg CA-008 group and the placebo group, and between the 2.1 mg CA-008 group and the 
placebo group will be tested using the same model as used for the primary (key secondary) 
analysis of the corresponding endpoint. 
All other AUC and quantitative endpoints will be analyzed using the same type of ANOVA 
model as described for the primary analysis.  All proportion endpoints will be analyzed using the 
same type of logistic regression model as described for the first key secondary efficacy analysis. 
All other efficacy analyses will be conducted using two-sided tests at the alpha=0.05 level of 
significance, with no adjustment for multiplicity. 
15.6.4. 
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 the study treatment; 
 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.   


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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 4 hours 
following the rescue use. 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. 
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. 
15.7. 
Analysis of Safety  
Safety analyses will be conducted using data from the Safety Population (as defined in 
Section 15.3).  
Safety will be assessed through treatment-emergent AEs (TEAEs); hematologic, biochemical, 
and urinalysis laboratory parameters; vital signs measurements; ECGs; physical exam, surgical 
site and neurosensory assessments.  
No formal statistical comparisons will be performed for safety endpoints. 
15.7.1. 
Adverse Events 
Adverse events will be coded by system organ class (SOC) and preferred term using the Medical 
Dictionary for Regulatory Activities (MedDRA) reporting system. Treatment-emergent AEs are 
defined as any of the following: 
 Non-serious AEs with onset on the date of treatment with the study treatment through Day 29 
or Early Termination, whichever occurs first;  
 Serious AEs with onset on the date of treatment with the study treatment through 30 days 
after Day 29 or Early Termination, whichever occurs first; 
 AEs that start before the start of treatment but increase in severity or relationship at the time 
of or following the start of treatment through Day 29 or Early Termination, whichever occurs 
first. 


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The number and percentage of subjects with TEAEs will be displayed for each treatment group 
by SOC and preferred term. Additionally, TEAEs will be tabulated for each treatment group by 
severity and by relationship to the study treatment. A listing of SAEs will be provided if 
applicable. 
15.7.2. 
Clinical Laboratory Evaluations 
For continuous laboratory parameters, descriptive statistics will be presented for the value at 
each assessment time and for the changes from baseline screening labs by treatment group.  
Additionally, clinical laboratory parameters will be categorized as low, normal, or high 
according to laboratory range specifications and the number and percentage of subjects in each 
category will be presented in shift tables. 
Laboratory values that are outside the normal range will also be flagged in the data listings, 
along with corresponding normal ranges. 
15.7.3. 
Vital Signs and ECG 
Descriptive summaries (mean, SD, median, minimum, and maximum) of actual values and 
changes from Baseline will be calculated for vital signs and ECG.  Detailed description of the 
analysis will be included in the Study SAP. 
The incidence of abnormal ECG findings will be summarized.  
15.7.4. 
Physical Examination Findings 
Physical and Surgical Site examination data will be presented in the listings. Abnormal or 
clinically significant physical exam and surgical site findings will be recorded as AEs. 


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16. 
SITE AND INVESTIGATOR RESPONSIBILITIES 
Additional details may be outlined in the Clinical Study Agreement between the sponsor and the 
investigational site.  
16.1. 
Regulatory and Ethical Considerations 
16.1.1. 
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. 
16.1.2. 
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. 
16.1.3. 
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 


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withdraw consent without prejudice at any time during the study. If the participant chooses to 
participate, he/she must sign the ICF before any study-related procedures are performed.  
Significant changes to the protocol or product safety information may require a revision of the 
ICF, which must be reviewed and signed by all applicable study participants. 
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. 
16.2. 
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. 


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All data will be considered the sole property of the Sponsor. Please refer to the Clinical Study 
Agreement for details. 
16.3. 
Study and Site Closure 
Upon completion of the study, all study data will be provided to the Sponsor following review of 
site study records for completeness, and data clarifications and resolutions. Accounting, 
reconciliation, and final disposition of used and unused study treatments, 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.  
16.4. 
Regulatory Documents and Records Retention 
The Investigator is responsible for creating and/or maintaining all study documentation required 
by 21 CFR 50, 54, 56 and 312, ICH E6 Section 8, as well as any other documentation defined in 
the protocol or Clinical Study Agreement. The Investigator must provide key documents to the 
Sponsor prior to the start of the study.  A complete list of required regulatory documents will be 
supplied by the Sponsor or its representative. 
Federal and local regulations require that the Investigator retain a copy of all regulatory 
documents and records that support the data for this study for whichever of the following is the 
longest period of time: 
 A period of 2 years following the final date of approval by the FDA or other regulatory 
agency of the study treatment for the purposes that were the subject of the investigation; 
or 
 A period of 5 years following the date on which the results of the investigation were 
submitted to the FDA or other regulatory agency in support of, or as part of, an 
application for a research or marketing permit for the study treatment for the purposes 
that were the subject of the investigation. 
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If the investigation does not result in the submission of the data in support of, or as part of, an 
application for a research or marketing permit, records must be retained for a period of 2 years 
following notification by the Sponsor that the entire clinical investigation (not merely the 
Investigator’s portion) is completed, terminated, or discontinued or 2 years following withdrawal 
of the Investigational New Drug application/Clinical Trial Authorization or request for 
marketing approval (New Drug Application/Marketing Authorization Application).  
If the Investigator retires, relocates, or for other reasons withdraws from the responsibility of 
keeping the study records, custody must be transferred to a person who will accept the 
responsibility. The Sponsor must be notified in writing of the name and address of the new 
custodian. Study records should not be destroyed without consultation with the Sponsor. 
16.5. 
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.  
16.6. 
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. 
16.7. 
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 § 


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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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17. 
INVESTIGATOR PROTOCOL AGREEMENT PAGE 
A 
Phase 
2, 
Randomized, 
Double-blind, 
Placebo-controlled 
Safety, 
Pharmacokinetics and Efficacy Study of CA-008 in subjects Undergoing 
Bunionectomy  
Version: 1.2  
Date: 06 June 2018 
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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18. 
REFERENCES 
1. Aasvang EK, Hansen JB, Kehlet H.  Late sensory function after intraoperative capsaicin wound instillation.  
Acta Anaesthesiol Scand. 2010 Feb;54(2):224-31. 
2. Aasvang EK, Hansen JB, Malmstrøm J, Asmussen T et al. The effect of wound instillation of a novel 
purified capsaicin formulation on postherniotomy pain: a double-blind, randomized, placebo-controlled 
study. Anesth Analg. 2008 Jul;107(1):282-91. 
3. Apfelbaum JL, Chen C, Mehta SS, Gan TJ: Postoperative pain experience: Results from a national survey 
suggest postoperative pain continues to be undermanaged. Anesth Analg 97:534-540, 2003 
4. 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. 
5. Caterina MJ, Julius D. The vanilloid receptor: a molecular gateway to the pain pathway.  Annu Rev 
Neurosci. 2001 24:487-517. 
6. Chaiyasit K, Khovidhunkit W, Wittayalertpanya S. Pharmacokinetic and the effect of capsaicin in 
Capsicum frutescens on decreasing plasma glucose level. J Med Assoc Thai 2009; 92:108 –113. 
7. Chanda S, Bashir M, Babbar S, Koganti A, Bley K. In vitro hepatic and skin metabolism of capsaicin. Drug 
Metab Dispos 2008; 36:670 – 675. 
8. Chou R, Gordon DB, de Leon-Casasola OA, Rosenberg JM et al. Management of Postoperative Pain: a 
clinical practice guideline from the American pain society, the American Society of Regional Anesthesia 
and Pain Medicine, and the American Society of Anesthesiologists' committee on regional anesthesia, 
executive committee, and administrative council. The Journal of Pain, 2016; 17(2): 131-157. 
9. Dudley-Cash AI, Brennan TJ.  The effect of low concentration capsaicin infiltration on acute pain from 
incision.  Society for Neuroscience 2012, New Orleans. 
10. FDA Guidance for Industry: Estimating the Maximum Safety Starting Dose in Initial Clinical Trials for 
Therapeutics in Adult Healthy Volunteers (July, 2005).  U.S. Department of Health and Human Services 
Food and Drug Administration Center for Drug Evaluation and Research (CDER). Available from 
https://www.fda.gov/downloads/drugs/guidances/ucm078932.pdf. Date accessed: August 24, 2017 
11. FDA Guidance for Industry: Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled 
in Preventive Vaccine Clinical Trials (September, 2007). U.S. Department of Health and Human Services, 
Food and Drug Administration, Center for Biologics Evaluation and Research. Available from 
https://www.fda.gov/biologicsbloodvaccines/guidancecomplianceregulatoryinformation/guidances/vaccine
s/ucm074775.htm. Date accessed: July 7, 2017. 
12. FDA Summary Basis for Regulatory Action (December 13, 2016, page 6) Available from 
https://www.fda.gov/downloads/BiologicsBloodVaccines/CellularGeneTherapyProducts/ApprovedProduct
s/UCM536121.pdf. Date accessed: August 24, 2017  
13. Federal Register 8 Feb 1983; vol 48, No. 27. Available from 
https://www.accessdata.fda.gov/drugsatfda_docs/nda/99/20612_admindocs_P5.pdf. Date accessed: August 
24, 2017 
14. Ferreira-Valente MA, Pais-Ribeiro JL, Jensen MP. Validity of three pain intensity rating scales. Pain. 2011 
Oct;152(10):2399-404. 
15. Gan TJ, Habib AS, Miller TE, White W, Apfelbaum JL: Incidence, patient satisfaction, and perceptions of 
postsurgical pain: Results from a US national survey. Curr Med Res Opin 30:149-160, 2014 
16. 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. 


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17. Hayman M, Kam P. Capsaicin: a review of its pharmacology and clinical applications. Curr Anaesth Crit 
Care 2008; 19:338 –343. 
18. Hjermstad MJ, Fayers PM, Haugen DF, Caraceni A et al.; European Palliative Care Research Collaborative 
(EPCRC). Studies comparing Numerical Rating Scales, Verbal Rating Scales, and Visual Analogue Scales 
for assessment of pain intensity in adults: a systematic literature review. J Pain Symptom Manage. 2011 
Jun;41(6):1073-93. 
19. Kawada T, Suzuki T, Takahashi M, Iwai K. Gastrointestinal absorption and metabolism of capsaicin and 
dihydrocapsaicin in rats. Toxicol Appl Pharmacol 1984; 72:449 – 456.  
20. Kehlet H, Jensen T, Woolf C: Persistent postsurgical pain: Risk factors and prevention. Lancet 367:1618-
1625, 2006. 
21. Leelahuta Y, Glinsukon T, and Wangpanish W. In vitro capsaicin metabolism in the rat, mouse and 
hamster. Toxicon 1983; 21 (Suppl 3):245–248. 
22. Pogatzki-Zahn EM, Schnabel A, Zahn PK.  Room for improvement: unmet needs in postoperative pain 
management.  Expert Rev Neurother. 2012 May;12(5):587-600 
23. Pollak R, Schiffgen T, McDonnell ME, Zimmerman JC et al. A Single Instillation of a Highly Purified 
Capsaicin Formulation Decreases Postoperative Pain and Analgesic Use After Bunionectomy Surgery: A 
Randomized, Double-Blind, Placebo-Controlled Study [Poster 2009, APS] 
24. Savage PL, Buvanendran A, Hollmann M, Koncelik JJ et al A Single Instillation of a Highly Purified 
Capsaicin Formulation Decreases Postoperative Pain and Analgesic Use After Primary Unilateral Total 
Knee Arthroplasty: A Randomized, Double-Blind, Placebo-Controlled Study [Poster 2009 APS] 
25. Singla NK, Desjardins PJ, Chang PD. A comparison of the clinical and experimental characteristics of 
three acute surgical pain models: Dental extraction, Bunionectomy, joint replacement, and soft tissue 
surgery. Pain. 2013(155):441-456. 
26. 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.  
27. 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. 
28. Tominaga M, Caterina MJ, Malmberg AB et al.The cloned capsaicin receptor integrates multiple pain-
producing stimuli. Neuron 1998; 21, 531–543. 
29. Wang H, Gargano C, Lukac S, et al. An enhanced Bunionectomy model as a potential tool for early 
decision-making in the development of new analgesics. Adv Ther. 2010 (27):963-980. 
 


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1. APPENDICES 
APPENDIX A: AMERICAN SOCIETY OF ANESTHESIOLOGISTS PHYSICAL STATUS 
CLASSIFICATION SYSTEM (ASA CLASS) 
I 
Normal healthy patient 
II  
Patient with mild systemic disease; no functional limitation – e.g. smoker with well-
controlled hypertension 
III  
Patient with severe systemic disease; definite functional impairment – e.g. diabetes and 
angina with relatively stable disease, but requiring therapy 
IV 
Patient with severe systemic disease that is a constant threat to life – e.g. diabetes and 
angina and congestive heart failure; patients with dyspnea on mild exertion and chest 
pain 
V 
Unstable moriBUNXd patient who is not expected to survive 24 hours with or without 
operation 
VI 
Brain dead patient whose organs are removed for donation to another 
E 
Emergency operation of any type, which is added to any of the above six categories, an 
in ASA II E 
 
 


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APPENDIX B: 0 TO 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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APPENDIX C: PATIENT GLOBAL EVALUATION [OF SATISFACTION WITH STUDY 
TREATMENT TREATMENT] (PGE) 
Patient Global Evaluation (PGE) 
Instructions to Subject:  Please respond to the question below. When completed, please 
initial at the bottom of the page. 
 
How would you rate your satisfaction with the study treatment that you received during 
surgery for postop pain? 
(Mark one box) 
 
 Excellent (3) 
 
 Good (2) 
 
 Fair (1) 
 
 Poor (0) 
 
Subject Initials: __________ 
 
 
 
 


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


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APPENDIX E: 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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APPENDIX F: SURGICAL WOUND STATUS ASSESSMENT  
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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APPENDIX G: NEUROSENSORY EXAMINATION FORM  
 


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APPENDIX H: GUIDANCE FOR INDUSTRY: TOXICITY GRADING SCALE FOR HEALTHY 
ADULT AND ADOLESCENT VOLUNTEERS ENROLLED IN PREVENTIVE VACCINE 
CLINICAL TRIALS, TABLE FOR LABORATORY ABNORMALITIES 
Serum * 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially Life 
Threatening 
(Grade 4)** 
Sodium – Hyponatremia mEq/L 
132 – 134 
130 – 131 
125 – 129 
< 125 
Sodium – Hypernatremia mEq/L 
144 – 145 
146 – 147 
148 – 150 
> 150 
Potassium – Hyperkalemia mEq/L 
5.1 – 5.2 
5.3 – 5.4 
5.5 – 5.6 
> 5.6 
Potassium – Hypokalemia mEq/L 
3.5 – 3.6 
3.3 – 3.4 
3.1 – 3.2 
< 3.1 
Glucose – Hypoglycemia mg/dL 
65 – 69 
55 – 64 
45 – 54 
< 45 
Glucose – Hyperglycemia 
Fasting – mg/dL 
Random – mg/dL 
  
100 – 110 
110 – 125 
  
111 – 125 
126 – 200 
  
>125 
>200 
Insulin requirements or 
hyperosmolar coma 
Blood Urea Nitrogen 
BUNX mg/dL 
23-26 
27 – 31 
> 31 
Requires dialysis 
Creatinine – mg/dL 
1.5 – 1.7 
1.8 – 2.0 
2.1 – 2.5 
> 2.5 or requires dialysis 
Calcium – hypocalcemia mg/dL 
8.0 – 8.4 
7.5 – 7.9 
7.0 – 7.4 
< 7.0 
Calcium – hypercalcemia mg/dL 
10.5 – 11.0 
11.1 – 11.5 
11.6 – 12.0 
> 12.0 
Alkaline phosphate – increase by 
factor 
1.1 – 2.0 x ULN 
2.1 – 3.0 x 
ULN 
3.1 – 10 x 
ULN 
> 10 x ULN 
Liver Function Tests –ALT, AST 
increase by factor 
1.1 – 2.5 x ULN 
2.6 – 5.0 x 
ULN 
5.1 – 10 x 
ULN 
> 10 x ULN 
Bilirubin – when accompanied by any 
increase in Liver Function Test 
increase by factor 
1.1 – 1.25 x ULN 
1.26 – 1.5 x 
ULN 
1.51 – 1.75 x 
ULN 
> 1.75 x ULN 
Bilirubin – when Liver Function Test 
is normal; increase by factor 
1.1 – 1.5 x ULN 
1.6 – 2.0 x 
ULN 
2.0 – 3.0 x 
ULN 
> 3.0 x ULN 
* The laboratory values provided in the tables serve as guidelines and are dependent upon institutional normal 
parameters. Institutional normal reference ranges should be provided to demonstrate that they are appropriate. 
** The clinical signs or symptoms associated with laboratory abnormalities might result in characterization of the 
laboratory abnormalities as Potentially Life Threatening (Grade 4). For example. a low sodium value that falls 
within a grade 3 parameter (125-129 mE/L) should be recorded as a grade 4 hyponatremia event if the subject had 
a new seizure associated with the low sodium value. 
***ULN" is the upper limit of the normal range. 
 
 


Clinical Trial Protocol 
              
CA-PS-201 
Version: 1.2, 06-June-2018 
 
 
 
 
 
Concentric Analgesics, Inc. 
CONFIDENTIAL 
 
 
 
 
 
 
Page 98 of 98 
APPENDIX I: GUIDANCE FOR INDUSTRY: TOXICITY GRADING SCALE FOR HEALTHY 
ADULT AND ADOLESCENT VOLUNTEERS ENROLLED IN PREVENTIVE VACCINE 
CLINICAL TRIALS, TABLE FOR CLINICAL 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. 
 

SAP_001.pdf: 
 
 
 
 
 
OFFICIAL TITLE: 
A Phase 2, Randomized, Double-blind, Placebo-controlled Safety, 
Pharmacokinetics and Efficacy Study of CA-008 in Subjects Undergoing 
Bunionectomy 
 
NCT NUMBER: 
03599089 
 
DOCUMENT DATE: 
09 Oct 2018 
 


Sponsor: Concentric Analgesics, Inc. 
 
Statistical Analysis Plan 
Protocol Number: CA-PS-201 
 
Date: 09OCT2018 
 
 
CONFIDENTIAL 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
A Phase 2, Randomized, Double-blind, Placebo-controlled Safety, 
Pharmacokinetics and Efficacy Study of CA-008 in Subjects Undergoing 
Bunionectomy 
Protocol Number:  CA-PS-201 
Protocol Version 1.2 (06JUN2018) 
 
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: 2EFAAC52-4E79-4A52-BBA3-EF9CF8BA2A35


Sponsor: Concentric Analgesics, Inc. 
 
Statistical Analysis Plan 
Protocol Number: CA-PS-201 
 
Date: 09OCT2018 
 
CONFIDENTIAL 
 Page 2 of 37 
 
 
 
 
DOCUMENT VERSION CONTROL 
Version Number 
Date 
Comments/Changes 
V1.0 
11SEP2018 
Final SAP 
V2.0 
09OCT2018 
Add the sensitivity analysis of   
imputing early drop out using 
median value for selected efficacy 
endpoints  
 
 
 
 
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Sponsor: Concentric Analgesics, Inc. 
 
Statistical Analysis Plan 
Protocol Number: CA-PS-201 
 
Date: 09OCT2018 
 
CONFIDENTIAL 
 Page 3 of 37 
 
 
 
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: 2EFAAC52-4E79-4A52-BBA3-EF9CF8BA2A35
10-Oct-18
10-Oct-18
10-Oct-18


Sponsor: Concentric Analgesics, Inc. 
 
Statistical Analysis Plan 
Protocol Number: CA-PS-201 
 
Date: 09OCT2018 
 
CONFIDENTIAL 
 Page 4 of 37 
 
 
 
 
TABLE OF CONTENTS 
 
LIST OF IN-TEXT TABLES AND FIGURES .................................................................... 7 
LIST OF ABBREVIATIONS (COMMONLY USED) .......................................................... 8 
1 
PURPOSE OF THE ANALYSES ....................................................................... 10 
2 
PROTOCOL SUMMARY ................................................................................... 10 
2.1 
Study Objectives ............................................................................................... 10 
2.1.1 
Primary Objective .............................................................................................. 10 
2.1.2 
Secondary Objectives ........................................................................................ 10 
2.1.3 
Exploratory Objectives ....................................................................................... 10 
2.2 
Overall Study Design and Plan .......................................................................... 10 
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 ............................................................................... 13 
3 
GENERAL ANALYSIS AND REPORTING CONVENTIONS .............................. 13 
4 
SUBJECT POPULATIONS ................................................................................ 14 
4.1 
Analysis Populations ......................................................................................... 15 
4.2 
Disposition of Subjects ...................................................................................... 15 
4.3 
Protocol Deviations............................................................................................ 15 
5 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ..................... 16 
5.1 
Demographics and Baseline Characteristics...................................................... 16 
5.2 
Medical/Surgical History .................................................................................... 16 
5.3 
Prior and Concomitant Medications ................................................................... 16 
6 
MEASUREMENTS OF TREATMENT EXPOSURE and COMPLIANCE ............ 16 
7 
EFFICACY EVALUATION ................................................................................. 18 
7.1 
Handling of Dropouts or Missing Data ............................................................... 18 
7.2 
Assessment Time Windows ............................................................................... 19 
7.3 
Adjustments for Multiplicity ................................................................................ 19 
7.4 
Efficacy Endpoints ............................................................................................. 19 
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Statistical Analysis Plan 
Protocol Number: CA-PS-201 
 
Date: 09OCT2018 
 
CONFIDENTIAL 
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7.4.1 
Primary Efficacy Endpoint .................................................................................. 20 
7.4.2 
Key Secondary Efficacy Endpoints .................................................................... 20 
7.4.3 
Other Efficacy Endpoints ................................................................................... 20 
7.5 
Analysis Methods .............................................................................................. 21 
7.5.1 
NRS Measurements .......................................................................................... 21 
7.5.2 
AUC Outcomes ................................................................................................. 21 
7.5.3 
Opioid Free (OF) Outcomes .............................................................................. 22 
7.5.4 
Total Opioid Consumption (in Daily Oral Morphine Equivalents) ........................ 22 
7.5.5 
Time to First Use of Rescue Medication ............................................................ 23 
7.5.6 
PGE and IGE ..................................................................................................... 24 
7.5.7 
Number and Percentage of Subjects Who Drop Out due to AE or Lack of Efficacy 
(LOE) During the Inpatient Period ...................................................................... 24 
7.5.8 
Healthcare Utilization (HCU) .............................................................................. 24 
7.5.9 
Percent of Subjects Taking Rescue / Use of Rescue Medication over Time ...... 24 
8 
SAFETY EVALUATION ..................................................................................... 25 
8.1 
Overview of Safety Analysis Methods ................................................................ 25 
8.2 
Adverse Events ................................................................................................. 25 
8.3 
Surgical Site Assessment/ Wound Evaluation ................................................... 27 
8.4 
Physical Examination ........................................................................................ 28 
8.5 
Vital Signs ......................................................................................................... 28 
8.6 
Neurosensory Assessment ................................................................................ 28 
8.7 
ECG Examination .............................................................................................. 28 
8.8 
Clinical Laboratory Evaluation ........................................................................... 28 
8.9 
Drugs of Abuse and Alcohol Screens, Pregnancy Test ...................................... 29 
8.10 
Subject Pain Assessment Training and Surgery Details .................................... 29 
9 
PHARMACOKINETIC EVALUATION ................................................................ 29 
10 
OTHER ANALYSES .......................................................................................... 31 
11 
INTERIM ANALYSES ........................................................................................ 31 
12 
CHANGES TO THE ANALYSES PLANNED IN THE PROTOCOL .................... 31 
13 
REFERENCES .................................................................................................. 31 
14 
APPENDICES ................................................................................................... 32 
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Statistical Analysis Plan 
Protocol Number: CA-PS-201 
 
Date: 09OCT2018 
 
CONFIDENTIAL 
 Page 6 of 37 
 
 
 
14.1 
Planned Tables, Figures and Listings ................................................................ 32 
14.1.1 Tables ............................................................................................................... 32 
14.1.2 Figures .............................................................................................................. 35 
14.1.3 Listings .............................................................................................................. 36 
 
 
 
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Statistical Analysis Plan 
Protocol Number: CA-PS-201 
 
Date: 09OCT2018 
 
CONFIDENTIAL 
 Page 7 of 37 
 
 
 
 
LIST OF IN-TEXT TABLES AND FIGURES 
Table 2-1 
Protocol-Specified Visits and Visit Windows .................................. 12 
Table 7-1 
Table of Equianalgesic Conversion ............................................... 23 
Table 8-1 
Table of Imputation Rules for Missing AE Start Dates ................... 27 
 
 
 
 
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Statistical Analysis Plan 
Protocol Number: CA-PS-201 
 
Date: 09OCT2018 
 
CONFIDENTIAL 
 Page 8 of 37 
 
 
 
LIST OF ABBREVIATIONS (COMMONLY USED) 
AC 
Analgesic Consumption 
ADaM 
Analysis Data Model 
AE 
Adverse Event 
ANOVA 
Analysis of variance 
ASA 
American Society of Anesthesiologists 
ATC 
Anatomical Therapeutic Chemical 
AUC 
Area Under the Curve 
BMI 
Body Mass Index 
BUNX 
Bunionectomy 
CDER 
Center for Drug Evaluation and Research 
CMH 
Cochran Mantel Haenszel Test 
CP 
Completer 
CRF 
Case Report Form 
CSR 
Clinical Study Report  
ECG 
Electrocardiogram 
ET 
Early Termination 
FDA 
Food and Drug Administration 
HCI 
Hydrochloride 
HCU 
Health care utilization 
ICF 
Informed Consent Form 
ICH 
 
International Conference on Harmonization  
IGE 
Investigator Global Evaluation 
LOCF 
Last Observation Carried Forward 
LOE 
Lack of Efficacy 
MedDRA 
Medical Dictionary for Regulatory Activities 
MED 
morphine equivalent dose 
NRS 
Numerical Rating Scale for Pain Intensity  
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Statistical Analysis Plan 
Protocol Number: CA-PS-201 
 
Date: 09OCT2018 
 
CONFIDENTIAL 
 Page 9 of 37 
 
 
OC 
Opioid Consumption in morphine equivalent dose 
OF 
Opioid-Free days 
PE 
Physical Exam 
PGE 
Patient Global Evaluation 
PK 
Pharmacokinetic 
PT 
Preferred Term 
SAE 
Serious Adverse Event/Experience 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SDTM  
Standard Data Table Model 
SOC 
System Organ Class 
TEAE 
Treatment Emergent Adverse Event 
TTFR 
Time to First use of Rescue medication 
WHO 
World Health Organization 
WOCF 
Worst Observation Carried Forward 
 
 
 
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Sponsor: Concentric Analgesics, Inc. 
 
Statistical Analysis Plan 
Protocol Number: CA-PS-201 
 
Date: 09OCT2018 
 
CONFIDENTIAL 
 Page 10 of 37 
 
 
 
1 
PURPOSE OF THE ANALYSES 
This statistical analysis plan (SAP) is based on protocol number CA-PS-201 Version 1.2 
(06JUN2018) from Concentric Analgesics, Inc. The SAP will be signed off before the final 
database lock. The SAP contains detailed information to aid in the performance of the statistical 
analysis and reporting of the study data for use in the final clinical study report (CSR). 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. 
This SAP describes the data that will be analyzed and the subject characteristics, safety, and 
efficacy assessments that will be evaluated. This SAP provides details of the specific statistical 
methods that will be used. If additional analyses are performed after database lock and unblinding 
to supplement the planned analyses described in this SAP, they will be clearly identified as post-
hoc in the CSR. 
2 
PROTOCOL SUMMARY 
2.1 
Study Objectives 
2.1.1 Primary Objective 
• 
To evaluate the efficacy of a single intraoperative administration of CA-008 vs placebo 
in subjects undergoing an elective bunionectomy (BUNX). 
2.1.2 Secondary Objectives 
• 
To evaluate the safety and tolerability of a single intraoperative administration of CA-
008 vs. placebo in subjects undergoing an elective BUNX. 
• 
To evaluate the PK profile of a single intraoperative administration of CA-008 vs. 
placebo in subjects undergoing an elective BUNX. 
• 
To explore the efficacy of various doses of CA-008 administered intraoperatively in 
subjects undergoing an elective BUNX.  
2.1.3 Exploratory Objectives 
• 
Pharmacoeconomic benefits from administration of CA-008 vs. placebo in subjects 
undergoing an elective BUNX (Addressed outside this SAP). 
2.2 
Overall Study Design and Plan 
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Sponsor: Concentric Analgesics, Inc. 
 
Statistical Analysis Plan 
Protocol Number: CA-PS-201 
 
Date: 09OCT2018 
 
CONFIDENTIAL 
 Page 11 of 37 
 
 
This is a Phase 2, multi-center, randomized, double-blind, placebo-controlled, parallel design 
study evaluating a single dose of one of three CA-008 dose groups vs. placebo injected during an 
elective BUNX under light to moderate sedation supplemented by a Mayo block with bupivacaine 
hydrochloride (HCl) and a multimodal analgesia regimen, including ketorolac and acetaminophen, 
and access to rescue medication (oxycodone). 
During the screening phase, subjects requiring bunionectomy between the ages of 18 and 75 
years, inclusive, will been screened at the study site in the United States within 45 days of 
surgery/study treatment administration. Subjects who meet the selection criteria and are eligible to 
participate in the study will be required to return to the study center for surgery.  
The study will be conducted in two parts: 
• 
Inpatient period which continues to 96h after completion of study treatment injection 
(T0) or T96h. 
• 
Outpatient period which begins on discharge from the inpatient unit through various 
follow up visits to D29±2 (W4) after surgery, or if necessary for ongoing safety 
assessments, to D36±2 (W5). 
Subjects will be undergoing unilateral transpositional first metatarsal osteotomy for the correction 
of hallux valgus deformity (bunionectomy or BUNX). The surgery is to be performed under light to 
moderate sedation anesthesia (what constitutes this level of sedation and the additional 
anesthetic medications used per discretion of the anesthesiologist). In accordance with standard 
of care, light to moderate sedation will be supplemented with a Mayo block to produce surgical 
anesthesia and postoperative analgesia. After administering light to moderate sedation, but prior 
to surgery, perform a Mayo block by infiltrating 0.5% bupivacaine hydrochloride (up to 30 mL total 
volume, 150 mg) at least 3 cm proximal to the “surgical site”. The Mayo block should be 
performed at 15-30 minutes prior to study treatment dosing. “Surgical site” is defined as the area 
extending approximately 2-3 cm in all directions (lateral/medial/proximal/distal) from the incision 
site and surrounding tissues which may be affected by the infiltration of study treatment.  
After the surgery, subjects will be monitored for 96 hours in an inpatient unit. Safety and efficacy 
evaluations will be performed. After the first week of enrollment, subjects may be enrolled for the 
pharmacokinetic (PK) portion of the study and have samples drawn prior to CA-008 injection and 
at various time points over 24h after surgery until the target of 48 PK subjects (12 per treatment 
group) are enrolled and complete PK assessments.  In the event that a subject cannot complete 
their PK assessments the Unblinded Randomization Contact will provide a replacement 
randomization number for the site.  Subjects will be required to meet certain pre-specified criteria 
prior to discharge. After completing the assessments through T96h hours after study treatment 
administration and prior to discharge from the inpatient unit, the site will 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.  
In their outpatient diary, subjects will assess their current pain intensity at rest and after 
ambulation each morning (08:00 ±3 hours), and each evening (20:00 ±3 hours) using the NRS. 
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Statistical Analysis Plan 
Protocol Number: CA-PS-201 
 
Date: 09OCT2018 
 
CONFIDENTIAL 
 Page 12 of 37 
 
 
The dose and time of any medication the subject takes, whether to treat their pain or for any other 
reasons, will also be recorded. Subjects are instructed to return to the study center on D8±1, 
D15±2 (W2) D29±2 (W4), and D36±2 (W5) for follow-up assessments. 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. 
A subject is free to withdraw his/her consent and discontinue participation in the study at any time 
for any reason. Subjects who elect to discontinue study participation during the inpatient phase of 
the study, will be asked to continue with assessments through T96h if they have not elected to 
withdraw from all aspects of study participation. Subjects who elect to discontinue participation 
after discharge from the inpatient unit but prior to D8 (W1) will be considered to have terminated 
as of the date of their election, however they will be asked to return to the site to reassess the 
surgical site for wound healing. 
The protocol-defined visits are presented in Table 2-1: 
Table 2-1 
Protocol-Specified Visits and Visit Windows 
Study Phase 
Visit Time 
Screening 
From days -45 to -1 
Prior to Surgery/ Surgery) 
Day 0 
In-Patient (Post Surgery) 
Hours 0 (post-surgery), 24, 48, 72 and 96  
Follow-up 
Days 8(±1 day), 15(±2 days), 29(±2 days), 36(±2 days)1 
 
 
1 Day 36 visit will occur if insufficient wound healing is assessed by the investigator at the Day 29 visit. 
All study assessments are outlined in Table 1 of the Protocol. 
2.2.1 Study Population 
The study population will consist of approximately 144 subjects (36 per treatment group) between 
the ages of 18 and 75 years who are planning to undergo an elective unilateral BUNX and 
otherwise meet eligibility criteria (as described in the protocol Sections 10.1 and 10.2) may be 
considered for enrollment into the study.  
2.2.2 Treatment Regimens 
Study Material 
The proposed doses of CA-008 to be evaluated in this study are:   
• 
CA-008, 0.7 mg in 14mL of saline (0.05 mg/mL) 
• 
CA-008, 2.1 mg in 14mL of saline (0.15 mg/mL) 
• 
CA-008, 4.2 mg in 14mL of saline (0.30 mg/mL) 
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Statistical Analysis Plan 
Protocol Number: CA-PS-201 
 
Date: 09OCT2018 
 
CONFIDENTIAL 
 Page 13 of 37 
 
 
Comparator Group 
• 
The placebo will use the same 14mL volume. 
2.2.3 Treatment Group Assignments or Randomization 
The study will be conducted in a randomized, double-blinded and placebo-controlled manner.  
The study includes 4 treatment groups (3 active and 1 placebo group). Subjects who meet the 
enrollment criteria will be randomly allocated in a 1:1:1:1 ratio to receive either active drug or 
placebo.  Randomization will be accomplished manually on the day of surgery. 
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. Prior to 
randomization, subjects must meet all inclusion and not meet any exclusion criteria (as described 
in Sections 10.1 and 10.2). Once any subject number or randomization number is assigned, it 
cannot be reassigned to any other subject.  
2.2.4 Sample Size Determination 
In the previously completed Phase 1 ascending dose safety study in bunionectomy (CA-008 vs. 
placebo), the mean difference between CA-008 (all dose groups combined) and placebo for the 
area under the curve (AUC) from 24 to 96 hours was -120. The standard deviation (SD) estimates 
for the six treatment arms in this study ranged from 70 to 190 with a median SD of 108. For the 
primary endpoint (AUC0 to 96h), the true treatment difference between the 4.2 mg CA-008 group 
and the placebo group is assumed to be equal to -100 and the assumed true SD is equal to 130. 
For these assumptions, and based on the use of a two-sided, two-sample comparison of means 
at the alpha=0.05 level of significance, a sample size of 36 subjects per arm will provide 90% 
power. Thus, the target sample size is 144 subjects. 
3 
GENERAL ANALYSIS AND REPORTING CONVENTIONS 
This section discusses general policies to be employed in the analysis and reporting of the data 
from the study. Departures from these general policies may be provided in the specific detailed 
sections of this SAP. When this situation occurs, the rules set forth in the specific section take 
precedence over the general policies. 
Each active dose will be presented separately in summaries and analyses as appropriate.  
All continuous study assessments will be summarized by treatment and time point (as applicable) 
using the descriptive statistics n, mean, SD, median, and range (minimum, and maximum). All of 
the categorical study assessments will be summarized by treatment and time point (as applicable) 
using frequency counts and rates of occurrence (%). Changes from baseline for continuous 
outcomes will be presented as their corresponding continuous measures for post-baseline visits. 
All study data will be listed by dose, 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 
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Statistical Analysis Plan 
Protocol Number: CA-PS-201 
 
Date: 09OCT2018 
 
CONFIDENTIAL 
 Page 14 of 37 
 
 
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. The domain (Study 
data tabulation Model [SDTM]) and analysis (Analysis Data Model [ADaM]) data sets will be taken 
as input to the SAS programs that generate the report-ready tables, figures and listings. The 
submission ready SDTM and ADaM data sets will be provided to the sponsor along with display 
deliveries.  
The following conventions will be used throughout the study analysis: 
• 
Time 0 (T0) is the time of completion of study drug administration.  
• 
Day of surgery is defined as Day 0 (D0). 
• 
Assessment visit times are defined by D0 and/or T0. 
• 
Baseline value is defined as the last valid measurement prior to the dosing of study 
treatment. 
• 
Change from baseline is defined as post-baseline value minus baseline value. 
• 
Duration of an AE will be computed in days for AEs lasting longer than 24 hours, and 
as hours for AEs lasting less than 24 hours. Duration in hours will be calculated as the 
stop date/time of the event minus the start date/time. Duration in days will be 
calculated by using stop date minus the start date +1 if AE occurs on or after taking 
study medication. If AE occurs prior to the study medication, then the duration will be 
calculated by using stop date minus the start date; If reported as ongoing at the time of 
database lock, the duration will be calculated using the date of the last visit or the last 
date of any AE for the subject in the database, whichever is later. Missing dates will be 
imputed as described in Table 8-1. 
• 
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 of wound healing.  
• 
The number of days in the study is computed as: [Date of study completion or 
withdrawal minus the date of study drug administration] + 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). 
4 
SUBJECT POPULATIONS 
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4.1 
Analysis Populations 
Six analysis populations are defined as follows: 
• 
Intent-to-treat (ITT) population: all subjects who are randomized. Subjects will be 
analyzed according to the treatment they were randomized to.  
• 
Modified intent-to-treat (mITT) population: all subjects who receive a full dose of 
study treatment and complete the first 3 pain assessments (through T2h). Subjects will 
be analyzed according to the treatment they were randomized to. 
• 
In patient study completer (Inpatient CP): all subjects who receive a full dose of 
study treatment and complete the inpatient assessment period (through T96h). 
Subjects will be analyzed according to the treatment they were randomized to. 
• 
Study Completers (CP):  all subjects who receive a full dose of study treatment and 
complete the entire study period through D29±2/W4. Subjects will be analyzed 
according to the treatment they were randomized to. 
• 
Safety Population will include all randomized subjects who received any amount of 
study drug. subjects will be analyzed by treatment group according to the actual 
treatment received, i.e., “as treated”. 
• 
Pharmacokinetic (PK) population:  All randomized participants who received a full 
dose of study drug and complete all PK assessments through the first 6 hours (T6h) 
time point. Note, subjects who fail to complete these PK assessments will be replaced. 
Analysis populations will be determined before study unblinding.  
The primary and secondary efficacy analyses will be performed using mITT population. Efficacy 
analyses will also be carried out using ITT, Inpatient CP and/or CP populations for selected 
endpoints as appropriate. Baseline characteristics will be summarized using ITT population and 
safety endpoints will be summarized using Safety population. PK summaries will be presented 
using the PK population. 
4.2 
Disposition of Subjects 
All subjects and the populations for which they qualify will be listed. Subjects who are screened 
and who fail screening or withdraw consent prior to randomization or are randomized but not 
treated will be listed and summarized in the disposition summary table. Subjects who are 
randomized, subject inclusion into each study population, subjects who are treated, subjects who 
complete follow-up as well as subjects who withdraw early from the study and the reason for 
withdrawal will be summarized by treatment group and overall in the subject disposition summary 
table. 
4.3 
Protocol Deviations 
Deviations are categorized as informed consent procedures, inclusion/exclusion criteria, study 
medication, prohibited medications, study procedures, study drug assignment/treatment, visit or 
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assessment time window, missed visit or assessment and/or other. All protocol deviations will be 
captured on case report forms (CRFs) and/or documented in site specific logs throughout the 
study. Deviations will be categorized and classified as major or minor by the project team and the 
medical monitor after database lock but before unbinding and will be discussed in the CSR. The 
number of subjects with protocol deviations, both minor and major, will be presented in a data 
listing and will be summarized by type of deviation and major/minor classification for the ITT 
population. 
5 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
5.1 
Demographics and Baseline Characteristics 
Demographic variables include age, sex, race, and ethnicity. Baseline characteristics include 
American Society of Anesthesiologists (ASA) physical status, target foot (Left/ Right), height, 
weight (kg), and body mass index (BMI; kg/m2). Demographics and baseline characteristics will 
be presented in a by-subject listing and summarized overall and by treatment group using ITT 
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 with missing stop dates 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 treatment group, for the safety 
population. 
All medications and non-medical therapies captured in CRFs will appear in data listings.  
6 
MEASUREMENTS OF TREATMENT EXPOSURE and COMPLIANCE 
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Because study medication is administered as a single dose at the study center by trained study 
personnel, compliance with respect to study medication will not be calculated. A listing of study 
drug administration and exposure data will be provided. 
After completing the assessments through 96 hours after study medication administration, the 
diary for at-home use will be distributed to the subject to collect pain intensity (twice daily on NRS) 
and pain medication through Day 15. Compliance with home diary use will be evaluated based on 
post-discharge home diary records. Compliance for each subject will be based on the number of 
days the subject participated in the outpatient study period, defined as: 
Compliance (%) =  
(N of non-missing NRS recorded on Diary) 
 
x 100 
(N of Expected NRS from Diary) 
 
Where the N of expected NRS records in the diary for each subject is calculated as 2 times the 
number of days the subject participated in the outpatient portion of the study.  The number of days 
of participation will be calculated as the date of the Day 15 visit or the date of the last study visit 
(whichever is earlier) minus the date of discharge. NRS recorded prior to a rescue use will not be 
included in this calculation of compliance. 
For example, Subject A was discharged on Day 4, if this subject discontinues the study on Day 
13, then the expected N of NRS records on diary will be 18 (2 * (13-4)). Assuming Subject A had 
10 NRS available from his/her diary, then compliance for this subject would be 55.6% ((10/18) 
*100). However, if subject A had discontinued the study on Day 10 (prior to Day 13), then the 
expected N of NRS for this subject would be 12 (2 * (10-4)) and compliance would be 83.3% 
((10/12) *100).  A summary of compliance will be provided overall and by treatment group. 
Compliance with recording an NRS prior to rescue in the diary will be calculated as the number of 
NRS recorded prior to taking rescue medications divided by the number of rescue medication 
uses recorded.  
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7 
EFFICACY EVALUATION 
7.1 
Handling of Dropouts or Missing Data 
All efforts will be made to minimize missing data. These efforts will include the following: 
• 
Subjects are required to consent to continuous data collection even after 
discontinuation of study medication; 
• 
Data collection will continue after subjects take rescue medication. 
With the procedures above, it is expected that missing data will be minimal. Missing at random is 
expected to be a reasonable assumption for this dose-escalation 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 the next 4 hours is 
considered invalid. Therefore, 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 4-hours 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 4 hours after taking the rescue medication (end of imputation period), then 
NRS will be considered as occurring before the 4 hours assessment and will be imputed. For 
example, if a rescue dose is taken at 1pm, all protocol-scheduled NRS will be imputed with the 
appropriate NRS value up to and including through 5pm. If multiple doses of rescue medication 
are taken within a 4-hour period, the pre-rescue NRS for the first rescue use will be carried 
forward continuously until 4 hours past the last use of rescue falling within the continuous window. 
For example, if rescue is used at Hour 2.3 and Hour 5.1, the pre-rescue NRS at Hour 2.3 will be 
carried forward till Hour 9.1 (5.1 +4). NRS 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.  
For subjects who take prohibited medication, NRS results collected after taking the prohibited 
medication will not be used for AUC calculations but will be imputed according to the methods 
used for discontinued subjects. 
 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 or take prohibited medication prior to Day 15, scheduled assessments will first be 
imputed using the worst prior pain score carried forward (WOCF).  
Two sensitivity analyses will be performed to evaluate the robust of the primary result:  
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1) AUC will be calculated where assessments after drop out will be imputed using LOCF, 
using the last scheduled non missing pain score prior to drop out.  
2) AUC will be calculated where assessments after dropping out will be imputed using the 
median score from the remainder of subjects in the group continuing in the study.  
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. 
7.2 
Assessment Time Windows 
For calculations of all AUC endpoints (including the primary endpoint), rate of consumption of 
rescue and time to first rescue medication 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 (eg, Hour 0.5, 1, 2, etc.), it is recognized that 
operationally the scores are collected as close to the target times as possible but there is 
some flexibility in terms of the actual times the scores are collected. Thus, to account for this 
inherent aspect of data collection, the ACTUAL TIMES will be used for the calculation of the 
AUC. The actual times will be based relative to the time of completion of study drug 
administration. 
Safety assessment summaries will be based on the nominal protocol-specified assessment times.  
7.3 
Adjustments for Multiplicity 
All efficacy endpoints will be listed in data listings. Unless otherwise indicated, two-sided p values 
will be reported. 
 
If the outcome of the primary analysis of the primary efficacy endpoint (AUC0to96h) is with a two-
sided p-value of <0.05, then key secondary endpoints will be compared between the 4.2 mg CA-
008 and placebo.  These key secondary endpoints are: 
 
• 
Percentage of subjects who do not require opioids or are opioid free (OF) from T0 to T96):  
OF0 to 96h 
 
• 
Total opioid consumption (in daily oral morphine equivalents) = OC from T0 to T96h: OC0 to 
96h 
• 
Using NRS at rest: AUC0 to W1 
 
Each of the above comparisons will be made using a two-sided test at the alpha=0.05 level of 
significance. Once a p value of >0.05 occurs, all subsequent key secondary endpoints analyses in 
the hierarchy will be exploratory rather than confirmatory. All other efficacy analyses will be 
conducted using a significant 2-sided p-value of 0.05, without adjustment for multiplicity.   
 
7.4 
Efficacy Endpoints 
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Efficacy will be evaluated using the numeric rating scale of pain intensity (NRS) scores (at rest 
and with ambulation), PGE, IGE, Rescue Use and Healthcare utilization.  A variety of time-specific 
summed pain intensity assessments (area under the curve (AUC) for pain intensity) will be 
calculated using NRS to compare treatment difference between CA-008 and placebo group.   
7.4.1 Primary Efficacy Endpoint 
• 
Area under the curve (AUC) of the numeric rating scale of pain intensity (NRS) from 0 
to 96 hours at rest (AUC0 to 96h).  
7.4.2 Key Secondary Efficacy Endpoints 
Following are key secondary endpoints (in descending order of importance): 
• 
Percent of subjects who do not require opioids or are opioid free (OF) from 0 to 96 
hours (OF0 to 96h) 
• 
Total opioid consumption (OC) (in daily oral morphine equivalents) from 0 to 96 hours 
(OC0 to 96h) 
• 
AUC of NRS through Week 1 at rest (AUC0 to w1) 
7.4.3 Other Efficacy Endpoints 
• 
AUC of subject’s NRS will be examined over various time periods: AUC0 to 6h, AUC0 to 
12h, AUC0 to 24h, AUC0 to 120h, AUC0 to w1 (walking), AUC0 to w2, AUC0 to w2 (walking), AUC12 to 24h, 
AUC24 to 48h, AUC24 to 72h, AUC24 to 96h, AUC96 to 120h, AUC96h to w1, AUC24h to w1 (walking), AUC96h 
to w2, AUC96h to w2 (walking).  
• 
Time-specific (“milestone”) mean pain intensity NRS at 6, 12, 24, 28, 72, 96, 120, 144, 
and 168 hours 
• 
Time-specific (“milestone”) mean pain intensity NRS by site at 6, 12, 24, 28, 72, 96, 
120, 144, and 168 hours 
• 
OC over following time periods: OC24 to 48h, OC24 to 72h, OC24 to 96h. 
• 
OF over following time periods: OF24 to 96h, OF96h to w1, OF96h to w2. 
• 
Time to first use of rescue medication (TTFRafter T0) and first use after 24 hours 
(TTFRafter T24h). For the analysis of time to use of rescue medication, only OPIOID 
rescue medication will be considered,  
• 
Analgesic consumption (AC) from T96h to W1 (AC96h to W1) and AC96h to W2. 
• 
Patient global evaluation (PGE) comparing the percentage of subjects reporting (poor 
or fair) versus (good or excellent) responses and the percentage reporting each 
category of response at W1, W2 and W4. 
• 
Investigator’s global evaluation (IGE) comparing the percentage of those reporting 
(poor or fair) versus (good or excellent) responses and the percentage reporting each 
category at W1, W2 and W4. 
• 
Number and percentage of subjects who drop out due to an AE or lack of efficacy 
(LOE) during the inpatient period: LOE24 to 96h, LOE0 to 96h. 
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• 
Health care utilization after discharge from the inpatient unit: HCU96h to W2 and  
HCU96h to W4. (Not included in this SAP) 
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). Subjects 
should be at rest for at least 10 minutes prior to completing NRS resting assessments and have 
ambulated approximately 10 yards within 15 minutes prior to completing NRS ambulation 
assessments. 
During the inpatient stay, NRS pain assessments will be collected at Hours 0.5, 1, 2, 4, 6, 8, 12, 
16, 20, 24, and every 4 hours (if awake at time of assessment and if no rescue opioid had been 
administered in the past 4 hours) until discharge from the inpatient unit. Pain scores may be 
skipped between the hours of midnight and 6 a.m., but the subject may not miss two consecutive 
assessments. A pre-rescue NRS will be collected prior to each use of rescue.  An additional NRS 
assessment must be obtained 4 hours (±15 min) after every rescue dose even if this time point 
occurs between midnight and 6 a.m. Hours 12, 24, 48, 72 and 96 assessments must be 
completed even if the subject is asleep at these times. Note, a 5-minute window is 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.   
During the outpatient period (up to Day 15), NRS will assessed twice daily at approximately 08:00 
(±3h) and 20:00 (±3h) at rest and with ambulation of approximately 10 yards. The results and the 
actual time of assessments will be documented in subjects’ diary.  In addition, the subject will be 
asked to complete a pre-rescue NRS each time they take rescue.  
Mean NRS scores over time (in-patient and diary) will be summarized and graphed over time by 
treatment. NRS over time by each subject will also be displayed graphically. 
7.5.2 AUC Outcomes 
All AUC calculations will be done using the standard trapezoidal rule  
AUC =     ∑
ቀ
𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑖𝑖+𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑖𝑖+1
2
ቁ
𝑥𝑥
𝑖𝑖=0
∗ (𝑇𝑇𝑖𝑖+1 − 𝑇𝑇𝑖𝑖) 
Where:  NRSi = NRS at rest at time i, and (Ti+1 – Ti) is the Time difference in hours between time i 
and time i+1.  
Missing NRS will be handled as discussed in Section 7.1.  A similar calculation of AUC and 
handling of missing data will be performed for the NRS scores with ambulation and are 
designated as AUC0-x (walking). Both pre-rescue and post-rescue scores will be used in the AUC 
calculations.  
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AUC values will be analyzed using a 1-factor (treatment) analysis of variance (ANOVA) model 
with treatment as the main effect.  In addition to the comparisons between each CA-008 group 
and the placebo group, the test for a linear trend across dose groups will be carried out using the 
contrast of -1.75, -1.05, 0.35 and 2.45 for placebo, 0.7 mg, 2.1 mg and 4.2 mg group, 
respectively.   
The AUC analyses will be presented in a summary table with standard summary statistics for 
each treatment group as well as active vs. placebo mean differences, standard errors, confidence 
intervals and comparison p-values as appropriate. Comparisons of individual treated group 
response may be presented for certain secondary AUC endpoints.   
The individual NRS and the computed AUC variables will be listed for all individual subjects. 
The primary analysis of the primary endpoint ((AUC0 to 96h) and secondary AUC endpoints will be 
based on the mITT population. In addition, the primary and other AUC efficacy endpoints may be 
analyzed using inpatient CP and/or CP population as appropriate for sensitivity.   
7.5.3 Opioid Free (OF) Outcomes 
Opioid use is recorded on the rescue medication eCRF from the end of surgery through the D15 
follow up/Early termination (ET). If additional opioids, other than the study rescue medications, 
appear on the concomitant medications page and can be identified, those opioids will also be 
considered. 
The percentage of subjects who do not require opioids (are Opioid Free or OF) will be analyzed 
using a logistic regression with treatment group (4 levels) as the main effect. The analysis will 
compare the odds ratios of the proportions of OF subjects between each treatment group and the 
placebo group. A summary of frequencies as well as odds ratio, 95% confidence intervals and p-
values will be presented for 0 to 96 hours (OF0 to 96h), 24-96 hours (OF24 to 96h), 96 hours to Week 1 
(OF96h to w1) and 96 hours to Week 2 (OF96h to w2).   
7.5.4 Total Opioid Consumption (in Daily Oral Morphine Equivalents) 
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 7-1 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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Table 7-1 
Table of Equianalgesic Conversion 
 
Opioid (Doses in mg) 
Conversion Factor 
Hydrocodone 
1 
Hydromorphone 
4 
Morphine 
1 
Oxycodone 
1.5 
Tramadol 
0.1 
Multiply the opioid dose by the conversion factor 
= morphine equivalent dose (MED): e.g., 
oxycodone 5 mgX1.5 = 7.5 mg MED 
 
Total opioid consumption will be calculated overall and for the same periods as the NRS AUC 
values: 0-96 hours (OC0 to 96h), 24-48 hours (OC24 to 48h), 24-72 hours (OC24 to 72h) and 24-96 hours 
(OC24 to 96h). in addition, analgesic consumption (AC) from T96h to W1 (AC96h to W1) and AC96h 
to W2 will also be summarized.  An ANOVA with treatment arm as the main effect will be 
performed and the same types of comparisons as described in Section 7.4.1 will be presented.  A 
separate summary containing only subjects that have taken at least one dose of rescue will be 
performed if warranted. 
7.5.5  Time to First Use of Rescue Medication  
For the analysis of time to use of rescue medication, only OPIOID rescue medication will be 
included,  
The time to first rescue will be measured from Time 0 (time of completion of study drug 
administration) and 24 hours post-dose. If a subject does not take rescue medication but 
prematurely discontinues from the study, then for analysis purposes the subject’s observation 
time will be the time of the discontinuation. The observation time will be considered to be a rescue 
event if the discontinuation was due to LOE, otherwise, it will be considered a censored 
observation.  
The distributions of time to first rescue in each treatment group will be presented graphically using 
Kaplan-Meier plots. 
If data warrant, a summary table will present the number of subjects receiving rescue medication, 
number of censored subjects, median time to first dose of rescue, and 95% confidence intervals 
of the medians by treatment groups. Individual times to event will be listed. Subjects will be 
followed at the time of discontinuation if no rescue medication was received prior to 
discontinuation. For the time to first rescue medication after 24 hours post-dose, subjects will be 
censored at 24 hours if the subject drop out the study prior to Hour 24. 
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Time to second rescue will also be explored for subjects who receive the first rescue prior to 60 
minutes post-dose.  Subjects will be censored at the time of discontinuation if the subject receives 
only 1 rescue mediation. The observation time will be considered to be a rescue event if the 
discontinuation was due to LOE, otherwise, it will be considered a censored observation 
7.5.6 PGE and IGE 
The proportions of subjects in each individual PGE or IGE category will be summarized by 
treatment group and analyzed using the Cochran-Mantel-Haenszel (CMH) mean score test (using 
equally spaced scores) at each time point (Weeks 1, 2 or 4) to compare treatments across the 4 
levels of outcomes (poor, fair, good, or excellent). In addition, Fisher’s exact test will be performed 
to compare treatments across 2 levels of outcomes (Poor/Fair versus Good/excellent).  
Individual PGE and IGE scores will be listed. 
7.5.7 Number and Percentage of Subjects Who Drop Out due to AE or Lack of 
Efficacy (LOE) During the Inpatient Period 
Proportion of subjects who drop out of the study due to AE or LOE during the inpatient periods (24 
to 96 (LOE24 to 96h) and 0 to 96 hours (LOE0 to 96h)) will be analyzed using Fisher’s exact tests. If a 
subject drops out of the study due to AE or LOE, it is assumed that drop out is pain related. The 
reasons for discontinuation as documented on the eCRF end of study page will be used to 
determine the subjects who drop out for AE or LOE.  Subjects who drop out of the study prior to 
24 hours will be excluded from LOE24 to 96h analysis. 
A summary table will present the active vs. placebo group proportions, 95% confidence intervals 
and two-sided Fisher’s exact p-values for the difference in proportions between each active group 
and placebo.   
7.5.8 Healthcare Utilization (HCU) 
HCU costs defined as an overall summary of costs related to prescription medications will be 
collected by the sponsor separate from the eCRF and are not covered by this SAP.  
7.5.9 Percent of Subjects Taking Rescue / Use of Rescue Medication over Time 
Subjects will be counted as having taken rescue on any particular day based on the rescue 
medication page of the eCRF and the at home rescue diary. If additional medications, other than 
the study rescue medications, appear on the concomitant medications page and can be identified 
as having been taken for bunion pain, those medications will also be counted.   
The proportion of subjects taking rescue will summarized for each study day through Day 15.  
In addition, the proportion of subjects taking any rescue medication during the following periods:  
0-96 hours, 24-48 hours, 24-72 hours, 24-96 hours, 96h to Week 1 and 96h to Week 2 and overall 
will be summarized and will be analyzed using Fisher’s exact tests.   
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Separate summaries for opioid and non-opioid rescue use will be presented if sufficient data are 
present in the groups. 
8 
SAFETY EVALUATION 
8.1 
Overview of Safety Analysis Methods 
All safety outcomes will be summarized using the safety population. Safety outcomes include: 
• 
Incidence of treatment emergent adverse events (TEAEs) or treatment emergent 
serious adverse events (SAEs) 
• 
Surgical site assessment/wound evaluations  
• 
Physical examination (PE) of the lower extremities and vital signs, including 
neurosensory testing of both lower extremities  
• 
Electrocardiogram (ECG) results 
• 
Clinical laboratory test results 
8.2 
Adverse Events 
Any untoward medical event that occurs after signing the informed consent form (ICF) is 
considered to be an adverse event (AE). All AEs will be recorded through 29 days (or 36 days as 
applicable) or ET, after the completion of surgery. SAEs will be recorded until 30 days after the 29 
day follow up visit or ET, whichever occurs earlier. Treatment-emergent AEs are defined as AEs 
that start or worsen in severity after the end of study treatment infiltration (post T0). Verbatim 
terms used by investigators to identify AEs in the CRFs will be mapped to the appropriate 
preferred term (PT) and system organ class (SOC) using a standardized coding dictionary 
(MedDRA Version 21.0). All coding will be reviewed prior to database lock. All recorded AEs will 
be listed, but only TEAEs will be summarized. 
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, severe or potentially 
life-threatening. 
In addition to a listing of all TEAEs, treatment related TEAEs, serious TEAEs, Deaths, and TEAEs 
leading to premature discontinuation from the study will be provided. 
An overall summary will be prepared giving for each treatment group and overall both the number 
of TEAEs, and the number of subjects with at least one TEAEs, as well as SAEs, treatment 
related TEAEs and TEAEs leading to premature discontinuation from study.  
The number of subjects with AEs will be summarized for each treatment group 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: 
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• 
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 8-1 will be used to 
impute any missing dates/times: 
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Table 8-1 
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 
Surgical Site Assessment/ Wound Evaluation 
Surgical site is defined as the area extending approximately 2-3 cm in all directions 
(lateral/medial/proximal/distal) from the incision site and surrounding tissues which may be 
affected by the infiltration of the Investigational Product. 
 
At T96h prior to discharge, 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.”. Surgical site wound status 
will be evaluated prior to discharge from the inpatient unit (T96h) and on Days 8, 15, and 29 or if 
necessary Day 36. Surgical site wound status will be assessed for erythema, drainage, edema, 
induration, and hematoma using a 5-point scale (0-4) where 0 means none and 4 means severe. 
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The surgical site and surgical wound assessment results will be listed and will be summarized by 
treatment and visit. 
8.4 
Physical Examination 
A complete medical history and physical examination including all major body systems will be 
performed at Screening. In addition, an interim medical history and targeted physical examination 
will be performed prior to surgery (if not done on D-1), and to capture changes after surgery, at 96 
hours (within 4 hours of discharge), and Days 8, 15 and 29/ET after the administration of study 
medication.  
 
Physical examination results will be listed for individual subjects. 
8.5 
Vital Signs 
Vital signs results including blood pressure (systolic and diastolic; mmHg), pulse rate (beats per 
minute), respiration rate (breaths/min), and body temperature will be listed for individual subjects.  
 
Baseline for vital signs measurements will be defined as the last evaluation before dosing with 
study medication. Summary statistics, including change from baseline, will be determined for each 
measure and will be summarized by treatment and time point. 
8.6 
Neurosensory Assessment 
Neurosensory testing at site of incision and the skin surrounding the incision will be performed at 
T96h (within 4 hours of discharge) and then as an outpatient on Days 8, 15, and D29/ET or if 
necessary Day 36. 
 
The neurosensory assessment results will be listed and the number of subjects with 
normal/abnormal assessments will be summarized descriptively by treatment, target foot and time 
point. 
8.7 
ECG Examination 
ECG examination will be assessed at screening and 24 hours (±2 hours) after study medication 
administration. 
  
Number of subjects with abnormal results will also be summarized by treatment and time point.  
All ECG data will be listed.  
8.8 
Clinical Laboratory Evaluation 
Clinical laboratory tests (blood chemistry, hematology and urinalysis) will be collected at 
screening and before discharge from the inpatient unit (T96h). All results will be listed. For each 
individual lab test value, the raw value and change from screening will be summarized by 
treatment.  
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Each clinical laboratory test will be defined by the clinical laboratory to be “Low”, “Normal”, or 
“High”, according to the normal reference range from the clinical laboratory. The number and 
percentage of subjects who have a shift from within to outside the normal reference range from 
screening to T96h will be summarized by treatment. 
8.9 
 Drugs of Abuse and Alcohol Screens, Pregnancy Test 
Pregnancy (for female subjects of childbearing potential), urine drug screen and alcohol (breath or 
saliva) tests will be performed at screening and pre-surgery.  
Results will be listed for individual subjects. Each test result will be defined to be “negative” or 
“positive”.  
8.10 Subject Pain Assessment Training and Surgery Details 
Patient pain assessment training and surgery details will be documented in CRFs and will be 
listed for each subject. 
9 
PHARMACOKINETIC EVALUATION 
It is anticipated that approximately 1/3rd of enrolled subjects at each site will participate in the PK 
study (48 in total; 12 in each treatment group). 
Blood draws for PK samples will be collected at baseline (within the 30 minutes before the start of 
study treatment dosing), and at minutes 5, 10, 15, 30, 45, hours 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, 
and 24 (a total of 17 samples). Actual sampling times will be used to calculate following plasma 
bupivacaine-derived PK parameters using noncompartmental analysis for CA-008, capsaicin and 
CA-101: 
• 
Cmax: The maximum measured plasma concentration, obtained directly from the data 
without interpolation 
• 
Clast: Last observed (quantifiable) concentration 
• 
Tmax: Time of Cmax 
• 
t½: The apparent first-order terminal elimination half-life, calculated as 0.693/λz 
• 
Tlag: Time delay between drug administration and first measurable (above lower limit of 
quantitation) concentration 
• 
Tlast: Time of occurrence of Clast 
• 
λz: Terminal first-order elimination rate constant 
• 
AUC0–t: Area under the plasma concentration-time curve from time 0 to the last 
measurable concentration (where time is post dose), calculated by the linear trapezoidal 
method 
• 
AUC0–∞: Area under the plasma concentration-time curve, from time of dosing to infinity. 
• 
AUClast: Area under the plasma concentration-time curve, from time of dosing to the time 
of the last measurable concentration 
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PK concentration data will be listed. There will be a separate PK Analysis Plan that will describe 
PK analyses.  
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10 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. 
11 INTERIM ANALYSES  
There are no planned interim analyses for this study.  
12 CHANGES TO THE ANALYSES PLANNED IN THE PROTOCOL 
Any deviations from the statistical plan will be described and a justification given in the CSR. 
13 REFERENCES 
US Federal Register. (1998) International Conference on Harmonization; Guidance for Industry:  
Statistical Principles for Clinical Trials. Department of Health and Human Services:  Food and 
Drug Administration. Federal Register, Vol. 63, No. 179, September 16, 1998, page 49583. 
US Federal Register. (1996) International Conference on Harmonization; Guidance for Industry:  
Structure and Content of Clinical Study Reports. Department of Health and Human Services:  
Food and Drug Administration. Federal Register Vol. 61, July 17, 1996, page 37320.  
Guidance for Industry (2014) Analgesic Indications:  Developing Drug and Biological Products -  
Draft Guidance.  Department of Health and Human Services:  Food and Drug Administration.  
Center for Drug Evaluation and Research (CDER) February 2014 Clinical/Medical. 
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14 APPENDICES 
14.1 Planned Tables, Figures and Listings  
14.1.1 Tables 
Table 14.1.1 
All Subjects 
Summary of Subject Disposition   
Table 14.1.2 
ITT Population 
Summary of Protocol Deviations   
Table 14.1.3 
ITT Population 
Summary of Demographic and Baseline Characteristics   
Table 14.1.4 
Safety Population 
Summary of Concomitant Medications by ATC Class and 
Preferred Term   
Table 14.1.5.1 
Safety Population 
Summary of Subject NRS and NRS at Rescue Diary 
Compliance (at Rest) 
Table 14.1.5.2 
Safety Population 
Summary of Subject NRS and NRS at Rescue Diary 
Compliance (After Ambulation) 
Table 14.2.1.1 
mITT Population 
ANOVA Analysis of AUC (0-96) of NRS at Rest – WOCF 
(Primary Analysis)  
Table 14.2.1.2 
mITT Population 
ANOVA Analysis of AUC (0-W1) of NRS at Rest – WOCF 
(Key Secondary Analysis) 
Table 14.2.1.3 
mITT Population 
ANOVA Analysis of AUC Over Various Time Periods of 
NRS at Rest and with Walking – WOCF (Exploratory 
Analyses) 
Table 14.2.1.4 
mITT Population 
ANOVA Analysis of AUC Over Various Time Periods of 
NRS at Rest and with Walking - LOCF (Sensitivity 
Analyses) 
Table 14.2.1.5 
mITT Population 
ANOVA Analysis of AUC Over Various Time Periods of 
NRS at Rest and with Walking – Median (Sensitivity 
Analyses) 
Table 14.2.2.1 
Inpatient Study 
Completer 
ANOVA Analysis of AUC (0-96) of NRS at Rest- WOCF 
(Sensitivity Analysis) 
Table 14.2.2.2 
Inpatient Study 
Completer 
ANOVA Analysis of AUC (0-96) of NRS at Rest- LOCF 
(Sensitivity Analysis) 
Table 14.2.2.3 
Study Completer 
ANOVA Analysis of AUC (0-96) of NRS at Rest - WOCF 
(Sensitivity Analysis) 
Table 14.2.2.4 
Study Completer 
ANOVA Analysis of AUC (0-96) of NRS at Rest- LOCF 
(Sensitivity Analysis) 
Table 14.2.2.5.1 
mITT Population 
Summary of NRS at Rest and with Walking by Time Point 
(WOCF) 
Table 14.2.2.5.2 
mITT Population 
Summary of NRS at Rest and with Walking by Time Point 
and by Site (WOCF)  
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Table 14.2.2.6 
mITT Population 
Summary of NRS at Rest and with Walking by Time Point 
(LOCF) 
Table 14.2.2.7.1 
mITT Population 
Summary of NRS at Rest and with Walking by Time Point 
(Observed Data, No Imputation for Drop Out) 
Table 14.2.2.7.2 
mITT Population 
Summary of NRS at Rest and with Walking by Time Point 
and by Site (Observed Data, No Imputation for Drop Out) 
Table 14.2.3 
mITT Population 
Logistic Analysis of Proportion of Subjects who are Opioid 
Free Outcome (Key Secondary and Exploratory Analyses) 
Table 14.2.4.1.1 
mITT Population 
ANOVA Analysis of Opioid Consumption (in Morphine 
equivalents) (Key Secondary and Exploratory Analyses) 
Table 14.2.4.1.2 
mITT Population 
ANOVA Analysis of Opioid Consumption by Site (in 
Morphine equivalents) (Key Secondary and Exploratory 
Analyses) 
Table 14.2.4.2.1 
mITT Population – 
Subjects Who Took 
Any Opioid 
Medication 
ANOVA Analysis Mean Daily Opioid Consumption (in 
Morphine Equivalents)  
Table 14.2.4.2.2 
mITT Population – 
Subjects Who Took 
Any Opioid 
Medication 
ANOVA Analysis Mean Daily Opioid Consumption by Site 
(in Morphine Equivalents)  
Table 14.2.5.1 
Safety Population 
Kaplan-Meier Analysis of Time to First Use of Opioid 
Rescue Medication  
Table 14.2.5.2 
Safety Population – 
Subjects Who Took 
First Opioid Rescue 
Medication Prior to 
60 Minutes Post-
Dose 
Kaplan-Meier Analysis of Time to Second Use of Opioid 
Rescue Medication 
Table 14.2.6 
mITT Population 
CMH and Fishers Analysis of Patient Global Evaluation 
(PGE) 
Table 14.2.7 
mITT Population 
CMH and Fishers Analysis of Investigator Global 
Evaluation (IGE) 
Table 14.2.8 
mITT Population 
Fishers Analysis of Proportion of Drop Out During the 
Inpatient Period  
Table 14.2.9.1 
Safety Population 
Fishers Analysis of Percent of Subjects using Rescue 
Medication Over Time 
Table 14.2.9.2 
Safety Population 
Summary of Percent of Subjects Using Rescue 
Medication 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 TEAEs by System Organ Class and 
Preferred Term 
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Table 14.3.1.3 
Safety Population 
Summary of Treatment Related TEAEs by System Organ 
Class and Preferred Term 
Table 14.3.1.4 
Safety Population 
Summary of SAEs by System Organ Class and Preferred 
Term 
Table 14.3.1.5 
Safety Population 
Summary of TEAEs Leading to Discontinuation from 
Study 
Table 14.3.1.6 
Safety Population 
Summary of TEAEs by System Organ Class, Preferred 
Term and Severity 
Table 14.3.1.7 
Safety Population 
Summary of TEAEs by System Organ Class, Preferred 
Term and Relationship to Study Drug 
Table 14.3.2.1.1 
Safety Population 
Summary of Blood Chemistry Laboratory Tests: Results 
and Change from Baseline 
Table 14.3.2.1.2 
Safety Population 
Summary of Blood Chemistry Laboratory Tests: Shifts 
from Baseline 
Table 14.3.2.2.1 
Safety Population 
Summary of Hematology Laboratory Tests: Results and 
Change from Baseline 
Table 14.3.2.2.2 
Safety Population 
Summary of Hematology Laboratory Tests: Shifts from 
Baseline 
Table 14.3.2.3.1 
Safety Population 
Summary of Urinalysis Laboratory Tests: Results and 
Change from Baseline 
Table 14.3.2.3.2 
Safety Population 
Summary of Urinalysis Laboratory Tests: Shifts from 
Baseline 
Table 14.3.4 
Safety Population 
Summary of Vital Signs: Results and Change from 
Baseline 
Table 14.3.5 
Safety Population 
Summary of Surgical Site Assessment 
Table 14.3.6.1 
Safety Population 
Summary of Neurosensory Exam –Target Foot 
Table 14.3.6.2 
Safety Population 
Summary of Neurosensory Exam –Non-Target Foot 
Table 14.3.7 
Safety Population 
Summary of ECG Exam Abnormal Findings   
 
 
 
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14.1.2 Figures 
Figure 14.2.1.1 
mITT Population 
Mean NRS Over Time by Treatment (WOCF) 
Figure 14.2.1.2 
mITT Population 
Mean NRS Over Time by Treatment (LOCF) 
Figure 14.2.1.3 
mITT Population 
Mean NRS Over Time by Treatment (median for remaining 
subjects in the group) 
Figure 14.2.2 
mITT Population 
Mean NRS Over Time by Treatment (Observed Data, No 
Imputation for Drop Out) 
Figure 14.2.3.1 
Safety Population 
Time to First Use of Opioid Rescue Medication 
Figure 14.2.3.2 
Safety Population 
Time to First Post-24 Hours Use of Opioid Rescue 
Medication 
Figure 14.2.3.3 
Safety Population – 
Subjects Who Took 
First Opioid Rescue 
Medication Prior to 
60 Minutes Post-
Dose 
Time to Second of Opioid Rescue Medication 
 
 
 
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14.1.3 Listings 
Listing 16.2.1 
All Subjects 
Randomization and Study Population 
Listing 16.2.2 
All Subjects 
Informed Consent and Re-Consent 
Listing 16.2.3 
All Subjects 
Eligibility 
Listing 16.2.4 
All Subjects 
Protocol Deviations 
Listing 16.2.5 
All Subjects 
Subject Disposition/ Early Termination   
Listing 16.2.6 
All Randomized 
Subjects 
Demographics and Baseline Characteristics 
Listing 16.2.7 
All Randomized 
Subjects 
Medical/Surgical History 
Listing 16.2.8.1 
All Randomized 
Subjects 
Prior and Concomitant Medications 
Listing 16.2.8.2 
All Randomized 
Subjects 
Rescue Medication Administration 
Listing 16.2.8.3 
All Randomized 
Subjects 
Non-Medication Therapies 
Listing 16.2.8.4 
All Randomized 
Subjects 
Time to Use of Opioid Rescue Medication  
Listing 16.2.9 
All Randomized 
Subjects 
X-Ray of Surgical Site and Surgery 
Listing 16.2.10 
All Randomized 
Subjects 
Study Drug Administration 
Listing 16.2.11 
All Randomized 
Subjects 
Subject NRS and NRS at Rescue Diary Compliance 
Listing 16.2.12 
All Randomized 
Subjects 
Discharge from Clinic 
Listing 16.2.13 
All Randomized 
Subjects 
Pain Assessment Training and Paper Diary Collection 
Listing 16.2.14.1.1 
All Randomized 
Subjects 
Pain Intensity Assessment (NRS at Rest) 
Listing 16.2.14.1.2 
All Randomized 
Subjects 
AUC of Pain Intensity Assessment (NRS) at Rest - 
WOCF 
Listing 16.2.14.1.3 
All Randomized 
Subjects 
AUC of Pain Intensity Assessment (NRS) at Rest - LOCF 
Listing 16.2.14.1.4 
 
All Randomized 
Subjects 
AUC of Pain Intensity Assessment (NRS) at Rest -  
Median 
Listing 16.2.14.2.1 
All Randomized 
Subjects 
Pain Intensity Assessment (NRS with Ambulation) 
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Listing 16.2.14.2.2 
All Randomized 
Subjects 
AUC of Pain Intensity Assessment (NRS) With 
Ambulation – WOCF and LOCF 
Listing 16.2.14.2.3 
All Randomized 
Subjects 
AUC of Pain Intensity Assessment (NRS) With 
Ambulation – Median 
Listing 16.2.15 
All Randomized 
Subjects 
List of Opioid Free and Opioid Consumption Endpoints 
Listing 16.2.16 
All Randomized 
Subjects 
Patient Global Evaluation (PGE) 
Listing 16.2.17 
All Randomized 
Subjects 
Investigator Global Evaluation (IGE) 
Listing 16.2.18.1 
All Randomized 
Subjects 
Adverse Events 
Listing 16.2.18.2 
All Randomized 
Subjects 
Serious Adverse Events 
Listing 16.2.18.3 
All Randomized 
Subjects 
Treatment Related Adverse Events 
Listing 16.2.18.4 
All Randomized 
Subjects 
Adverse Events Leading to Premature Study 
Discontinuation 
Listing 16.2.19.1 
All Randomized 
Subjects 
Blood Chemistry Laboratory Results 
Listing 16.2.19.2 
All Randomized 
Subjects 
Hematology Laboratory Results 
Listing 16.2.19.3 
All Randomized 
Subjects 
Urinalysis Laboratory Test Results 
Listing 16.2.20 
All Randomized 
Subjects 
Alcohol Breath and Urine Drug Screen Tests   
Listing 16.2.21 
All Randomized 
Subjects 
Pregnancy Test 
Listing 16.2.22 
All Randomized 
Subjects 
Vital Signs 
Listing 16.2.23 
All Randomized 
Subjects 
Physical Exam and Targeted Physical Exam Assessment 
Listing 16.2.24 
All Randomized 
Subjects 
Surgical Site Assessment 
Listing 16.2.25 
All Randomized 
Subjects 
Neurosensory Exam 
Listing 16.2.26 
All Randomized 
Subjects 
12-Lead Electrocardiogram  
Listing 16.2.27 
PK Population 
Pharmacokinetic (PK) Concentration Data 
 
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