Conditions: Hallux Valgus Deformity
Keywords: Unilateral Transpositional First Metatarsal Osteotomy
Allocation: RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 40
Healthy volunteers: no

Brief summary:
This is a single-center, randomized, double-blind, placebo-controlled, single ascending dose, sequential-group Phase 1 study. The study will be conducted utilizing a cohort design, with sequential groups of 8 subjects. Within each dose cohort, 6 subjects will be randomized to active, and 2 will be randomized to placebo.

Detailed description:
This is a single-center, randomized, double-blind, placebo-controlled, single ascending dose, sequential-group Phase 1 study.

The study will be conducted utilizing a cohort design, with sequential groups of 8 subjects. Within each dose cohort, 6 subjects will be randomized to active, and 2 will be randomized to placebo. Placebo patients from each cohort were pooled for analysis. The initial cohort will receive the lowest planned dose of CA-008, and sequential cohorts will receive escalating doses of CA-008 in a fixed volume of administration. There will be at least a 6-day period between cohorts, in order to ensure a minimum of 3 days to review safety data from the last subject in a cohort and to allow the meeting of the Data Monitoring Committee (DMC) to review the safety data from the entire cohort prior to a making decision for dose escalation. Dose escalation rules will be protocol defined.

Subjects will be undergoing unilateral transpositional first metatarsal osteotomy for the correction of hallux valgus deformity (bunionectomy). In accordance with standard of care, subjects will receive regional anesthesia (MAYO block) with 0.5% bupivacaine. Prior to wound closure, 10 mL of study drug will be injected into the soft tissues and periosteum of the surgical site.

After the surgery, subjects will be monitored for 48 hours at the trial site. Safety and efficacy evaluations will be performed as described herein. Subjects will be required to meet certain pre-specified criteria prior to discharge.

Arms:
arm 1: Intra-operative, local administration arm 2: Intra-operative, local administration arm 3: Intra-operative, local administration arm 4: Intra-operative, local administration arm 5: Intra-operative, local administration arm 6: Intra-operative, local administration of saline (equivalent volume in active comparator arm)

Interventions: intervention 1: CA-008 intervention 2: Placebo
Intervention descriptions: intervention 1: Local administration during surgery intervention 2: Local administration during surgery

Protocol document:
Prot_000.pdf: 
1 
 
 
 
 
OFFICIAL TITLE: 
 
A Phase 1/Single Ascending Dose (SAD) Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and 
Preliminary Efficacy of a Single Intraoperative Administration of CA-008 in Subjects Undergoing 
Unilateral Transpositional First Metatarsal Osteotomy for the Correction of Hallux Valgus Deformity 
 
 
NCT NUMBER: 
NCT03307837 
 
 
DOCUMENT DATE: 
30 Jan 2018 


Clinical Trial Protocol 
Concentric Analgesics, Inc. 
CA-PS-2017-101 
CONFIDENTIAL 
 
Version: 3.0 (Final), 30-Jan-2018 
Page 1 of 78 
 
 
Clinical Trial Protocol CA-PS-2017-101 
A Phase 1/Single Ascending Dose (SAD) Study to Evaluate the Safety, 
Tolerability, Pharmacokinetics, and Preliminary Efficacy of a Single 
Intraoperative Administration of CA-008 in Subjects Undergoing 
Unilateral Transpositional First Metatarsal Osteotomy for the 
Correction of Hallux Valgus Deformity 
 
Investigational Product:  Subcutaneous Injectable CA-008 
IND: 129-114 
 
Version:   
 
3.0 
Amendment:  
 
2 
Amendment 2 Date:  30-Jan-2018 
Amendment 1 Date:  12-Oct-2017 
Original Protocol 
07-Sep-2017 
 
 
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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Concentric Analgesics, Inc. 
CA-PS-2017-101 
CONFIDENTIAL 
 
Version: 3.0 (Final), 30-Jan-2018 
Page 2 of 78 
 
Amendment 2 changes from Amendment 1 include: 
The main objective of Amendment 2 of the study protocol, CA-PS-2017-101, is the addition of a 
5th cohort, allowing for exploration of a higher dose level than previously defined.  
 
With the goal of finding the maximum tolerated dose (concentration and volume) a decision was 
made to add another cohort to this study.  This decision was made following review of all previous 
cohorts, with the finding that these previous dosed cohorts were safe and well tolerated without 
any dose limiting side effect or toxicity at a regional or systemic level.  Subjects in Cohorts 1-4 
were all reviewed by the DMC and the decision to study a higher dose was supported by the 
DMC. 
 
In order to increase the dose, a decision was made to maintain the concentration and increase 
the total volume.  The maximum recommended volume for this surgical condition was a total of 
9ml infiltrated and a total of 5 ml instilled.  With this recommendation from, it was decided that 
one additional cohort would be studied, with no plan for study of any cohorts beyond this 
planned cohort 5.  This cohort #5 (study of a total dose of 4.2mg of CA-008), now represents the 
study of the highest possible dose for this post-surgical condition based on a) maximum 
concentration 0.3mg/mL, and b) maximum recommended volume for infiltration and instillation.  
As such, no further dose escalation is expected for this study. 
 
 
Amendment 2 changes from Amendment 1 include: 
o Addition of NCT number to synopsis (previously TBD) 
o Addition of Cohort 5 and associated updates required: 
▪ Increase in total enrollment by 8 subjects 
▪ Addition of new dose level and details surrounding dosing technique 
▪ Addition of rationale for addition of cohort 5 
o Addition of Capsaicin-glucuronide in the PK analysis, as previously detailed in the 
PK Manual 
 
 
 
 
 
 
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CA-PS-2017-101 
CONFIDENTIAL 
 
Version: 3.0 (Final), 30-Jan-2018 
Page 3 of 78 
 
Amendment 1 changes from the original protocol include: 
• Use of ice as method of post-surgical analgesia removed throughout 
• Updates to clinical laboratory tests  
• Updates to allowable inpatient and outpatient medications 
• X-ray of Surgical Site added at Screening and on Day 29/Early Termination (ET) 
• Relationship to Study Drug (causality) definitions added 
• Updates to the exclusion section to remove duplicative requirements and further 
enhance subject safety 
• Addition of Audio-Visual Recording section 
• Draw time and date remove from details captured on cryogenic storage (PK) tubes 
• Removal of 15-minute wait time between completion of NPRS pain score and taking 
rescue medication 
• Addition of 10-minute rest period prior to administration of NPRS 
• Clarification regarding intra-operative administration of study drug 
• Updates regarding management of subjects requiring analgesic relief beyond what is 
allowed per protocol 
• Addition of Vital Signs and Labs to the ‘Category’ column in Table 2: Study Stopping 
Rules 
• Addition of Appendix K: Physical / Neurological Examination of the Foot and Great Toe 
and associated details regarding the Neurosensory Exam 
• Administrative changes to: 
o Update of title page and headers throughout  
 
 
 
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CA-PS-2017-101 
CONFIDENTIAL 
 
Version: 3.0 (Final), 30-Jan-2018 
Page 4 of 78 
 
SIGNATURE PAGE 
 
Reviewed by: 
 
 
 
 
_____________________________________          
_______________________ 
 
John Donovan, MD 
 
Date 
Chief Executive Officer 
Concentric Analgesics, Inc. 
 
 
 
 
_____________________________________          
_______________________
 
Carole Hodge, PhD 
 
Date 
 
Clinical Operations Director 
 
 
Concentric Analgesics, Inc. 
 
 
 
Approved by: 
 
 
 
 
_____________________________________          
_______________________
 
Rob Allen, MD 
 
Date 
 
Chief Medical Officer 
 
 
Concentric Analgesics, Inc. 
 
 
 
 
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30-Jan-18
30-Jan-18
31-Jan-18


Clinical Trial Protocol 
Concentric Analgesics, Inc. 
CA-PS-2017-101 
CONFIDENTIAL 
 
Version: 3.0 (Final), 30-Jan-2018 
Page 5 of 78 
 
1. 
SPONSOR AND KEY PERSONNEL CONTACT INFORMATION 
Role in Study  
Name 
 Contact Information 
Study Sponsor 
Concentric Analgesics, Inc. 
 
 
John Donovan, MD 
 
Chief Executive Officer 
John@concentricanalgesics.com  
415-676-8940 
 
Carole Hodge, PhD 
Clinical Operations Director 
Carole@concentricanalgesics.com 
858-442-9884 
 
Rob Allen, MD 
Chief Medical Officer 
Rob@concentricanalgesics.com  
610-393-1303 
Medical Monitors 
Primary: Jon L. Ruckle, MD, CPI 
MedicalMonitorCA-PS-2017-
101@Lotuscr.com 
808-349-9812 
 
Secondary: Royce Morrison, MD 
MedicalMonitorCA-PS-2017-
101@Lotuscr.com 
206-799-7386 
 
 
 
 
 
 
 
 
 
 
 
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CA-PS-2017-101 
CONFIDENTIAL 
 
Version: 3.0 (Final), 30-Jan-2018 
Page 6 of 78 
 
2. 
PROTOCOL SYNOPSIS 
Sponsor:  
Concentric Analgesics, Inc. 
Protocol 
Number: 
 CA-PS-2017-101 
NCT: 
 03307837 
Study Title: 
A Phase 1/Single Ascending Dose (SAD) Study to Evaluate the Safety, 
Tolerability, Pharmacokinetics, and Preliminary Efficacy of a Single 
Intraoperative Administration of CA-008 in Subjects Undergoing Unilateral 
Transpositional First Metatarsal Osteotomy for the Correction of Hallux 
Valgus Deformity 
Investigational 
Product: 
CA-008 infiltrated into the surgical site at various concentrations (Cohorts 
1-4 doses in a 10 mL volume of administration; Cohort 5 dose in a 14 mL 
volume of administration) 
Comparator 
Product(s): 
Saline (10 mL for Cohorts 1-4, 14 mL for Cohort 5) 
Indication: 
Bunionectomy 
Planned Study 
Center: 
1 study center  
Phase of 
Development: 
Phase 1 
Study Design: 
 
This is a single-center, randomized, double-blind, placebo-controlled, 
single ascending dose, sequential-group Phase 1 study. 
The study will be conducted utilizing a cohort design, with sequential 
groups of 8 subjects. Within each dose cohort, 6 subjects will be 
randomized to active, and 2 will be randomized to placebo. The initial 
cohort will receive the lowest planned dose of CA-008, and sequential 
cohorts will receive escalating doses of CA-008 in a fixed volume of 
administration. There will be at least a 6-day period between cohorts, in 
order to ensure a minimum of 3 days to review safety data from the last 
subject in a cohort and to allow the meeting of the Data Monitoring 
Committee (DMC) to review the safety data from the entire cohort prior 
to a making decision for dose escalation.  Dose escalation rules will be 
protocol defined. 
Subjects will be undergoing unilateral transpositional first metatarsal 
osteotomy for the correction of hallux valgus deformity (bunionectomy). 
In accordance with standard of care, subjects will receive regional 
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CA-PS-2017-101 
CONFIDENTIAL 
 
Version: 3.0 (Final), 30-Jan-2018 
Page 7 of 78 
 
anesthesia (MAYO block) with 0.5% bupivacaine. Prior to wound closure, 
10 mL (Cohorts 1-4) or 14mL (Cohort 5) of study drug will be injected into 
the soft tissues and periosteum of the surgical site. 
After the surgery, subjects will be monitored for 48 hours at the trial site. 
Safety and efficacy evaluations will be performed as described herein. 
Subjects will be required to meet certain pre-specified criteria prior to 
discharge. 
Number of 
Subjects: 
Up to 40 enrolled subjects (Up to 5 groups of 8 subjects per group) 
Population: 
Subjects (male or female; aged 18 - 65 years old) who are planning to 
undergo bunionectomy, and who meet all inclusion and exclusion criteria, 
may be considered for enrollment in this study. 
Dosing 
Schedule: 
Single administration per subject, via wound infiltration, prior to wound 
closure. 
Route of 
Administration: 
 
Administration of the study drug into the surgical site:  A total of 10 mL (for 
Cohorts 1-4) and a total of 14 mL (for Cohort 5) of the investigative product 
will be administered into the surgical site as follows: 
• At time of closure of capsule: 
o Infiltration of deep soft tissue and capsule with a total of: 
▪ 6 mL volume for Cohorts 1-4  
▪ 9 mL volume for Cohort 5  
o Instillation at cut bone with a total of 2 mL volume for all cohorts 
• Following closure of the capsule and prior to closure of the skin and 
subcutaneous layer:  
o Instillation of wound with 2 mL volume for Cohorts 1-4, and with 
a 3 mL for Cohort 5  
▪ For Cohorts 1-4 study drug is applied to all exposed 
surfaces prior to subcutaneous and skin closure 
▪ For cohort 5, 2 mL of study drug will be instilled into 
the space under closed capsule and 1 mL of study 
drug applied to all exposed surfaces prior to 
subcutaneous and skin closure 
Surgical 
Procedures: 
 
Surgical Anesthesia:  
Light to moderate sedation which will include propofol, midazolam and/or 
fentanyl.  Regional anesthesia (MAYO Block) utilizing 0.5% bupivacaine (up 
to 30 cc total).  MAYO block should be done proximal to the surgical site 
and should not involve the immediate area of the planned surgical 
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incision. 
The area starting 1-inch lateral/medial/proximal/distal of the incision site 
and surrounding tissue that may be affected by the infiltration of the 
Investigational Product (IP) will subsequently be referred to as the 
“surgical site.” 
Dose Groups: 
 
• CA -008, 0.5 mg in 10 mL of saline (50 μg/mL) 
• CA-008, 1.0 mg in 10 mL of saline (100 μg/mL) 
• CA-008, 2.0 mg in 10 mL of saline (200 μg/mL) 
• CA-008, 3.0 mg in 10 mL of saline (300 μg/mL) 
• CA-008, 4.2 mg in 14mL of saline (300 ug/mL) 
Note: Weights of CA-008 are provided for the free base, without 
counterions.  
Within each cohort of 8 subjects, 6 will be randomized to active 
treatment, and 2 will be randomized to placebo. 
Duration of 
Treatment and 
Study Duration: 
 
• Screening period - up to 28 days  
• Surgery – Day 1  
• In-Clinic – through Day 3 (48 hours) 
• In-Clinic – Day 8 Visit 
• In-Clinic – Day 15 Visit 
• Follow-up visit – Day 29 Visit (includes the in-clinic days) 
• Follow-up visit: Day 36 Visit (Visit is only required to assess wound 
healing if wound is not considered healed by Day 29). If the wound 
is considered healed at Day 29, Day 36 is not required. 
Assumptions:  
• Up to five cohorts of 8 subjects each.  
• The first cohort will employ sentinel dosing, whereby the first 4 
subjects in the first cohort will be dosed initially, before the 
remaining 4 subjects are dosed. 
• If the available safety assessments for the first 4 subjects are 
acceptable through the first 24 hours, then the second group of 4 
subjects will be dosed. 
• Subsequent cohorts will not include sentinel dosing. 
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• There must be a minimum of 6 days between the dosing of each 
cohort to allow for the review of all available safety assessments. 
• This cycle will repeat until all planned cohorts are completed, or 
the study is stopped due to safety considerations (as detailed 
below). 
Visit Schedule: 
 
A. Screening. Subjects will undergo a screening visit up to 28 days prior to 
surgery; All screening assessments (including ICF) must be completed 
at least 1 day prior to surgery. 
B. Study Unit Admission. Day 1 Prior to surgery, subjects will be enrolled 
and randomized, and baseline evaluations will be performed prior to 
surgery. 
C. Day 1 Surgery. Subjects will undergo bunionectomy procedure, and 
study drug will be infiltrated prior to wound closure. Time 0 will be 
defined as the time of completion of drug administration. 
D. Day 1 Post-surgery through 48 hours post-surgery. Subject will remain 
at the Study Unit site for monitoring and PK assessments. 
E. Day 2 Safety follow-up and PK assessments 
F. Day 3 Safety follow-up, PK assessments, and discharge from Study Unit  
G. Day 8 Clinic visit for study assessments  
H. Day 15 Clinic visit for study assessments  
I. Day 29 Clinic visit for study assessments 
J. Day 36 Clinic visit for wound healing evaluation and Surgical Site 
assessment (only for subjects who will need a follow up visit after Day 
29) 
Note: For subjects who terminate early, an early termination (ET) visit will 
be required. Safety and subject-reported outcome assessments will be 
performed at the ET visit. 
Postsurgical 
Analgesia: 
 
Day 1 (Hours 0 – 24): 
• If needed for management of NPRS score of 4 or higher, oxycodone 
5 mg PO q 2 hours prn.  
Day 2 (Hours 25 – 48): 
• If needed for management of NPRS score of 4 or higher, oxycodone 
5 mg PO q 2 hours prn.  
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Day 3 – Day 15:   
• Over-the-counter standard of care analgesics may be used for 
management of pain.   
• If needed for management of NPRS score of 4 or higher, oxycodone 
5 – 15 mg PO q 4 - 6 hours prn.  
Day 15 (post-visit) – Day 29/ET: 
• Over-the-counter standard of care analgesics should be used for 
management of pain. 
Study Objectives: 
Primary: 
To evaluate the safety and tolerability of a single intraoperative 
administration of CA-008 in subjects undergoing bunionectomy.  
To evaluate the pharmacokinetics of a single intraoperative administration 
of CA-008. 
Secondary: 
To evaluate the efficacy of CA-008 in the management of acute 
postoperative pain in subjects undergoing bunionectomy. 
Evaluated Parameters/Outcome Measures: 
Primary: 
Safety: 
1. Adverse events, physical examination (PE), vital signs, 
electrocardiogram, Surgical Site assessments, neurosensory testing 
(neurosensory assessments at site of incision and the skin surrounding 
the incision and neurosensory monitoring will be performed at 24 and 
48 hours post-infiltration, and at follow up clinic visits), clinical labs 
(standard hematology, clinical chemistry/coagulation, urinalysis), 
concomitant medications.   
 
Pharmacokinetics: 
2. Plasma samples to measure appropriate analyte concentrations will be 
collected from all subjects.  The PK time points will be adequate to 
determine the PK profiles of the following analytes: 
• CA-008 
• CA-101 
• Capsaicin 
• Capsaicin-glucuronide 
 
The time points for collection are at baseline (before dosing), and at 5 
minutes, 15 minutes, 30 minutes, 45 minutes, and 1, 1.5, 2, 2.5, 3, 3.5, 
4, 6, 8, 12, 16, 24, 36, and 48 hours after dosing. 
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Secondary: 
1. Pain as assessed by a standard 11-point (0–10) NPRS at post-
infiltration time points of 15, 30, 45 min, 1, 2, 4, 8, 12 hours, then 
every 4 hours (if awake at time of assessment) until discharge or ET.  
Subjects will report pain twice daily through Day 15 or early 
termination (method of reporting – Subject Diary). 
2. Use of postoperative analgesic therapy/treatments and NPRS scores 
prior to use of the analgesics will be collected during the study period 
through Day 15 or early termination (by site staff during in-patient 
stay, and via Subject Diary during outpatient portion). 
Endpoints: 
 
Primary 
(Safety): 
 
1. Incidence and severity of abnormalities in physical / neurosensory 
examination, vital signs, ECG, Surgical Site assessments, or clinical labs. 
2. Incidence and severity of adverse events and serious adverse events. 
Secondary 
(efficacy): 
1. Area-under-the-curve (AUC) over various time points using NPRS score 
(0–10), with adjustment for use of analgesic therapy/medication. 
2. Mean average daily NPRS score of 2 daily diary assessments.  
3. Mean daily opioid consumption (in morphine equivalents). 
4. Proportion of patients who drop out of the study due to inadequate 
analgesia from Day 1 to 15. 
5. Brief Pain Inventory-short form (BPI-SF) scores at the Day 8 (Week 1), 
Day 15 (Week 2) and Day 29 (Week 4) or ET clinic visits. 
6. Patient Global Evaluation (PGE) at the Day 8 (Week 1), Day 15 (Week 
2) and Day 29 (Week 4) clinic visits. 
7. Investigator Global Evaluation (IGE) at the Day 8 (Week 1), Day 15 
(Week 2) and Day 29 (Week 4) clinic visits. 
Eligibility: 
 
Inclusion 
Criteria: 
1. Male or female aged 18 - 65 years old, inclusive. 
2. Planning to undergo a primary unilateral first metatarsal 
bunionectomy repair, without collateral procedures. 
3. Be American Society of Anesthesiology (ASA) physical Class 1 or 2. 
Appendix J 
4. In good health and capable of undergoing a bunionectomy under 
regional anesthesia. 
5. No additional planned surgeries other than a bunionectomy during the 
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course of the study. 
6. Male subjects must be either sterile (surgically or biologically), or 
commit to an acceptable method of birth control while participating in 
the study.   
7. Female subjects are eligible only if all of the following apply: 
a. Not pregnant (female subject of child bearing potential must 
have a negative serum pregnancy tests at screening and 
negative urine pregnancy test before surgery); 
b. Not lactating; 
c. Not planning to become pregnant during the study; 
d. Be surgically sterile; or at least two years post-menopausal; or 
have a monogamous partner who is surgically sterile; or is 
practicing double-barrier contraception; or practicing 
abstinence (must agree to use double-barrier contraception in 
the event of sexual activity); or using an insertable, injectable, 
transdermal, or combination oral contraceptive approved by 
the FDA for greater than 2 months prior to screening visits and 
commits to the use of an acceptable form of birth control for 
the duration of the study and for 30 days from completion of 
the study. 
8. Have a body mass index ≤ 35 kg/m2. 
9. Willing and able to sign the informed consent form (ICF) approved by 
the Institutional Review Board (IRB). 
10. Willing and able to complete the study procedures and pain scales, 
and to communicate meaningfully in English with study personnel. 
Exclusion 
Criteria: 
1. Subjects with a history of hypertension, cardiovascular disease or a 
history of cerebrovascular events. 
2. Subjects with concurrent painful conditions that may require analgesic 
treatment during the study period, or, in the opinion of the 
Investigator, may confound post-operative pain assessments. 
3. Have been receiving or have received chronic opioid therapy defined 
as greater than 15 morphine equivalents units per day for greater than 
3 out of 7 days per week over a one-month period within 12 months of 
study treatment initiation. 
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4. Have a known allergy or intolerance to the following medications or 
related substances: capsaicin, chili peppers, propofol, bupivacaine, 
benzodiazepines, midazolam, oxycodone, fentanyl or ondansetron.  
5. Have a clinically significant abnormal clinical laboratory test value that 
places the subject at an undue risk according to the judgment of the 
investigator. 
6. Have, as determined by the investigator or the study’s medical 
monitor, a history or clinical manifestations of significant renal, 
hepatic, cardiovascular, metabolic, neurologic, psychiatric, or other 
condition that would preclude participation in the study. 
7. Use concurrent therapy that could interfere with the evaluation of 
efficacy or safety, such as any drugs which, in the investigator’s 
opinion, may exert significant analgesic properties or act synergistically 
with CA-008. 
8. Use of disallowed pain medications within 2 days prior to Day 1 
(NSAIDs, COX-2 inhibitors, tramadol, ketamine, clonidine, gabapentin, 
pregabalin, or cannabinoids). 
9. Use of central nervous system (CNS) active drugs such as 
benzodiazepines, tricyclic antidepressants, SNRIs, or SSRIs for pain 
within seven days prior to Day 1. These drugs are permitted for non-
pain indications if the dose has been stable for at least 30 days prior to 
Day 1 and is planned to remain stable throughout the study. The use of 
lorazepam and other sleep medications, except those containing 
analgesic properties, is permitted. 
10. Have evidence of a clinically significant 12-lead ECG abnormality 
according to the judgment of the investigator, including QTcF >450 for 
men and >470 for women. 
11. Use of dietary supplements or over-the-counter (OTC) medications 
containing significant amounts of capsaicin within 1 day prior to Day 1, 
and throughout the hospitalization period. 
12. Subjects with active cutaneous disease, or other disease, at the 
anticipated site of surgery. 
13. History of peripheral vascular disease, sickle cell disease, vascular 
grafts, or vasospastic disorders. 
14. Use of parenteral or oral corticosteroid(s) within 14 days prior to Day 
1. 
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15. Known bleeding disorder or is taking agents affecting coagulation 
preoperatively. Deep venous thrombosis (DVT) prophylaxis of the 
surgeon’s choice is permitted postoperatively. 
16. A medical condition that in the investigator’s opinion could adversely 
impact the subject’s participation or safety, conduct of the study, or 
interfere with the pain assessments. 
17. Diabetes mellitus. 
18. Use of 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 throughout the study. 
19. Use of digoxin, warfarin (see exception below), lithium, theophylline 
preparations, aminoglycosides, and all antiarrhythmics except beta-
blockers, and use of anticonvulsants except benzodiazepines within 7 
days prior to Day 1 and throughout the study. (Use of warfarin is 
allowed, at the investigator’s discretion, for DVT prophylaxis after the 
surgery). 
20. History of illicit drug use, or prescription medicine or alcohol abuse 
(regularly drinks > 4 units of alcohol per day; 8 oz. beer, 3 oz. wine, 
1 oz. spirits) within the past 2 years, in the opinion of the Investigator. 
21. Have positive results on the alcohol breath test indicative of alcohol 
abuse or urine drug screen indicative of illicit drug use (unless results 
can be explained by a current prescription or acceptable over-the-
counter medication at screening as determined by the investigator) at 
screening, and/or prior to surgery. 
22. 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. 
23. Previously participated in a clinical study with CA-008 or capsaicin. 
24. Subjects with peripheral neuropathies which would potentially 
confound the planned neurosensory testing. 
25. Subjects who donated blood or plasma within the 30 days prior to 
screening. 
Monitored Parameters: 
Safety:  
• ECG  
• Clinical laboratory tests (standard hematology, clinical 
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chemistry/coagulation, urinalysis) (at screening, Day 1 pretreatment, 
and Day 1 post-treatment): All routine samples will be analyzed by a 
clinical laboratory. The clinical laboratories tests are as follows:  
o Hematology: hemoglobin, hematocrit, white blood cell 
count with differential, red blood cell count, platelet count, 
activated partial thromboplastin time (aPTT), prothrombin 
time (PT), and international normalization ratio. 
o Blood Chemistry/Coagulation: Alanine aminotransferase 
(ALT; SGPT) and Aspartate aminotransferase (AST; SGOT), 
total bilirubin, direct bilirubin, gamma-glutamyl transferase 
(GGT), blood urea nitrogen (BUN), creatinine, alkaline 
phosphatase, lactate dehydrogenase (LDH), sodium, 
potassium, calcium, chloride, albumin, uric acid, and 
glucose. 
o Serum and urine pregnancy test: βhCG test for female 
subjects of child bearing potential, usually to be done 
within 24 hours prior to study intervention. The results 
must be available prior to administration of study drug. 
o Urinalysis: Urinalysis will include macroscopic analysis and 
microscopic analysis only when indicated by dipstick.  
Analyses will include: color, turbidity, specific gravity, pH, 
glucose, protein, ketones, urobilinogen, bilirubin, blood 
nitrite, and leukocyte esterase. 
• 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.  Once resolved, the appropriate AE/SAE eCRF page(s) will 
be updated.   
• Surgical Site assessments (screening, baseline (Day 1, pre-treatment), 
24 and 48 hours after study drug administration, and at every follow-
up visit).  If there are skin reactions, for example, erythema, pain, 
pruritus, bruising, swelling, bruising or other skin changes, they will be 
evaluated and graded for severity regularly until resolution. 
Efficacy: 
 
• Pain as assessed by a standard 11-point (0–10) NPRS at post-
infiltration time points of 15, 30, 45 min, 1, 2, 4, 8, 12 hours, then 
every 4 hours (if awake at time of assessment) until discharge or ET.  
After discharge, subjects will report pain twice daily through Day 15 or 
early termination (method of reporting - Subject Diary) 
• Use of postoperative rescue medication and NPRS pain scores prior to 
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use of the rescue therapy/medication will be collected through Day 15 
or early termination (by site staff during the inpatient stay, and via 
Subject Diary during the outpatient portion). 
AE 
Considerations: 
The following is a partial list of additional AE considerations for the 
protocol, based on FDA comments:  
• Vital signs-based adverse event definitions will be pre-specified in the 
protocol.  
• Any sensory deficits or clinically significant persistent sensory change 
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 is most likely going to be a permanent 
change and, consequently, classified as an adverse event.  
• Numbness at or near the incision need not be considered a neurologic 
AE since this could occur as a result of tissue trauma and inflammation 
from the surgery.  
• If a subject develops cardiac adverse events (chest pain, change in 
heart rate, shortness of breath or diaphoresis) a 12-lead ECG must be 
performed and read by a qualified physician. 
Study Stopping 
Rules: 
Dose escalation, or continuation of dosing, will not occur if subjects in a 
cohort experience intolerable treatment related AEs on active drug, as 
defined below: 
• 1 or more treatment-related AE of grade 4 or higher (per Table 2, 
Appendix G or Appendix H); 
• 2 or more treatment-related AEs of grade 3 or higher (per Table 2, 
Appendix G or Appendix H) 
Sample Size 
Justification: 
Sample size is appropriate for Phase 1 dose ranging safety study. 
Data Analysis 
Plan: 
Two analysis populations will be defined as follows: 
• Safety Population will include all subjects who received at least one 
dose of study drug. 
• PK Population: will include all subjects who received a full dose of 
study drug and have sufficient concentration-time profiles for 
estimation of PK parameters. 
All safety assessments and baseline characteristics will be summarized 
using the Safety Population.  PK analyses will be performed using the PK 
population. All summaries will be grouped by the actual treatment 
received. Placebo subjects will be combined for summaries. 
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Safety and tolerability will be evaluated by examining the occurrence of 
AEs, including Treatment-Emergent AEs.  AEs leading to discontinuation 
from the study, AEs related to the study dose, and AE severity will be 
summarized by treatment group.  
 
Actual and change from baseline in clinical laboratory measures, vital 
signs, and ECGs will also be assessed and summarized by treatment group. 
These data will be summarized using descriptive statistics including n, 
mean, SD, SEM (if appropriate), median, minimum and maximum.  
Abnormal values will be determined and flagged in the listings.  Laboratory 
shift tables displaying the change (number of subjects) relative to the 
normal range from baseline to each study visit will also be presented by 
treatment for each test.  The Investigator should exercise medical and 
scientific judgment in deciding whether an abnormal laboratory finding or 
other abnormal assessment is clinically significant. 
 
The study is not designed to detect a significant difference in analgesia 
between the two treatment groups.  All secondary efficacy endpoints 
(e.g., NPRS scores), will be summarized over time by treatment using 
descriptive statistics including confidence intervals as appropriate. 
Data 
Monitoring 
Committee 
(DMC): 
Safety data will be reviewed by a DMC after the final dosing within each 
cohort to determine appropriate dose escalation in the next planned 
cohort.   
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Table 1 Schedule of Assessments 
Assessment  
Screening 
In Patient 
Discharge 
through 
EOS 
Follow-Up 
ET2 
Prior to 
Surgery 
Surgery 
Post-
Surgery 
24 hr 
48 hr 
Study Day 
-28 to -1 
1 
1 
1 
2 
3 
8 ±1 
day 
15 ±2 
days 
29 ±2 
days 
36 ±2 
days1 
Informed Consent 
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 
X 
 
 
 
 
 
 
 
 
 
 
Surgery 
 
 
X 
 
 
 
 
 
 
 
 
 
Infiltration 
 
 
X 
 
 
 
 
 
 
 
 
 
Safety Evaluations 
Pregnancy Test  
X 
(serum) 
X3 
(urine) 
 
 
 
 
 
 
 
 
 
 
Vital Signs 
X 
X 
 
X4 
X4 
X4 
 
X 
X 
X 
 
X 
Physical Exam5 
X5 
X5 
 
X5 
X5 
X5 
 
 
 
X5 
 
X 
12-Lead ECG 
X 
 
 
X6 
 
 
 
 
 
 
 
 
Surgical Site assessment 
X 
X 
 
 
X7 
X7 
 
X 
X 
X 
X 
X 
Neurosensory Exam 
X 
X 
 
 
X8 
X8 
 
X 
X 
X 
X 
X 
Blood draw for hematology and serum 
chemistry/coagulation 
X 
X 
 
X9 
 
 
 
 
 
 
 
 
Urine sample for urinalysis 
X 
X 
 
X9 
 
 
 
 
 
 
 
 
X-ray of Surgical Site 
X 
 
 
 
 
 
 
 
 
X 
 
X 
Concomitant Medication Assessment 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
Adverse Event Assessment 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
Efficacy Evaluations 
NPRS pain assessments 
 
 
 
X10 
X10 
X10 
 
X 
X 
X 
 
X 
Subject home diary record (NPRS) 
 
 
 
 
 
X 
X11 
X11 
X11 
 
 
X 
Subject home diary (pain medication) 
 
 
 
 
 
X 
 
X14 
X14 
 
 
X 
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Assessment  
Screening 
In Patient 
Discharge 
through 
EOS 
Follow-Up 
ET2 
Prior to 
Surgery 
Surgery 
Post-
Surgery 
24 hr 
48 hr 
Study Day 
-28 to -1 
1 
1 
1 
2 
3 
8 ±1 
day 
15 ±2 
days 
29 ±2 
days 
36 ±2 
days1 
Paper Diary (review, distribution and 
collection) 
 
 
 
X12, 13 
 
 
 
 
X14 
 
 
X 
Supplemental Pain Medication 
dispensing 
 
 
 
X 
 
 
 
 
 
 
 
X 
BPI-SF assessment 
 
 
 
 
 
 
 
X 
X 
X 
 
X 
PGE assessment 
 
 
 
 
 
 
 
X 
X 
X 
 
X 
IGE assessment 
 
 
 
 
 
 
 
X 
X 
X 
 
X 
Pharmacokinetics 
Blood draw for PK analysis 
 
X 
 
X15 
X15 
X15 
 
 
 
 
 
 
1. 
Day 36 visit will occur if insufficient wound healing is assessed by the Investigator at the Day 29 visit. 
2. 
Early Termination (ET); Subjects who discontinue participation, or who are discontinued after Day 3 but prior to Day 29. 
3. 
Within 24 hours of scheduled surgery 
4. 
Vital signs: 0.5, 1, 1.5, 2, 4, 6, 8,10 and 12 hours after study drug administration, and then every 4 hours until discharge. Vital sign assessments between 00:00 and 06:00 may 
be skipped if the subject is sleeping; however, consecutive assessments may not be skipped, and the Hour 12, Hour 24, and Hour 48 assessments must be completed even if 
the subject is asleep. 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. 
5. 
A complete physical examination including all major body systems will be performed at Screening, prior to Surgery, and at the Day 29 Follow-Up visit. In addition, at the 
following times, an abbreviated review of systems will be performed to capture changes since Surgery: 1 hour (±30 minutes), 24 hours (± 2 hours), and 48 hours (± 4 hours) 
after the administration of study medication. Body weight (kg), in indoor clothing, but without shoes, will be measured at Screening, at 48 hours, and on Day 29, or at the time 
of discontinuation.  Height (in cm) will be measured and BMI will be calculated at Screening only. 
6. 
Post-Surgery ECG should be performed at 1.5 hours (±0.5 hour) after administration of study medication. 
7. 
Surgical Site assessment: 24 hours (±2 hours) and 48 hours (±4 hours) after study drug administration. 
8. 
Neurosensory Exam of the Foot / Great toe (bilateral): 24 hours (±2 hours) and 48 hours (±4 hours) after study drug administration. 
9. 
Clinical Laboratory tests (chemistry/coagulation, hematology and urinalysis) should be performed at 1.5 hours (±0.5 hour) after administration of study medication 
10. NPRS pain assessments at: 0.25, 0.5, 0.75, 1, 2, 4, 8, 12 hours, then every 4 hours (if awake at time of assessment) until discharge or ET, and prior to supplemental pain therapy 
or medication. NPRS assessments between 00:00 and 06:00 may be skipped if the subject is sleeping; however, consecutive assessments may not be skipped, and the Hour 
12, Hour 24, and Hour 48 assessments must be completed even if the subject is asleep. There will be a ±5 minute window allowed for the collection of each pain intensity 
assessment in the first 4 hours after the end of surgery, after which will be a ±15 minute window allowed. 
11. 2x/day through Day 15 
12. Review Subject Diary instructions with subject 
13. Dispense Subject Diary 
14. Collect Subject Diary 
 
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15. Collect blood samples.  The time points for collection are at baseline (before dosing), and at 5 minutes, 15 minutes, 30 minutes, 45 minutes, and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 
12, 16, 24, 36, and 48 hours after dosing. There will be a ±2 minute window allowed for the 5 and 15 minute collections, a ±5 minute window allowed for collections through 
4 hours, and a ±15 minute window for collections through 48 hours. 
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3. 
TABLE OF CONTENTS 
1. 
Sponsor and Key Personnel Contact Information ............................................................ 5 
2. 
Protocol Synopsis ........................................................................................................... 6 
3. 
Table of Contents ......................................................................................................... 21 
4. 
List of Abbreviations and Definition of Terms ............................................................... 23 
5. 
Introduction ................................................................................................................. 25 
5.1. 
Background .......................................................................................................... 25 
5.2. 
Study Rationale .................................................................................................... 28 
6. 
Study Objectives .......................................................................................................... 29 
6.1. 
Primary Objectives ............................................................................................... 29 
6.2. 
Secondary Objectives ........................................................................................... 29 
7. 
Investigational Plan ...................................................................................................... 30 
7.1. 
Overall Study Design and Plan .............................................................................. 30 
7.2. 
Discussion of Study Design .................................................................................... 34 
8. 
Selection of Study Population ...................................................................................... 35 
8.1. 
Inclusion Criteria .................................................................................................. 35 
8.2. 
Exclusion Criteria .................................................................................................. 35 
8.3. 
Removal of Subjects from Therapy or Assessment ................................................ 37 
8.4. 
Study Stopping Rules ............................................................................................ 37 
8.5. 
Safety Oversight ................................................................................................... 38 
8.6. 
Study Restrictions ................................................................................................. 38 
9. 
Treatments .................................................................................................................. 39 
9.1. 
Treatment Administration .................................................................................... 39 
9.2. 
Identity of Investigational Product(s) .................................................................... 40 
9.3. 
Method of Assigning Subjects to Treatment Groups .............................................. 40 
9.4. 
Selection of Doses ................................................................................................ 41 
9.5. 
Selection and Timing of Dose ................................................................................ 41 
9.6. 
Blinding ................................................................................................................ 42 
9.7. 
Prior and Concomitant Therapy ............................................................................ 42 
9.8. 
Treatment Compliance ......................................................................................... 42 
10. 
Study Procedures and Assessments .......................................................................... 43 
10.1. Demographics and Other Baseline Characteristics ................................................. 43 
10.2. Eligibility Review and Randomization .................................................................... 43 
10.3. Subject Pain Assessment Training ......................................................................... 44 
10.4. Efficacy Assessments ............................................................................................ 44 
10.5. Safety Assessments .............................................................................................. 45 
10.6. Efficacy and Safety Variables ................................................................................ 48 
11. 
ADVERSE EVENTS, SERIOUS ADVERSE EVENTS, AND SERIOUS SUSPECTED ADVERSE 
REACTIONS .......................................................................................................................... 50 
11.1. Adverse Events and Serious Adverse Events .......................................................... 50 
11.2. Pregnancy ............................................................................................................ 52 
12. 
Data Quality Assurance ............................................................................................ 53 
12.1. Data Collection ..................................................................................................... 53 
12.2. Study Auditing and Monitoring ............................................................................. 53 
13. 
Statistical Methods and Determination of Sample Size ............................................. 54 
13.1. Statistical and Analytical Plans .............................................................................. 54 
13.2. Analysis Populations ............................................................................................. 54 
13.3. Planned Analyses .................................................................................................. 54 
13.4. Study Subjects and Demographics......................................................................... 54 
13.5. Determination of Sample Size ............................................................................... 57 
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14. 
Study Administration and Investigator Responsibilities ............................................. 58 
14.1. Regulatory and Ethical Considerations .................................................................. 58 
14.2. Privacy and Confidentiality ................................................................................... 58 
14.3. Study and Site Closure .......................................................................................... 59 
14.4. Regulatory Documents and Records Retention...................................................... 59 
14.5. Delegation of Responsibilities and Adequate Resources ........................................ 60 
14.6. Protocol Amendments .......................................................................................... 60 
14.7. Financial Disclosure .............................................................................................. 60 
15. 
Investigator Protocol Agreement Page ...................................................................... 61 
16. 
References ............................................................................................................... 62 
17. 
Appendices .............................................................................................................. 65 
 
 
LIST OF TABLES 
Table 1 Schedule of Assessments ......................................................................................... 18 
Table 2 Study Stopping Rules ............................................................................................... 38 
Table 3 Human Equivalent Dose and Safety Margins for the CA-008 Starting Dose ............... 41 
Table 4 Clinical Laboratory Assessments .............................................................................. 45 
 
 
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4. 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Term 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of Covariance 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
AUC 
Area Under the Curve 
BP 
Blood Pressure 
BPI-SF 
Brief Pain Inventory-Short Form 
BUN 
Blood Urea Nitrogen 
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) 
CS 
Clinically significant 
CSA 
Clinical Study Agreement 
DBP 
Diastolic Blood Pressure 
DIP 
Distal interphalangeal 
DMC 
Data Monitoring Committee 
DVT 
Deep Venous Thrombosis 
ECG 
Electrocardiogram 
EDC 
Electronic data capture 
ET 
Early Termination 
FDA 
Food and Drug Administration 
FIH 
First-In-Human 
FSH 
Follicle Stimulating Hormone 
G 
Gram 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transferase 
GLP 
Good Laboratory Practice 
HED 
Human Equivalent Dose 
HEENT 
Head, Eye, Ear, Nose and Throat 
HRS 
Hours 
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 
MedDRA 
Medical Dictionary of Regulatory Activities 
Mg 
Milligram 
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Abbreviation 
Term 
mL 
Milliliter 
NCS 
Not clinically significant 
NOAEL 
No Observed Adverse Effect Level 
NPRS 
Numeric Pain Rating Scale 
OTC 
Over-the-counter 
PGE 
Patient Global Evaluation 
PHN 
Postherpetic Neuralgia 
PI 
Principal Investigator 
PK 
Pharmacokinetic 
PRN 
As needed 
PT 
Prothrombin time 
QID 
Four times a day 
RBC 
Red blood cell 
SAE 
Serious adverse event  
SAD 
Single Ascending Dose 
SAP 
Statistical analysis plan 
SBP 
Systolic blood pressure 
SC 
Subcutaneous 
SD 
Standard deviation 
SOC 
System Organ Class 
SNRIs 
Serotonin-norepinephrine reuptake inhibitors 
SSRIs 
Selective serotonin reuptake inhibitors 
TEAEs 
Treatment emergent adverse events 
TID 
Three times a day 
T1/2  
Half-life 
Tmax 
Time to maximum plasma concentration 
TRPV1 
Transient receptor potential vanilloid-1 
Ug 
microgram 
US 
United States 
V 
Volume of distribution 
WHO 
 
 
 
 
 
 
 
 
 
 
 
World Health Organization 
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5. 
INTRODUCTION 
5.1. 
Background 
Concentric Analgesics, Inc. 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), a transient receptor potential cation channel, subfamily V, 
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 
(Caterina and Julius, 2001). TRPV1 responds to noxious stimuli including capsaicin, heat, and 
extracellular acidification, and integrates simultaneous exposures to these stimuli (Tominaga et 
al., 1998).  Capsaicin exposure results in initial excitation followed by a functional desensitization 
of TRPV-1-expressing nociceptors which continues for some time after removal of capsaicin from 
the site. 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 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 products 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 recently 
approved in the US for the management of neuropathic pain associated with postherpetic 
neuralgia (PHN).  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 for intraarticular 
injection for chronic osteoarthritis. Anesiva, Inc. previously had an early stage program for 
intraarticular injection for osteoarthritis as well as a late-stage program evaluating capsaicin 
instillation during surgery for the management of post-surgical pain.   
5.1.1. 
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.  Local administration to the source of pain 
either topically, by infiltration or by instillation into a surgical site results in low systemic levels of 
capsaicin.  Systemic capsaicin is heavily protein-bound, with levels rapidly diminishing to non-
detectable levels (e.g., systemic capsaicin from Qutenza is 93% protein bound, present in 
maximum levels of 17.8 ng/mL immediately following patch administration, and is undetectable 
within 3 hours after patch removal; FDA Summary Basis for Regulatory Action, page 6).  Based on 
capsaicin’s mechanism of action, the duration of pain relief extends well beyond the relatively 
limited time of exposure. 
Capsaicin, however, is virtually insoluble in aqueous media or local anesthetic solutions.  Anesiva, 
which had been developing capsaicin for the management of post-surgical pain and 
osteoarthritis, solubilized capsaicin in polyethylene glycol (Hartrick et al., 2011).  The product was 
instilled in the 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 surfaces of cut 
tissue and bone. 
CA-008 was created to improve upon the solubility profile of capsaicin and allow for an aqueous 
formulation that could be simply infiltrated in the wound site to achieve a maximal effect.  The 
free base form of this molecule rapidly cyclizes at physiological pH to yield capsaicin and a cyclic 
urea, shown in the scheme below: 
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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, completely decomposes to capsaicin and CA-101 as the sole 
degradants. 
The cyclic urea formed, CA-101, has not been previously evaluated for biological activity and it 
was shown to be inactive.  While not a known compound in the literature, its safety was 
inherently evaluated in all nonclinical studies with CA-008.  The toxicokinetic profiles for CA-008, 
CA-101, and capsaicin were determined in GLP safety studies. 
The synthesis of CA-008 is relatively straightforward, and can be achieved in three synthetic steps 
from capsaicin starting material.  
The current form of CA-008 is a hydrochloride salt (HCl) in a crystalline powder. The HCl salt was 
chosen to provide a counter ion commonly used in injectable pharmaceutical products, and 
significant aqueous solubility (>50 mg/mL in deionized water). 
5.1.2. 
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 et al., 2012) 
and clinical studies (Savage  et al., 2009; Pollak et al., 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). Activation of TRPV1 receptor with an agonist such as 
capsaicin immediately results in hyperalgesia, erythema, and localized burning sensation.  
Subsequently, exposure of the receptor to capsaicin leads to a functional desensitization that 
results in less response to both spontaneous and evoked painful stimuli.  This desensitization 
leads to a sustained analgesia for a long period of time.  Given its rapid conversion to capsaicin, 
a similar profile would be expected following the administration of CA-008 alone. 
It is anticipated that CA-008 will be used with a standard of care multimodal analgesia (systemic 
medications +/- local anesthetic administered by regional block or local infiltration) to manage 
pain for the first 24 hours after which the TRPV1 agonism may provide adequate pain relief.  
Alternatively, CA-008 may be used with co-administration of other standard of care local 
anesthetics to improve analgesia in the initial hours after surgery.  Concentric is initially planning 
to confirm the efficacy of CA-008 as a monotherapy in combination with standard of care 
systemic analgesic therapy or peripheral nerve blocks for treatment of post-surgical pain for 
periods of up to 96 hours.  
5.1.3. 
Management of Acute Post-Operative Pain 
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 (Chou et al., 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 experience acute post-surgical pain 
and approximately 75% of those with post-surgical pain report the severity as moderate, severe, 
or extreme (Apfelbaum et al., 2003; Gan TJ et al., 2014). Evidence suggests that less than half of 
patients who undergo surgery report adequate post-surgical pain relief (Apfelbaum et al., 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 (Kehlet et al., 
2006).  The publication recommends strategies for the management of post-surgical pain ranging 
from preoperative education and perioperative pain management planning, multimodal 
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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 et al., 2012), and there is no ideal way to provide continuous, effective pain relief 
beyond 12 -18 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, especially due to 
known safety issues such as respiratory depression, gastrointestinal dysfunction, and abuse.  
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 et al., 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 with local anesthetics such as bupivacaine are attractive as a 
component of multi-modal 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 is highly effective, but limited due to its typically short duration of 
action.  
Liposomal bupivacaine (Exparel®) is approved for single-dose infiltration into the surgical site to 
produce post-surgical analgesia and is part of the current pain management approach for 
appropriate surgical procedures. 
5.1.4. 
Clinical burden and unmet need of current standard of care 
Opioids are often used to treat short and long-term pain or other indications, but have both 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 2013 there were 21,932 drug 
overdose deaths from prescription opioid analgesics, not including illicit drug use, and this 
number has increased significantly over time with increased use of opioid products to treat pain. 
During the past decade, prescription opioid use became more prevalent in the United States.  The 
death rate due to overdose of opioid analgesics increased considerably.  Each day according to 
statistics, 120 persons die from overdose in the United States and another 6,748 are treated in 
emergency departments for opioid misuse or abuse of drugs (1).  Of these overdose cases, in 
2013, 35,663 (81.1%) of the deaths caused by opioid overdose were a result of accidental 
overdose and unintentional.  Pediatric cases (children 18 or younger) account for approximately 
50,000 cases of opioid overdose a year and as many as 10,000 deaths. 
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. 
In addition, accidental or intentional overdose is a life-threatening situation in which severe 
respiratory depression can result in respiratory and cardiac arrest.  Those most at risk of opioid 
overdose are typically chronic users of opioids for chronic pain or those persons who become 
addicted to opioids either after initial legitimate use or from illicit use.  Risk increases when being 
treated with rotating opioid medication regimens, which may not allow for complete tolerance 
to develop to any one opioid.  The risk of opioid overdose is also increased with persons 
discharged from emergency medical care after opioid intoxication or poisoning, and with persons 
who combine legitimate use of opioids with illicit use. 
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As outlined above in Section 5.1.3 local anesthetics are effective in reducing post-surgical pain 
and the need for opioids, but have limitations.  Significantly pain relief is short term ranging from 
6 to up to 24 hours.  Repeat administration of local analgesics are also limited due to increasing 
toxicity and side effects.  Thus, while currently available local anesthetics are effective and 
appropriate for post-surgical treatment to manage pain for the first 24 hours after surgery, there 
is an unmet need for safe non-opioid analgesics that would provide pain relief for a period from 
24 to 96 hours post-surgery. 
5.1.5. 
Previous Human experience 
CA-008 has not been previously studied in humans. There is, however, clinical support for the 
potential safety and efficacy of capsaicin, the parent molecule released by CA-008 in vivo.  
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) and has 
been studied clinically for wound instillation for postsurgical analgesia (Anesiva; Adlea; capsaicin 
for instillation). 
5.2. 
Study Rationale 
CA-008 is being investigated as a potential therapy for treatment of pain following surgery.  In 
the rat paw incisional model for post-surgical pain, CA-008 and bupivacaine (243 mg in 0.25% 
bupivacaine and 1:200,000 epinephrine) administered by intraplantar injection demonstrated 
efficacy on days 1-2. A full battery of toxicology (with toxicokinetic analyses) and safety 
pharmacology studies have been conducted in two species, rat and beagle dog. In all of these 
studies, CA-008 was administered as a single dose by subcutaneous administration. CA-008 was 
well-tolerated in both species with no adverse effects. Additionally, the effect of CA-008 in wound 
healing was investigated in a rat osteotomy model (a single dose of CA-008 instilled on the 
femoral bone fracture) and in a pig wound healing model (a single dose of CA-008 administered 
by wound infiltration). CA-008 had no adverse effects on bone/wound healing in both studies. 
No repeat dose studies have been conducted so far.     
This first-in-human study will evaluate the safety and tolerability of CA-008 in subjects 
undergoing Unilateral Transpositional First Metatarsal Osteotomy for the Correction of Hallux 
Valgus Deformity, also termed Bunionectomy.  This study will allow for pharmacokinetic and 
pharmacodynamic (safety and preliminary efficacy) assessment of CA-008 in this study 
population in order to inform future clinical / surgical studies in our clinical development plan.  
CA-008 is administered (injected and instilled) directly into the postoperative wound during the 
surgery, and this study will also be looking at regional safety i.e. wound healing in a double-
blinded manner, utilizing study subjects in each dose cohorts that will receive either active or 
placebo treatment.  An independent DMC will be charged with evaluating the safety of each study 
dose, and will monitor / guide the planned dose escalation within the study. 
This study was originally designed  to look at four different doses of CA-008, and based on the 
overall safety and tolerability profile we expected to be able to select one or more doses for our 
planned phase 2 bunionectomy study.  This study was also intended to inform us about the 
potential regional safety and PK/PD profiles to be expected when CA-008 is used in the treatment 
of pain associated with other surgeries.   The goal from the beginning was to find the maximum 
tolerated and safe dose (volume/concentration) of CA-008. 
At this point, we have studied the first four cohorts and there have been no safety and tolerability 
concerns identified.  After discussion and presentation with the DMC, it was determined that it 
was safe to proceed to study a higher dose in Cohort 5.     
It should be noted, that the planned assessments and study of cohort 5 will be the same as that 
implemented in the study for the previous 4 cohorts.  This final cohort will also be presented to 
the DMC for final review / safety evaluation. 
 
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6. 
STUDY OBJECTIVES 
6.1. 
Primary Objectives 
The primary objectives of the study are:  
• 
To evaluate the safety and tolerability of a single intraoperative administration of CA-008 in 
subjects undergoing bunionectomy. 
• 
To evaluate the pharmacokinetics of a single intraoperative administration of CA-008. 
6.2. 
Secondary Objectives 
The secondary objective of the study is to evaluate the efficacy of CA-008 in the management of 
acute postoperative pain in subjects undergoing bunionectomy. 
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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design and Plan 
This is a single-center, randomized, double-blind, placebo-controlled, single ascending dose, 
sequential-group Phase 1 study. 
The study will be conducted utilizing a cohort design, with sequential groups of 8 subjects. Within 
each dose cohort, 6 subjects will be randomized to active, and 2 will be randomized to placebo. 
The initial cohort will receive the lowest planned dose of CA-008, and sequential cohorts will 
receive escalating doses of CA-008 in a fixed volume of administration. There will be at least a 6-
day period between dosing the last subject in a cohort and the first subject in the subsequent 
cohort, to evaluate safety prior to dose escalation (i.e., dosing in a given cohort may only proceed 
after all subjects in the previous cohort are discharged). Dose escalation rules will be protocol 
defined. 
Subjects will be undergoing unilateral transpositional first metatarsal osteotomy for the 
correction of hallux valgus deformity (bunionectomy). In accordance with standard of care, 
subjects will receive regional anesthesia (MAYO Block) utilizing 0.5% bupivacaine (up to 30 cc 
total). Prior to wound closure, 10 mL (for Cohorts 1-4) and 14 mL (for Cohort 5) of study drug will 
be injected into the soft tissues and periosteum of the surgical site. 
After the surgery, subjects will be monitored for 48 hours at the trial site. Safety and efficacy 
evaluations will be performed as described herein. Subjects will be required to meet certain pre-
specified criteria prior to discharge. 
7.1.1. 
Screening Phase (Day -28 to Day -1):   
Subjects requiring bunionectomy between the ages of 18 and 65 years, inclusive, will be screened 
for participation at the study site in the United States within 28 days of surgery/study drug 
administration. The following assessments will be completed: 
• 
Informed Consent 
• 
Inclusion / Exclusion 
• 
Demographics 
• 
Medical and surgical history 
• 
Prior/current medications 
• 
Physical Exam (PE)  
• 
X-ray of Surgical Site 
• 
Neurosensory Exam of the Foot / Great toe (bilateral) 
• 
Clinical laboratory tests (chemistry/coagulation, hematology, and urinalysis) 
• 
Urine Drug Screening (UDS)  
• 
Alcohol breath test 
• 
Serum Pregnancy test (FOCBP) 
• 
Surgical Site Assessment  
• 
Vital signs (resting blood pressure, resting pulse, oral temperature and resting respiration 
rate). Tests must be obtained after resting (seated/reclined) for ≥ 5 minutes. 
• 
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 
• 
Adverse Event (AE) Assessment 
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7.1.2. 
Day 1- Prior to surgery (baseline) up to the end of surgery   
7.1.2.1. 
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 28 days of screening. The following 
assessments will be performed: 
• 
Inclusion / Exclusion 
• 
Medical and surgical history 
• 
Prior medications 
• 
PE  
• 
Neurosensory Exam of the Foot / Great toe (bilateral) 
• 
Clinical laboratory tests (chemistry/coagulation, hematology, and urinalysis) 
• 
Urine Pregnancy test (FOCBP) 
• 
Urine Drug Screening (UDS)  
• 
Alcohol breath test 
• 
Blood draw for PK analysis 
• 
Vital signs (resting blood pressure, resting pulse, oral temperature and resting respiration 
rate). Tests must be obtained after resting (seated/reclined) for ≥ 5 minutes. 
• 
Subject pain assessment training 
• 
Surgical Site Assessment  
• 
AE Assessment 
• 
Randomize to treatment 
7.1.2.2. 
Surgery 
Subjects will then undergo primary, unilateral, transpositional first metatarsal osteotomy for 
correction of hallux valgus deformity. The bunionectomy surgery will be performed under light 
to moderate sedation which include propofol, fentanyl and/or midazolam.  Subjects will receive 
regional anesthesia (MAYO Block) utilizing 0.5% bupivacaine (up to 30 cc total).  The MAYO block 
should be done proximal to the surgical wound and should not involve the immediate area of the 
planned surgical incision. Upon completion of surgery, subjects will be observed for 48-hours in 
the clinic. AEs will be assessed during the surgery. 
7.1.3. 
Audio-Visual Recording 
As this is the first in human use of the study drug, CA-008, the Sponsor may wish to observe its 
intra-operative application by recording a number of the procedures and/or taking still images of 
the surgical site during the follow-up period. This will allow for review of the video/images at a 
later date to better understand the surgical injection technique and visual healing of the surgical 
site, and educate the study team on the procedure. 
During the informed consent process, subjects will be asked if they would like to participate in 
audio-visual recording of their surgery, or allow subsequent photographs to be taken. This is 
optional, and their response will in no way affect their inclusion in the study. Their response will 
be included on the ICF.  
If a subject agrees to participate, the sponsor may perform intra-operative audio-visual recording 
which will be focused only in the area where the study drug will be administered. The recording 
will start prior to the anticipated time of study drug administration and will end after the 
completion of study drug administration. Additionally, Site staff may take photographs of the 
surgical site during follow-up visits. 
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7.1.4. 
Administration of Study Medication 
Administration of the study drug into the surgical site:  A total of 10 mL (for Cohorts 1-4) and a 
total of 14 mL (for Cohort 5) of the investigative product will be administered into the surgical 
site as follows: 
• At time of closure of capsule: 
o Infiltration of deep soft tissue and capsule with a total of: 
▪ 6 mL volume for Cohorts 1-4  
▪ 9 mL volume for Cohort 5  
o Instillation at cut bone with a total of 2 mL volume for all Cohorts 
• Following closure of the capsule and prior to closure of the skin and subcutaneous layer:  
• Instillation of wound with 2 mL volume for Cohorts 1-4; study drug is applied to all 
exposed surfaces prior to subcutaneous and skin closure 
• Instillation of wound with 3 mL volume for Cohort 5; 2 mL of study drug will be instilled 
into the space under closed capsule, and 1 mL of study drug applied to all exposed 
surfaces prior to subcutaneous and skin closure) 
7.1.5. 
Time 0 will be defined as the time of completion of drug administration.Day 1 (Post-
Surgery) to Day 3 (Discharge) 
Following surgery, subjects will be transferred to the appropriate recovery unit where they will 
undergo an assessment of safety and efficacy over the next 48 hours. The schedule of 
assessments are as follows:  
• 
Pain intensity (assessed with NPRS): at 0.25, 0.5, 0.75, 1, 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 
44, and 48 hours after the administration of study medication. Assessments between the 
hours of 00:00 and 06:00 may be skipped if the subject is sleeping; however, consecutive 
assessments may not be skipped, and the Hour 12, Hour 24, and Hour 48 assessments must 
be completed even if the subject is asleep. 
• 
Vital signs: 0.5, 1, 1.5, 2, 4, 6, 8, 10, 12, 16, 20, 24, 28, 32, 36, 40, 44, and 48 hours after the 
administration of study medication. Assessments between the hours of 00:00 and 06:00 may 
be skipped if the subject is sleeping; however, consecutive assessments may not be skipped, 
and the Hour 12, Hour 24, and Hour 48 assessments must be completed even if the subject is 
asleep. 
• 
Physical exam: 1.0, 24, and 48 hours after the administration of study medication.  
• 
ECG: 1.5 hours after the administration of study medication.  
• 
Surgical Site assessment: 24 and 48 hours after the administration of study medication.  
• 
Neurosensory Exam of the Foot / Great toe (bilateral): 24 and 48 hours after the administration 
of study medication. 
• Clinical laboratory tests (chemistry/coagulation, hematology, and urinalysis): 1.5 hours after 
the administration of study medication. 
• 
 Blood draw for PK analysis: are at baseline (before dosing), and at 5 minutes, 15 minutes, 30 
minutes, 45 minutes, and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 16, 24, 36, and 48 hours after dosing. 
• 
Subjects with inadequately controlled pain may request rescue at any time; however, subjects 
will be encouraged to receive rescue medication only with an NPRS ≥ 4. Additionally, subjects 
should be encouraged to wait at least 1 hour after completion of surgery (i.e. completion of 
sutures) before utilizing pain rescue medication, if possible.  Pain intensity (NPRS) will also be 
completed within 15 minutes prior to use of pain rescue medication.    
• 
Concomitant medications. 
• 
All SAEs that occur from the time a subject's informed consent will be captured. All SAEs and 
non-serious AEs will be documented and followed from the time of administration of study 
drug. Non-serious AEs that occur between Screening and the study procedure should be 
considered medical history, and be added to the subject’s medical record.  
 
After completing the assessments through 48 hours after study medication administration, the 
diary for at-home use will be reviewed and subjects will be discharged from the study center with 
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diary to record pain assessments and pain medication at home.  Subjects will be provided routine 
standard of care for pain management after discharge from the study center.  Subjects will be 
instructed to return to the study center on Day 8 [±1 day] for follow-up assessments.  
7.1.6. 
Days 3 through 8: 
In their diary, subjects will assess their pain intensity once in the morning (08:00 ±4 hours), and 
once in the evening (20:00 ±4 hours) using the NPRS. Subjects will also record any medication 
they take to treat their pain, and will capture an additional NPRS within 15 minutes prior to each 
dose of pain medication. 
Subjects will return to the study center on Day 8 [±1 day] for the following assessments:  
• 
Subject home diary review (pain intensity and pain medication) 
• 
Pain Intensity (NPRS) 
• 
Vital signs 
• 
Surgical Site assessment 
• 
Neurosensory Exam of the Foot / Great toe (bilateral) 
• 
Concomitant Medication Use 
• 
AE Assessment 
• 
Brief Pain Inventory-Short Form (BPI-SF) 
• 
Patient Global Evaluation (PGE) 
• 
Investigator Global Evaluation (IGE) 
7.1.7. 
Days 9 through 15: 
In their take-home Diary, subjects will assess their pain intensity once in the morning (08:00 ±4 
hours), and once in the evening (20:00 ±4 hours) using the NPRS. Subjects will also record any 
medication they take to treat their pain. 
Subjects will return to the study center on Day 15 [±2 days] for the following assessments:  
• 
Subject home diary review (pain intensity and pain medication) 
• 
Pain Intensity (NPRS) 
• 
BPI-SF 
• 
PGE 
• 
IGE 
• 
Vital signs 
• 
Surgical Site assessment 
• 
Neurosensory Exam of the Foot / Great toe (bilateral) 
• 
Concomitant Medication Use 
• 
AE Assessment 
7.1.8. 
Day 29 / Early Termination 
Subjects will return to the study center on Day 29 [±2 days], or at the time of discontinuation, for 
the following assessments:  
• 
Subject home diary review (pain intensity and pain medication, if ET is ≤ Day 15) 
• 
Pain Intensity (NPRS) 
• 
BPI-SF 
• 
PGE 
• 
IGE 
• 
PE 
• 
Vital signs 
• 
X-ray of Surgical Site 
• 
Surgical Site assessment (when assessed, if the Investigator observes insufficient wound 
healing, the subject will be scheduled for a follow-up visit on Day 36. If the wound is 
considered healed at Day 29, Day 36 is not required.) 
• 
Neurosensory Exam of the Foot / Great toe (bilateral) 
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• 
Concomitant Medication Use 
• 
AE Assessment  
7.1.9. 
Day 36 (if required) 
If required due to insufficient wound healing noted at Day 29 visit, Subjects will return to the 
study center on Day 36 [±2 days] for the following assessments:  
• 
Surgical Site assessment 
• 
Neurosensory Exam of the Foot / Great toe (bilateral) 
• 
Concomitant Medication Use 
• 
AE Assessment 
7.1.10. 
Unscheduled Visit 
Assessments performed at Unscheduled Visits will be at the discretion of the Investigator. 
7.2. 
Discussion of Study Design 
This trial is designed to determine the recommended dose and define the toxicity profile of CA-
008.  
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 deformities 
of the first metatarsal and is used as a model to assess adequate duration of acute pain to 
measure multiple-day efficacy (Singla et al., 2013; Wang et al., 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) 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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8. 
SELECTION OF STUDY POPULATION 
8.1. 
Inclusion Criteria 
Subjects must meet all of the following criteria to be considered eligible to participate in the 
study: 
1. Male or female aged 18 - 65 years old, inclusive. 
2. Planning to undergo a primary unilateral first metatarsal bunionectomy repair, without 
collateral procedures. 
3. Be American Society of Anesthesiology (ASA) physical Class 1 or 2. Appendix J 
4. In good health and capable of undergoing a bunionectomy under regional anesthesia. 
5. No additional planned surgeries other than a bunionectomy during the course of the study. 
6. Male subjects must be either sterile (surgically or biologically), or commit to an acceptable 
method of birth control while participating in the study.   
7. Female subjects are eligible only if all of the following apply: 
a. Not pregnant (female subject of child bearing potential must have a negative serum 
pregnancy tests at screening and negative urine pregnancy test before surgery); 
b. Not lactating; 
c. Not planning to become pregnant during the study; 
d. Be surgically sterile; or at least two years post-menopausal; or have a monogamous 
partner who is surgically sterile; or is practicing double-barrier contraception; or 
practicing abstinence (must agree to use double-barrier contraception in the event of 
sexual activity); or using an insertable, injectable, transdermal, or combination oral 
contraceptive approved by the FDA for greater than 2 months prior to screening visits 
and commits to the use of an acceptable form of birth control for the duration of the 
study and for 30 days from completion of the study. 
8. Have a body mass index ≤ 35 kg/m2. 
9. Willing and able to sign the informed consent form (ICF) approved by the Institutional Review 
Board (IRB). 
10. Willing and able to complete the study procedures and pain scales, and to communicate 
meaningfully in English with study personnel. 
8.2. 
Exclusion Criteria 
Subjects will not be eligible to participate in this study if any one of the following exclusion criteria 
is met: 
1. Subjects with a history of hypertension, cardiovascular disease or a history of cerebrovascular 
events. 
2. Subjects with concurrent painful conditions that may require analgesic treatment during the 
study period, or, in the opinion of the Investigator, may confound post-operative pain 
assessments. 
3. Have been receiving or have received chronic opioid therapy defined as greater than 15 
morphine equivalents units per day for greater than 3 out of 7 days per week over a one-
month period within 12 months of study treatment initiation. 
4. Have a known allergy or intolerance to the following medications or related substances: 
capsaicin, chili peppers, propofol, bupivacaine, benzodiazepines, midazolam, oxycodone, 
fentanyl or ondansetron.  
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5. Have a clinically significant abnormal clinical laboratory test value that places the subject at 
undue risk according to the judgment of the investigator. 
6. Have, as determined by the investigator or the study’s medical monitor, a history or clinical 
manifestations of significant renal, hepatic, cardiovascular, metabolic, neurologic, 
psychiatric, or other condition that would preclude participation in the study. 
7. Use concurrent therapy that could interfere with the evaluation of efficacy or safety, such as 
any drugs which, in the investigator’s opinion, may exert significant analgesic properties or 
act synergistically with CA-008. 
8. Use of disallowed pain medications within 2 days prior to Day 1 (NSAIDs, COX-2 inhibitors, 
tramadol, ketamine, clonidine, gabapentin, pregabalin, or cannabinoids). 
9. Use of central nervous system (CNS) active drugs such as benzodiazepines, tricyclic 
antidepressants, SNRIs, or SSRIs for pain within seven days prior to Day 1. These drugs are 
permitted for non-pain indications if the dose has been stable for at least 30 days prior to Day 
1 and is planned to remain stable throughout the study. The use of lorazepam and other sleep 
medications, except those containing analgesic properties, is permitted. 
10. Have evidence of a clinically significant 12-lead ECG abnormality according to the judgment 
of the investigator, including QTcF >450 for men and >470 for women. 
11. Use of dietary supplements or over-the-counter (OTC) medications containing significant 
amounts of capsaicin within 1 day prior to Day 1, and throughout the hospitalization period. 
12. Subjects with active cutaneous disease, or other disease, at the anticipated site of surgery. 
13. History of peripheral vascular disease, sickle cell disease, vascular grafts, or vasospastic 
disorders. 
14. Use of parenteral or oral corticosteroid(s) within 14 days prior to Day 1. 
15. Known bleeding disorder or is taking agents affecting coagulation preoperatively. Deep 
venous thrombosis (DVT) prophylaxis of the surgeon’s choice is permitted postoperatively. 
16. A medical condition that in the investigator’s opinion could adversely impact the subject’s 
participation or safety, conduct of the study, or interfere with the pain assessments. 
17. Diabetes mellitus. 
18. Use of 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 throughout the study. 
19. Use of digoxin, warfarin (see exception below), lithium, theophylline preparations, 
aminoglycosides, and all antiarrhythmics except beta-blockers, and use of anticonvulsants 
except benzodiazepines within 7 days prior to Day 1 and throughout the study. (Use of 
warfarin is allowed, at the investigator’s discretion, for DVT prophylaxis after the surgery). 
20. History of illicit drug use, or prescription medicine or alcohol abuse (regularly drinks > 4 units 
of alcohol per day; 8 oz. beer, 3 oz. wine, 1 oz. spirits) within the past 2 years, in the opinion 
of the Investigator. 
21. Have positive results on the alcohol breath test indicative of alcohol abuse or urine drug 
screen indicative of illicit drug use (unless results can be explained by a current prescription 
or acceptable over-the-counter medication at screening as determined by the investigator) 
at screening, and/or prior to surgery. 
22. 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. 
23. Previously participated in a clinical study with CA-008 or capsaicin. 
24. Subjects with peripheral neuropathies which would potentially confound the planned 
neurosensory testing. 
25. Subjects who donated blood or plasma within the 30 days prior to screening. 
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8.3. 
Removal of Subjects from Therapy or Assessment 
A subject is free to withdraw his/her consent and discontinue participation in the study at any 
time for any reason. A subject’s participation must therefore be terminated immediately upon 
his/her request, and the reason(s) for discontinuation appropriately documented. 
A subject may be discontinued from the study for any of the following reasons: 
▪ Safety reasons, including AEs or significant concomitant illness, injury, or urgent 
surgeries/procedures that would, in the judgment of the Investigator, affect assessments of 
clinical status to a significant extent, require discontinuation of study drug, or both 
▪ At the request of the Sponsor, regulatory agency, or Institutional Review Board (IRB) 
▪ Subject is lost to follow-up 
▪ Subject treatment allocation is unblinded (i.e., individual code break; Section 9.6) 
▪ Death of subject 
A subject may also be discontinued from the study, at the discretion of the Investigator and/or 
Sponsor, for any of the following reasons:  
▪ Subject refuses or is unable to adhere to the study protocol 
▪ Major protocol violation 
▪ Pregnancy 
▪ Use of unacceptable concomitant medication(s) 
▪ It is not considered in the best interest of the subject to continue 
▪ Administrative reasons (e.g., termination of enrollment or study) 
The Investigator must maintain a record of all subjects who discontinue from the study prior to 
completion; the reason(s) for study discontinuation will be documented. In the event that a 
subject chooses to withdraw from the study, the Investigator should make a reasonable attempt 
to obtain and record the reason(s) for withdrawal in as much detail as possible, although the 
subject is not obligated to provide such a reason.  
In the event that a subject is discontinued while at the clinical site, the early termination 
procedures shown in the Schedule of Assessments (Table 1) should be performed prior to 
discharge from the clinical site. The Investigator should ask the subject to for the Follow-up 
procedures, provided that the subject has not withdrawn consent for those procedures. If a 
subject refuses to complete early termination/Follow-up procedures or continued data 
collection, this information will be recorded. 
8.4. 
Study Stopping Rules 
Dose escalation, or continuation of dosing, will not occur if subjects in a cohort experience 
intolerable treatment related AEs on active drug, as defined below: 
• 1 or more treatment-related AE of grade 4 or higher (per Table 2, Appendix G, or Appendix 
H); 
• 2 or more treatment-related AEs of grade 3 or higher (per Table 2, Appendix G, or 
Appendix H) 
 
 
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Table 2 Study Stopping Rules 
Category 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially Life 
Threatening  
(Grade 4) 
Abnormal 
Wound Healing: 
Infection 
Dehiscence 
Necrosis 
 
Mild symptoms; 
clinical or diagnostic 
observations only; 
intervention not 
indicated. No 
interference with age-
appropriate 
instrumental ADL 
Minimal, local or 
noninvasive 
intervention 
indicated; May 
require local wound 
care or medical 
intervention (e.g., 
dressings or topical 
medications) 
Severe or medically 
significant 
but not immediately life-
threatening; hospitalization 
or 
prolongation of existing 
hospitalization indicated; 
limiting ADLs. May require IV 
antibiotics, antifungals, or 
antivirals or radiologic 
intervention. 
Life-threatening 
consequences; 
urgent intervention 
indicated 
ECG/Cardiac 
issues 
Vital Signs 
Labs 
Asymptomatic, 
intervention not 
indicated 
 
Non-urgent medical 
intervention 
indicated 
 
Severe or medically 
significant 
but not immediately life-
threatening; hospitalization 
or 
prolongation of existing 
hospitalization indicated  
Life-threatening 
consequences; 
urgent intervention 
indicated 
Focused 
Neurosensory 
Testing 
(performed by 
trained 
Investigator) 
Mild symptoms  
 
Moderate symptoms; 
limiting instrumental 
ADL 
 
Severe symptoms requiring 
medical intervention; 
limiting self-care ADL 
Life-threatening and 
urgent 
intervention 
indicated 
8.5. 
Safety Oversight 
A Data Monitoring Committee (DMC) comprised of independent consultants with appropriate 
medical expertise will regularly monitor all aspects of patient safety throughout this study. The 
DMC will be responsible for adjudicating all available data in a blinded fashion (which may 
include: vital signs, ECGs, clinical laboratory tests, Surgical Site assessments, Neurosensory 
evaluations, incidence of SAE and TEAE) to assess the safety of each dose level of CA-008 prior to 
escalating to the next dose level. Details regarding the DMC will be included in the DMC Charter. 
8.6. 
Study Restrictions 
In addition to the criteria described in Sections 8.1 and 8.2, the subject must agree to abide by 
the following study restrictions:  
▪ Subjects will be asked to abstain from consuming more than 1 (women) or 2 drinks (men) per 
day of alcohol throughout the study. 
▪ Subjects will be asked to abstain from illicit drug use or non-medical use of therapeutic drugs 
throughout the study. 
▪ Subjects will be asked to abstain from taking prohibited medications described in Section 9.7 
throughout the study. 
 
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9. 
TREATMENTS 
9.1. 
Treatment Administration 
9.1.1. 
Study Medication 
The proposed doses of CA-008 to be evaluated in this study are: 
• CA-008, 0.5 mg in 10 mL of saline (50 μg/mL) 
• CA-008, 1.0 mg in 10 mL of saline (100 μg/mL) 
• CA-008, 2.0 mg in 10 mL of saline (200 μg/mL) 
• CA-008, 3.0 mg in 10 mL of saline (300 μg/mL) 
• CA-008, 4.2 mg in 14 mL of saline (300 ug/mL) 
 
In addition, saline for injection, USP will be used. 
The study drug is provided as a concentrate that will be diluted just before use in the surgical 
setting, 1:10 with saline for injection, USP.  The study drug will be stored at -20°C (-15°C to -30°C)   
until the day of surgery.  The study drug will be blinded before introduction to surgical setting. 
Note: Weights of CA-008 are provided for the free base, without counterions. The drug product 
uses CA-008 HCl as drug substance, the weights and concentrations of the drug product are 
shown based on the free base. 
9.1.2. 
Placebo  
The placebo will be 10 mL of saline for Cohorts 1-4, and 14 mL of saline for Cohort 5. 
The placebo is provided identical to the study drug, and will be “diluted” just before use in the 
surgical setting, 1:10 with saline for injection, USP.  The study drug will be stored at -20°C (-15°C 
to -30°C) until the day of surgery. The study drug will be blinded before introduction to surgical 
setting. 
9.1.3. 
Rescue Medications 
While in-clinic, subjects will be treated with the prescribed analgesic regimen (oxycodone 5 mg 
every 2 hours); however, if subjects do not get adequate analgesic relief they will be 
discontinued from the efficacy portion of the study. At this point, subject’s will receive standard 
of care analgesics (which may or may not include intravenous opioids). Regardless of 
discontinuation status, subjects will be followed for safety. Discontinuation affects the 
computation of the analgesic endpoint only. In previous post-operative Day 1 bunionectomy 
studies, oxycodone 5 mg every 2 hours has provided adequate analgesic relief to >90% of 
placebo subjects.  
Day 1: Hours 0-24 
• If needed for management of NPRS score of 4 or higher, oxycodone 5 mg every 2 hours. 
• An NPRS should be completed within 15 minutes prior to use of rescue medication. 
Day 2: Hours 25-48 
• If needed for management of NPRS score of 4 or higher, oxycodone 5 mg every 2 hours. 
• Subjects should complete their NPRS within 15 minutes prior to taking rescue medication. 
Day 3 - Day 15: 
• Over-the-counter standard of care analgesics may be used for management of pain.   
• If needed for management of NPRS score of 4 or higher, oxycodone 5 - 15 mg every 4 - 6 
hours. 
• Subjects should complete their NPRS within 15 minutes prior to taking rescue medication. 
Day 15 (post-visit) - Day 29/ET 
• Over-the-counter standard of care analgesics may be used for management of pain. 
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9.2. 
Identity of Investigational Product(s) 
9.2.1. 
Handling, Storage, and Accountability 
All study drug 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.  
All study drug should be stored in a secured area and in accordance with the product labeling 
and all applicable laws, regulations, and local/institutional requirements.  The Drug product will 
need to be stored at -20°C (-15°C to -30°C) in a freezer.  A description of storage conditions for 
all investigational products will be provided in the Pharmacy Manual. 
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. 
Mishandling, potential theft, significant loss of clinical supplies, including Investigational Product 
and Rescue Medication 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 product complaint form, including documenting if a subject sold drug or gave drug to a 
friend or relative, if there was a discrepancy in drug accountability and suspected diversion, if a 
subject had drug stolen, or if there was diversion or theft by site staff or others. 
9.2.2. 
Dispensing and Administration 
Only eligible subjects participating in the study will receive the study drug. Only authorized 
research site staff may supply, prepare or administer the study drugs. Once dispensed, study drug 
may not be relabeled or reassigned for use by other subjects.  
All study drug will be administered by designated blinded healthcare professional(s).  
9.3. 
Method of Assigning Subjects to Treatment Groups 
Randomization will be used to avoid bias in the assignment of subjects to treatments, to increase 
the likelihood that known and unknown subject attributes (e.g., demographics, baseline 
characteristics) are evenly balanced across treatment groups, and to enhance the validity of 
statistical comparisons across treatment groups.  
Subjects who have provided written informed consent will be assigned a unique number in the 
screening process. This number will be used to identify the subject throughout the study. 
There will be up to 5 cohorts of subjects, each cohort consisting of 8 subjects.  Cohorts of subjects 
will be randomized to either the following active medications or placebo in a 3:1 ratio.  The first 
4 subjects in cohort one will be dosed initially before the remaining 4 subjects are dosed. Three 
of these subjects will randomly receive active treatment and 1 will be randomized to placebo.  If 
the safety assessments are acceptable through the first 24 hours, then the second group of 4 
subjects will be dosed.  Three of these subjects will randomly receive active treatment and 1 will 
be randomized to placebo. 
Once any subject number or randomization number is assigned, it cannot be reassigned to any 
other subject. This study will use central randomization, as described in Section 10.2. 
Subjects may be rescreened if the screening window is exceeded due to scheduling issues.  
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9.4. 
Selection of Doses 
9.4.1. 
 Dose Rationale   
In Good Laboratory Practice (GLP) toxicology studies conducted, the NOAEL was identified as 1.5 
mg/kg in the rat and 0.25 mg/kg in the dog.  The estimation of the maximum safe starting dose 
for the first-in-human (FIH) study followed the procedure proposed in the FDA Guidance for 
Industry document “Estimating the Maximum Safety Starting Dose in Initial Clinical Trials for 
Therapeutics in Adult Healthy Volunteers” (FDA, 2005).  Using a conversion factor of 6.2 for rat 
and 1.8 for dog, the human equivalent dose (HED) is:  
• Rat HED = 1.5/6.2 = 0.24 mg/kg 
• Dog HED = 0.25/1.8 = 0.14 mg/kg 
The most relevant and sensitive species was determined to be the dog (HED = 0.14 mg/kg).  Using 
the recommendation of 1/10th of the HED, a safe starting dose for an FIH would be 0.014 mg/kg.  
In a 60 kg person, this supports a conservative starting dose of 0.84 mg with a maximum dose of 
8.4 mg.  The clinical dosing is based on CA-008 and not the salt form.  Converting the starting 
dose to the free base results in a conservative starting dose of 0.77 mg with a maximum dose of 
7.7 mg.   
As presented in Table 3, Concentric will round down to 0.5 mg as a starting dose and dose 
escalate to up to 3 mg (cohorts of 0.5, 1, 2, and 3 mg).  The 0.5 mg starting dose represents a 
safety margin from 15.4 at the low dose and the 3 mg maximum dose planned represents a safety 
margin of 2.6 at the high dose.  The rationale to dose escalate to a maximum of 3 mg is based on 
published clinical data with Capsaicin that demonstrates that this dose should achieve a maximal 
pharmacologic effect while remaining tolerable.  Specifically, studies performed by Anesiva using 
capsaicin for wound instillation in hernia (Aasvang et al., 2008 and 2010) and bunionectomy 
(Pollak et al., 2009). 
Table 3 Human Equivalent Dose and Safety Margins for the CA-008 Starting Dose 
NOAEL 
(mg/kg) 
HED 
(mg/kg) 
HED for CA-
008 HCl1 
(mg) 
HED for free 
base1 
(mg) 
Proposed 
Human Clinical 
Dose (mg) 
Safety Margin 
of FIH Dosing 
0.25 
0.14 
8.4 
7.7 
0.5 
15.4 
1 
7.7 
2 
3.9 
3 
2.6 
4.2 
1.8 
1 
Based on a 60 kg human 
Thus, the safety of CA-008 was established in relevant animal models and is partially based on 
knowledge from prior human studies with Capsaicin.  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 0.5 mg/person and 
a maximum dose of 4.2 mg/person, has a minimal risk of causing adverse events.  Taken together, 
the characterization of the pharmacology, pharmacokinetics, and toxicology profiles are 
considered sufficient to support the intended use of CA-008 in the initial Phase 1 study for the 
treatment of acute post-surgical pain. 
9.5. 
Selection and Timing of Dose 
CA-008 is a pH labile prodrug of capsaicin that rapidly releases capsaicin after administration into 
tissue.   Decision for single administration at the time of surgery is based on capsaicin’s 
mechanism of action. Capsaicin exposure results in initial excitation followed by a functional 
desensitization of TRPV-1-expressing nociceptors which continues for some time after removal 
of capsaicin from the site.   Administration while the patient is under anesthesia for the procedure 
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addresses the pain that results from TRPV1 agonism.  Administration of CA-008 during the closure 
process is ideal for delivering therapy to the surgical site, thus optimizing target engagement.  
During closure, the surgical tissue is exposed and visible we can ensure that we have complete 
and adequate delivery of drug to the potential areas where pain is being generated. 
What is unknown is whether CA-008 will behave the same as Capsaicin, however we expect that 
it will.  To this end, administration methods that were followed in previous successful post-
surgical pain studies will be applied in this 1st in man study. 
9.6. 
Blinding 
In order 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.  
Under normal circumstances, the blind will not be broken until all participants have completed 
treatment. In case of emergency, and only if the information is required by the Investigator to 
ensure subject’s safety in managing a medical condition, the treatment may be unblinded at the 
site by using a code break module.  The code break module will be provided by the Sponsor or 
designee. If possible, the Investigator should contact the Sponsor prior to unblinding and after 
any actions have been taken. Whenever a treatment sequence is prematurely unblinded, the 
reason, date and time of the unblinding, and the individual who broke the blind must be 
documented. Individual code breaks will result in withdrawal of the participant from the study. 
Safety reviews of cohorts of subjects will be performed in a blinded manner unless the data 
warrant unblinding due to safety concerns.  It is assumed that the need to unblind a study 
subject’s treatment assignment will occur in the setting of an SAE, and therefore, all procedures 
for the reporting of a SAE must be followed (see Section 11.1.3). 
9.7. 
Prior and Concomitant Therapy 
All non-study medications, including prescription, over-the-counter, or herbal therapies, used by 
the subject will be documented for the 30 days prior to Screening and throughout the study. The 
Investigator will determine if the prior/concomitant medication(s) affect the subject’s eligibility 
to participate or continue to participate in the study. The following concomitant medications and 
therapies may be permitted during the study: 
▪ Rescue medication, as described in Section 9.1.3 
On a case-by-case basis, the Investigator is permitted to allow the use of some concomitant 
medications, for example, to treat an AE, as long as the Investigator determines that the 
medication will not affect the subject’s safety or study integrity (e.g., topical medications). 
Wherever possible, the Investigator should obtain approval from the Medical Monitor prior to 
administering the medication.  
9.8. 
Treatment Compliance  
Because all study medication is being administered by study personnel, no compliance 
procedures are necessary. Diversion will be monitored and recorded through rescue medication 
accountability. Any suspected or confirmed diversion will be documented and reported. 
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10. 
STUDY PROCEDURES AND ASSESSMENTS 
All study assessments will be performed at the visits and timepoints outlined in the Schedule of 
Assessments (Table 1); the following sections outline the details and procedures associated with 
the assessments.  
10.1. 
Demographics and Other Baseline Characteristics 
10.1.1. 
Informed Consent 
The nature of the study and its risks and benefits will be explained to the subject by the 
Investigator or designated study personnel. The subject must voluntarily provide written 
informed consent on an ethics-approved informed consent form (ICF), prior to performing any 
study-related procedures. The subject’s medical records must document that the consent 
process has been completed and that written informed consent has been obtained from the 
subject prior to the initiation of any study-specific procedures. Documentation that the subject 
was given adequate time to ask the Investigator (or designee) questions about their participation 
in the study and that a signed and dated copy of the ICF was provided to the subject should also 
be included in the medical records or clinical chart. 
10.1.2. 
Demographics 
The following demographics will be recorded: age (birthdate), sex, race, and ethnicity.  
10.1.3. 
Medical and Surgical History 
The complete medical and surgical history will include histories of acute, chronic, or infectious 
disease; surgical or oncologic histories; and any reported conditions affecting major body 
systems. All findings on medical history will be evaluated by the Investigator for clinical 
significance. 
10.1.4. 
Medication History  
All medications (prescription and non-prescription, herbal medications/natural health products, 
or investigational drugs) taken by the subjects during the 30 days prior to Screening will be 
recorded in the source documentation as medication history.  
10.1.5. 
Contraceptive Requirements 
Female subjects of childbearing potential must be using and willing to continue using medically 
acceptable contraception during the study. Examples of medically acceptable forms of 
contraception include true abstinence, hormonal contraceptives (combined oral pill, patch or 
vaginal ring, intrauterine device or system, progestin implant or injection), bilateral tubal ligation, 
or double-barrier methods (i.e., male condom in addition to a diaphragm or a contraceptive 
sponge).  
Female subjects of non-childbearing potential are not required to use contraception or undergo 
pregnancy tests; however, they must be surgically sterile (hysterectomy and/or bilateral 
oophorectomy/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 2 years without another cause. 
10.2. 
Eligibility Review and Randomization 
Prior to randomization, subjects must meet all inclusion and not meet any exclusion criteria as 
outlined in Sections 8.1 and 8.2. 
The Investigator or designee must document that the subjects meet each individual criterion via 
a signed note or eligibility and inclusion/exclusion checklist during Screening and at Day 1 prior 
to surgery. Signatures on these documents must be dated on or before the date of randomization 
on the day of surgery.  
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Randomization will be accomplished manually. 
10.3. 
Subject Pain Assessment Training 
Subjects will undergo study participation education on pain assessments and written testing 
procedures according to the Schedule of Study Procedures. 
10.4. 
Efficacy Assessments 
Details regarding primary and secondary endpoints are provided in Section 10.6 (Efficacy 
Variables); and discussed further in Section 13 (Statistical Analysis). The following sections 
provide an overview of the efficacy assessments included in the study.   
10.4.1. 
Numerical Pain Rating Scale (NPRS) for Pain Intensity 
The NPRS is an 11-point scale with anchors 0 (no pain) and 10 (worst possible pain) (Appendix B;  
Ferreira-Valente MA et al., 2011; Hjermstad MJ, 2011). Subjects will record the intensity of their 
current pain at the following times over the initial 48-hour period in a diary:  at 0.25, 0.5, 0.75, 1, 
2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, and 48 hours after the administration of study medication 
and within 15 minutes prior to use of pain medication. Subjects should be at rest for at least 10 
minutes prior to completing NPRS assessments. NPRS Assessments between the hours of 00:00 
and 06:00 may be skipped if the subject is sleeping; however, consecutive assessments may not 
be skipped, and the Hour 12, Hour 24, and Hour 48 assessments must be completed even if the 
subject is asleep. There will be a ±5 minute window allowed for the collection of each pain 
intensity assessment in the first 4 hours after the end of surgery, after which will be a ±15 minute 
window allowed. 
 
After discharge and through Day 15, subjects will rate their pain intensity using the NPRS once in 
the morning (08:00 ±4 hours) and once in the evening (20:00 ±4 hours), and will capture an 
additional NPRS within approximately 15 min prior to each dose of pain medication.  Subjects will 
also rate their pain intensity using the NPRS at the Day 8, Day 15 and Day 29/Early Termination 
(ET) visit. 
10.4.2. 
Patient Global Evaluation (PGE) 
At the clinic visits on Day 8, Day 15 and Day 29/ET, each subject will be asked to report their 
satisfaction with the study treatment for pain using a 4-point scale Each subject will be asked the 
following question: How would you rate the study medication that you have received for pain? 
Poor (0), Fair (1), Good (2), or Excellent (3). Appendix E 
10.4.3. 
Investigator Global Evaluation (IGE) 
At the clinic visits on Day 8, Day 15 and Day 29/ET, the investigator will report their satisfaction 
with the subject’s study treatment for pain using a 4-point scale.  A study Investigator will be 
asked the following question: How would you rate the study medication that the patient received 
for pain? Poor (0), Fair (1), Good (2), or Excellent (3). Appendix F 
10.4.4. 
Brief Pain Inventory-short form (BPI-SF) 
At the clinic visits on Day 8, Day 15 and Day 29/ET, the Brief Pain Inventory- Short Form be 
assessed. Appendix D 
10.4.5. 
Rescue Medications 
The details of rescue medication will be recorded beginning from the end of surgery through 14 
days after the end of surgery (Day 15 visit) or to Early Termination Visit. Subjects will be instructed 
on the proper use and timing of rescue medication.  
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10.5. 
Safety Assessments 
Safety monitoring will be performed throughout the study for all subjects. All AEs, regardless of 
causality or severity, will be recorded on the AE CRF. 
10.5.1. 
Clinical Laboratory Assessments 
All protocol-specified laboratory tests on blood and urine samples will be performed at a selected 
central laboratory. The lab will generate laboratory reports and forward them to the clinical site 
in a timely manner. It is the responsibility of the Investigator to review and sign all lab reports 
expeditiously, in order to document appropriate safety monitoring of study subjects. The 
Investigator should sign and date each lab report concurrent with her or his review, and should 
indicate the clinical significance of each abnormal/flagged value by noting “NCS” (not clinically 
significant) or “CS” (clinically significant), for example. Notations indicating that a value is 
clinically significant should also include a brief description of the underlying disease or condition 
that is associated with the value, e.g., “CS/mild anemia.” In general and as determined by the 
investigator, abnormal, clinically significant laboratory values are expected to be associated with 
an item recorded in medical history or with an AE. 
Blood and urine samples will be collected, processed, and shipped according to instructions from 
the safety laboratory. Additional laboratory samples may be taken at the discretion of the 
Investigator if the results of any tests fall outside reference ranges or clinical symptoms 
necessitate testing to ensure safety. Specific hematology, coagulation, biochemistry, and 
urinalysis assessments are listed in Table 4. 
Table 4 Clinical Laboratory Assessments 
Hematology 
Biochemistry 
Urinalysis 
Hematocrit 
Hemoglobin 
Red blood cell (RBC) count  
Total and differential (absolute) 
white blood cell count 
Platelet count 
Sodium 
Potassium  
Calcium  
Chloride 
Glucose   
Creatinine 
Blood urea nitrogen (BUN) 
Albumin 
Total bilirubin 
Direct bilirubin 
Alanine aminotransferase (ALT) 
Aspartate aminotransferase (AST) 
Lactic dehydrogenase (LDH) 
Gamma-glutamyl transferase (GGT) 
Alkaline phosphatase  
Uric acid 
 
Color 
Turbidity 
pH 
Specific gravity 
Ketones 
Protein 
Glucose 
Bilirubin 
Blood Nitrite 
Urobilinogen 
Leukocyte esterase 
Microscopic examination of 
sediment, only if urinalysis 
dipstick results are abnormal 
 
 
Coagulation 
Activated partial 
thromboplastin time (aPTT) 
Prothrombin time (PT) 
International normalized ratio 
(INR) 
 
The clinical laboratory tests will be completed at Screening, Prior to surgery, and at 1.5 hours 
(±0.5 hour) after the administration of study medication.  In addition to the clinical laboratory 
tests, a serum pregnancy test will be performed at the Screening Visit and a urine pregnancy test 
will be performed prior to surgery for women of childbearing potential. ALT or AST > 3x ULN / 
Tot. Bili > 2 X ULN/ Alk Phos. >2X ULN will be considered an adverse event, as well as any other 
changes deemed clinically significant by the Investigator.  
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10.5.2. 
Urine Drug Screen and Alcohol Breath Test 
Urine drug screen and alcohol breath tests will be completed at screening and pre-procedure. All 
subjects will be tested for drugs-of-abuse (i.e. amphetamines, barbiturates, benzodiazepines, 
cocaine, opiates, phencyclidine, tetrahydrocannabinol, methadone, methamphetamine, tricyclic 
anti-depressants, oxycodone and propoxyphene). 
 
The drug and alcohol screens will be performed in-house at the Clinical Unit. If any of these tests 
are positive, the subject will not be allowed further participation in the trial. However, a positive 
test may be repeated at the discretion of the PI.  
10.5.3. 
X-Ray 
An X-ray of the surgical site will be performed during screening and at Day 29/ET. 
10.5.4. 
Vital Signs 
Vital signs will consist of temperature, blood pressure (systolic and diastolic blood pressure, 
mmHg), pulse rate (beats per minute), and respiratory rate (breaths/min) collected while sitting, 
following a rest period of at least 5 minutes. Vital signs will be assessed at Screening, Prior to 
Surgery, and then 0.5, 1, 1.5, 2, 4, 6, 8, 10, 12, 16, 20, 24, 28, 32, 36, 40, 44, and 48 hours after 
the administration of study medication.  Vital sign assessments between the hours of 00:00 and 
06:00 may be skipped if the subject is sleeping; however, consecutive assessments may not be 
skipped, and the Hour 12, Hour 24, and Hour 48 assessments must be completed even if the 
subject is asleep. 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. 
Vital signs will also be assessed on the Days 8, 15 and 29 Follow-up (or at the time of 
discontinuation).  Elevated BP will be defined as SBP > 150 / DBP >95; depressed SBP will be 
defined as <90; Elevated HR will be defined as HR > 100 / min). If one or more of these 
measurements is met, and in the opinion of the Investigator is considered clinically significant, it 
will be considered an adverse event.  
10.5.5. 
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, QTcB 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, prior to 
surgery, and at 1.5 hours (± 0.5 hour) after the administration of study medication. Clinically 
significant changes in ECG (i.e., QTCf should be <450 msec / < 470 msec for Female / Male subjects 
respectively; increase of QTCf of 30msec or greater, as well as any other changes as deemed by 
the Investigator) will be considered an adverse event. 
10.5.6. 
Physical Examination 
A complete physical examination including all major body systems (HEENT, neurologic, 
cardiovascular, respiratory, gastrointestinal, dermatologic and musculoskeletal systems) will be 
performed at Screening, prior to Surgery, and on the Day 29/ET. In addition, at the following 
times, an abbreviated review of systems will be performed to capture changes since Surgery: 1 
hour (± 30 minutes), 24 hours (± 2 hours), and 48 hours (± 4 hours) after the administration of 
study medication. 
Body weight (kg), in indoor clothing, but without shoes, will be measured at Screening, on Day 3 
(48 hours) and Day 29/ET.  Height in centimeters (cm) will be measured, and BMI will be 
calculated at Screening only. BMI shall be calculated as kg/m2.  The site should use the NIH 
website BMI calculator http://www.nhlbi.nih.gov/health/educational/lose_wt/BMI/bmi-m.htm. 
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10.5.7. 
Surgical Site Assessment  
Surgical Sites should be assessed to determine if any site related AEs have occurred.  Assessments 
will be conducted at screening, baseline and then at 24 hours (±2 hours) and 48 hours (±4 hours) 
after the administration of study medication.   During the first 48 hours, 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 C 
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 I 
If there are skin reactions, for example, erythema, pain, pruritus, bruising, swelling, bruising or 
other skin changes, they will be evaluated and graded for severity regularly until resolution. 
10.5.8. 
Neurosensory Exam 
A Neurosensory Exam of the Foot and Great toe (bilateral) will be conducted at screening, 
baseline and then at 24 hours (±2 hours) and 48 hours (±4 hours) after the administration of study 
medication. The exam will involve the dorsal aspect of the great toe, midway between the nail 
fold and the DIP joint.  
This evaluation will include the following (details described in Appendix K): 
• Visual exam of the foot 
• Deep Tendon Reflexes (normal, reduced or absent) 
• Vibratory sensation (normal, reduced or absent) 
• Monofilament Sensation (normal, reduced or absent) 
• Allodynia to brush (pain (allodynia), hyperesthesia, normal, reduced or absent) 
• Hyperalgesia to pin (increased pain (hyperalgesia), hyperesthesia, normal, reduced or 
absent) 
The Neurosensory Exam will also be performed at each of the Follow-up visits on Days 8, 15 and 
29, or at the time of discontinuation, and on Day 36, if the visit is needed. Appendix A 
A persistent sensory change after 3 days, such as allodynia or hyperalgesia will be reported as 
an AE.  Numbness at or near the incision need not be considered an AE since this could occur as 
a result of tissue trauma and inflammation from the surgery. 
10.5.9. 
Assessment of Adverse Events 
All SAEs will be documented and followed from the time the subject has signed the ICF until Day 
29 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 drug until Day 29 or, if 
necessary, Day 36 after the completion of surgery. AEs that occur between Screening and the 
study procedure should be considered medical history, and be added to the subject’s medical 
record. Serious AEs and AEs that have been designated as possibly related to study drug will be 
followed until resolution or stabilization. Further details on AEs, including definitions, elicitation, 
and reporting are provided in Section 11. 
10.5.10. 
Pharmacokinetic Assessments 
The time points for collection are at baseline (before dosing), and at 5 minutes, 15 minutes, 30 
minutes, 45 minutes, and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 16, 24, 36, and 48 hours after dosing. 
There will be a ±2 minute window allowed for the 5 and 15 minute collections, a ±5 minute 
window allowed for collections through 4 hours, and a ±15 minute window for collections 
through 48 hours. 
10.5.11. 
Processing, Storing, and Shipping of Pharmacokinetic Samples 
The time points for bioanalytical samples are the following: Baseline (before dosing), and at 5 
minutes, 15 minutes, 30 minutes, 45 minutes, and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 16, 24, 36, and 
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48 hours after dosing.  Two bioanalytical samples will be drawn at each specified time point, 
described below: 
10.5.11.1. Samples for quantitation of CA-008, Capsaicin, and CA-101: 
This sample will be the first bioanalytical sample drawn at each time point.  The blood collection 
tubes for these samples will be 6 mL, plastic vacutainer tubes with K2EDTA.  The tubes will be pre-
loaded with citrate buffer and stored as described in the Clinical Laboratory Manual.  Prior to use, 
the tubes will be placed in wet ice for at least 30 minutes.  Sample, with a target blood volume 
of 6 mL, will be drawn using a catheter set for sterility purposes. 
 
Immediately after the collection of each sample, the collection tube will be gently inverted 8-10 
times, and then placed in wet ice. Within 30 minutes of withdrawal, the tubes will be centrifuged 
at about 1300 x gravity ± (100 x gravity) (e.g. 2500 rpm for 19 cm rotor radius) for 10 minutes at 
4°C to separate the cells from the plasma. No aids for separation will be used. Two aliquots of 
plasma will be transferred from each sample with clean pipettes and placed in two labeled 
polypropylene cryogenic storage tubes. The plasma samples should contain at least 500 µL in the 
primary sample and the remaining volume in the secondary sample, with a goal of approximately 
equal volume in each cryovial in the case that over 1 mL of the plasma is divided.  The cryogenic 
storage tubes will be labelled with the following information: protocol number, randomization 
number, sample timepoint, subject initials, and biologic matrix to be analyzed (e.g. K2EDTA 
plasma). Cap and place the tubes immediately into the freezer or hold on dry ice. Within 60 
minutes of the collection time, the storage tubes will be placed into a freezer at approximately -
20°C (-15°C to -35°C).  They will remain in the freezer until shipped. At a time designated by the 
sponsor, the samples will be packed with sufficient dry ice to keep them frozen for at least 48 
hours and shipped to the bioanalytical facility. On the day prior to shipment, clinical staff will 
notify (via email) the analytical laboratory of the pending shipment and provide the tracking 
number information.  The address will be provided in the Clinical Laboratory Manual. 
 
These samples will be analyzed for quantitation of CA-008, capsaicin, and CA-101.  These samples 
also will be analyzed for capsaicin-glucuronide metabolite. 
10.5.11.2. Samples for exploratory analysis of Capsaicin-glucuronide metabolite: 
A separate sample will be drawn second at each time point defined in section 10.5.10 for an 
exploratory analysis of the metabolite Capsaicin-glucuronide.  This method is currently qualified 
but has not been fully validated and thus will be considered an exploratory PK assessment.  The 
blood collection tubes for these samples will be 4 mL, plastic vacutainer tubes with K2EDTA.  Prior 
to use, the tubes will be placed in wet ice for at least 30 minutes.  Sample, with a target blood 
volume of 4 mL, will be drawn using standard techniques.  The processing and shipping 
instructions are analogous to those for the samples for quantitation of CA-008, Capsaicin, and 
CA-101. 
 
Samples previously collected by this approach will not be analyzed for capsaicin-glucuronide (see 
Section 10.5.11.1), and future patients in the study will not have these samples collected.   
10.6. 
Efficacy and Safety Variables 
10.6.1. 
Safety Endpoints 
Safety endpoints include the following: 
• Incidence of TEAEs 
• Clinical laboratory test results 
• Vital sign measurements 
• Electrocardiogram (ECG) results 
• Physical Exam findings  
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• Surgical Site assessment findings 
• Neurosensory Exam results 
• Concomitant medications 
10.6.2. 
Pharmacokinetic Endpoints 
Planned pharmacokinetic endpoints will be described in a separate PK Analysis Plan.  
10.6.3. 
Efficacy Endpoints 
The following endpoints will be explored for efficacy: 
1. Area-under-the-curve (AUC) over various time points using NPRS score (0–10), with 
adjustment for use of analgesic medication. 
2. Mean average daily NPRS score of 2 daily diary assessments (once in the morning (08:00 ±4 
hours), and once in the evening (20:00 ±4 hours)) 
3. Mean daily opioid consumption (in morphine equivalents) 
4. Proportion of patients who drop out of the study due to inadequate analgesia from Day 1 to 
15. 
5. Brief Pain Inventory-short form (BPI-SF) scores at the Day 8 (Week 1), Day 15 (Week 2) and 
Day 29 (Week 4) clinic visits. 
6. Patient Global Evaluation (PGE) and Investigator Global Evaluation (IGE) at the Day 8 (Week 
1), Day 15 (Week 2) and Day 29 (Week 4) clinic visits. 
7. Investigator Global Evaluation (IGE) at the Day 8 (Week 1), Day 15 (Week 2) and Day 29 (Week 
4) clinic visits. 
 
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11. 
ADVERSE EVENTS, SERIOUS ADVERSE EVENTS, AND SERIOUS 
SUSPECTED ADVERSE REACTIONS 
11.1. 
Adverse Events and Serious Adverse Events 
The following definitions, developed in accordance with the United States (US) Code of Federal 
Regulations (CFR) and the International Conference on Harmonization (ICH) Clinical Safety Data 
Management Guidance for Industry, E2A, will be used for the purpose of identifying AEs in this 
clinical 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. 
11.1.1. 
Relationship to Study Drug 
An Investigator who is qualified in medicine 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 
investigational product.  For purposes of the definitions below, “temporal sequence” is defined 
as an association between administration of a drug and the observed reaction or event such that 
the drug was present prior to the reaction or event. 
 
Causality Category 
Description 
Unlikely 
A clinical event, including laboratory test abnormality, with a temporal 
relationship to drug administration which makes a causal relationship 
improbable, and in which other drugs, chemicals or underlying disease 
provide plausible explanations. For the purpose of this protocol, the 
term unlikely will be considered not related to study medication and an 
“Adverse Event”. 
Possible 
A clinical event, including laboratory test abnormality, with a 
reasonable time sequence to administration of the drug, but which 
could also be explained by concurrent disease or other drugs or 
chemicals. Information on drug withdrawal may be lacking or unclear. 
For the purpose of this protocol, an event that has possible relationship 
to study medication will be defined as a “Suspected Adverse Drug 
Reaction”.  
Probable 
A clinical event, including laboratory test abnormality, with a 
reasonable time sequence to administration of the drug, unlikely to be 
attributed to concurrent disease or other drugs or chemicals, and 
which follows a clinically reasonable response on withdrawal. For the 
purpose of this protocol, an event that has probable relationship to 
study medication will be defined as an “Adverse Drug Reaction”. 
 
11.1.2. 
Adverse Event Reporting 
All AEs must be entered on the AE CRF, regardless of causality or severity. AEs include new AEs, 
worsening baseline conditions, clinically significant laboratory findings, disease-related signs and 
symptoms that were not present at baseline, and any events or findings that the Investigator 
feels are clinically significant. 
Disease-related signs and symptoms that are present at baseline should not be recorded as AEs 
unless they worsen in severity or increase in frequency. 
 
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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 drug 
▪ Action and outcome 
▪ Seriousness of event 
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 drug until Day 29 or, 
if necessary, Day 36 after the completion of surgery. AEs that occur between Screening and the 
study procedure should be considered medical history, and be added to the subject’s medical 
record. Serious AEs and AEs that have been designated as possibly related to study drug will be 
followed until resolution or stabilization. 
11.1.3. 
Serious Adverse Event (SAE) 
An SAE or reaction is any adverse drug experience occurring at any dose that results in any of the 
following outcomes: 
▪ Death 
▪ Is life-threatening (at the time of the event) 
▪ Requires subject hospitalization or prolongation of existing hospitalization, 
▪ Results in persistent or significant disability/incapacity 
▪ Is a congenital anomaly/birth defect (in an offspring) 
▪ An Important medical event that may not result in death, be life-threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical judgment, 
the event may jeopardize the subject and/or may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition. 
All AEs requiring hospitalization or prolongation of a pre-existing hospitalization should be 
reported as SAEs unless they occur greater than 14 days after the Day 29 visit, or 21 days after 
early termination AND are not considered to be study drug-related by the Investigator. 
Hospitalizations meeting the following criteria will not be reported as an SAE but must be 
recorded on the appropriate CRF: study specified hospitalization, short-term administrative 
hospitalization for procedures, tests or treatments of conditions that would not otherwise 
constitute an SAE, elective hospitalizations. 
11.1.3.1. Serious Adverse Event Reporting 
Serious AEs must be reported to the Sponsor or designee within 24 hours of knowledge of the 
event. All SAEs that occur while a subject is receiving study drug and within 14 days following the 
Follow-up visit (or 21 days following early termination) are reportable within 24 hours. During 
the follow-up period beyond 14 days from Follow-up (or 21 days following early termination), 
only those SAEs that are considered to be possibly related to study drug should be reported 
within 24 hours. 
 
 
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The procedure for reporting an SAE is as follows: 
▪ All SAEs must be reported immediately (within 24 hours of discovery) by email to the Medical 
Monitor or designee. Calls related to SAEs should first be directed to the Medical Monitor or 
designee.  
Medical Monitor: Jon L. Ruckle, MD, CPI  
24/7 Emergency contact: 808-349-9812  
SAE Reporting email: MedicalMonitorCA-PS-2017-101@Lotuscr.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 drug was discontinued 
o Investigator’s assessment of causality 
The 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/Independent Ethics Committee (IEC) of the occurrence of and details 
surrounding the event. In the event there is a question as to whether the AE is serious, the event 
should be reported. 
11.2. 
Pregnancy 
In the event that a female subject does become pregnant at any time during the study, the 
Investigator must notify the 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 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 Medical Monitor or designee. Any premature termination of the pregnancy will also be 
reported on this form. Although pregnancy occurring in a clinical study is not considered to be an 
SAE, any pregnancy complication or elective termination of a pregnancy for medical reasons will 
be recorded as an AE and will be followed as such. A spontaneous abortion is considered to be 
an SAE. 
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12. 
DATA QUALITY ASSURANCE 
This study will be conducted under Good Clinical Practice (GCP) and all applicable regulatory 
requirements. To ensure compliance, the Sponsor or designee may conduct a quality assurance 
audit, as outlined in Section 12.2.  
Actions to ensure the accuracy and reliability of data include the selection of qualified 
investigators and appropriate study centers; the review of protocol procedures with the 
Investigator and study personnel prior to study start; the design of suitable source documents 
with appropriate instructions for use (where applicable); the internal audit of source data 
according to GCP and internal procedures to ensure their accuracy, completeness, and 
verifiability; as well as the periodic site monitoring by the Sponsor. The Sponsor or designee will 
review source documents for accuracy and completeness during on-site monitoring visits and 
after their return to the Sponsor; any discrepancies will be resolved with the Investigator, as 
appropriate.  
Significant and/or repeated non-compliance will be investigated and remedial action instituted 
when appropriate. Failure to comply with remedial actions may result in investigational site 
termination and regulatory authority notification. 
12.1. 
Data Collection  
Source documents include, but are not limited to, original documents, data and records such as 
hospital/medical records (including electronic health records), clinic charts, lab results, 
participant diaries, data recorded in automated instruments, microfilm or magnetic media, and 
pharmacy records, etc. This study will use electronic data capture (EDC). At a minimum, all data 
required by the protocol should have supporting source documentation for entries in the EDC 
system. 
All CRFs will be completed by the site staff prior to review by the Sponsor’s monitor or designated 
representative. The Sponsor’s monitor or designated representative will review all source records 
on-site and compare them to the data collected on the CRF.  All entries, corrections, and 
alterations will be made by the Investigator or other authorized study personnel. All data entries 
will be verified for accuracy and correctness by independent monitors. The electronic data 
capture system maintains a full audit trail.  
12.2. 
Study Auditing and Monitoring 
Monitoring of the study site (including, but not limited to, reviewing CRFs for accuracy and 
completeness) will be performed by the Sponsor’s designated monitor(s). The extent, nature, 
and frequency of on-site visits will be based on such considerations as the study objectives and/or 
endpoints, the purpose of the study, study design complexity, and enrollment rate. By signing 
the protocol, the Investigator agrees that, within local regulatory restrictions and institutional 
and ethical considerations, authorized representatives of the Sponsor, a regulatory authority, 
and/or an IRB may visit the site to perform audits or inspections, including the drug storage area, 
study drug stocks, drug accountability records, participant charts and source documents, and 
other records related to study conduct. The purpose of the Sponsor audit or inspection is to 
systematically and independently examine all study-related activities and documents to 
determine whether the study-related activities were conducted, and data recorded, analyzed, 
and accurately reported according to the protocol, the site’s standard operating procedures, GCP 
guidelines of the ICH, and any applicable regulatory requirements. The Investigator should 
contact the Sponsor immediately if contacted by a regulatory agency regarding an inspection. 
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13. 
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE 
13.1. 
Statistical and Analytical Plans 
The sections of the Statistical Considerations describe the statistical methods to be used to 
analyze the efficacy and safety.  These methods may be revised and updated due to reasons such 
as regulatory requirements or need for further clarifications.  The final analysis will be 
documented in a formal Statistical Analysis Plan (SAP) that must be finalized before database 
lock.  The SAP will include details on how variables will be derived, how missing data will be 
handled, and how data will be presented as well as the details on statistical methods to be used 
for safety and efficacy analyses.  The final clinical study report will discuss deviations from the 
SAP, if any. 
13.2. 
Analysis Populations 
The following three analysis populations are planned for this study:  
• Safety Population will include all subjects who received any amount of study drug 
• PK Parameter Population: will include all subjects who also have sufficient concentration-time 
profiles for estimation of PK parameters. 
Membership in the analysis populations will be determined before unblinding. 
13.3. 
Planned Analyses 
Unless otherwise indicated, all testing of statistical significance will be 2-sided, and a difference 
resulting in a P value of less than or equal to 0.05 will be considered statistically significant.  
Furthermore, the baseline will be the last assessment before the dosing of study medication. All 
p-values will be considered nominal in this dose-finding study and no adjustments for multiplicity 
will be performed.    
Summary statistics will be provided for the variables described in the following sections. For 
continuous variables, these statistics will typically include the number of subjects, mean, 
standard deviation (SD), median, minimum, and maximum. For categorical variables, these 
statistics will typically include the number and percentage of subjects in each category. 
13.4. 
Study Subjects and Demographics 
13.4.1. 
Disposition and Withdrawals 
The numbers of subjects randomized, completing, and withdrawing, along with reasons for 
withdrawal, will be tabulated overall and by treatment group. The number of subjects in each 
analysis population will be reported. 
13.4.2. 
Protocol Deviations 
Major protocol deviations will be classified and documented before database lock and will be 
discussed in the CSR.  All protocol deviations, both minors and majors, will be presented in a data 
listing. 
13.4.3. 
Demographics and Other Baseline Characteristics 
Demographic and baseline characteristics (including age, sex, race, weight, and height) will be 
summarized for each treatment group and for the overall population by descriptive statistics. 
Medical history and clinical laboratory tests will be listed. 
Prior and concomitant medications will be summarized by treatment group, by the number and 
percentage of subjects taking each medication, classified using World Health Organization Drug 
Dictionary Anatomical Therapeutic Chemical classes and preferred terms. 
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13.4.4. 
Exposure  
Since this is a single dose study, study drug administration will be summarized in terms of total 
exposure by cohort and treatment group. 
13.4.5. 
Analysis of Efficacy Measures 
Efficacy variables will be summarized and analyzed.  
The primary efficacy parameter is the area-under-the-curve (AUC) for NPRS scores across various 
time points, with adjustment for use of analgesic therapy/medication.  The primary efficacy 
variable will be analyzed using an ANCOVA model with treatment as the main effect and baseline 
PI as the covariate.  The overall treatment effect will be presented along with specific treatment 
arm differences and the two-sided 95% confidence intervals of the differences. 
In this study, subjects are permitted to take rescue medication for analgesia.  It is expected 
subjects randomized to placebo arm will take rescue medication often. During both inpatient and 
outpatient portions of the studies, the subjects will be instructed to record NPRS immediately 
prior (within approximately 15 min) to taking rescue medication. 
For subjects who take rescue, the pre-rescue pain score will be used to impute scheduled 
assessments for 4 hours.  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 due to Lack of Efficacy or Adverse Events, scheduled assessments 
may be imputed using worst prior pain score carried forward.  All other subjects who drop out 
will have their last pain score carried forward. 
Sensitivity analysis of the primary efficacy variable using different methods of imputation for 
rescue medication may also be performed.    
Additional sensitivity analysis with different missing value imputation methods for subjects who 
drop out of the study may also be performed.    
All imputation methods for pain intensity will be documented in the SAP. 
13.4.5.1. Handling of Dropouts or Missing Data 
All efforts will be made to minimize missing data.  These efforts will include the following: 
• Subjects are required to consent continuous data collection even after subjects 
discontinue the study medication; 
• Continue data collection after subjects taking rescue medication; 
• Establish robust efficacy data collection procedures. 
With the procedures above, it is expected that the missing would be minimal.  Missing at random 
is expected to be a reasonable assumption and the primary analyses are expected to be sufficient 
for this dose escalation study. Additional sensitivity analyses will be performed to support robust 
conclusions, if warranted and details are presented in a detailed SAP prior to database lock.  
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13.4.5.2. Analysis of Secondary Efficacy Endpoints 
Time to first rescue (analgesia/nausea) medication will be presented using Kaplan-Meier graphs 
and analyzed using a log rank test with a model including treatment effect.  The median time to 
rescue medication and 95% confidence interval of the median time for each treatment cohort 
will be presented.   
The percent of days that rescue medication is used will also be analyzed via ANCOVA model 
including treatment effect as the independent variable.  The 95% confidence interval of the 
treatment differences will be presented. 
13.4.6. 
Analysis of Safety  
Safety analyses will be conducted using data from the Safety Population (as defined in 
Section 13.2).  
Safety will be assessed through treatment-emergent AEs (TEAEs); hematologic, biochemical, and 
urinalysis laboratory parameters; vital signs measurements; ECGs; physical exam, surgical site 
and neurosensory assessments.  
No formal statistical comparisons will be performed for safety endpoints. 
13.4.6.1. Adverse Events 
Adverse events will be coded by system organ class (SOC) and preferred term using the Medical 
Dictionary for Regulatory Activities (MedDRA) reporting system. Treatment-emergent AEs are 
defined as any of the following: 
▪ Non-serious AEs with onset on the date of treatment with the study drug through Day 29 or 
Early Termination, whichever occurs first;  
▪ Serious AEs with onset on the date of treatment with the study drug through 30 days after 
Day 29 or Early Termination, whichever occurs first; 
▪ AEs that start before the start of treatment but increase in severity or relationship at the time 
of or following the start of treatment through Day 29 or Early Termination, whichever occurs 
first. 
The number and percentage of subjects with TEAEs will be displayed for each treatment group 
by SOC and preferred term. Additionally, TEAEs will be tabulated for each treatment group by 
severity and by relationship to the study drug. A listing of SAEs will be provided if applicable. 
13.4.7. 
Clinical Laboratory Evaluations 
For continuous laboratory parameters, descriptive statistics will be presented for the value at 
each assessment time and for the changes from baseline by treatment group.  
Additionally, clinical laboratory parameters will be categorized as low, normal, or high according 
to laboratory range specifications and the number and percentage of subjects in each category 
will be presented in shift tables. 
Laboratory values that are outside the normal range will also be flagged in the data listings, along 
with corresponding normal ranges. 
13.4.8. 
Vital Signs and ECG 
Descriptive summaries (mean, SD, median, minimum, and maximum) of actual values and 
changes from Baseline will be calculated for vital signs and ECG.  Detailed description of the 
analysis will be included in the Study SAP. 
The incidence of abnormal ECG findings will be summarized for each visit.  
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13.4.9. 
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. 
13.5. 
Determination of Sample Size 
Sample size is appropriate for Phase 1 dose, ranging safety study. 
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14. 
STUDY ADMINISTRATION AND INVESTIGATOR RESPONSIBILITIES 
Additional details may be outlined in the Clinical Study Agreement between the sponsor and the 
investigational site.  
14.1. 
Regulatory and Ethical Considerations 
14.1.1. 
Ethical Conduct of the Study 
The Investigator will conduct the study in accordance with GCP and all applicable regulations, 
including, where applicable, the Declaration of Helsinki. The study will also be carried out in 
keeping with applicable national and local laws and regulations. This may include an inspection 
by the Sponsor’s representatives and/or regulatory authority’s representatives at any time. 
14.1.2. 
Ethics Approval 
The investigational site’s IRB must meet all relevant regulatory requirements. The study protocol 
and ICF will be reviewed by the IRB prior to enrolling participants into the study; written approval 
from the committee must be received by the sponsor before drug will be released to the 
Investigator.  The Investigator is responsible for submitting all protocol or ICF changes and SAE 
reports to the IRB according to local procedures. At a minimum, all SAEs requiring an 
investigational new drug safety report must be immediately reported. 
In accordance with applicable local regulatory requirements, the Investigator may be obligated 
to provide periodic safety updates on the conduct of the study at his or her research site and 
notification of study closure to the IRB. Such periodic safety updates and notifications are the 
responsibility of the Investigator and not of the Sponsor. The Sponsor will be provided with copies 
of all notifications sent to the IRB. 
All relevant correspondence from the IRB will be forwarded by the respective study site to the 
Sponsor in a timely fashion. 
14.1.3. 
Subject Informed Consent 
The Investigator (or authorized designee) will ensure that the participant (or the participant’s 
legal representative) is given full and adequate oral and written information about the nature, 
purpose, potential and possible risks and benefits of the study. Each prospective subject will 
receive an IRB-approved ICF that summarizes the pertinent study information and will be given 
ample time to read the form and ask questions about the study. All information is to be provided 
in a language understandable to the participant and must not include any language that waives 
the participant’s legal rights. Prospective participants must also be informed of their right to 
withdraw consent without prejudice at any time during the study. If the participant chooses to 
participate, he/she must sign the ICF before any study-related procedures are performed.  
Significant changes to the protocol or product safety information may require a revision of the 
ICF, which must be reviewed and signed by all applicable study participants. 
The time that informed consent is obtained must be documented. The Investigator must 
maintain the original, signed ICF in the participant’s source documents. A copy of the signed ICF 
must be given to the study participant. 
14.2. 
Privacy and Confidentiality 
The Investigator is responsible for complying with applicable privacy regulations, per his or her 
jurisdiction. Only information identified in this protocol will be collected. The information 
collected will only be used for the purposes identified in this protocol. 
To ensure anonymity and to limit disclosure, participants will be assigned a unique identifier at 
their first assessment. This identifier will be cross-referenced in the participant’s chart. The 
identifier will not contain any potentially identifiable information. An identifier log will be 
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maintained, linking each participant’s name to the corresponding identifier. This log will be 
stored at the research site in a secure location. 
The knowledge gained through this study is the property of the Sponsor. The Sponsor, 
representatives and affiliated companies of the Sponsor, the IRB, and regulatory agencies (such 
as the United States FDA) may inspect medical records related to the study to check the validity 
and accuracy of the data gathered in this study. Participant medical records (with participant’s 
initials and/or date of birth) may be copied. Confidentiality of participant records will be 
maintained except where release of information is required by law.  
The results of this study will be reported in such a manner that participants will not be identifiable 
in any way. Published reports or presentations will refer to grouped data or coded individual data 
and not to any identifiable individuals. Study reports sent to the Sponsor or drug regulatory 
agencies will not include participant names. 
By signing the ICF, the participant consents to the collection, access, use, and disclosure of his or 
her information as described in the ICF document. If a participant withdraws consent, some of 
the subject’s information may still be collected, used, and disclosed by those involved in this 
study, per applicable laws.  
By signing this protocol, the Investigator affirms that he or she will maintain in confidence 
information furnished to him or her by the Sponsor and will divulge such information to his or 
her respective IRB or IEC under an appropriate understanding of confidentiality with such board. 
All data will be considered the sole property of the Sponsor. Please refer to the Clinical Study 
Agreement for details. 
14.3. 
Study and Site Closure 
Upon completion of the study, all study data will be provided to the Sponsor following review of 
site study records for completeness, and data clarifications and resolutions. Accounting, 
reconciliation, and final disposition of used and unused study drugs, treatment codes, and 
emergency code break envelopes will be performed, as applicable. 
In addition, the Sponsor reserves the right to temporarily suspend or prematurely discontinue 
this study at any time and for any reason. If such action is taken, the Sponsor will discuss this with 
the Investigator (including the reasons for taking such action) at that time. The Sponsor will 
promptly inform any other investigators and/or institutions conducting the study, if the study is 
suspended or terminated for safety reasons and will inform the regulatory authorities of the 
suspension or termination of the study and the reason(s) for the action. If required by applicable 
regulations, the Investigator will inform the IRB promptly and provide the study participants with 
the reason for the suspension or termination. If the study is prematurely discontinued, all study 
data will be returned to the Sponsor.  
14.4. 
Regulatory Documents and Records Retention 
The Investigator is responsible for creating and/or maintaining all study documentation required 
by 21 CFR 50, 54, 56 and 312, ICH E6 section 8, as well as any other documentation defined in 
the protocol or Clinical Study Agreement. The Investigator must provide key documents to the 
Sponsor prior to the start of the study.  A complete list of required regulatory documents will be 
supplied by the Sponsor or its representative. 
Federal and local regulations require that the Investigator retain a copy of all regulatory 
documents and records that support the data for this study for whichever of the following is the 
longest period of time: 
▪ A period of 2 years following the final date of approval by the FDA or other regulatory 
agency of the study drug for the purposes that were the subject of the investigation; or 
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▪ A period of 5 years following the date on which the results of the investigation were 
submitted to the FDA or other regulatory agency in support of, or as part of, an application 
for a research or marketing permit for the study drug for the purposes that were the 
subject of the investigation. 
The Sponsor will notify investigators once one of the above 2 timeframes has been satisfied. 
If the investigation does not result in the submission of the data in support of, or as part of, an 
application for a research or marketing permit, records must be retained for a period of 2 years 
following notification by the Sponsor that the entire clinical investigation (not merely the 
Investigator’s portion) is completed, terminated, or discontinued or 2 years following withdrawal 
of the Investigational New Drug application/Clinical Trial Authorization or request for marketing 
approval (New Drug Application/Marketing Authorization Application).  
If the Investigator retires, relocates, or for other reasons withdraws from the responsibility of 
keeping the study records, custody must be transferred to a person who will accept the 
responsibility. The Sponsor must be notified in writing of the name and address of the new 
custodian. Study records should not be destroyed without consultation with the Sponsor. 
14.5. 
Delegation of Responsibilities and Adequate Resources 
The Investigator should have adequate time to conduct the study properly and should have an 
adequate number of qualified staff to assist with the conduct of the study.  
The term “Investigator” used throughout this protocol refers to the principal investigator and/or 
qualified sub-investigators. However, the Investigator may delegate responsibilities to other 
investigational site personnel. The Investigator shall delegate tasks only to individuals qualified 
by education, training and experience to perform the delegated tasks. The Investigator shall have 
direct oversight of all delegated activities and shall document delegation of responsibilities. The 
Investigator is responsible for ensuring all delegated staff has been properly trained on the 
protocol and their assigned study responsibilities. A delegation log identifying all delegated duties 
and the individual to whom they have been delegated will be maintained at the investigational 
site.  
14.6. 
Protocol Amendments 
Approval of a protocol amendment by the Investigator’s IRB must be obtained before 
implementation of the protocol amendment, unless a change is necessary to eliminate an 
apparent immediate hazard to the participant or when the change involves logistical or 
administrative aspects of the study. The protocol amendment must be signed and dated by both 
the Sponsor and the Investigator. The Sponsor or designee will submit protocol amendments to 
the appropriate regulatory authorities, if required. 
14.7. 
Financial Disclosure 
Clinical investigators are required to provide financial disclosure information for the submission 
of certification or disclosure statements required under 21 CFR § 54. As defined in 21 CFR § 54.2, 
a clinical investigator is a listed or identified investigator or sub-investigator who is directly 
involved in the treatment or evaluation of research participants. The term also includes the 
spouse and each dependent child of the investigator. In addition, investigators must promptly 
update financial disclosure information if any relevant changes occur during the course of the 
investigation and for 1 year following completion of the study. 
 
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15. 
INVESTIGATOR PROTOCOL AGREEMENT PAGE 
A Phase 1/Single Ascending Dose (SAD) Study to Evaluate the Safety, Tolerability, 
Pharmacokinetics, and Preliminary Efficacy of a Single Intraoperative 
Administration of CA-008 in Subjects Undergoing Unilateral Transpositional First 
Metatarsal Osteotomy for the Correction of Hallux Valgus Deformity 
Version: 3.0  
Date: 30-Jan-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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16. 
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, Gennevois D, Struys MM, Kehlet H. 
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. Caterina MJ, Julius D. The vanilloid receptor: a molecular gateway to the pain pathway.  
Annu Rev Neurosci. 2001 24:487-517. 
5. Chou, R., Gordon, D.B., de Leon-Casasola, O.A., Rosenberg, J.M., Bickler, S., Brennan, T., 
Carter, T., Cassidy, C.L., Chittenden, E.H., Degenhardt, E. and Griffith, S. 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. 
6. Dudley-Cash AI, Brennan TJ.  The effect of low concentration capsaicin infiltration on 
acute pain from incision.  Society for Neuroscience 2012, New Orleans. 
7. 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 
8. 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/guidancecomplianceregulatoryinformatio
n/guidances/vaccines/ucm074775.htm. Date accessed: July 7, 2017. 
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9. FDA Summary Basis for Regulatory Action (December 13, 2016, page 6) Available from 
https://www.fda.gov/downloads/BiologicsBloodVaccines/CellularGeneTherapyProducts
/ApprovedProducts/UCM536121.pdf. Date accessed: August 24, 2017  
 
10. 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 
 
11. Ferreira-Valente MA, Pais-Ribeiro JL, Jensen MP. Validity of four pain intensity rating 
scales. Pain. 2011 Oct;152(10):2399-404. 
 
12. 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 
13. 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. 
14. Hjermstad MJ, Fayers PM, Haugen DF, Caraceni A, Hanks GW, Loge JH, Fainsinger R, 
Aass N, Kaasa S; 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. 
15. Kehlet H, Jensen T, Woolf C: Persistent postsurgical pain: Risk factors and prevention. 
Lancet 367:1618-1625, 2006 
16. 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 
17. Pollak R, Schiffgen T, McDonnell ME, Zimmerman JC, Diamond EL, Golf M, Houghton 
WC, and Donovan J. 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] 
18. Savage PL, Buvanendran A, Hollmann M, Koncelik JJ, Minkowitz HS, and Houghton WC., 
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] 
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19. Singla NK, Desjardins PJ, Chang PD. A comparison of the clinical and experimental 
characteristics of four acute surgical pain models: Dental extraction, bunionectomy, 
joint replacement, and soft tissue surgery. Pain. 2013(155):441-456. 
20. Tominaga, M., Caterina, M.J., Malmberg, A.B., Rosen, T.A., Gilbert, H., Skinner, K., 
Raumann, B.E., Basbaum, A.I., Julius, D., 1998. The cloned capsaicin receptor integrates 
multiple pain-producing stimuli. Neuron 21, 531–543. 
21. 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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17. 
APPENDICES 
APPENDIX A: NEUROSENSORY EXAMINATION FORM 
Subject Number 
Subject Initials 
Date:__ __/ __ __ __/ 2 0__ __ 
(DD-MMM-20YY) 
Protocol Number 
___ ___ ___ -___ ___ ___  
___ ___ ___ 
CA-PS-2017-101 
Instructions to the Investigator: Please assess both feet and answer the questions below for each 
foot. Please enter the time of assessment (in 24H clock format) below and enter your initials.  
Time of 
Assessment: 
 
 
: 
 
 
H 
H 
 
M 
M 
 
 
 Not Done, Reason:____________________ 
 
Investigator Initials: ___________ 
Neurosensory Examination of the Foot / Great toe (bilateral) 
 
1. Was the Neurosensory Exam of the Foot / Great toe completed?      ☐ Yes             
☐ No 
 
 
LEFT FOOT 
RIGHT FOOT 
2. Visual Exam of the foot: 
☐ Normal   ☐ Abnormal, describe: 
____________________   
☐ Normal   
☐ Abnormal, describe: 
___________________ 
3. Deep Tendon Reflexes:       ☐ Normal   ☐ Reduced   ☐ Absent 
☐ Normal   
☐ Reduced   ☐ Absent 
4. Vibratory Sensation:           ☐ Normal   ☐ Reduced   ☐ Absent 
☐ Normal   
☐ Reduced   ☐ Absent 
5. Monofilament Sensation 
☐ Normal   ☐ Reduced   ☐ Absent 
☐ Normal   
☐ Reduced   ☐ Absent 
6. Allodynia to Brush: 
☐ Pain (Allodynia)     ☐ Hyperesthesia   ☐ Pain (Allodynia)     ☐ Hyperesthesia    
 
 
☐ Normal   ☐ Reduced   ☐ Absent 
☐ Normal   
☐ Reduced   ☐ Absent 
7. Hyperalgesia to Pin:            ☐ Increased Pain       ☐ Hyperesthesia 
☐ Increased Pain       ☐ Hyperesthesia 
 
 
☐ Normal   ☐ Reduced   ☐ Absent 
☐ Normal   
☐ Reduced   ☐ Absent 
  
 
 
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APPENDIX B: NUMERICAL PAIN RATING SCALE (NPRS) FOR PAIN INTENSITY 
Pain Intensity - Numerical Pain Rating Scale (NPRS) 
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: POST-OPERATIVE 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 D: BRIEF PAIN INVENTORY – SHORT FORM (BPI-SF) 
Page 1 of 2 
 
 
 
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BRIEF PAIN INVENTORY – SHORT FORM (BPI-SF) 
(Page 2 of 2) 
  
 
 
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APPENDIX E: PATIENT GLOBAL EVALUATION (PGE) 
Patient Global Evaluation (PGE) 
Instructions to Subject:  Please respond to the question below. When completed, please 
initial at the bottom of the page. 
 
How would you rate the study medication that you have received for pain? 
(Mark one box) 
 
 Excellent (3) 
 
 Good (2) 
 
 Fair (1) 
 
 Poor (0) 
 
Subject Initials: __________ 
 
 
 
 
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APPENDIX F: 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 medication that this patient received for pain? 
(Mark one box) 
 
 Excellent (3) 
 
 Good (2) 
 
 Fair (1) 
 
 Poor (0) 
 
Investigator Initials: __________ 
 
 
 
 
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APPENDIX G: 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. 
 
 
DocuSign Envelope ID: B4031F13-42A4-4C4D-86D9-E0138CA1A4C3


Clinical Trial Protocol 
Concentric Analgesics, Inc. 
CA-PS-2017-101 
CONFIDENTIAL 
 
Version: 3.0 (Final), 30-Jan-2018 
Page 73 of 78 
 
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 
BUN 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 
Magnesium – hypomagnesemia 
mg/dL 
1.3 – 1.5 
1.1 – 1.2 
0.9 – 1.0 
< 0.9 
Phosphorous – hypophosphatemia 
mg/dL 
2.3 – 2.5 
2.0 – 2.2 
1.6 – 1.9 
< 1.6 
CPK – mg/dL 
1.25 – 1.5 x 
ULN*** 
1.6 – 3.0 x 
ULN 
3.1 –10 x 
ULN 
> 10 x ULN 
Albumin – Hypoalbuminemia g/dL 
2.8 – 3.1 
2.5 – 2.7 
< 2.5 
-- 
Total Protein – Hypoproteinemia 
g/dL 
5.5 – 6.0 
5.0 – 5.4 
< 5.0 
-- 
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 
Cholesterol 
201 – 210 
211 – 225 
> 226 
--- 
DocuSign Envelope ID: B4031F13-42A4-4C4D-86D9-E0138CA1A4C3


Clinical Trial Protocol 
Concentric Analgesics, Inc. 
CA-PS-2017-101 
CONFIDENTIAL 
 
Version: 3.0 (Final), 30-Jan-2018 
Page 74 of 78 
 
Serum * 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially Life 
Threatening 
(Grade 4)** 
Pancreatic enzymes – amylase, lipase 1.1 – 1.5 x ULN 
1.6 – 2.0 x 
ULN 
2.1 – 5.0 x 
ULN 
> 5.0 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. 
 
 
DocuSign Envelope ID: B4031F13-42A4-4C4D-86D9-E0138CA1A4C3


Clinical Trial Protocol 
Concentric Analgesics, Inc. 
CA-PS-2017-101 
CONFIDENTIAL 
 
Version: 3.0 (Final), 30-Jan-2018 
Page 75 of 78 
 
APPENDIX I: 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 
 
 
 
 
 
 
DocuSign Envelope ID: B4031F13-42A4-4C4D-86D9-E0138CA1A4C3


Clinical Trial Protocol 
Concentric Analgesics, Inc. 
CA-PS-2017-101 
CONFIDENTIAL 
 
Version: 3.0 (Final), 30-Jan-2018 
Page 76 of 78 
 
APPENDIX J: AMERICAN SOCIETY OF ANESTHESIOLOGISTS PHYSICAL STATUS 
CLASSIFICATION SYSTEM 
 
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 moribund 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 
 
 
DocuSign Envelope ID: B4031F13-42A4-4C4D-86D9-E0138CA1A4C3


Clinical Trial Protocol 
Concentric Analgesics, Inc. 
CA-PS-2017-101 
CONFIDENTIAL 
 
Version: 3.0 (Final), 30-Jan-2018 
Page 77 of 78 
 
APPENDIX K: PHYSICAL / NEUROLOGICAL EXAMINATION OF THE FOOT AND 
GREAT TOE 
For all assessments, the foot should be warm.  
• Foot Inspection: The feet are inspected for evidence of excessively dry skin, callous 
formation, fissures, frank ulceration or deformities. Deformities include flat feet, hammer 
toes, overlapping toes, hallux valgus, joint subluxation, prominent metatarsal heads, 
medial convexity (Charcot foot) and amputation.  
 
• Vibration Sensation: Vibration sensation should be performed with the great toe 
unsupported. Vibration sensation will be tested bilaterally using a 128 Hz tuning fork 
placed over the dorsum of the great toe on the boney prominence of the DIP joint. 
Patients, whose eyes are closed, will be asked to indicate when they can no longer sense 
the vibration from the vibrating tuning fork. In general, the examiner should be able to 
feel vibration from the hand-held tuning fork for 5 seconds longer on his distal forefinger 
than a normal subject can at the great toe (e.g. examiner’s DIP joint of the first finger 
versus patient’s toe). If the examiner feels vibration for 10 or more seconds on his or her 
finger, then vibration is considered decreased. A trial should be given when the tuning 
fork is not vibrating to be certain that the patient is responding to vibration and not 
pressure or some other clue. Vibration is scored as 1) present if the examiner senses the 
vibration on his or her finger for < 10 seconds, 2) reduced if sensed for ≥ 10 or 3) absent 
(no vibration detection.)  
 
• Deep Tendon Reflexes: The ankle reflexes will be examined using an appropriate reflex 
hammer (e.g. Trommer or Queen square). The ankle reflexes should be elicited in the 
sitting position with the foot dependent and the patient relaxed. For the reflex, the foot 
should be passively positioned and the foot dorsiflexed slightly to obtain optimal stretch 
of the muscle. The Achilles tendon should be percussed directly. If the reflex is obtained, 
it is graded as present. If the reflex is absent, the patient is asked to perform the Jendrassic 
maneuver (i.e., hooking the fingers together and pulling). Reflexes elicited with the 
Jendrassic maneuver alone are designated “present with reinforcement.” If the reflex is 
absent, even in the face of the Jendrassic maneuver, the reflex is considered absent.  
 
• Monofilament Testing: For this examination, it is important that the patient’s foot be 
supported (i.e., allow the sole of the foot to rest on a flat, warm surface). The filament 
should initially be prestressed (4-6 perpendicular applications to the dorsum of the 
examiner’s first finger). The filament is then applied to the dorsum of the great toe 
midway between the nail fold and the DIP joint. Do not hold the toe directly. The filament 
is applied perpendicularly and briefly, (<1 second) with even pressure.  When the filament 
bends, the force of 10 grams has been applied.  The subject, whose eyes are closed, is 
asked to respond yes if he / she feels the filament.  Eight correct responses out of 10 
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Clinical Trial Protocol 
Concentric Analgesics, Inc. 
CA-PS-2017-101 
CONFIDENTIAL 
 
Version: 3.0 (Final), 30-Jan-2018 
Page 78 of 78 
 
applications is considered normal: one to seven correct responses indicate reduced 
sensation and no correct responses translates into absent sensation. 
 
• Testing for Allodynia and Hyperalgesia: testing should be performed bilaterally with the 
great toe unsupported. Allodynia will be tested using a foam brush, and hyperalgesia will 
be tested using a safety pin; both will be applied to the dorsum of the great toe on the 
boney prominence of the DIP joint.   
For allodynia assessment the foam brush will be lightly stroked 3 times across the skin over the 
dorsum of the great toe.  Subject will be asked to compare sensation of toe on the surgical side 
with the toe on the nonsurgical side.  If the sensation is described as painful or very unpleasant 
then allodynia will be reported as present.  If sensation is slightly unpleasant or mildly irritating 
compared to the controlled side then hyperaesthesia will be reported as present. If subject 
reports the stimulus as the same as the controlled side then sensation will be reported as normal. 
If sensation is less than the controlled side then sensation will be reported as reduced, and if 
sensation is not felt as all then it will be reported as absent.   
For hyperalgesia assessment, a sterile safety pin will be lightly applied 3 times at 1 second 
intervals over the dorsum of the great toe on the boney prominence of the DIP joint.  Subject will 
be asked to compare sensation of toe on the surgical side with the toe on the nonsurgical side.  
If the sensation on the side of surgery is described as more painful or very unpleasant in 
comparison to the sensation on the normal or controlled side then hyperalgesia will be reported 
as present.  If sensation is slightly unpleasant or mildly irritating compared to the controlled side 
then hyperaesthesia will be reported as present. If subject reports the stimulus as the same as 
the controlled side then sensation will be reported as normal. If sensation is less than the 
controlled side then sensation will be reported as reduced, and if sensation is not felt as all then 
it will be reported as absent.   
 
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SAP_001.pdf: 
1 
 
 
 
 
OFFICIAL TITLE: 
 
A Phase 1/Single Ascending Dose (SAD) Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and 
Preliminary Efficacy of a Single Intraoperative Administration of CA-008 in Subjects Undergoing 
Unilateral Transpositional First Metatarsal Osteotomy for the Correction of Hallux Valgus Deformity 
 
 
NCT NUMBER: 
NCT03307837 
 
 
DOCUMENT DATE: 
31 Mar 2018 
 
 


Sponsor: Concentric Analgesics, Inc. 
 
Statistical Analysis Plan 
Protocol Number: CA-PS-2017-101 
 
Date: 31Mar2018 
 
 
CONFIDENTIAL 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
A Phase 1/Single Ascending Dose (SAD) Study to Evaluate the Safety, Tolerability, 
Pharmacokinetics, and Preliminary Efficacy of a Single Intraoperative Administration of 
CA-008 in Subjects Undergoing Unilateral Transpositional First Metatarsal Osteotomy for the 
Correction of Hallux Valgus Deformity 
Protocol Number:  CA-PS-2017-101 
Protocol Version 3.0 Amendment 2 (30JAN2018) 
 
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: 425E9A58-18E3-43B5-8B90-E816481BA9E7


Sponsor: Concentric Analgesics, Inc. 
 
Statistical Analysis Plan 
Protocol Number: CA-PS-2017-101 
 
Date: 31Mar2018 
 
CONFIDENTIAL 
 Page 2 of 32 
 
 
 
 
DOCUMENT VERSION CONTROL 
Version Number 
Date 
Comments/Changes 
V1.0 
26FEB2018 
Final SAP 
 
 
 
 
DocuSign Envelope ID: 425E9A58-18E3-43B5-8B90-E816481BA9E7


Sponsor: Concentric Analgesics, Inc. 
 
Statistical Analysis Plan 
Protocol Number: CA-PS-2017-101 
 
Date: 31Mar2018 
 
CONFIDENTIAL 
 Page 3 of 32 
 
 
 
APPROVALS 
Author: 
 
 
 
 
 
 
Thomas Graves / Song Liou 
Biostatistician 
Lotus Clinical Research®, LLC  
 
Date: 
 
 
Reviewed:  
 
 
 
 
 
 
 
 
Jennifer Nezzer 
Director, Biometrics 
Lotus Clinical Research®, LLC  
 
Date: 
 
 
Approved: 
 
 
 
 
 
 
 
Rob Allen, MD 
Chief Medical Officer  
Concentric Analgesics, Inc. 
 
 
Date: 
 
 
 
DocuSign Envelope ID: 425E9A58-18E3-43B5-8B90-E816481BA9E7
02-Apr-18
05-Apr-18
02-Apr-18


Sponsor: Concentric Analgesics, Inc. 
 
Statistical Analysis Plan 
Protocol Number: CA-PS-2017-101 
 
Date: 31Mar2018 
 
CONFIDENTIAL 
 Page 4 of 32 
 
 
 
 
TABLE OF CONTENTS 
 
LIST OF IN-TEXT TABLES AND FIGURES .................................................................... 6 
LIST OF ABBREVIATIONS (COMMONLY USED) .......................................................... 7 
1 
PURPOSE OF THE ANALYSES ......................................................................... 9 
2 
PROTOCOL SUMMARY ..................................................................................... 9 
2.1 
Study Objectives ................................................................................................. 9 
2.1.1 
Primary Objectives .............................................................................................. 9 
2.1.2 
Secondary Objective ........................................................................................... 9 
2.2 
Overall Study Design and Plan ............................................................................ 9 
2.2.1 
Study Population ............................................................................................... 12 
2.2.2 
Treatment Regimens ......................................................................................... 12 
2.2.3 
Treatment Group Assignments or Randomization ............................................. 13 
2.2.4 
Sample Size Determination ............................................................................... 13 
3 
GENERAL ANALYSIS AND REPORTING CONVENTIONS .............................. 13 
4 
SUBJECT POPULATIONS ................................................................................ 14 
4.1 
Analysis Populations ......................................................................................... 14 
4.2 
Disposition of Subjects ...................................................................................... 15 
4.3 
Protocol Deviations............................................................................................ 15 
5 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ..................... 15 
5.1 
Demographics and Baseline Characteristics...................................................... 15 
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 ............................................................................... 18 
7.3 
Exploratory Efficacy Endpoints .......................................................................... 18 
7.4 
Analysis Methods .............................................................................................. 19 
7.4.1 
AUC Outcomes ................................................................................................. 19 
DocuSign Envelope ID: 425E9A58-18E3-43B5-8B90-E816481BA9E7


Sponsor: Concentric Analgesics, Inc. 
 
Statistical Analysis Plan 
Protocol Number: CA-PS-2017-101 
 
Date: 31Mar2018 
 
CONFIDENTIAL 
 Page 5 of 32 
 
 
 
7.4.2 
Average Daily NPRS score of 2 daily diary assessments .................................. 19 
7.4.3 
Total daily opioid consumption (in oral morphine equivalents) ........................... 20 
7.4.4 
Proportion of patients who drop out of the study due to inadequate analgesia 
from Day 1 to 15. ............................................................................................... 21 
7.4.5 
Brief Pain Inventory-short form (BPI-SF) ........................................................... 21 
7.4.6 
PGE and IGE ..................................................................................................... 21 
7.4.7 
Time to First Use of Rescue Medication ............................................................ 22 
7.4.8 
Percent of Subjects Taking Rescue / Use of Rescue Medication over Time ...... 22 
8 
SAFETY EVALUATION ..................................................................................... 22 
8.1 
Overview of Safety Analysis Methods ................................................................ 22 
8.2 
Adverse Events ................................................................................................. 23 
8.3 
Clinical Laboratory Evaluation ........................................................................... 25 
8.4 
Vital Signs ......................................................................................................... 25 
8.5 
Physical Examination ........................................................................................ 25 
8.6 
Surgical Site Assessment .................................................................................. 25 
8.7 
Neurosensory Assessment ................................................................................ 25 
8.8 
ECG Examinations ............................................................................................ 25 
8.9 
Drugs of Abuse and Alcohol Screens, Pregnancy Test. ..................................... 25 
8.10 
Patient Pain Assessment Training and Surgery Details ..................................... 26 
9 
PHARMACOKINETIC EVALUATION ................................................................ 26 
10 
OTHER ANALYSES .......................................................................................... 27 
11 
INTERIM ANALYSES AND DATA MONITORING ............................................. 27 
12 
CHANGES TO THE ANALYSES PLANNED IN THE PROTOCOL .................... 27 
13 
REFERENCES .................................................................................................. 27 
14 
APPENDICES ................................................................................................... 28 
14.1 
Tables, Figures and Listings for Final Study Report........................................... 28 
14.1.1 Tables ............................................................................................................... 28 
14.1.2 Figures .............................................................................................................. 30 
14.1.3 Listings .............................................................................................................. 30 
 
 
 
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LIST OF IN-TEXT TABLES AND FIGURES 
Table 2-1 
Protocol-Specified Visits and Visit Windows .................................. 12 
Table 7-1 
Table of Morphine Milligram Equivalents ....................................... 20 
Table 8-1 
Table of Imputation Rules for Missing AE Start Dates ................... 24 
 
 
 
 
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LIST OF ABBREVIATIONS (COMMONLY USED) 
ADaM 
Analysis Data Model 
AE 
Adverse Event 
ANCOVA 
Analysis of covariance 
ANOVA 
Analysis of variance 
ASA 
American Society Of Anesthesiologists 
ATC 
Anatomical Therapeutic Chemical 
AUC 
Area Under the Curve 
BMI 
Body Mass Index 
BP 
Blood Pressure 
BPI-SF 
Brief Pain Inventory – Short Form 
CDER 
Center for Drug Evaluation and Research 
CMH 
Cochran Mantel Haenszel Test 
CRF 
Case Report Form 
CSR 
Clinical Study Report  
DMC  
Data Monitoring Committee 
ECG 
Electrocardiogram 
EOS 
End of Study 
ET 
Early Termination 
FDA 
Food and Drug Administration 
ICF 
Informed Consent Form 
ICH 
 
International Conference on Harmonization  
IGE 
Investigator Global Evaluation 
LOCF 
Last Observation Carried Forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
MEQ 
morphine milligram equivalents 
MMRM 
Mixed Model for Repeated Measures 
NPRS 
Numerical Pain Rating Scale  
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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 
TFLs 
Tables, Figures and Listings 
UDS 
Urine Drug Screen 
WHO 
World Health Organization 
WOCF 
Worst Observation Carried Forward 
 
 
 
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1 
PURPOSE OF THE ANALYSES 
This statistical analysis plan (SAP) is based on protocol number CA-PS-2017-101 Version 3.0 
Amendment 2 (30JAN2018) 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 Objectives 
• 
To evaluate the safety and tolerability of a single intraoperative administration of CA-
008 in subjects undergoing bunionectomy. 
• 
To evaluate the pharmacokinetics of a single intraoperative administration of CA-008.  
2.1.2 Secondary Objective 
• 
To evaluate the efficacy of CA-008 in the management of acute postoperative pain in 
subjects undergoing bunionectomy.  
2.2 
Overall Study Design and Plan 
This is a single-center, randomized, double-blind, placebo-controlled, single ascending dose, 
sequential-group Phase 1 study in subjects undergoing bunionectomy. This trial is designed to 
determine the recommended dose and define the toxicity profile of CA-008. 
The study will be conducted utilizing an escalating dose cohort design, with sequential groups of 8 
subjects each. Within each dose cohort, 6 subjects will be randomized to active, and 2 will be 
randomized to placebo. The initial cohort will receive the lowest planned dose of CA-008 in a fixed 
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volume of administration, and will employ sentinel dosing, whereby the first 4 subjects in the first 
cohort will be dosed initially, before the remaining 4 subjects are dosed. If the available safety 
assessments for the first 4 subjects are acceptable through the first 24 hours, then the second 
group of 4 subjects will be dosed. Subsequent cohorts will not include sentinel dosing. There will 
be at least a 6-day period between cohorts, to ensure a minimum of 3 days to review safety data 
from the last subject in a cohort and to allow the meeting of the Data Monitoring Committee 
(DMC) to review the safety data from the entire cohort prior to making a decision for dose 
escalation. Dose escalation, or continuation of dosing, will not occur if subjects in a cohort 
experience intolerable treatment related AEs on active drug, as defined in the protocol.  
Subjects will be screened for participation at the study site in the United States within 28 days of 
surgery/study drug administration. The following screening assessments will be completed:  
informed consent, inclusion / exclusion, demographics, medical and surgical history, prior/current 
medications, physical exam (PE), x-ray of surgical site, neurosensory exam of the foot / great toe 
(bilateral), clinical laboratory tests (chemistry/coagulation, hematology, and urinalysis), urine drug 
screening (UDS), alcohol breath test, serum pregnancy test, surgical site assessment, vital signs 
(resting blood pressure, resting pulse, oral temperature and resting respiration rate), 12-lead 
electrocardiograms (ECGs), subject pain assessment training, and adverse event (AE) 
assessment. 
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 28 days of screening. At that time, the 
screening assessments will again be performed (minus the x-ray and ECG) to confirm continued 
eligibility, and a blood draw for PK analysis will be collected. If eligible, the subject will then be 
randomized to treatment.  
Subjects will then undergo surgery. During surgery, a total of 10 mL (for Cohorts 1-4) or 14 mL 
(for Cohort 5) of the investigative product will be administered into the surgical site in two 
applications. At time of closure of capsule, infiltration of deep soft tissue and capsule with a total 
of 6 mL (for Cohorts 1-4) or 9 mL (for Cohort 5) volume and instillation at cut bone with a total of 2 
mL volume will be done. Then, following closure of the capsule and prior to closure of the skin and 
subcutaneous layer, the wound will be instilled for Cohorts 1- 4 with 2 mL volume (study drug is 
applied to all exposed surfaces prior to subcutaneous and skin closure) and for Cohort 5 with 2 
mL of study drug will be instilled into the space under closed capsule and 1 mL of study drug 
applied to all exposed surfaces prior to subcutaneous and skin closure. 
Time 0 will be defined as the time of completion of study drug administration. After the surgery, 
subjects will be monitored for 48 hours at the trial site. Safety and efficacy evaluations will be 
performed as follows: 
• 
Concomitant medications and AEs will be recorded. 
• 
Pain intensity assessed with the Numerical Pain Rating Scale (NPRS), an 11-point 
scale where 0 is “No Pain” and 10 is “Worst Pain Imaginable:  at 0.25, 0.5, 0.75, 1, 2, 
4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, and 48 hours after the administration of study 
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medication. Assessments between the hours of 00:00 and 06:00 may be skipped if the 
subject is sleeping; however, consecutive assessments may not be skipped, and the 
subject must be awakened to complete the Hour 12, Hour 24, and Hour 48 
assessments. 
• 
Vital signs:  0.5, 1, 1.5, 2, 4, 6, 8, 10, 12, 16, 20, 24, 28, 32, 36, 40, 44, and 48 hours 
after the administration of study medication. Assessments between the hours of 00:00 
and 06:00 may be skipped if the subject is sleeping; however, consecutive 
assessments may not be skipped, and the subject must be awakened to complete the 
Hour 12, Hour 24, and Hour 48 assessments must be completed even if the subject is 
asleep. 
• 
Physical exam:  1, 24, and 48 hours after the administration of study medication. 
• 
ECG:  1.5 hours after the administration of study medication. 
• 
Surgical Site assessment:  24 and 48 hours after the administration of study 
medication. 
• 
Neurosensory Exam of the Foot / Great toe (bilateral):  24 and 48 hours after the 
administration of study medication. 
• 
Clinical laboratory tests (chemistry/coagulation, hematology, and urinalysis):  1.5 hours 
after the administration of study medication. 
• 
Blood draw for PK analysis:  are at baseline (before dosing), and at 5 minutes, 15 
minutes, 30 minutes, 45 minutes, and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 16, 24, 36, and 
48 hours after dosing. 
Subjects with inadequately controlled pain may request rescue at any time. However, subjects will 
be encouraged to receive rescue medication only with an NPRS ≥ 4. Additionally, subjects should 
be encouraged to wait at least 1 hour after completion of surgery (i.e. completion of sutures) 
before utilizing pain rescue medication, if possible. Pain intensity (NPRS) will be completed within 
15 minutes prior to use of pain rescue medication. While in-clinic, subjects will be treated with the 
prescribed analgesic regimen (oxycodone 5 mg every 2 hours); however, if subjects do not get 
adequate analgesic relief they will be discontinued from the efficacy portion of the study. At this 
point, subjects will receive standard of care analgesics (which may or may not include intravenous 
opioids). Regardless of discontinuation status, subjects will be followed for safety. Discontinuation 
affects the computation of the analgesic endpoint only. From Day 3 to 15, over-the-counter 
standard of care analgesics may be used for management of pain. If needed for management of 
NPRS score of 4 or higher, oxycodone 5 - 15 mg every 4 - 6 hours.  
After completing the assessments through 48 hours after study medication administration, the 
diary for at-home use will be reviewed and subjects will be discharged from the study center with 
the diary to record pain assessments and pain medication at home. Subjects will be provided 
routine standard of care for pain management after discharge from the study center. In their diary, 
subjects will assess their pain intensity once in the morning (08:00 ±4 hours), and once in the 
evening (20:00 ±4 hours) using the NPRS. Subjects will also record any medication they take to 
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treat their pain, and will capture an additional NPRS within 15 minutes prior to each dose of pain 
medication. 
Subjects will return to the study center on Day 8 [±1 day], Day 15 [±2 days] and Day 29 [±2 days], 
or at the time of discontinuation, for the following assessments:  subject home diary review (pain 
intensity and pain medication at Day 8 and 15 only), in-clinic pain intensity (NPRS), vital signs, 
surgical site assessment, neurosensory exam of the foot / great toe (bilateral), concomitant 
medication use, AE assessment, brief pain inventory-short form (BPI-SF), patient global 
evaluation (PGE), and investigator global evaluation (IGE).  
Additionally, on Day 29 [±2 days], or at the time of discontinuation, subjects will have a foot x-ray 
and a physical exam.  
If required due to insufficient wound healing noted at the Day 29 visit, subjects will return to the 
study center on Day 36 [±2 days] for the following assessments:  surgical site assessment, 
neurosensory exam of the foot / great toe (bilateral), concomitant medication use and AE 
assessment. 
A subject is free to withdraw his/her consent and discontinue participation in the study at any time 
for any reason.  
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 -28 to -1 
In-Patient 
Days 1 and 2 
Follow-up 
Days 8(±1 day), 15(±2 days), 29(±2 days) 
Additional follow-up (if necessary) 
Day 36(±2 days) 
 
2.2.1 Study Population 
The study population will consist of 40 healthy subjects between the ages of 18 and 65 years who 
require bunionectomy. 
2.2.2 Treatment Regimens 
Study Material 
The proposed doses of CA-008 to be evaluated in this study are:   
• 
CA-008, 0.5 mg in 10 mL of saline (50 μg/mL)  
• 
CA-008, 1.0 mg in 10 mL of saline (100 μg/mL)  
• 
CA-008, 2.0 mg in 10 mL of saline (200 μg/mL)  
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• 
CA-008, 3.0 mg in 10 mL of saline (300 μg/mL)  
• 
CA-008, 4.2 mg in 14 mL of saline (300 μg/mL) 
Comparator Group 
• 
The placebo will be saline for injection. 
2.2.3 Treatment Group Assignments or Randomization 
The study will be conducted in a double-blinded manner. A computer-generated randomization 
scheme will be prepared prior to the study start. Subjects who meet the enrollment criteria will be 
randomly allocated in a 3:1 ratio to receive either active drug or placebo.   
Upon enrollment, the site will assign each subject a 3-digit site-specific sequential screening 
number. The unique subject identification number will consist of a 3-digit original site number 
followed by a 3-digit screening number. The subject will keep the same number throughout the 
study. Upon randomization, a unique 4-digit study-specific randomization number will be 
assigned.  
2.2.4 Sample Size Determination 
The sample size is not based on statistical considerations but is considered appropriate for a 
Phase 1 dose ranging safety study. 
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 cohort will be presented separately, along with a combined active dose group. 
Placebo subjects will be pooled across all cohorts in all summaries and analyses.  
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 cohort, subject, and time point (as applicable).  
No preliminary rounding will be performed; rounding will only occur after the analysis. To round, 
consider the digit to the right of the last significant digit:  if <5, then round down; if ≥5, then round 
up. Means and medians will be presented with one more decimal place than the precision of the 
data. Standard deviations will be presented with two more decimal places than the precision of 
the data. Percentages will be presented with one decimal place. A percentage of 100% will be 
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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 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 drug administration.  
• 
Assessment visit times are defined by time T0. 
• 
Baseline value is defined as the last valid measurement prior to beginning study drug 
administration. 
• 
Change from baseline is defined as post-baseline value minus baseline value. 
• 
Duration of an AE will be computed in days for AEs lasting longer than 24 hours, and 
as hours for AEs lasting less than 24 hours. Duration in hours will be calculated as the 
stop date/time of the event minus the start date/time. Duration in days will be 
calculated by using stop date minus the start date +1 if AE occur on or after taking 
study medication. If AE occur prior to the study medication, then the duration will be 
calculated by using stop date minus the start date; If reported as ongoing at the time of 
database lock, the duration will be calculated using the date of the last visit or the last 
date of any AE for the subject in the database, whichever is later. Missing dates will be 
imputed as described in Table 8-1. 
• 
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). 
• 
If a pre-rescue NPRS is recorded in the same minute as a rescue medication is 
recorded, the NPRS will be assumed to have occurred PRIOR to the administration of 
rescue.  
• 
If a subject experiences inadequate analgesic relief and are discontinued from the 
efficacy portion of the study the date/time of the discontinuation will be assumed to be 
the date/time of the start of standard of care analgesic rescue.  
4 
SUBJECT POPULATIONS 
4.1 
Analysis Populations 
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Two analysis populations are defined as follows: 
• 
Safety Population will include all randomized subjects who received any amount of 
study drug  
• 
Pharmacokinetic (PK) population:  All randomized participants who received any 
amount of study drug and have sufficient plasma concentrations for estimation of at 
least one PK parameter. 
Membership in the safety analysis population will be determined before unblinding any study 
treatment codes. Membership in the PK analysis population will be determined after unblinding 
and receipt of the PK concentration and PK parameter data from the analytical lab. For all 
analyses, subjects will be analyzed by treatment group according to the actual product received 
during treatment, i.e., “as treated.”  
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. Subjects who are discontinued from the efficacy portion of the study will also be presented. 
A listing of CRF comments by time point and CRF section will also be presented. 
4.3 
Protocol Deviations 
Deviations are categorized as informed consent procedures, inclusion/exclusion criteria, study 
medication, prohibited medications, study procedures, study drug assignment/treatment, visit or 
assessment time window, missed visit or assessment and/or other. All protocol deviations will be 
captured on CRFs and 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. 
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, height, weight (kg), and BMI 
(kg/m2). Demographics and baseline characteristics will be presented in a by-subject listing and 
summarized overall and by treatment group.  
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5.2 
Medical/Surgical History 
Medical and Surgical history, as collected at screening, will be coded using the Medical Dictionary 
for Regulatory Activities (MedDRA) version 20.1 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 at screening and updated throughout the study 
as needed. Prior and concomitant medications will be coded using WHO/ATC classification index 
version September 2017. 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 
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 48 hours after study medication administration, the 
diary for at-home use will be distributed to the subject to collect pain intensity (twice daily on 
NPRS) 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 NPRS recorded on Diary) 
 
x 100 
(N of Expected NPRS from Diary) 
 
Where the N of expected NPRS 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. NPRS recorded prior to a rescue use will not 
be included in this calculation of compliance. 
For example, Subject A was discharged on Day 2, if this subject discontinues the study on Day 
18, then the expected N of NPRS records on diary will be 36 (2 * (15-2)). Assuming Subject A had 
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10 NPRS available from his/her diary, then compliance for this subject would be 27.8% ((10/36) 
*100). However, if subject A had discontinued the study on Day 10 (prior to Day 15), then the 
expected N of NPRS for this subject would be 16 (2 * (10-2)) and compliance would be 62.5 % 
((10/16) *100).  A summary of compliance will be provided overall and by treatment group. 
Compliance with recording an NPRS prior to rescue in the diary will be calculated as the number 
of NPRS 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 subjects who take protocol allowed 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, or who are discontinued from efficacy and 
given SOC analgesics for inadequate pain relief, scheduled assessments will first be imputed 
using the worst prior pain score carried forward (WOCF) using the worst scheduled non missing 
pain score prior to drop out within the AUC period being calculated (e.g., if the AUC being 
calculated includes hours 12-24, the worst observed pain score between hours 12 and 24 will be 
used). As a sensitivity, 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.  
7.2 
Assessment Time Windows 
Safety assessment summaries will be based on the nominal protocol-specified assessment times. 
NPRS scores will be based on actual collection dates/times wherever possible. If no collection 
date/time is available the nearest protocol specified assessment time will be used.  
7.3 
Exploratory Efficacy Endpoints 
• 
Area under the curve (AUC) of subject’s NPRS will be examined over various time 
periods, including but not limited to:  AUC(0-12), AUC(12-24), AUC(24-48), AUC(24-
72), AUC(24-96), AUC(24h to Week 1), and AUC(24h to Week 2).   
• 
Mean daily opioid consumption (in morphine equivalents) over the same time periods 
as the AUC calculations above. 
• 
Proportion of patients who drop out of the study due to inadequate analgesia from Day 
1 to 15. 
• 
Brief Pain Inventory-short form (BPI-SF) scores at the Day 8 (Week 1), Day 15 (Week 
2) and Day 29 (Week 4) or ET clinic visits. 
• 
Patient Global Evaluation (PGE) at the Day 8 (Week 1), Day 15 (Week 2) and Day 29 
(Week 4) clinic visits. 
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• 
Investigator Global Evaluation (IGE) at the Day 8 (Week 1), Day 15 (Week 2) and Day 
29 (Week 4) clinic visits. 
• 
Time to first use of rescue medication. 
• 
Percent of days that rescue medication was used. 
7.4 
Analysis Methods 
Formal hypotheses testing will be not conducted. All p-values will be considered nominal in this 
study and no adjustments for multiplicity will be performed. All efficacy analyses will be based on 
the safety population.  
7.4.1 AUC Outcomes 
All AUC calculations will be done using the standard trapezoidal rule  
AUC =     ∑
(
𝑁𝑃𝑅𝑆𝑖+𝑁𝑃𝑅𝑆𝑖+1
2
)
𝑥
𝑖=0
∗ (𝑇𝑖+1 − 𝑇𝑖) 
Where:  NPRSi = NPRS at time i, and (Ti+1 – Ti) is the Time difference in hours between time i and 
time i+1.  
Missing NPRS will be handled as discussed in Section 7.1.   
AUC values will be analyzed using a 1-factor (treatment) analysis of variance (ANOVA) model 
with treatment as the main effect.  In addition to the individual comparisons between each of the 
five CA-008 groups and the placebo group, the test for a linear trend across dose groups will be 
carried out using the scores 0, 0.5, 1.0, 2.0, 3.0 and 4.2 for the placebo group and the five active 
groups, respectively.   
The AUC analyses will be presented in a summary table with standard summary statistics for 
each dose cohort and placebo as well as active vs. placebo mean differences, standard errors, 
confidence intervals and comparison p-values as appropriate. Comparisons of individual dose 
cohorts for dose response may be presented for certain secondary AUC endpoints.   
Mean NPRS scores over time (in-clinic and diary) will be graphed over time by dose cohort. 
NPRS over time by each subject may also be displayed graphically as warranted. The individual 
NPRS and the computed AUC variables will be listed for all individual subjects.   
7.4.2 Average Daily NPRS score of 2 daily diary assessments 
The Average Daily NPRS scores will be computed for each subject using the NPRS scores 
recorded in the take-home diary from study days 3 – 15.  
The Average Daily NPRS will be the average of the AM and PM scores within each day. If 
individual AM or PM NPRS scores are missing, the score that is present will be used as the daily 
average. If both scores are missing for any day, then that day will not have a daily average. The 
mean across all subjects of the average daily scores on each day will be graphed by day and 
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dose cohort.  If rescue medication was taken within 4 hours of the AM or PM PI assessment, it will 
be replaced with the pre-rescue NPRS (if available) in the daily average. 
The average daily NPRS scores will be analyzed using the same type of ANOVA model as 
described in Section 7.4.1 at each time point. In addition, actual date/time NPRS assessed over 
the outpatient period from T48h onward will be used to calculate AUC between 24 hours and 
Week 1 and between 24 and Week 2 and compared versus placebo.   
7.4.3 Total daily opioid consumption (in 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. For summaries of opioid consumption, the rescue medications 
for subjects who are discontinued from the efficacy portion of the study will be counted two ways.  
First, all medications on days up to and including the date of the discontinuation from efficacy will 
be included, but medications that were continued after the date of discontinuation from efficacy 
will not be counted. In a second analysis, all the medication for these subjects will be counted, 
regardless of whether it was taken before or after the subject discontinued from the efficacy 
portion.  
Table 7-1 will be used to calculate the morphine milligram equivalents (MEQ) for each medication. 
The total opioid consumption for each day for each subject will be calculated as the sum of the 
MEQs of all of the medications taken on that day. For example, if a subject takes 5 MEQ 
morphine on Day 1 and Day 2, and 10 MEQ of Oxycodone on Day 2, the total consumption for 
Day 1 is 5 MEQ, and the total consumption for Day 2 is 15 MEQ. Subjects that take no opioids on 
a day will have a total opioid consumption value of zero for that day.  
Table 7-1 
Table of Morphine Milligram Equivalents  
(from cdc.gov/drugoverdose/pdf) 
Opioid (Doses in mg/day) 
Conversion Factor 
Codeine 
0.15 
Fentanyl transdermal (in mcg/hr) 
2.4 
Hydrocodone 
1 
Hydromorphone 
4 
Morphine 
1 
Oxycodone 
1.5 
Oxymorphone 
3 
 
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Total opioid consumption will be calculated overall and for the same periods as the NPRS AUC 
values: 0-12 hours, 12-24 hours, 24-48 hours, 24-72 hours and 24-96 hours in addition, the 
periods 24h to Week 1 and 24h to Week 2 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.  
7.4.4  Proportion of patients who drop out of the study due to inadequate analgesia from Day 1 
to 15. 
Proportion of subjects who drop out of the study due to inadequate analgesia from Day 1 to 15 will 
be analyzed using Fisher’s exact tests. Inadequate analgesia will be assumed if a subject drops 
out of the efficacy portion of the study due to inadequate analgesia, or if a subject drops out of the 
study entirely due to lack of efficacy or for an AE that 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 of the study for inadequate analgesia.  
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.   
7.4.5 Brief Pain Inventory-short form (BPI-SF) 
Individual questions will be listed.  
In addition, two sub scores of the BPI will be calculated as follows:   
Pain Severity Score = Mean of items 3-6  
Pain Interference Score = Mean of items 9A-9G calculated only if more than 50%, or four 
of seven, of the total items have been completed on a given administration. 
Questions 3-6, the Pain Severity Score and the Pain Interference Score will be analyzed using 
ANOVA with treatment as the main effect similar to previous analyses. The analysis results will be 
presented in a summary table with active vs. placebo difference means, standard errors, 
confidence intervals and p-values.  
7.4.6 PGE and IGE 
The proportions of subjects in each individual PGE and IGE category will be summarized by 
treatment group and time point and analyzed using the Cochran-Mantel-Haenszel mean score 
test (using equally spaced scores) at each time point 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). The 
continuous PGE and IGE scores will also be analyzed using ANOVA with treatment as a main 
effect similar to presented previously. Individual PGE and IGE scores will be listed.  
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7.4.7 Time to First Use of Rescue Medication 
The time to first rescue will be measured from Time 0 (time of completion of study drug 
administration). If a subject does not take rescue medication but prematurely discontinues from 
the study or discontinues from the efficacy portion of the study, then for analysis purposes the 
subject’s observation time will be the time of the discontinuation. For subjects who discontinue 
from the efficacy portion of the study, the discontinuation time will be considered to be a rescue 
event.  The time will be considered to be a rescue event if the discontinuation from the study was 
due to lack of efficacy, 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 dose cohort. Individual times to event will be listed.  
7.4.8 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 be summarized for each study day through Day 15. 
For summaries, subjects who discontinued from the efficacy portion of the study will be counted 
two ways.  First, all medications on days up to and including the date of the discontinuation from 
efficacy will be included, but medications that were continued after the date of discontinuation 
from efficacy will not be counted. In a second analysis, all the medication for these subjects will be 
counted, regardless of whether it was taken before or after the subject discontinued from the 
efficacy portion. 
In addition, the proportion of subjects taking any rescue medication during the following periods:  
0 to 48 hours, 0 to 72 hours, 0 to 96 hours, Days 1 to 8, Days 3-8, and Days 9-15 and overall will 
be summarized and will be analyzed using Fisher’s exact tests.   
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 TEAEs 
• 
Clinical laboratory test results 
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• 
Vital sign measurements 
• 
Electrocardiogram (ECG) results 
• 
Physical Exam findings  
• 
Surgical Site assessment findings 
• 
Neurosensory Exam results 
8.2 
Adverse Events 
Any untoward medical event that occurs after signing the ICF is considered to be an adverse 
event (AE). Treatment-emergent AEs are defined as AEs that start or worsen in severity after the 
first exposure to study drug and up to Day 29 for non-SAEs (up to Day 59 for SAEs). 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 19.1). 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 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 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 system organ class (SOC), and then by preferred term (PT) within 
SOC. These summaries will be given by treatment in separate tables for each of the following 
TEAE event sets: 
• 
All events 
• 
Treatment related events 
• 
Serious events 
• 
Events leading to premature discontinuation from study 
• 
Events by maximum severity 
If a given subject experiences a TEAE that maps to the same PT/SOC more than once, the 
subject will be counted only once for the SOC/PT at the greatest severity (i.e., mild, moderate, or 
severe) and causality (i.e., attribution to study material).  
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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: 
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 11:59 
 
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.  
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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 
Clinical Laboratory Evaluation 
Clinical laboratory test results (blood chemistry/coagulation, hematology and urinalysis) will be 
listed for individual subjects. Baseline for clinical laboratory parameters will be defined as the last 
evaluation before dosing with study treatment. For each individual lab test value, the raw value 
and change from baseline will be summarized by treatment and time point.  
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 
baseline (and vice versa) to each follow-up visit will be summarized by treatment and time point.  
8.4 
Vital Signs 
Vital signs results including BP (systolic and diastolic), pulse rate, respiration rate, 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.  
8.5 
Physical Examination 
Physical examination abnormality results will be listed for individual subjects. 
8.6 
Surgical Site Assessment 
The surgical site abnormality results and assessment score results will be listed and will be 
summarized by treatment and visit. 
8.7 
Neurosensory Assessment 
The neurosensory assessment results will be listed and the number of subjects with 
normal/abnormal assessments will be summarized descriptively by treatment and time point. 
8.8 
ECG Examinations 
ECG examination abnormality results will be listed for individual subjects and number of subjects 
with abnormal results will be summarized descriptively by treatment and time point. 
8.9 
 Drugs of Abuse and Alcohol Screens, Pregnancy Test. 
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Pregnancy (for female subjects of childbearing potential), urine drug screen and alcohol breath 
tests will be performed at screening and pre-procedure. Results will be listed for individual 
subjects. Each test result will be defined to be “negative” or “positive”.  
8.10 
Patient 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 
Blood draws for PK analysis will be done at baseline (before dosing), and at 5 minutes, 15 
minutes, 30 minutes, 45 minutes, and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 16, 24, 36, and 48 hours 
after dosing. Blood levels of CA-008, CA-101, capsaicin and capsaicin glucuronide metabolite will 
be determined. PK sample collections and drug levels will be listed.  
There will be a separate PK Analysis Plan that will describe the analyses of all PK concentrations.  
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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 AND DATA MONITORING 
There are no planned interim analyses for this study. 
A DMC will regularly monitor safety data in a blinded fashion throughout the study. To determine 
appropriate dose escalation in the next planned cohort, safety data will be reviewed by a DMC 
after the final dosing within each cohort. Details regarding the DMC are included in the DMC 
Charter.  
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 
Tables, Figures and Listings for Final Study Report 
 
14.1.1 Tables 
Table 14.1.1 
All Subjects 
Summary of Subject Disposition   
Table 14.1.2 
All Randomized 
Population 
Summary of Protocol Deviations   
Table 14.1.3 
All Randomized 
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 
Safety Population 
Summary of Subject NPRS and NPRS at Rescue Diary 
Compliance 
Table 14.2.1.1 
Safety Population 
ANOVA Analysis of AUC of NPRS - WOCF 
Table 14.2.1.2 
Safety Population 
ANOVA Analysis of AUC of NPRS - LOCF 
Table 14.2.2.1 
Safety Population 
ANOVA Analysis Mean Average Daily NPRS of 2 Daily 
Diary Assessments 
 
 
 
Table 14.2.3.1.1 
Safety Population 
Summary of Daily Opioid Consumption (in Morphine 
equivalents) by Study Day 
Table 14.2.3.1.2 
Safety Population 
Summary of Daily Opioid Consumption (in Morphine 
equivalents) by Study Day up to Discontinuation of 
Efficacy Portion 
Table 14.2.3.2.1 
Safety Population 
ANOVA Analysis Mean Daily Opioid Consumption (in 
Morphine Equivalents)  
Table 14.2.3.2.2 
Safety Population  
ANOVA Analysis Mean Daily Opioid Consumption (in 
Morphine Equivalents) up to Discontinuation of Efficacy 
Portion 
Table 14.2.3.3 
Safety Population – 
Subjects Who Took 
Any Opioid 
Medication 
ANOVA Analysis Mean Daily Opioid Consumption (in 
Morphine Equivalents)  
Table 14.2.4 
Safety Population 
Fishers Analysis of Proportion of Drop Out Due to 
Inadequate Analgesia  
Table 14.2.5 
Safety Population 
ANOVA Analysis Brief Pain Inventory (BPI-SF) Pain and 
Interference Subscales  
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Table 14.2.6 
Safety Population 
CMH and Fishers Analysis of Patient Global Evaluation 
(PGE) 
Table 14.2.7 
Safety Population 
CMH and Fishers Analysis of Investigator Global 
Evaluation (IGE) 
Table 14.2.8.1.1 
Safety Population 
Fishers Analysis of Percent of Subjects using Rescue 
Medication Over Time 
Table 14.2.8.1.2 
Safety Population 
Fishers Analysis of Percent of Subjects using Rescue 
Medication Over Time up to Discontinuation of Efficacy 
Portion 
Table 14.2.8.2.1 
Safety Population 
Summary of Percent of Subjects Using Rescue 
Medication by Day 
Table 14.2.8.2.2 
Safety Population 
Summary of Percent of Subjects Using Rescue 
Medication by Day up to Discontinuation of Efficacy 
Portion 
Table 14.2.9 
Safety Population 
Kaplan-Meier Analysis of Time to First Use of Rescue 
Medication by Dose (if needed) 
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 
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/Coagulation Laboratory 
Tests: Results and Change from Baseline 
Table 14.3.2.1.2 
Safety Population 
Summary of Blood Chemistry/Coagulation 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 
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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   
 
14.1.2 Figures 
Figure 14.2.1.1 
Safety Population 
Mean NPRS Over Time by Treatment (WOCF) 
Figure 14.2.1.2 
Safety Population 
Mean NPRS Over Time by Treatment (LOCF) 
Figure 14.2.2 
Safety Population 
Mean NPRS Over Time by Subject (Observed Data, no 
imputation for Drop Out) 
Figure 14.2.3 
Safety Population 
Average Daily NPRS of 2 Daily Diary Assessments by 
Treatment 
Figure 14.2.4 
Safety Population 
Time to First Use of Rescue Medication 
 
14.1.3 Listings 
Listing 16.2.1 
All Subjects 
Informed Consent, Randomization and Study Population 
Listing 16.2.2 
All Randomized 
Subjects 
Eligibility 
Listing 16.2.3 
All Randomized 
Subjects 
Protocol Deviations 
Listing 16.2.4 
All Randomized 
Subjects 
Subject Completion/Early Termination   
Listing 16.2.5 
All Randomized 
Subjects 
Demographics and Baseline Characteristics 
Listing 16.2.6 
All Randomized 
Subjects 
Medical/Surgical History 
Listing 16.2.7.1 
All Randomized 
Subjects 
Prior and Concomitant Medications 
Listing 16.2.7.2 
All Randomized 
Subjects 
Rescue Medication Administration 
Listing 16.2.7.3 
All Randomized 
Subjects 
Non-Medication Therapies 
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Listing 16.2.7.4 
All Randomized 
Subjects 
Time to First Use of Rescue Medication and AUC of 
Total MEQ  
Listing 16.2.8 
All Randomized 
Subjects 
X-Ray of Surgical Site   
Listing 16.2.9 
All Randomized 
Subjects 
Bunionectomy Surgery 
Listing 16.2.10 
All Randomized 
Subjects 
Study Drug Administration 
Listing 16.2.11 
All Randomized 
Subjects 
Subject NPRS and NPRS at Rescue Diary Compliance 
Listing 16.2.12 
All Randomized 
Subjects 
Discharge from Clinic 
Listing 16.2.13 
All Randomized 
Subjects 
Paper Diary Collection 
Listing 16.2.14.1 
All Randomized 
Subjects 
Pain Intensity Assessment (NPRS) 
Listing 16.2.14.2 
All Randomized 
Subjects 
AUC of Pain Intensity Assessment (NPRS) - WOCF 
Listing 16.2.14.3 
All Randomized 
Subjects 
AUC of Pain Intensity Assessment (NPRS) - LOCF 
Listing 16.2.15.1 
All Randomized 
Subjects 
Brief Pain Inventory (BPI-SF) – Pain Scale 
Listing 16.2.15.2 
All Randomized 
Subjects 
Brief Pain Inventory (BPI-SF) – Pain Interference 
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/Coagulation Laboratory Results 
Listing 16.2.19.2 
All Randomized 
Subjects 
Hematology Laboratory Results 
DocuSign Envelope ID: 425E9A58-18E3-43B5-8B90-E816481BA9E7


Sponsor: Concentric Analgesics, Inc. 
 
Statistical Analysis Plan 
Protocol Number: CA-PS-2017-101 
 
Date: 31Mar2018 
 
CONFIDENTIAL 
 Page 32 of 32 
 
 
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 Brief 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 
 
 
DocuSign Envelope ID: 425E9A58-18E3-43B5-8B90-E816481BA9E7


Certificate Of Completion
Envelope Id: 425E9A5818E343B58B90E816481BA9E7
Status: Completed
Subject: Please DocuSign: CA-PS-2017-101 SAP_Final_v2.0_31Mar2018.pdf
Source Envelope: 
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Caitlyn Avila
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Record Tracking
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             4/2/2018 9:19:48 AM
Holder: Caitlyn Avila
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Jennifer Nezzer
jnezzer@lotuscr.com
Director of Biometrics
Lotus Clinical Research
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Rob Allen
rob@concentricanalgesics.com
Concentric Analgesics
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Song Liou
sliou@lotuscr.com
Lotus Clinical Research
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Electronic Record and Signature Disclosure


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Electronic Record and Signature Disclosure created on: 8/14/2017 10:16:15 AM
Parties agreed to: Jennifer Nezzer, Rob Allen, Song Liou


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