Clinical trial NCT03731364
Conditions: Postsurgical Pain
Sponsor: Concentric Analgesics
Start date: 2018-10-29; Completion date: 2019-05-31
Enrollment: 55 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a two-part, Phase 2, multi-center, randomized, double-blind, placebo-controlled, parallel design study of CA-008 (vocacapsaicin) vs. placebo injected/instilled during an elective TKA.

Detailed description:
This is a Phase 2, multi-center, randomized, double-blind, placebo-controlled, parallel design study evaluating, in a pilot stage of the study, up to 3 ascending dose level cohorts each evaluating a single dose of CA-008 vs. placebo injected/instilled during an elective TKA. Up to 54 subjects will be randomized in the pilot stage. During the optional second stage of the study, subjects will be randomized to one of either 2 or 3 CA-008 dose levels (to be determined) or placebo. The Sponsor made the decision not to proceed with the second stage.

Arms: arm 1: Cohort 1 (5 mg), was prepared at 0.05 mg/mL CA-008 (vocacapsaicin) arm 2: Placebo for Cohort 1

Placebo comparator identical in appearance to the investigational product, containing the same excipients as the active arm 3: Cohort 2 (10 mg), was prepared at 0.1 mg/mL CA-008 (vocacapsaicin) arm 4: Cohort 3 (15 mg), was prepared at 0.15 mg/mL CA-008 (vocacapsaicin) arm 5: Placebo - Cohorts 2 and 3

Placebo comparator identical in appearance to the investigational product, containing the same excipients as the active
Interventions: intervention 1: CA-008 intervention 2: Placebo
Intervention descriptions: intervention 1: 5 mg CA-008 (0.05 mg/mL), 10 mg CA-008 (0.1 mg/mL) and 15 mg CA-008 (0.15 mg/mL) intervention 2: Placebo

Protocol documents:
Prot_000.pdf: 
OFFICIAL TITLE:  
A Phase 2,Randomized, Double-blind, Placebo-Controlled Efficacy, Pharmacokinetics and Safety Study of 
CA-008 in Subjects Undergoing Total Knee Arthroplasty 
 
NCT NUMBER: 
NCT03731364 
 
DOCUMENT DATE:  
Version 3.2  
19 February 2019 


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Clinical Trial Protocol 
Version 3.2 
19 February 2019 
 
Version 3.1: 14 January 2019 
Version 3.0: 11 December 2018 
Version 2.0: 10 October 2018 
Version 1.0: 07 September 2018 
 
A Phase 2, Randomized, Double-blind, Placebo-Controlled Efficacy, 
Pharmacokinetics and Safety Study of CA-008 in Subjects Undergoing 
Total Knee Arthroplasty 
 
Investigational Product: CA-008 by Injection/Instillation 
IND: 129114 
 
Concentric Analgesics, Inc. 
 
 
 
 
 
CONFIDENTIAL 
This protocol is the property of Concentric Analgesics, Inc. (Concentric) and is intended solely 
for the guidance of the clinical investigation. This protocol may not—in full or part—be passed 
on, reproduced, published, or distributed to any person or entity who is not bound by written 
confidentiality agreement, for any purpose, without the prior consent of Concentric. 
 
 




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1. 
KEY PERSONNEL CONTACT INFORMATION 
Sponsor 
Concentric Analgesics, Inc. (Concentric) 
Carole Hodge, PhD 
Clinical Operations Director 
Carole@concentricanalgesics.com 
858-442-9884 
Mike A. Royal, MD 
Chief Medical Officer 
Sponsor Medical Monitor 
Mike@concentricanalgesics.com  
858-204-1112 
 
CRO 
Lotus Clinical Research, LLC (Lotus) 
Primary 
Contact 
Caitlyn Avila 
 
Project Manager 
cavila@lotuscr.com  
530-902-3070 
CRO Medical 
Monitors 
Primary: Jon L. Ruckle, MD, CPI 
MedicalMonitorCA-PS-
203@Lotuscr.com 
808-349-9812 
Secondary: Royce Morrison, MD 
MedicalMonitorCA-PS-
203@Lotuscr.com 
206-799-7386 
 
 
 
 
 
 


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Table of Changes Protocol V 3.2 (19 FEB 2019) vs. V 3.1 (14 JAN 2018) 
 
Table of Changes Protocol V 3.1 (14 JAN 2019) vs. V 3.0 (11 DEC 2018) 
Material changes 
V 3.0 
V 3.1 
Synopsis: Sample Size p11/Dose 
Groups p14/Injection of Study 
Treatment p15 
§§6.1 p50, 9.1.2 p 58 and 10.1.3 
p65 
Cohorts #2 and #3 anticipated 16 subjects randomized 
3:1 to CA-008 vs. placebo using 75 mL of study 
treatment 
Elected to return to 100 mL of study treatment with Cohorts 
#2 and #3 including 18 subjects each with 2:1 randomization. 
Study treatment administration instructions remain the same 
as in cohort #1. 
Synopsis: Anesthesia p13 
§10.1.2.2 p65 
Spinal or general anesthesia allowed 
Ropivacaine 0.2% for AC block; 50 mL for site infiltration 
Restrict anesthesia to general anesthesia only 
Increase concentration of ropivacaine to 0.5% from 0.2% for 
the ac (adductor canal) block and reduce the volume for site 
infiltration from 50 to 30 mL 
Synpsis: Intraoperative Analgesia 
p15/Postsurgical Care p16/Rescue 
Medication During the Inpatient 
Period p16 
§9.2.1 p59 
§9.2.2 p60 
No IV hydromorphone during surgery 
IV fentanyl 100 – 300 mcg intraoperatively per 
anesthesia discretion 
Minimal PACU stay 
Modified intraoperative and immediate postoperative 
analgesia regimen to remove potential confusion and improve 
pain control. 
Within 30 min of anesthesia induction give the subject IV 
hydromorphone 1.5 mg. 
Material changes 
V 3.1 
V 3.2 
Synopsis: Rescue Medication 
during the Inpatient Period p13; 
§9.2.2 Inpatient Rescue 
Medicaiton p57 
From the time of PACU discharge through T12h 
administer IV hydromorphone 0.5 mg q15 min prn for 
NRS ≥ 4 as reported by subjects. 
From the time of PACU discharge through T48h administer IV 
hydromorphone 0.5 mg q15 min prn for NRS ≥ 4 as reported 
by subjects.  From T12 through T48h the IV hydromorphone 
may be used as rescue in addition to PO oxycodone for 
moderate-to-severe pain.  After T48, only PO oxycodone may 
be used as rescue.  If a subject still requires IV opioid rescue 
after T48, then the subject should undergo an early 
termination due to lack of efficacy. 
The rationale for the change was poorly controlled pain noted 
during the recently enrolled Cohort 2 subjects who 
complained of poor pain control with oral opioids alone.  Dr. 
Leiman and I discussed his request/concern and agreed to the 
immediate change to be followed by this minimalistic 
amendment. 


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Confusion as to PO or IV choice early postoperatively 
During the surgery, ensure that each subject has received at 
least 100 mcg of IV fentanyl with adjustments above this dose 
per anesthesiologist discretion. 
Within 15 min of the end of surgery, give the subject IV 
hydromorphone 0.5 mg 
Within 15 min of the end of surgery, administer IV ketorolac 
and IV acetaminophen. 
Synopsis: Inclusion Criteria p18 
§8.2.1 p55 
English only 
Added Spanish to inclusion criteria (note this will not apply 
until the IRB approves the Spanish language ICF and related 
documents) 
§17.10 Appendix J p 113 
Guidance for Industry: Toxicity Grading Scale for Healthy 
Adult and Adolescent Volunteers Enrolled in Preventive 
Vaccine Clinical Trials 
Given that patients receiving TKA are not “healthy adult or 
adolescent volunteers” the CTCAE v5 is a more appropriate 
guidance. 
 
Table of Changes Protocol V 3.0 (10 DEC 2018) vs. V 2.0 (10 OCT 2018) 
Material changes 
V 2.0 
V 3.0 
Synospsis, Study Duration; 
Synopsis, Visit Schedule; Table 1, 
Schedule of Assessments; §7.2, 
Duration of Participation; §9.5, 
Prior and Concomitant Therapy; 
§10.1.1, Screening Phase (Day -45 
to Day -1); §10.1.2.1, Prior to 
Surgery (D-1 to D0); §10.3.4, 
Medication History 
Approximately 61 days per subject from screening to the 
day 29 (D29) visit (however this could be longer to follow 
any AE to resolution or establishment of a new baseline). 
Approximately 76 days per subject from screening to the day 
29 (D29) visit (however this could be longer to follow any AE 
to resolution or establishment of a new baseline). 
Universal were made changes throughout. 
Synopsis, Overall Study Design; 
Dose Groups; Section 6.1; §8.1.1 
Number of Participants; §9.1.2 
Study Treatment Description 
 
Anticipated a single pilot (exploratory) cohort prior to 
the parallel design stage 2. 
Added two additional exploratory cohorts: Cohort #2 CA-008 
10 mg vs. placebo and Cohort #3 CA-008 15 mg vs. placebo 
(with each cohort enrolling n=16 randomized 3:1, 
respectively) with a volume of 75 mL for each treatment 
group in Cohort #2 and #3. 
Modified text throughout to reflect this change. 
Synopsis, Injection of Study 
Treatment; §10.1.3 Surgery Phase: 
Study treatment infiltration 100 mL with instructions as 
follows: 
Decreased study treatment volume to 75 mL (universal 
change throughout) with instructions as follows: 


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Administration of Study 
Medication into the Surgical Site 
With the leg in full extension, perform the following 
(working from top to bottom or using another 
standardized method per surgeon discretion) : 
1. Infiltrate 15 mL circumferentially around the 
distal femur  
2. Infiltrate a total of 30 mL divided equally into 
the medial and lateral gutters ensuring 
coverage of the periosteal borders 
3. Infiltrate 10 mL around the peripatellar region 
4. Infiltrate 10 mL divided equally medial and 
lateral to the tibial tubercle 
Following closure of the joint capsule, 
5. Instill 20 mL “intra-articularly” (lateral 
approach) and move the joint through full range 
of motion 
Cohorts #2 and #3: Prior to hardware placement, 75 mL of 
study treatment should be infiltrated/instilled as follows: 
1. Infiltrate 15 mL divided equally throughout the 
posterior capsule  
With the leg in full extension, perform the following (working 
from top to bottom or using another standardized method per 
surgeon discretion) : 
2. Infiltrate 15 mL circumferentially around the distal 
femur  
3. Infiltrate a total of 10 mL divided equally into the 
medial and lateral gutters ensuring coverage of the 
periosteal borders, and infiltrate 10 mL divided 
equally medial and lateral to the tibial tubercle 
4. Infiltrate 5 mL around the peripatellar region 
Following closure of the joint capsule, 
5. Instill 20 mL “intra-articularly” (lateral approach) and 
move the joint through full range of motion 
Synopsis, Intraoperative and 
Postoperative Analgesia; §9.2.1 
Inpatient Analgesia 
Anticipated a single dose of IV ketorolac and IV 
acetaminophen administered intraoperatively. 
Added additional doses of IV ketorolac and IV acetaminophen: 
Beginning at T6h (±0.5h) administer IV ketorolac 15 mg and IV 
acetaminophen 1 g with additional doses of each at T12h 
(±0.5h) and T18h (±0.5h). 
Synopsis, Inclusion Criteria; §8.2 
Eligibility Criteria 
BMI ≤ 40 kg/m2 allowed 
BMI threshold reduced to ≤ 36 kg/m2 
Synopsis, PK Endpoints; Table 1 
Schedule of Assessments, 
footnote 15; §10.1.4 Inpatient 
Phase: Time 0 (Post-Surgery) to 
Day 4 (Discharge) 
17 samples for PK 
Added 3 additional PK samples at T30, T36 and T48h for a 
total of 20 samples.  This was done due to the higher doses 
anticipated in cohorts 2 and 3 to ensure adequate assessment 
of the AUC for CA-101 in plasma. 
Urine collections will continue for each of the additional 
cohorts. 


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§5.3 Previous Human Experience 
At the time of the prior protocol amendment, the results 
were not available. 
Added safety results from the Phase 2 bunionectomy study 
(CA-PS-201).  The addition of numerous tables required 
renumbering of all subsequent tables. 
§10.4.3.1 Primary Efficacy 
Endpoint 
 
With the addition of 2 more exploratory cohorts, it was 
decided to pool placebos from each cohort for exploratory 
efficacy analyses. 
 
Table of Changes Protocol V 2.0 (10 OCT 2018) vs. V 1.0 (07 SEP 2018) 
Material changes 
V 1.0 
V 2.0 
Synopsis, Study Duration 
Synopsis, Visit Schedule 
76 days (including a 45-day screening period and 31-day 
follow up) 
61 days (including a 30-day screening period and 31-day follow up):  
A shorter screening period was requested by the site. 
Synopsis, Overall Study Design, Study 
Objectives, Dose Groups 
Section 6 Study Objectives, Section 
9.1.2 Study Treatment Description 
Study treatment infiltration 75 mL 
Increased study treatment volume to 100 mL (universal change 
throughout) 
Synopsis, Study Objectives 
Section 6.1.2, Secondary Objectives, 
Section 7.1 Overall Study Design and 
Plan 
 
Added a 3rd “Secondary Objective” to the Pilot Stage of the study and 
the Second Stage of the Study: “to evaluate the opioid-sparing effect 
of CA-008 vs. placebo” 
Synopsis, Anesthesia 
Section 10.1.2.2, Anesthesia and 
Surgery 
No AC or IPACK blocks when spinal anesthesia is 
administered. 
Modified anesthesia regimen such that all subjects will have the AC 
and IPACK blocks regardless of whether a general or spinal 
anesthesia is administered.  This was done to improve analgesia in 
the first several hours after surgery for all enrolled subjects.  
Modified the volumes to be used with ropivacaine blocks or surgical 
site infiltration with the maximum dose not to exceed 200 mg.   
Added language re: use of tourniquet prior to surgical incision: “A 
tourniquet will be used in all subjects. After exsanguination, but prior 
to surgical incision, perform surgical site infiltration with RopiHCl 
0.2% 50 mL (100 mg).” 
Added language: “The dose of fentanyl administered during surgery 
should be 100 to 300 mcg per anesthesiologist discretion.” This was 
done to standardize opioid administration during surgery. 
Synopsis, Injection of Study Treatment 
Section 10.1.3 Surgery Phase: 
Administration of Study Medication 
into the Surgical Site 
Prior to wound closure, study treatment will be 
infiltrated/instilled with a total volume of 75 mL.  Study 
treatment will be injected/instilled into the soft tissues, 
periosteal and osteotomy sites and capsule around 
surgical sites as follows: 
Prior to hardware placement, study treatment should be 
infiltrated/instilled as follows: 
1. 
Infiltrate 15 mL divided equally throughout the posterior 
capsule  


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1. 
Instill 7.5 mL into each osteotomy location with 
particular attention to the periosteal borders 
and intramedullary bone (total 15 mL) using 
either a catheter or needle 
2. 
Instill 10 mL into the posterior capsule using 
either a catheter or needle prior to closing 
3. 
Infiltrate 5 mL in and around each collateral 
ligament (total 10 mL) 
4. 
Infiltrate 40 mL into the surrounding soft tissues  
 
With the leg in full extension, perform the following (working from 
top to bottom or using another standardized method per surgeon 
discretion) : 
2. 
Infiltrate 15 mL circumferentially around the distal femur  
3. 
Infiltrate a total of 30 mL divided equally into the medial 
and lateral gutters ensuring coverage of the periosteal 
borders 
4. 
Infiltrate 10 mL around the peripatellar region 
5. 
Infiltrate 10 mL divided equally medial and lateral to the 
tibial tubercle 
Following closure of the joint capsule, 
6. 
Instill 20 mL “intra-articularly” (lateral approach) and move 
the joint through full range of motion 
Synopsis, Rescue Medication during 
the Inpatient Period 
Section 9.2.2, Inpatient Rescue 
Medication 
IV fentanyl 25-50 mcg q2h through T4 
Removed text referring to time after surgery. 
Provided a graded approach to rescue to allow for more rescue for 
severe pain. 
Reduced frequency of fentanyl dosing to 15 min per site request. 
Added additional IV opioid choices for use per investigator discretion 
to supplement oral rescue during the first 24h. 
Removed references to pain at rest triggering rescue. 
Moved discussion re: opioid rescue in the 12h prior to discharge to 
the section “Analgesia during the Outpatient Period” AND increased 
number of tablets in the oxycodone prescription to “9” in case the 
patient is discharged prior to a long holiday weekend. 
Synopsis, Inclusion Criteria #1 
Section 8.1, Study Population 
Section 8.2.1, Inclusion Criteria #1 
 
Removed “reasonably healthy” language 
Synopsis, Inclusion Criteria #2 
Section 8.1, Study Population 
Section 8.2.1, Inclusion Criteria #2 
Adult aged 18-75 years to be enrolled. 
Per site request, increased age to 80 years for eligibility 
Synopsis, Exclusion Criteria #6 
Section 8.2.1, Exclusion Criteria #6 
 
Removed redundant language and collapsed the indented text into 
the main body 
Synopsis, Monitored Parameters and 
Parameter Assessment Times 
 
Added rebound pain assessments 
Synopsis, Safety Parameter 
Assessment Times, Table 1 
 
Removed surgical site assessment and neurosensory testing at 24h 
per site request: surgeons were quite adamant about not removing 


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Section 10.1.4, Inpatient Phase: Time 
0 (Post-Surgery) to Day 4 (Discharge) 
dressings until discharge from the unit due to concerns about 
infection with manipulation of the dressing. 
Synopsis, Efficacy Parameter 
Assessment Times, Table 1 
Section 10.1.4, Inpatient Phase: Time 
0 (Post-Surgery) to Day 4 (Discharge) 
 
Added time range (±15 min) for NRS assessment at the time of rescue 
request. 
Removed NRS assessment 4h after rescue administration. 
Made text clarifications to reduce potential for misunderstanding. 
Synopsis, Key Secondary Efficacy 
Endpoints for Pilot Stage 
 
Added as 3rd bullet for consistence with protocol body text: Total 
opioid consumption (in daily oral morphine equivalents) = OC from 
T0 to T96h: OC0 to 96h 
Synopsis, Other Endpoints for Stage 2 
Section 10.4.4.3, Other Endpoints 
AUC endpoints at rest and with ambulation were merged 
into one bullet 
Split AUC endpoints at rest and those with ambulation are split into 
separate bullets to reduce confusion. 
In Section 4.4, removed redundant boxed text. 
Synopsis, PK Endpoints 
Modified text re: urine collections 
Clarified that urine collections are to be done during Stage 2 only. 
Synopsis, Stopping Rules 
Section 7.2, Study Stopping Rules 
Clarified text relating to stopping rule triggers per FDA 
input 
Modified text: 
• 
1 or more subjects with any grade 4 “related” TEAE in any of the 
categories shown in the table below 
• 
2 or more subjects with the same grade 3 “related” TEAE in any 
of the categories shown in the table below 
Synopsis, Sample Size Justification 
Section 9.4, Blinding 
 
Removed reference to use of an external unblinded biostatistician. 
Table 1, Schedule of Assessments 
 
Made several corrections to clarify timing for specific assessments. 
Modified footnotes to ensure consistency with text in synopsis and 
protocol proper. 
Added knee x-ray to the list of required safety assessments. 
Section 9.1.2, Study Treatment 
Description 
 
Clarified text describing formulation for CA-008 
Section 10.1, Study Visits 
 
Added temperature assessments to all mentions of vital signs 
Section 10.3.7, Digital Photographs of 
the Surgical Site 
 
Added clarifying text to make it clear that it is optional 
Section 10.3.13 Rescue Medications 
 
Augmented the Equianalgesic Conversion Table to accommodate 
additional opioids requested by the site.   
Section 10.3.17, 12-Lead 
Electrocardiogram (ECG) 
 
Fixed broken sentences. 
 


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2. 
PROTOCOL SYNOPSIS 
Sponsor:  
Concentric Analgesics, Inc. (Concentric) 
One Ferry Building, Suite 255 
San Francisco, CA 94111 
CRO: 
Lotus Clinical Research (Lotus) 
100 W. California Blvd., Unit 25 
Pasadena CA  91105 
Protocol Number: 
CA-PS-203 
IND# 
129114 
Study Title: 
A Phase 2, Randomized, Double-blind, Placebo-Controlled Efficacy, Pharmacokinetics 
and Safety Study of CA-008 in Subjects Undergoing Total Knee Arthroplasty 
Study Treatment 
CA-008, the investigational product (IP), and matching placebo vehicle are collectively 
referred to as study treatment 
Planned Study 
Center(s): 
1 US site 
Indication: 
Acute postsurgical pain 
Sample Size: 
Pilot stage of the study:  
• 
Cohort #1: total N=18 (randomized 1:1 active or placebo)  
• 
Cohort #2: total N=18 (randomized 2:1 active or placebo) 
• 
Cohort #3: total N=18 (randomized 2:1 active or placebo)  
A second stage of the study is anticipated with a sample size to be determined after an 
interim analysis of cohort #3 of the pilot stage is conducted. 
Population: 
Adults ages 18 to 80 years, inclusive, who are planning to undergo an elective 
unilateral total knee arthroplasty (TKA) and otherwise meet eligibility criteria may be 
considered for enrollment into the study. 
Study Duration: 
Approximately 76 days per subject from screening to the day 29 (D29) visit (however 
this could be longer to follow any AE to resolution or establishment of a new baseline). 
Overall Study 
Design: 
 
 
 
 
This is a Phase 2, single-center, randomized, double-blind, placebo-controlled, parallel 
design study evaluating, in a pilot stage of the study involving 3 exploratory cohorts, 
each with a single dose of CA-008 or placebo. 
After an interim unblinded analysis of the pilot stage results and review of pilot stage 
topline results, a protocol amendment will be performed with a second stage using the 
doses, sample size and number of CA-008 treatment groups vs. placebo to be 
determined. 


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For each subject, the study will be conducted in two parts: 
• 
Inpatient period which continues to 96h (T96h) after completion of study 
treatment injection (T0).   
• 
Outpatient period which begins on discharge from the inpatient unit through 
various follow visits to D29±2 (W4) after surgery.  Note that additional follow 
up visits may occur at any time or even after D29/W4 to follow adverse events 
(AEs) to resolution or establishment of a new baseline. 
Study Objectives: 
Pilot Stage (3 Exploratory Cohorts): 
Primary Objective: 
• 
To evaluate the efficacy of a single intraoperative administration of either 
CA-008 vs. placebo in subjects undergoing an elective TKA.  
Secondary Objectives: 
• 
To evaluate the safety and tolerability of a single intraoperative 
administration of CA-008 vs. placebo in subjects undergoing an elective 
TKA.  
• 
To evaluate the PK profile of a single intraoperative administration of CA-
008 in subjects undergoing an elective TKA.  
• 
To evaluate the opioid-sparing effect of CA-008 vs. placebo. 
Second Stage (Parallel Design): 
After an interim unblinded analysis of the 3rd cohort of the pilot stage of the study: 
Primary Objective: 
• 
To evaluate the efficacy of a single intraoperative administration of CA-
008 (the doses and number of active treatment groups to be determined) vs. 
placebo in subjects undergoing an elective TKA.  
Secondary Objectives: 
• 
To evaluate the safety and tolerability of a single intraoperative 
administration of CA-008 vs. placebo in subjects undergoing an elective 
TKA.  
• 
To determine the efficacy of various doses of CA-008 vs. placebo to be 
administered intraoperatively in subjects undergoing an elective TKA.  
• 
To evaluate the opioid-sparing effect of various doses of CA-008 vs. 
placebo. 
• 
To evaluate the PK profile of a single intraoperative administration of 
various doses of CA-008 in subjects undergoing an elective TKA.  
Exploratory Objectives: 
Pharmacoeconomic benefits from administration of CA-008 vs. placebo in subjects 
undergoing an elective TKA. 


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Study Treatment 
Dosing Schedule: 
Study treatment is to be administered intraoperatively as a single administration via 
“surgical site” infiltration/instillation prior to wound closure.   
“Surgical site” is defined as the area extending approximately 5 cm in all directions 
(lateral/medial/proximal/distal/deep) from the incision and osteotomy sites and 
surrounding tissues. 
Anesthesia:  
The surgery will be performed under general anesthesia supplemented by an adductor 
canal (AC) block AND an IPACK infiltration (Interspace between the Popliteal Artery 
and the Capsule of the posterior Knee between the femoral condyles).  Recent 
literature suggests the AC+IPACK approach is the new “best practice” to supplement 
anesthesia as part of an enhanced recovery after surgery (ERAS) for TKA (Cullom 
2017, Sankineani 2018).  Perform the AC+IPACK local anesthetic regional blocks 
under ultrasound guidance prior to the start of surgery.   
• 
Using ropivacaine hydrochloride (RopiHCl) 
o AC block: 20 mL using 0.5% (100 mg)  
o IPACK infiltration: 20 mL using 0.2% (40 mg) 
A tourniquet will be used in all subjects. After exsanguination, but prior to surgical 
incision, perform surgical site infiltration with RopiHCl 0.2% 30 mL (60 mg).   
The total RopiHCl should not exceed 200 mg.  See Appendix M (Section 17.12) for 
guidance on RopiHCl dosing.  
Dose Groups: 
Pilot Stage (3 Exploratory Cohorts): 
• 
Cohort #1: total N=18 randomized 1:1 CA-008 5 mg or placebo (100 mL) 
• 
Cohort #2: total N=18 randomized 2:1 CA-008 10 mg or placebo (100 mL) 
• 
Cohort #3: total N=18 randomized 2:1 CA-008 15 mg or placebo (100 mL)  
Second Stage (100 mL volume): 
• 
CA-008 (dose groups to be determined) 
• 
Placebo 
Injection of Study 
Treatment: 
Prior to hardware placement, 100 mL of study treatment should be infiltrated/instilled 
as follows: 
1. Infiltrate 15 mL divided equally throughout the posterior capsule  
With the leg in full extension, perform the following (working from top to bottom or 
using another standardized method per surgeon discretion) : 
2. Infiltrate 15 mL circumferentially around the distal femur  
3. Infiltrate a total of 30 mL divided equally into the medial and lateral gutters 
ensuring coverage of the periosteal borders 
4. Infiltrate 10 mL around the peripatellar region 
5. Infiltrate 10 mL divided equally medial and lateral to the tibial tubercle 
Following closure of the joint capsule, 


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6. Instill 20 mL “intra-articularly” (lateral approach) and move the joint through 
full range of motion 
Note that T0 is the time that the study treatment injection/instillation is completed. 
Intraoperative 
Analgesia: 
Within 30 min of anesthesia induction give the subject IV hydromorphone 1.5 mg. 
During the surgery, ensure that each subject has received at least 100 mcg of IV 
fentanyl with adjustments above this dose per anesthesiologist discretion. 
Within 15 min of the end of surgery, give the subject IV hydromorphone 0.5 mg 
Within 15 min of the end of surgery, administer the following: 
• 
IV ketorolac 30 mg (for example, ketorolac full prescribing information is 
available at: http://www.sagentpharma.com/wpcproduct/ketorolac-tromethamine-
injection-usp/ [Sagent Pharmaceuticals 2018]).  Dose adjustments may be made 
per surgeon/anesthesiologist discretion to accommodate the subject’s age and 
health status. 
• 
IV acetaminophen 1g (Ofirmev® full prescribing information at 
http://ofirmev.com/)  
After these have been administered, no additional non-opioid analgesics are to be 
administered during the inpatient phase (through T96h). 
Postsurgical Care: 
After surgery, subjects will be monitored in the post-anesthesia care unit (PACU) for at 
least 90 min during which time efficacy asssessments can begin once the subject is 
awake.  During this time, IV fentanyl 25-50 mcg q5 min prn for moderate-to-severe 
pain (≥ 4) as reported by subjects using the 0 to 10 numerical rating scale of current 
pain intensity (NRS).  After discharge from the PACU, subjects are followed through 
T96h as an inpatient.  Safety and efficacy evaluations will be performed and blood 
drawn and urine collected for pharmacokinetic (PK) assessments.  Subjects will be 
required to meet standard criteria for discharge to outpatient status.  Subjects will 
continue to be monitored as an outpatient after discharge through D29/W4 for various 
safety and efficacy assessments, and later if necessary for safety follow up. 
Rescue Medication 
during the Inpatient 
Period: 
From the time of PACU discharge through T48h administer IV hydromorphone 0.5 mg 
q15 min prn for NRS ≥ 4 as reported by subjects. 
After T12h, administer PO oxycodone 5 mg q2h prn moderate pain (NRS ≥ 4 and ≤ 6) 
or 10 mg q2h prn severe pain (NRS ≥ 7).  From T12 through T48h, IV hydromorphone 
may be used as rescue in addition to PO oxycodone for moderate-to-severe pain.  After 
T48, only PO oxycodone may be used as rescue.  If a subject still requires IV opioid 
rescue after T48, then the subject should undergo an early termination due to lack of 
efficacy. 
After T24, administer PO oxycodone 5 mg q4h prn moderate pain (NRS ≥ 4 and ≤ 6) 
or 10 mg q4h prn severe pain (NRS ≥ 7) 


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Subjects will be encouraged to rescue only for moderate-to-severe pain scores (NRS ≥ 
4), however rescue may be requested at any time and medication will be provided 
when requested. 
Analgesia during the 
Outpatient Period: 
 
Once discharged from the inpatient unit, all study participants will be instructed to take 
a combination of over-the-counter (OTC) analgesics at an appropriate dose per medical 
judgment to manage any residual or breakthrough postsurgical pain. 
If a subject is still requiring opioid rescue in the 12h prior to discharge from the 
inpatient unit (i.e., from T84h on regardless of whether discharge is delayed), then 
prescribe no more than 9 tablets of oxycodone 5 mg (1 PO tid prn) per investigator 
discretion for the initial outpatient period. 
Document the number of tablets prescribed and also document any additional 
prescriptions required if the subject’s pain continues to be an issue requiring additional 
opioid medication. 
If needed for pain management, the following oral OTC analgesics will be 
recommended for subjects to self-administer (note that these medications will not be 
provided by the Sponsor):  
• 
A nonsteroidal anti-inflammatory drug (NSAID) (e.g., ibuprofen 200 mg prn 
up to qid [Advil® or Motrin®] or naproxen 220 mg prn up to tid [Aleve®]) or 
other NSAID per investigator discretion and  
• 
Acetaminophen 1000 mg prn up to tid or 650 mg up to qid (3g daily maximum 
limit) 
Persistent pain or pain exacerbations during the outpatient period may suggest the need 
for an unscheduled in-person visit to assess the surgical site.  If such a situation occurs, 
the Investigator should use clinical discretion on adequacy of analgesic treatment, but to 
capture this event as an adverse event (AE) and document any required treatments. 
Inclusion Criteria: 
In order to participate, subjects must meet all inclusion criteria:  
1. Plan to undergo an elective primary unilateral total knee arthroplasty (TKA or 
knee replacement), without collateral procedure or additional surgeries. 
2. In the medical judgment of the investigator, be an adult aged 18 - 80 years old, 
inclusive, and American Society of Anesthesiology (ASA) physical Class 1, 2 
or 3 at the time of randomization (Section 17.1 Appendix A). 
3. If a male, unless he has a same sex partner, be either sterile (surgically or 
biologically) or commit to an acceptable method of birth control while 
participating in the study.  The site personnel will provide instructions on what 
is an acceptable method. 
4. If a female, must meet all of the following: 
a. A female of child-bearing potential (FCBP) must have a negative 
serum pregnancy test at screening and negative urine pregnancy test 
before surgery; 
b. No plan to become pregnant or to breast feed during the study; and 


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c. Be surgically sterile or at least one year post-menopausal, have a 
monogamous partner who is surgically sterile, have a same sex partner 
or (one of the following must apply) 
i. is practicing double-barrier contraception  
ii. is practicing abstinence (must agree to use double-barrier 
contraception in the event of sexual activity) 
iii. is using an insertable, injectable, transdermal or combination 
oral contraceptive approved by the FDA for at least 2 months 
prior to screening and commits to the use of an acceptable 
form of birth control while participating in the study. 
5. Have a body mass index ≤ 36 kg/m2. 
6. Be willing and able to sign the informed consent form (ICF) approved by an 
Institutional Review Board (IRB). 
7. Be willing and able to complete study procedures and pain scales and to 
communicate meaningfully in English or Spanish with study personnel and 
return for outpatient follow up visits as required. 
Exclusion Criteria: 
If any of the following exclusion criteria apply, subjects may not participate in the 
study:  
1. In the opinion of the Investigator,  
a. have a concurrent painful condition, other than pain in the knee to be 
replaced, that may require analgesic treatment during the study period or 
may confound post-surgical pain assessments. 
b. have active skin disease or other clinically significant abnormality at the 
anticipated site of surgery that could interfere with the planned surgery. 
2. Have a known allergy to chili peppers, capsaicin or the components of CA-008, 
ropivacaine HCl, ketorolac, acetaminophen, fentanyl, hydromorphone, morphine or 
oxycodone. 
3. As determined by the investigator (with input from the study’s medical monitor if 
requested by the investigator), have a history or clinical manifestation of 
significant medical, neuropsychiatric or other condition, including a clinically 
significant existing arrhythmia, left bundle branch block or abnormal ECG, 
myocardial infarction or coronary arterial bypass graft surgery within the prior 12 
months, significant abnormal clinical laboratory test value, or known bleeding 
abnormality that could preclude or impair study participation or interfere with 
study assessments. 
4. The following are considered disallowed medications: 
a. Be tolerant to opioids defined as those who have been receiving or have 
received chronic opioid therapy greater than 15 mg of oral morphine 
equivalents (Table 9) per day for greater than 3 out of 7 days per week 
over a one-month period within 6 months of screening. 


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b. Within 1 day prior to surgery and throughout the inpatient period, be 
taking or using any capsaicin-containing products, such as dietary 
supplements or over-the-counter (OTC) preparations, including topical 
formulations, and prescription medications. 
c. Within the 7 days prior to surgery, be taking any central nervous system 
(CNS) active agent as an analgesic adjunct medication, such as 
anticonvulsants, antidepressants (such as SNRIs, SSRIs, and tricyclic 
antidepressants), benzodiazepines, sedative-hypnotics, clonidine and other 
central alpha-2 agents (e.g., tizanidine), ketamine or muscle relaxants.   
[Note that SNRIs = Serotonin and norepinephrine reuptake inhibitors and 
SSRI = Selective serotonin reuptake inhibitors.] 
i. These drugs are permitted if prescribed for non pain indications 
and the dose has been stable for at least 30 days prior to surgery.  
Note that the dose must remain stable throughout the study.  
ii. If the subject is taking centrally- and/or peripherally-acting 
analgesic medications, such as acetaminophen, NSAIDs, tramadol 
or opioids, FOR knee-related pain, the subject may participate in 
the study if 4(a) above is not applicable and the subject is willing 
to discontinue these medications 3 days prior to surgery.  Note that 
baby aspirin for cardiovascular prophylaxis is allowed during the 
study. 
iii. The use of benzodiazepines and the non-benzodiazepines 
(eszopiclone, ramelteon, zaleplon and zolpidem) are permitted to 
treat insomnia during the postoperative period.  
d. Within the 7 days prior to the planned surgery and throughout the study, be 
taking antiarrhythmics except beta-blockers, digoxin, warfarin (see 
exception below), lithium, or aminoglycosides or other antibiotics for an 
infection (except for ophthalmic use or for treatment or prophylaxis of 
postoperative surgical site infections).  At the investigator’s discretion, 
agents intended for deep venous thrombosis (DVT) prophylaxis after the 
surgery is allowed. 
e. Within the 14 days prior to surgery, be taking parenteral or oral 
corticosteroids (steroid inhaler for allergy or asthma treatment, topical 
steroid for a non-clinically significant skin condition not involving the area 
of surgery or ophthalmic steroids are permissible). 
f. Be on an antianginal, antihypertensive agent or diabetic regimen at a dose 
that has not been stable for at least 30 days or which is not expected to 
remain stable while participating in the study. 
5. In the opinion of the Investigator, within the past year have a history of illicit drug 
use or prescription medicine or alcohol abuse (regularly drinks > 4 units of alcohol 
per day; where a unit = 8 oz. beer, 3 oz. wine or 1 oz. spirits).   


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6. Have positive results on the alcohol breath/saliva test indicative of alcohol abuse or 
urine drug screen indicative of illicit drug use (unless results can be explained by a 
current prescription or acceptable over-the-counter medication at screening as 
determined by the investigator) at screening, and/or prior to surgery.  Note that for 
those subjects who test positive for tetrahydrocannabinol (THC), if they are willing 
to abstain from use or consumption of THC-containing products from 3 days prior 
to surgery to the day 8 visit, they may be allowed to participate in the study.   
7. Willing and able to avoid foods containing capsaicin for 24 hours prior to surgery. 
8. Have previously participated in a clinical study with CA-008. 
9. Have participated in another clinical trial or used an investigational product within 
30 days or five half-lives (whichever is longer) prior to the planned surgery, or is 
scheduled to receive an investigational product other than CA-008 while 
participating in the study. 
Visit Schedule: 
• 
Screening D-45 to D-1: Subjects undergo screening during this period. All 
screening assessments (including informed consent form [ICF]) must be 
completed at least 1 day prior to surgery.   
• 
Site Unit Admission D0: Day of surgery, subjects will be randomized and 
baseline evaluations will be performed prior to surgery.   
• 
Surgery D0: TKA procedure is performed; study treatment is injected prior to 
wound closure with T0 defined as the time of study treatment completion of 
administration.  PK assessments are to be done per protocol-specified time 
points through T48h. 
• 
Post-surgery T0 to T96h: Subject remains at the surgical and then site facility 
for study assessments and PK blood draws.  Discharge to outpatient status after 
T96±4h assessments with follow up instructions, particularly on diary 
completion. 
• 
Follow Up D8±1 (W1): clinic visit for study assessments 
• 
Follow Up D15±2 (W2): clinic visit for study assessments 
• 
Follow Up D29±2 (W4): clinic visit for study assessments and study 
completion visit, unless follow up for wound healing is needed 
• 
If needed, Unscheduled visits or Follow Up after D29±2: Clinic visit as 
needed for any ongoing safety issue occurring between scheduled visits or 
continuing after the D29 visit 
• 
Early Termination (ET): For subjects who terminate early, an ET visit will 
be required if the subject is agreeable. Safety and subject-reported outcome 
assessments will be performed.  If the subject does not wish to participate in 
these assessments, he/she should be asked to at least return for a wound check. 
Monitored 
Parameters: 
• 
Treatment-emergent AEs (TEAEs) 
• 
Medical history (MHx) 


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• 
Physical examination (PE) findings, particularly neurosensory findings at the 
site of incision and the skin proximal and distal to the incision  
• 
Surgical site assessment for wound healing  
• 
Neurosensory testing near the surgical site 
• 
Clinical laboratory testing (standard chemistry, CBC, coagulation, urinalysis), 
drug and alcohol testing, pregnancy testing 
• 
X-ray of the knee  
• 
Electrocardiograms (ECGs) 
• 
Blood draws for pharmacokinetics (PK)  
• 
NRS scores at rest and after physical therapy or transfers to/from bed or 
wheelchair (inpatient) or ambulation for approximately 10 yards (inpatient or 
outpatient) using a 0 to 10 numeric rating scale for pain intensity  
• 
Presence of rebound pain at the surgical site  
• 
Knee injury and Osteoarthritis Outcome Score (KOOS) 
• 
Total postsurgical opioid consumption converted to an oral morphine 
equivalent dose (MED) 
• 
Patient global evaluation (PGE) of satisfaction with study treatment  
• 
Investigator global evaluation (IGE) satisfaction with study treatment 
(performed by any qualified investigator) 
• 
Postsurgical health economic outcome assessments focusing on the use of 
health services following discharge (phone calls related to postsurgical pain, 
unscheduled visits and/or treatments related to postsurgical pain and visits to 
emergency department) 
Safety 
Parameter 
Assessment Times:  
• 
Incidence of spontaneous reported TEAEs or SAEs from T0 through D29/W4 
or later if necessary:  
o TEAEs are defined as AEs occurring post T0 
o AEs recorded from the time the informed consent form (ICF) is signed 
up to D0/T0 will be recorded in medical history.   
• 
PE: full PE at screening (without a breast, genital or rectal examination). 
Interim targeted PE on D-1 or D0 prior to surgery (to be conducted on D0 if 
not done on D-1), T96h, and as an outpatient on D8/W1, D15/W2, and 
D29/W4 (later if necessary). 
• 
Vital signs (heart rate [HR], blood pressure [BP], respiratory rate [RR]) at 
screening, D0 prior to surgery, post-surgery T1, T2, T4, T6, T12, and T24h, 
and every 8 hours thereafter until T96h, and as an outpatient on D8/W1, 
D15/W2, and D29/W4 or later if necessary.  Assess temperature on D-1 or D0 
prior to surgery. Daily temps can be recorded along with vital signs per site 
SOPs at 1, 2, 4, 6, 12, 24, and every 8 hours thereafter until discharge from the 


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inpatient facility (if awake at the time of assessment between hours of 
midnight and 6 a.m.). 
• 
Surgical site assessments at T96h (prior to discharge from the unit) and then as 
an outpatient on D8/W1, D15/W2, and D29/W4 (later if necessary).  If there 
are skin reactions atypical for the type of surgery, e.g., more than expected 
erythema, drainage, bruising or hematoma, induration, swelling or other skin 
changes, they should be documented as AEs, graded for severity and followed 
regularly until resolution or establishment of a new baseline. 
• 
Neurosensory testing near the incision (compared to a similar site on the 
opposite leg) will be performed at Screening visit, T96h (prior to discharge 
from the unit) and then as an outpatient on D8/W1, D15/W2, and D29/W4. 
o Numbness at or near the incision need not be considered a neurologic 
AE since this could occur because of tissue trauma and inflammation 
from the surgery. 
o Sensory deficits or clinically significant persistent sensory change 
beyond the area proximal/distal to the incision at time of discharge, 
such as allodynia or hyperalgesia, must be designated as a neurologic 
AE. Subjects will be followed until there is a return to baseline or 
establishment of a new baseline. 
• 
X-ray of the operated knee at D29 and later if any evidence of abnormalities in 
bone healing until resolution or stabilization 
• 
Query subjects as to whether they have experienced any rebound or worsening 
pain at the surgical site at D8, 15 and 29. 
• 
ECGs, standard clinical labs at screening and post-surgery as specified in the 
Schedule of Assessments and outlined below   The Investigator is responsible 
for determining if out of range laboratory values are clinically significant or 
not.  All clinically significant values will be recorded in the eCRF and 
followed until resolution.   
o ECG at screening and T24±2 h 
o Hematology/Coagulation at screening and T96±4h: hemoglobin, 
hematocrit, white blood cell count with differential, red blood cell 
count, platelet count, activated partial thromboplastin time (aPTT) and 
prothrombin time (PT) or international normalization ratio (INR).    
o Blood Chemistry at screening and T96±4h to include at least the 
following: Alanine aminotransferase (ALT; SGPT) and Aspartate 
aminotransferase (AST; SGOT), total bilirubin (TBili), gamma-
glutamyl transferase (GGT), albumin, blood urea nitrogen (BUN), 
creatinine, alkaline phosphatase (ALK), sodium, potassium, calcium, 
chloride and glucose. 
o Serum and urine pregnancy test for FCBP: βhCG test at screening and 
urine test usually to be done within 24 hours prior to surgery.  
o Urinalysis at screening and T96±4h: including macroscopic analysis 


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and, if indicated, microscopic analysis.  
Efficacy 
Parameter 
Assessment Times: 
1. NRS scores will be assessed as follows: 
• 
During the inpatient stay, NRS at rest beginning with the PACU admission 
may be assessed once the subject is awake.  If the subject is able to provide 
responses, obtain NRS scores at 0.5, 1, 2, 4, 6, 8, 12, 16, 20, 24, and every 4 
hours (if awake at time of assessment) until discharge from the inpatient unit.  
Time windows: for T0.5 to T2 (±5 min) and from T4 onward (±15 min). 
• 
Pain scores may be skipped between the hours of midnight and 6 a.m., but the 
subject may not miss two consecutive assessments. 
• 
An additional NRS assessment must be obtained prior to rescue medication 
request (±15 min).  The T12, T24, T48, T72 and T96h assessments must be 
completed even if the subject is asleep at these times. 
• 
During the inpatient stay, starting on postoperative day 1 (after T24) perform 
the following each morning at 0800h (±2h) and each evening at 2000h (±2h) 
document the NRS at rest and after physical therapy or transfers to/from bed or 
wheelchair (inpatient) or ambulation for approximately 10 yards (inpatient or 
outpatient).  Actual assessment times must be documented.  If however these 
twice daily assessments coincide with timed assessments of NRS at rest, then 
the time assessment at rest is used in place of the twice daily assessments, but 
the assessment with ambulation should still be performed.  Resting pain scores 
are performed on the schedule noted above in the first bullet. 
• 
During the outpatient period (after T96h through W2), instruct the patient to 
document, if possible, their NRS scores twice daily at 0800h (±4h) and 2000h 
(±4h) at rest and on ambulation (e.g. with the use of a walker or a cane) for 
approximately 10 yards.  Note that the actual time of these assessments must 
be documented in the diary whenever possible.  Instruct the patient to: 
o Obtain the morning NRS assessment prior to taking any pain 
medication or 2 (±15min) hours after taking any pain medication 
o 
Obtain the evening NRS assessment 2 (±15min) hours after taking any 
pain medication 
2. Total opioid consumption (OC) and daily opioid (rescue medication) consumption in 
MEDs will be recorded during the inpatient period.   
• 
Document subject days in which no rescue medication or analgesic 
consumption is required (opioid free, OF) during the inpatient and outpatient 
period.   
• 
Document daily use of OTC analgesics (and oxycodone if prescribed) during 
the outpatient period.   
• 
Document each opioid prescription provided to the subject and the number of 
and type of tablets provided to the subject. 
• 
Document the fraction of subjects who rescue at T6, T12, T24, T48, T72 and 
T96h 


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3. Knee Injury and Osteoarthritis Outcome Score (KOOS) at Screening, T96h, D8/W1, 
D15/W2 and D29/W4 
4. Patient Global Evaluation (PGE) at T96±4h prior to discharge, D8/W1, D15/W2 and 
D29/W4 clinic visits. 
5. Investigator Global Evaluation (IGE) at T96±4h prior to discharge, D8/W1, D15/W2 
and D29/W4 clinic visits. 
6.  Healthcare utilization (HCU) costs defined as an overall summary of costs related to 
prescription medications, additional visits related to post discharge treatments, 
particularly for pain crises, and other related outpatient or inpatient treatments 
Primary Efficacy 
Endpoint for the 
Pilot Stage: 
For each cohort in the pilot stage, time-specific mean pain intensity scores at T96h for 
CA-008 vs. placebo. 
Key Secondary 
Efficacy Endpoints 
for Pilot Stage: 
For each cohort in the pilot stage, CA-008 vs. placebo comparison: 
• 
Weighted sum of pain intensity (SPI) assessments = Area Under the Curve 
(AUC) of the NRS current pain intensity scores from T0 to 96h at rest (AUC0 to 
96h).  
• 
Percentage of subjects who do not require opioids (i.e., opioid free; OF) from 
T0 to T96: OF0 to 96h 
• 
Total opioid consumption (in daily oral morphine equivalents) = OC from T0 
to T96h: OC0 to 96h 
Primary Efficacy 
Endpoint for Second 
Stage: 
For each CA-008 dose vs. placebo comparison: AUC0 to 96h    
Key Secondary 
Efficacy Endpoints 
for Second Stage: 
For each CA-008 dose vs. placebo comparison: 
• 
Percentage of subjects who do not require opioids (i.e., opioid free; OF) from 
T0 to T96: OF0 to 96h 
• 
Total opioid consumption (in daily oral morphine equivalents) = OC from T0 
to T96h: OC0 to 96h  
• 
Using NRS at rest: AUC0 to W1 
Other Endpoints for 
Stage 2: 
 
For each CA-008 dose vs. placebo comparison: 
• 
Using NRS at rest: AUC 0 to 24h, AUC 0 to 120h, AUC 6 to 96h, AUC24 to 96h, AUC96h to 
W1, AUC96h to W2  
• 
AUC 0 to 96h (ambulation), AUC 0 to W1 (ambulation), AUC24h to W1(ambulation), AUC96h to W2 
(ambulation) 
• 
Time-specific mean NRS scores at T48, T72, T96, T120, T144 and T168h 
• 
OC24 to 48h, OC24 to 72h, OC24 to 96h 
• 
OF24 to 96h, OF96h to W1 and OF96h to W2 
• 
KOOS improvement from T96h to D8/W1, D15/W2 and D29/W4 
• 
TTFRafter T0 and TTFRafter T24h  


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• 
The fraction of subjects who rescue at T6, T12, T24, T48, T72 and T96h 
• 
Analgesic consumption from T96h to W1 (AC96h to W1) and AC96h to W2 
• 
PGE comparing the %age of subjects reporting “poor” + “fair” vs. “good” + 
“excellent” responses, and the %age reporting each category of response at 
T96h, D8/W1, D15/W2 and D29/W4 
• 
IGE comparing the %age of those reporting “poor” + “fair” vs. “good” + 
“excellent” responses, and the %age reporting each category at T96h, D8/W1, 
D15/W2 and D29/W4 
• 
Number and %age subjects with an AE of lack of efficacy (LOE) during the 
inpatient period: LOE0 to 96h 
• 
HCU96h to W2 and HCU96h to W4 
PK Endpoints: 
The time points for whole blood collection will be at baseline (from checkin and up to 
30 min before the start of surgery), and T5min, T10 min, T15min, T30min, T45min, 
and T1, T1.5, T2, T2.5, T3, T4, T6, T8, T12, T16, T24, T30, T36 and T48h for a total 
of 20 samples) with T0 = end of study treatment administration.  Actual sampling times 
will be used to calculate plasma-derived PK parameters.  The PK will be documented 
in the PK Analysis Plan document. 
Additionally, immediately post surgery begin a 24h urine collection to assess urinary 
CA-101 excretion to be collected in two aliquots: after surgery to T6h and T6h to 
T24h.   
Stopping Rules: 
Study enrollment will be paused if subjects experience intolerable “possibly related” 
TEAEs, as defined below: 
• 
1 or more subjects with any grade 4 “related” TEAE in any of the categories 
shown in the table below 
• 
2 or more subjects with the same grade 3 “related” TEAE in any of the 
categories shown in the table below 
Refer to the in-text table below for descriptions of AE grading. 


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Should a stopping rule be triggered, an external independent safety review committee 
(SRC) will review the data to determine whether or not it is appropriate to continue 
with enrollment.  The SRC Charter details the membership, roles and responsibilities 
of the SRC. 
Sample Size 
Justification: 
Given the uncertainty in estimating a sample size for TKA surgery, the Pilot Stage will 
be conducted using multiple cohorts to augment the guidance from the results from the 
Phase 2 bunionectomy study to determine the sample size for Stage 2 parallel design 
portion of this study. 
Study Populations: 
The following three analysis populations are planned for this study:  
• 
The Safety Population will include all subjects who received any part of a dose of 
study treatment.   
• 
The PK Population will include all subjects who receive a full dose of study 
treatment and have PK assessments through 6h. 
• 
The intent-to-treat (ITT) population will include all subjects as randomized to 
study treatment.  The modified intent-to-treat (mITT) Population will include all 
subjects who receive a full dose of study treatment and complete the first 3 pain 
assessments (through T2h).   
• 
Study completers (Study Completers) will include all subjects who receive a full 
dose of study treatment and complete the entire study period through D29±2/W4. 
Subjects who elect to discontinue study participation (early termination or ET) after 
randomization but prior to receiving study treatment will be replaced.   
Subjects who elect to ET after receiving study treatment will not be replaced, however 
those who ET during the inpatient phase of the study, will be asked to continue with 


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assessments through T96h if they have not elected to withdraw from all aspects of 
study participation.  Subjects who elect to discontinue participation prior to D8 (W1) 
will be considered to have terminated as of the date of their election, however they will 
be asked to return to the site one time, if willing and at their convenience, to ensure that 
adequate wound healing has occurred. 
Statistical 
Considerations: 
 
All safety assessments and baseline characteristics will be summarized using the Safety 
Population.  Efficacy analyses will be performed using the mITT population.  PK 
analyses will be performed using the PK population.  All summaries will be grouped 
by the actual treatment received.  Subjects receiving vehicle placebo will be combined 
for summaries.  
Safety and tolerability will be evaluated by examining the occurrence of AEs, 
including Treatment-Emergent AEs.  AEs leading to discontinuation from the study, 
AEs related to study treatment and AE severity will be summarized by treatment 
group.   
Actual and change from baseline in clinical laboratory measures, vital signs, and ECGs 
will also be assessed and summarized by treatment group.  These data will be 
summarized using descriptive statistics including n, mean, SD, SEM (if appropriate), 
median, minimum and maximum.  Abnormal values will be determined and flagged in 
the listings.  Laboratory shift tables displaying the change (number of subjects) relative 
to the normal range from baseline to each study visit will also be presented by 
treatment for each test.  The Investigator should exercise medical and scientific 
judgment in deciding whether an abnormal laboratory finding or other abnormal 
assessment is clinically significant.  
While the study is not specifically designed to detect a significant difference in efficacy 
between CA-008 and placebo, efficacy analyses will be performed as secondary 
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Table 1. Schedule of Assessments  
Assessment  
Screening 
In Patient 
Follow-Up 
Unscheduled 
Visit1 
Early 
Termination19 
Prior to 
Surgery 
Surgery 
Post-
Surgery 
24h 
48h 
72h 
96h 
Study Day 
-45 to -1 
0 
0 
0 
1 
2 
3 
4 
8±1 
days 
15±2 
days 
29±2 
days 
Informed Consent 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Screening Medical and 
Surgical History 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Screens for alcohol/drugs of 
abuse 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Enroll/Randomize 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Subject Pain Assessment 
Training 
X2 
X2 
 
 
 
 
 
 
 
 
 
 
 
Surgery 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Study treatment 
Infiltration/instillation 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test  
X3 
(serum) 
X3 
(urine) 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs 
X 
X 
 
X4 
X4 
X4 
X4 
X4 
X 
X 
X 
X 
X 
Temperature 
X 
X 
 
X4 
X4 
X4 
X4 
X4 
X 
X 
X 
X 
X 
Physical Examination 
X5 
X5 
 
 
 
 
 
X5 
X5 
X5 
X5 
X5 
X5 
12-Lead ECG 
X 
 
 
 
X6 
 
 
 
 
 
 
 
 
Surgical Site assessment 
 
 
 
 
 
 
 
X7 
X7 
X7 
X7 
X7 
X7 
Neurosensory Exam 
X 
 
 
 
 
 
 
X8 
X8 
X8 
X8 
X8 
X8 
Blood draw for laboratory 
tests 
X9 
 
 
 
 
 
X9 
 
 
 
 
 
Urine sample for urinalysis 
X9 
 
 
 
 
 
 
X9 
 
 
 
 
 
Rescue Medication 
consumption 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
Concomitant Medication 
Assessment 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Event Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
NRS pain assessments 
 
 
 
X10 
X10 
X10 
X10 
X10 
X10 
X10 
 
X10 
X10 
Subject home diary record 
(NRS) 
 
 
 
 
 
 
 
X11 
X11 
X11 
 
X11 
X11 


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Assessment  
Screening 
In Patient 
Follow-Up 
Unscheduled 
Visit1 
Early 
Termination19 
Prior to 
Surgery 
Surgery 
Post-
Surgery 
24h 
48h 
72h 
96h 
Study Day 
-45 to -1 
0 
0 
0 
1 
2 
3 
4 
8±1 
days 
15±2 
days 
29±2 
days 
Paper Diary (review, 
distribution and/or 
collection) 
 
 
 
 
 
 
 
X12 
X12,13 
X12,13 
 
X12,13 
X13 
Subject home diary 
(analgesic consumption) 
 
 
 
 
 
 
 
X 
X 
X 
 
X 
X 
Prescription for outpatient 
opioid rescue if needed 
 
 
 
 
 
 
 
X14 
 
 
 
 
 
KOOS Survey 
X 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
PGE assessment 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
IGE assessment 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
Blood draw for PK analysis 
 
X16 
 
X15, 16 
X15, 16 
X15, 
16 
 
 
 
 
 
 
 
24h Urine Collection 
 
 
 
X16, 17 
X16, 17 
 
 
 
 
 
 
 
 
Rebound pain 
 
 
 
 
 
 
 
 
X18 
X18 
X18 
X18 
X18 
Knee x-ray 
 
 
 
 
 
 
 
 
 
 
X20 
X20 
X20 
1 
Unscheduled visit may occur at any time, however if after Day 29 it should occur if insufficient wound healing is assessed by the Investigator at the Day 29 visit or to follow up any ongoing AE to 
resolution or establishment of a new baseline.  For unscheduled visits prior to Day 15, collect efficacy assessments, including NRS scores and diary logs. 
2 
Pain assessment training with test during screening; rewatch video only prior to surgery. 
3 
Note pregnancy tests are for FCBP; urine pregnancy test is to be performed within 24 hours of scheduled surgery. 
4 
Vital signs and temperature assessed together at 1, 2, 4, 6, 12, 24 and every 8 hours thereafter (if awake at time of assessment between the hours of 00:00 and 06:00) until discharge from the 
inpatient unit (may not miss two consecutive assessments).  There will be a ±5-minute window allowed for the collection of vital signs in the first 4 hours after the end of surgery, after which for 
vital signs and temperatures there will be a ±15-minute window allowed. 
5 
A complete medical history and physical examination including all major body systems will be performed at Screening.  In addition, at the following times, an interim medical history and targeted 
physical examination will be performed prior to surgery (if not done on D-1), and to capture changes after Surgery, at 96 hours (± 4 hours) after the administration of study medication, but prior to 
discharge, and Day 8, Day 15 and Day 29 after the administration of study medication or if the subject terminates early, at that time if allowed.  Body weight (kg), in indoor clothing, but without 
shoes, will be measured at Screening and at 96 hours.  Height (in cm) will be measured and BMI will be calculated at Screening only. 
6 
Post-Surgery ECG should be performed at 24 hours (±2 hours) after study medication administration. 
7 
Surgical Site assessment: 96 hours (±4 hours after study medication administration but prior to discharge from the inpatient unit) and Day 8, 15 and 29. 
8 
Neurosensory Exam of the area proximal to the surgical incision approximately 3 cm from the incision at Screening visit, 96 hours (±4 hours, but prior to discharge) and Day 8, Day 15 and Day 
29 after the administration of study medication or if the subject terminates early, at that time if allowed. 
9 
Clinical Laboratory tests (chemistry, hematology, coagulation and urinalysis) should be performed at screening and prior to discharge from the inpatient unit (Lab collection window for 96h is 
±4h hours). 
10 
NRS pain assessments during the inpatient stay, NRS at rest assessments start in the PACU once the subject is awake at 0.5, 1, 2, 4, 6, 8, 12, 16, 20, 24, and every 4 hours (if awake at time of 
assessment) until discharge from the inpatient unit. Pain scores may be skipped between the hours of midnight and 6 a.m., but the subject may not miss two consecutive assessments.  Also assess 
NRS at the time of rescue request (±15 min). The T12, T24, T48, T72 and T96h assessments must be completed even if the subject is asleep at these times. There will be a ±5-minute window 


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allowed for the collection of each assessment in the first 2 hours after PACU admission, after which will be a ±15-minute window allowed.  During the inpatient period document the NRS at rest 
and on ambulation (e.g., transitioning from a recumbent position to a sitting or standing position or during transfers to or from a bed to a wheelchair and then to the bathroom) twice daily at 
0800h (±2h) and 2000h (±2h) with the actual time of these assessments documented. These twice daily scores are performed independently of pain scores at rest during the inpatient period. If 
however these twice daily assessments coincide with timed assessments of NRS at rest, then the time assessment at rest is used in place of the twice daily assessments.  During the outpatient 
period, instruct the subject to document, if possible, their NRS scores twice daily at 0800h (±4h) and 2000h (±4h) at rest and on ambulation (e.g. with the use of a walker or a cane) for 
approximately 10 yards after T96 through D15 (not through D29).  Note that the actual time of these assessments must be documented in the diary.  Instruct the subject to: 
• 
Obtain the morning NRS assessment prior to taking any pain medication or 2 (±15-min) hours after taking any pain medication. 
• 
Obtain the evening NRS assessment 2 (±15-min) hours after taking any pain medication. 
If an early termination is elected before Day 15, collect efficacy assessments, including NRS scores and diary logs. 
11 
The subject is expected to document NRS pain scores at rest and on ambulation 2x/day through Day 15 (at the times and qualifications noted above).   
12 
The diary and instructions are provided to the subject prior to discharge (T96h).  At each subsequent visit, review Subject Diary instructions with subject and collect their NRS scores and other 
study-related assessments. 
13 
Collect Subject Diary Data  
14 
If the subject is continuing to require opioids during the 12 hours prior to discharge (any time from T84h onward), then write a prescription for no more than 9 tablets of oxycodone 5 mg tablets 
for use tid prn per investigator discretion.   
15 
Collect blood samples for PK. The time points for whole blood collection will be at baseline (from Check-in and up to 30 min prior to surgery), and T5min, T10 min, T15min, T30min, T45min, 
and T1, T1.5, T2, T2.5, T3, T4, T6, T8, T12, T16, T24, T30, T36 and T48h for a total of 20 samples) where T0 = end of study treatment administration. There will be a ±2-minute window 
allowed for the 5 to 15-minute collections, a ±5-minute window allowed for collections T30 min through T4h, and a ±15-minute window for collections after T4 hours. 
16 
Subjects must abstain from foods containing capsaicin for 24 hours prior to all PK blood draws. 
17 
Collect the subject’s urine for 24 hours after surgery in two aliquots: post surgery to T6h and T6h to T24h.   
18 
Assess for presence of rebound pain at the surgical site (yes/no response). 
19 
If the subject terminates early and is willing to come in to complete all safety and efficacy assessments then complete all procedures listed. If unwilling to come in for all such assessments, at least 
attempt to bring the subject in for a surgical site assessment. 
20 
X-ray of the operated knee on D29 and later if any evidence of abnormal bone healing until resolution or stabilization.  Also perform this at early termination if subject gives consent. 


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3. 
TABLE OF CONTENTS 
1. 
Key Personnel Contact Information ................................................................................... 3 
Table of changes Protocol V 3.1 (14 JAN 2019) vs. V 3.0 (11 DEC 2018)................................ 4 
Table of changes Protocol V 3.0 (10 DEC 2018) vs. V 2.0 (10 OCT 2018) ............................... 5 
Table of changes Protocol V 2.0 (10 OCT 2018) vs. V 1.0 (07 SEP 2018) ................................ 7 
2. 
Protocol Synopsis ................................................................................................................ 10 
3. 
Table of Contents ................................................................................................................ 28 
4. 
List of Abbreviations and Definition of Terms .................................................................... 31 
5. 
Introduction ......................................................................................................................... 34 
5.1. 
Background .............................................................................................................................. 34 
5.2. 
CA-008 Product Introduction ................................................................................................. 35 
5.3. 
Previous Human experience ................................................................................................... 35 
5.4. 
Study Rationale ........................................................................................................................ 46 
5.5. 
Dose Rationale ......................................................................................................................... 46 
6. 
Study Objectives.................................................................................................................. 47 
6.1. 
Pilot (Exploratory) Stage of the Study ................................................................................... 47 
6.2. 
Second (Parallel Design) Stage of the Study.......................................................................... 47 
7. 
Investigational Plan ............................................................................................................ 49 
7.1. 
Overall Study Design and Plan ............................................................................................... 49 
7.2. 
Duration of Participation ........................................................................................................ 49 
7.3. 
Study Stopping Rules .............................................................................................................. 49 
8. 
Selection of Study Population ............................................................................................ 51 
8.1. 
Study Population ..................................................................................................................... 51 
8.2. 
Eligibility Criteria ................................................................................................................... 51 
9. 
Study Treatments ................................................................................................................ 55 
9.1. 
Study Treatment ...................................................................................................................... 55 
9.2. 
Other Interventions ................................................................................................................. 56 
9.3. 
Method of Assigning Subjects to Treatment Groups ........................................................... 58 
9.4. 
Blinding .................................................................................................................................... 58 
9.5. 
Prior and Concomitant Therapy ............................................................................................ 58 
9.6. 
Study Restrictions .................................................................................................................... 59 
9.7. 
Treatment Compliance............................................................................................................ 59 
10. 
Conduct of the study ....................................................................................................... 60 
10.1. 
Study Visits ............................................................................................................................... 60 
10.2. 
Subject Completion and Withdrawal .................................................................................... 67 
10.3. 
Study Procedures and Assessments ....................................................................................... 68 
10.4. 
Safety, PK and Efficacy Endpoints ........................................................................................ 74 
11. 
ADVERSE EVENTS ...................................................................................................... 77 


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11.1. 
Adverse Events and Serious Adverse Events ........................................................................ 77 
12. 
Data Quality Assurance .................................................................................................. 82 
12.1. 
Data Collection ......................................................................................................................... 82 
12.2. 
Study Auditing and Monitoring ............................................................................................. 82 
13. 
Statistical Methods and Determination of Sample Size............................................... 84 
13.1. 
Statistical and Analytical Plans .............................................................................................. 84 
13.2. 
Sample Size Justification......................................................................................................... 84 
13.3. 
Analysis Populations ............................................................................................................... 84 
13.4. 
Planned Analyses ..................................................................................................................... 85 
13.5. 
Study Subjects and Demographics ......................................................................................... 85 
14. 
Site and Investigator Responsibilities ........................................................................... 91 
14.1. 
Regulatory and Ethical Considerations ................................................................................. 91 
14.2. 
Privacy and Confidentiality .................................................................................................... 92 
14.3. 
Study and Site Closure ............................................................................................................ 93 
14.4. 
Regulatory Documents and Records Retention .................................................................... 93 
14.5. 
Delegation of Responsibilities and Adequate Resources ...................................................... 94 
14.6. 
Protocol Amendments ............................................................................................................. 94 
14.7. 
Financial Disclosure ................................................................................................................ 94 
15. 
Investigator Protocol Agreement Page ......................................................................... 95 
16. 
References ........................................................................................................................ 96 
17. 
Appendices ....................................................................................................................... 97 
17.1. 
Appendix A: American Society of Anesthesiologists Physical Status Classification System 
(ASA Class) ........................................................................................................................................... 97 
17.2. 
Appendix B: 0 to 10 Numerical Rating Scale of Pain Intensity (NRS) ............................... 98 
17.3. 
Appendix C: Assessment of Rebound Pain at the Surgical Site (Rebound Pain) .............. 99 
17.4. 
Appendix D: Patient Global Evaluation [of Satisfaction with Study Treatment] (PGE) 100 
17.5. 
Appendix E: Investigator Global Evaluation of Study Treatment] (IGE) ....................... 101 
17.6. 
Appendix F: Surgical Site Assessment ................................................................................. 102 
17.7. 
Appendix G: Surgical Wound Adverse Event Grading Guide.......................................... 103 
17.8. 
Appendix H: Neurosensory Examination Form ................................................................. 104 
17.9. 
Appendix I: Toxicity Grading Scale for Clinical Laboratory Abnormalities .................. 106 
17.10. 
Appendix J: Toxicity Grading Scale for Clinical Vital Sign Abnormalities ................ 109 
17.11. 
Appendix K: Toxicity Grading Scale for Systemic (General) Adverse Events ........... 111 
17.12. 
Appendix L: Ropivacaine Dosage Recommendations ................................................... 112 
17.13. 
Appendix M: Knee Injury and Osteoarthritis Outcome Survey (KOOS) ................... 113 
 
 
LIST OF TABLES 
Table 1. 
Schedule of Assessments .................................................................................. 25 
Table 2. 
Summary of Adverse Events (CA-PS-201) ........................................................... 36 
Table 3. 
Summary of TEAEs by MedDRA SOC/PT (CA-PS-201) ......................................... 37 


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Table 4. 
Summary of Related TEAEs by MedDRA SOC/PT ................................................ 42 
Table 5.  
Summary of Related TEAEs by Frequency .......................................................... 44 
Table 6. 
Summary of Related Local TEAEs by Frequency ................................................. 45 
Table 7. 
Summary of Severe TEAEs by Frequency ........................................................... 46 
Table 8.  
Study Stopping Rules ....................................................................................... 50 
Table 9. 
Equianalgesic Conversion Table ......................................................................... 70 
Table 10. 
Clinical Laboratory Assessments ........................................................................ 72 
 
 


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


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


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


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5. 
INTRODUCTION 
5.1. 
Background 
Concentric Analgesics, Inc. (Concentric) is developing CA-008 to provide long-lasting pain 
relief of post-surgical pain following a single local administration (for 96h and beyond).  CA-008 
is a prodrug of trans-capsaicin (trans-8-methyl-N-vanillyl-6-nonenamide), the substance in chili 
peppers that produces the sensation of spiciness.  Capsaicin is a transient receptor potential 
cation channel, subfamily V (vanilloid), member 1 (TRPV1) agonist.  TRPV1 is a ligand-gated, 
nonselective, cation channel preferentially expressed most densely in C-fiber nociceptors and to 
a lesser extent on Aδ–fiber nociceptors (Babbar 2009, Caterina 2001). TRPV1 responds to 
noxious stimuli including capsaicin, heat, and extracellular acidification, and integrates 
simultaneous exposures to these stimuli (Suresh 2010, Surh 1995, Tominaga 1998).   
Capsaicin exposure to TRPV-1-expressing nociceptor peripheral terminals results in initial 
excitation of the nociceptor followed by a functional desensitization which continues for some 
time after removal of capsaicin from the site.  Capsaicin, however, is virtually insoluble in 
aqueous media or local anesthetic solutions which means that capsaicin formulations tend to be 
quite hydrophobic and viscous making them hard to inject and less likely to permeate surgical 
site tissues.  Anesiva, which had been developing capsaicin for the management of post-surgical 
pain and osteoarthritis, solubilized capsaicin in polyethylene glycol 300 (Hartrick 2011).  The 
product was instilled into the open surgical site and after waiting for 5 minutes, was removed via 
surgical suction.  This route of administration while simple and perhaps convenient, limited 
exposure of capsaicin only to the exposed surfaces of cut tissue and bone with little to no ability 
to penetrate into the affected soft tissues. 
To work around the solubility limitations of capsaicin, the highly water soluble capsaicin pro-
drug CA-008 was developed for local infiltration.  It avoids the physicochemical limitations of 
capsaicin while providing greater target engagement which theoretically would produce superior 
local analgesia, particularly after surgical trauma.  Based upon this mechanism of action, local 
delivery of a TRPV1 agonist throughout the tissues around the surgical site prior to wound 
closure to maximize target engagement should result in a meaningful reduction of post-surgical 
pain over several days to weeks.  This improved long-term pain relief has the ability to augment 
current multimodal analgesia or enhanced recovery programs which may help to avoid the need 
for supplemental opioid use after surgery.  
While no capsaicin products have been approved for injection or instillation into a wound site in 
the US, several companies have or had clinical development programs for such products.  
Centrexion Therapeutics has an active development program (CTNX-4975) for intraarticular 
injection of capsaicin for chronic osteoarthritis and Morton’s neuroma (see 
http://centrexion.com/our-pipeline/).  Note that Centrexion is using the Anesiva highly viscous 
polyethylene glycol formulation for its intraarticular knee joint injections.  


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5.2. 
CA-008 Product Introduction 
The active moiety of CA-008, capsaicin, has certain attractive properties for treatment of post-
operative pain from a pharmaceutical perspective.  CA-008 is water soluble and easy to inject 
through a 25 g needle or larger.  It readily penetrates surgical site tissues where it releases 
capsaicin through a non-enzymatic pH-driven process.  Local administration of CA-008 at or 
near the source of pain either topically, by infiltration or by instillation into a surgical site results 
in low systemic levels of capsaicin.   
CA-008 was created to improve delivery of capsaicin without having to account for its poor 
solubility profile in tissues.  CA-008 provides an aqueous formulation that could be simply 
infiltrated in the wound site to achieve local capsaicin release to produce a maximal effect.  The 
free base form of CA-008 rapidly breaks down at physiological pH to yield capsaicin and a 
cyclic urea, as shown in the scheme below: 
 
CA-008 was specifically selected for development due to its short half-life (<5 min) at neutral 
pH.  In Tris buffer at pH 7.4 and 37°C, it completely breaks apart to capsaicin and CA-101 as the 
sole degradants. 
The cyclic urea (CA-101) formed has not been previously evaluated for biological activity.  
While not a known compound in the clinical literature, its safety was evaluated in all nonclinical 
studies with CA-008 and it was shown to be inactive.  The toxicokinetic profiles for CA-008, 
CA-101, and capsaicin were determined in GLP safety studies and the PK profile for various 
doses were determined in a Phase 1 ascending dose safety study in patients undergoing 
bunionectomy. 
5.3. 
Previous Human experience 
There is substantial clinical support for the potential safety of capsaicin, the active molecule 
released by CA-008 in vivo.  In addition to consumption in hot spicy foods (chili peppers), 
capsaicin is an approved product for dermal applications for OTC and prescription use (Qutenza; 
8% patch for management of neuropathic pain associated with post herpetic neuralgia), is 
frequently used intradermally in experimental pain models, and has been studied clinically for 
wound instillation for postsurgical analgesia (Anesiva; Adlea; capsaicin for instillation).  
A first-in-human study (Study CA-PS-2017-101) evaluated the safety and tolerability of CA-008 
in subjects undergoing a unilateral transpositional first metatarsal osteotomy for correction of 
hallux valgus deformity, more commonly known as a bunionectomy.  This study also evaluated 


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


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


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


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Table 5.  Summary of Related TEAEs by Frequency 
 
 


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Table 6. Summary of Related Local TEAEs by Frequency 
 
 
 


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Table 7. Summary of Severe TEAEs by Frequency 
 
5.4. 
Study Rationale 
CA-008 is being investigated as a potential therapy for treatment of pain following surgery.   
5.5. 
Dose Rationale 
5.5.1. 
 Selection of Doses 
The safety of CA-008 was established in relevant animal models and supported by two studies 
after bunionectomy (CA-PS-2017-101 and CA-PS-201) and knowledge from prior human 
studies with an injectable formulation of capsaicin.  Taken together, the characterization of the 
pharmacology, pharmacokinetics, and toxicology profiles are considered sufficient to support the 
intended use of CA-008 in this study. 
5.5.2. 
Selection and Timing of Dose 
CA-008 is a pH labile prodrug of capsaicin that rapidly releases capsaicin after administration 
into tissue.   Decision for single administration at the time of surgery is based on capsaicin’s 
mechanism of action. Capsaicin exposure results in initial excitation followed by a functional 
desensitization of TRPV-1-expressing nociceptors which continues for some time after removal 
capsaicin from the site.   Administration while the patient is under anesthesia for the procedure 
supplemented by a regional local anesthetic block or local anesthetic infiltration of the surgical 
site should sufficiently address any transient pain that results from TRPV1 agonism.  
Administration of CA-008 during the wound closure process is ideal for delivering therapy to the 
surgical site, thus optimizing target engagement.  During closure, the surgical tissue is exposed 
and visible which allows for complete and adequate delivery of CA-008 (and capsaicin) to the 
potential areas where noxious pain is generated. 


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6. 
STUDY OBJECTIVES 
6.1. 
Pilot (Exploratory) Stage of the Study 
6.1.1. 
Primary Objectives  
• To evaluate the efficacy of a single intraoperative administration of CA-008 vs. placebo 
(100 mL volume) in subjects undergoing an elective TKA.   
Note that in the pilot stage cohort #1 evaluates 5 mg CA-008 vs. placebo (100 mL volume).  For 
cohort #2, CA-008 10 mg will be evaluated vs. placebo (100 mL volume) and in cohort #3, CA-
008 15 mg will be evaluated vs. placebo (100 mL volume).   
6.1.2. 
Secondary Objectives 
• To evaluate the safety and tolerability of a single intraoperative administration of CA-008 
vs. placebo in subjects undergoing an elective TKA.  
• To evaluate the PK profile of a single intraoperative administration of CA-008 in subjects 
undergoing an elective TKA.  
• To evaluate the opioid-sparing effect of CA-008 vs. placebo in subjects undergoing an 
elective TKA. 
6.2. 
Second (Parallel Design) Stage of the Study 
6.2.1. 
Primary Objectives 
• After an interim unblinded analysis of the pilot stage of the study, to evaluate the efficacy 
of a single intraoperative administration of CA-008 vs. placebo in subjects undergoing an 
elective TKA 
Note that for the second (parallel design) stage, an amendment will be performed after receiving 
the cohort #3 results from the pilot stage.  This amendment will designate the number and doses 
of active treatment groups, and volume to be used for active and placebo groups. 
6.2.2. 
Secondary Objectives  
• To evaluate the safety and tolerability of a single intraoperative administration of CA-008 
vs. placebo in subjects undergoing an elective TKA.  
• To determine the efficacy of various doses of CA-008 vs. placebo administered 
intraoperatively in subjects undergoing an elective TKA.  
• To evaluate the PK profile of a single intraoperative administration of CA-008 in subjects 
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6.2.3. 
Exploratory Objective 
• Pharmacoeconomic benefits from administration of CA-008 vs. placebo in subjects 
undergoing an elective TKA. 


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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design and Plan 
This is a Phase 2, multi-center, randomized, double-blind, placebo-controlled, two stage study 
(exploratory pilot stage followed by a parallel design stage) evaluating a single dose of CA-008 
vs. placebo injected/instilled during an elective TKA.   
The choice between the two doses of CA-008 for cohort #1 of the pilot stage of the study was 
based upon the topline results from the Phase 2 bunionectomy study.  Additionally, two more 
pilot stage cohorts will be added. 
After an interim unblinded analysis of the pilot stage results (cohorts #1 through #3), a second 
stage will be performed with dose and volume levels, sample size and number of CA-008 
treatment groups vs. placebo to be determined. 
For each subject, the postoperative assessments will be conducted in two parts: 
• Inpatient period which starts with completion of study treatment injection (T0) and 
continues through 96h (T96h).   
• Outpatient period which begins on discharge from the inpatient unit through various 
follow-up visits to day 29 (D29±2) (W4) after surgery or later if necessary for ongoing 
safety assessments.  Note that additional follow up visits could occur after D29/W4 to 
follow adverse events (AEs) to resolution or establishment of a new baseline. 
7.2. 
Duration of Participation 
Each subject is expected to be in the study up to 76 days (screening through end-of-study visit). 
7.3. 
Study Stopping Rules 
Study enrollment will be paused if subjects experience intolerable possibly related TEAEs 
(shown in Table 8) as defined: 
• 1 or more subjects with any grade 4 “related” TEAE in any of the categories  
• 2 or more subjects with the same grade 3 “related” TEAE in any of the categories  
Refer to Table 8 below for descriptions/definitions of AE severity grading.   
An external independent Safety Review Committee (SRC) will be consulted should a stopping 
rule be triggered to determine whether it is appropriate to continue with dosing in the study.  This 
committee will be independent of the Sponsor or CRO and will in no way be involved with study 
conduct.  The SRC Charter details the membership, roles and responsibilities of the SRC. 


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Table 8.  
Study Stopping Rules 
Category 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially Life 
Threatening  
(Grade 4) 
Abnormal 
Wound Healing: 
Infection 
Dehiscence 
Necrosis 
 
Mild symptoms; 
clinical or diagnostic 
observations only; 
intervention not 
indicated. No 
interference with age-
appropriate 
instrumental ADL 
Minimal, local or 
noninvasive 
intervention 
indicated; May 
require local wound 
care or medical 
intervention (e.g., 
dressings or topical 
medications) 
Severe or medically 
significant 
but not immediately life-
threatening; hospitalization 
or 
prolongation of existing 
hospitalization indicated; 
limiting ADLs. May require IV 
antibiotics, antifungals, or 
antivirals or radiologic 
intervention. 
Life-threatening 
consequences; 
urgent intervention 
indicated 
ECG/Cardiac 
issues 
Vital Signs 
Labs 
Asymptomatic, 
intervention not 
indicated 
 
Non-urgent medical 
intervention 
indicated 
 
Severe or medically 
significant 
but not immediately life-
threatening; hospitalization 
or 
prolongation of existing 
hospitalization indicated  
Life-threatening 
consequences; 
urgent intervention 
indicated 
Focused 
Neurosensory 
Testing 
(performed by 
trained 
Investigator) 
Mild symptoms  
 
Moderate symptoms; 
limiting instrumental 
ADL 
 
Severe symptoms requiring 
medical intervention; 
limiting self-care ADL 
Life-threatening and 
urgent 
intervention 
indicated 
 
 


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8. 
SELECTION OF STUDY POPULATION 
8.1. 
Study Population 
The study population consists of adults, aged 18-80 years old inclusive, who are undergoing 
elective TKA. 
8.1.1. 
Number of Participants 
Pilot (exploratory) Stage: 
• Cohort #1: N=18 randomized 1:1, CA-008 vs. placebo 
• Cohort #2: N=18 randomized 2:1, CA-008 vs. placebo, respectively 
• Cohort #3: N=18 randomized 2:1, CA-008 vs. placebo, respectively 
A second (parallel design) stage of the study is anticipated with a much larger sample size to be 
determined after an interim analysis of the pilot stage cohort #3 is conducted. 
8.2. 
Eligibility Criteria 
8.2.1. 
Inclusion Criteria 
Subjects must meet all of the following criteria to be considered eligible to participate in the study: 
1. Plan to undergo an elective primary unilateral total knee arthroplasty (TKA or knee 
replacement), without collateral procedure or additional surgeries. 
2. In the medical judgment of the investigator, be an adult aged 18 - 80 years old, inclusive, 
and American Society of Anesthesiology (ASA) physical Class 1, 2 or 3 at the time of 
randomization (Section 17.1 Appendix A). 
3. If a male, unless he has a same sex partner, be either sterile (surgically or biologically) or 
commit to an acceptable method of birth control while participating in the study.  The site 
personnel will provide instructions on what is an acceptable method. 
4. If a female, must meet all of the following: 
a. A female of child-bearing potential (FCBP) must have a negative serum pregnancy 
test at screening and negative urine pregnancy test before surgery; 
b. No plan to become pregnant or to breast feed during the study; and 
c. Be surgically sterile or at least one year post-menopausal, have a monogamous 
partner who is surgically sterile, have a same sex partner or (one of the following 
must apply) 
i. is practicing double-barrier contraception  
ii. is practicing abstinence (must agree to use double-barrier contraception in 
the event of sexual activity) 
iii. is using an insertable, injectable, transdermal or combination oral 


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contraceptive approved by the FDA for at least 2 months prior to screening 
and commits to the use of an acceptable form of birth control while 
participating in the study. 
5. Have a body mass index ≤ 36 kg/m2. 
6. Be willing and able to sign the informed consent form (ICF) approved by an Institutional 
Review Board (IRB). 
7. Be willing and able to complete study procedures and pain scales and to communicate 
meaningfully in English or Spanish with study personnel and return for outpatient follow 
up visits as required. 
8.2.2. 
Exclusion Criteria 
Subjects will not be eligible to participate in this study if any one of the following exclusion criteria 
is met: 
1. In the opinion of the Investigator,  
a. have a concurrent painful condition, other than pain in the knee to be replaced, that 
may require analgesic treatment during the study period or may confound post-
surgical pain assessments. 
b. have active skin disease or other clinically significant abnormality at the anticipated 
site of surgery that could interfere with the planned surgery. 
2. Have a known allergy to chili peppers, capsaicin or the components of CA-008, ropivacaine 
HCl, ketorolac, acetaminophen, fentanyl, hydromorphone, morphine or oxycodone. 
3. As determined by the investigator (with input from the study’s medical monitor if requested 
by the investigator), have a history or clinical manifestation of significant medical, 
neuropsychiatric or other condition, including a clinically significant existing arrhythmia, left 
bundle branch block or abnormal ECG, myocardial infarction or coronary arterial bypass graft 
surgery within the prior 12 months, significant abnormal clinical laboratory test value, or 
known bleeding abnormality that could preclude or impair study participation or interfere with 
study assessments. 
4. The following are considered disallowed medications: 
a. Be tolerant to opioids defined as those who have been receiving or have received 
chronic opioid therapy greater than 15 mg of oral morphine equivalents (Table 9) 
per day for greater than 3 out of 7 days per week over a one-month period within 6 
months of screening. 
b. Within 1 day prior to surgery and throughout the inpatient period, be taking or using 
any capsaicin-containing products, such as dietary supplements or over-the-counter 
(OTC) preparations, including topical formulations, and prescription medications. 
c. Within the 7 days prior to surgery, be taking any central nervous system (CNS) 
active agent as an analgesic adjunct medication, such as anticonvulsants, 


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antidepressants (such as SNRIs, SSRIs, and tricyclic antidepressants), 
benzodiazepines, sedative-hypnotics, clonidine and other central alpha-2 agents 
(e.g., tizanidine), ketamine or muscle relaxants.   [Note that SNRIs = Serotonin and 
norepinephrine reuptake inhibitors and SSRI = Selective serotonin reuptake 
inhibitors.] 
i. These drugs are permitted if prescribed for non pain indications and the dose 
has been stable for at least 30 days prior to surgery.  Note that the dose must 
remain stable throughout the study.  
ii. If the subject is taking centrally- and/or peripherally-acting analgesic 
medications, such as acetaminophen, NSAIDs, tramadol or opioids, FOR 
knee-related pain, the subject may participate in the study if 4(a) above is 
not applicable and the subject is willing to discontinue these medications 3 
days prior to surgery.  Note that baby aspirin for cardiovascular prophylaxis 
is allowed during the study. 
iii. The use of benzodiazepines and the non-benzodiazepines (eszopiclone, 
ramelteon, zaleplon and zolpidem) are permitted to treat insomnia during 
the postoperative period.  
d. Within the 7 days prior to the planned surgery and throughout the study, be taking 
antiarrhythmics except beta-blockers, digoxin, warfarin (see exception below), 
lithium, or aminoglycosides or other antibiotics for an infection (except for 
ophthalmic use or for treatment or prophylaxis of postoperative surgical site 
infections).  At the investigator’s discretion, agents intended for deep venous 
thrombosis (DVT) prophylaxis after the surgery is allowed. 
e. Within the 14 days prior to surgery, be taking parenteral or oral corticosteroids 
(steroid inhaler for allergy or asthma treatment, topical steroid for a non-clinically 
significant skin condition not involving the area of surgery or ophthalmic steroids 
are permissible). 
f. Be on an antianginal, antihypertensive agent or diabetic regimen at a dose that has 
not been stable for at least 30 days or which is not expected to remain stable while 
participating in the study. 
5. In the opinion of the Investigator, within the past year have a history of illicit drug use or 
prescription medicine or alcohol abuse (regularly drinks > 4 units of alcohol per day; where a 
unit = 8 oz. beer, 3 oz. wine or 1 oz. spirits).   
6. Have positive results on the alcohol breath test indicative of alcohol abuse or urine drug 
screen indicative of illicit drug use (unless results can be explained by a current prescription 
or acceptable over-the-counter medication at screening as determined by the investigator) at 
screening, and/or prior to surgery.  Note that for those subjects who test positive for 


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tetrahydrocannabinol (THC), if they are willing to abstain from use or consumption of THC-
containing products from 3 days prior to surgery to the day 8 visit, they may be allowed to 
participate in the study.   
7. Willing and able to avoid foods containing capsaicin for 24 hours prior to surgery and PK 
blood draws. 
8. Have previously participated in a clinical study with CA-008. 
9. Have participated in another clinical trial or used an investigational product within 30 days or 
five half-lives (whichever is longer) prior to the planned surgery, or is scheduled to receive an 
investigational product other than CA-008 while participating in the study. 


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9. 
STUDY TREATMENTS 
9.1. 
Study Treatment  
Complete details of study drug packaging, storage, dispensation, preparation and tracking are 
provided in the pharmacy manual. 
9.1.1. 
CA-008 HCl Description 
CA-008, provided as the hydrochloride salt is a white solid, highly soluble in water.  It degrades 
rapidly to capsaicin at neutral pH but is stable for several days at room temperature in aqueous 
solution at pH~3.  Capsaicin is known to be irritating to mucous membranes when aerosolized 
and is a skin irritant. 
9.1.2. 
Study Treatment Description 
The active drug product will be provided as CA-008 frozen concentrate solution for injection in a 
1.0 mL vial with doses calculated as the freebase.   
The placebo comparator is identical in appearance. 
The proposed doses of CA-008 to be evaluated in the Pilot Stage of the study are:  
• Cohort #1: CA-008 5 mg vs. placebo in 100 mL of vehicle 
• Cohort #2: CA-008 10 mg vs. placebo in 100 mL of vehicle 
• Cohort #3: CA-008 15 mg  vs. placebo in 100 mL of vehicle  
An unblinded pharmacist or designee may use unblinded vials identified as to contents.  
However, at the time of reconstitution, the anesthesia and surgical team and study site personnel 
will be blinded as to study treatment.  At time of use, the concentrate will be completely 
reconstituted and used for treatment (see the Pharmacy Manual).  These details will be reflected 
in the Unblinding Plan and the Pharmacy Manual. 
9.1.3. 
Study Treatment Storage 
Study treatments will be shipped to sites and stored at -20°C (-15°C to -30°C) until the day of 
surgery.  All study treatment should be stored in a secured area and in accordance with the 
product labeling and all applicable laws, regulations, and local/institutional requirements.  A 
description of storage conditions for all investigational products will be provided in the 
Pharmacy Manual. 
9.1.4. 
Study Treatment Accountability 
All study treatment will be transported, received, stored, and handled strictly in accordance with 
the container or product label, the instructions provided to the research site, and applicable 
regulations.  Detailed drug accountability records must be maintained, including the dates 


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shipments are received, the quantity of material received, the dates dispensed and the running 
inventory.  The unused quantities will be returned to the Sponsor’s drug supply vendor at the end 
of the trial. All unused supplies will be checked against the drug accountability records during 
the study and/or at the end of the study. The Investigator or designee must maintain an inventory 
record of all dispensed rescue medications to subjects. Additional details are provided in the 
Pharmacy Manual. 
Only eligible subjects participating in the study will receive the study treatment. Only authorized 
research site staff may supply, prepare or administer the study treatments. Once dispensed, study 
treatment may not be relabeled or reassigned for use by other subjects.  
9.1.5. 
Control of Study Treatment and Rescue Medication 
Mishandling, potential theft, significant loss of clinical supplies, including study treatments, 
systemic analgesia medications and rescue medications at the site, or other suspected diversion 
must be reported to the Sponsor or designee within 24 hours of first knowledge of the issue. If 
diversion is confirmed or suspected (e.g., excessive use of rescue medications), the study staff 
will be required to complete a clinical supply documentation form, including information related 
to situations in which a subject sold drug or gave drug to a friend or relative, there is a 
discrepancy in drug accountability and suspected diversion, or a subject had drug stolen, or if 
there was diversion or theft by site staff or others. 
9.2. 
Other Interventions 
9.2.1. 
Inpatient Analgesia  
Within 30 min of anesthesia induction give the subject IV hydromorphone 1.5 mg. 
During the surgery, ensure that each subject has received at least 100 mcg of IV fentanyl with 
adjustments above this dose per anesthesiologist discretion. 
Within 15 min of the end of surgery, give the subject IV hydromorphone 0.5 mg 
Within 15 min of the end of surgery, administer the following: 
• IV ketorolac 30 mg (for example, ketorolac full prescribing information is available at: 
http://www.sagentpharma.com/wpcproduct/ketorolac-tromethamine-injection-usp/ [Sagent 
Pharmaceuticals 2018]).  Dose adjustments may be made per surgeon/anesthesiologist 
discretion to accommodate the subject’s age and health status. 
• IV acetaminophen 1 g (Ofirmev®, Mallinckrodt Pharmaceuticals 2018) full prescribing 
information at http://ofirmev.com/.  


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After these non-opioids have been administered, no additional non-opioid analgesics are to be 
administered during the inpatient phase of the study. 
9.2.2. 
Inpatient Rescue Medications 
After surgery, subjects will be monitored in the post-anesthesia care unit (PACU) for at least 90 
min during which time efficacy asssessments can begin once the subject is awake.  During this 
time, IV fentanyl 25-50 mcg q5 min prn for moderate-to-severe pain (≥ 4) as reported by 
subjects using the 0 to 10 numerical rating scale of current pain intensity (NRS).  After discharge 
from the PACU, subjects are followed through T96h as an inpatient.  
From the time of discharge from the PACU through T48h administer IV hydromorphone 0.5 mg 
q15 min prn for NRS ≥ 4 as reported by subjects. 
After T12h, administer PO oxycodone 5 mg q2h prn moderate pain (NRS ≥ 4 and ≤ 6) or 10 mg 
q2h prn severe pain (NRS ≥ 7).  From T12 through T48h, IV hydromorphone may be used as 
rescue in addition to PO oxycodone for moderate-to-severe pain.  After T48, only PO oxycodone 
may be used as rescue.  If a subject still requires IV opioid rescue after T48, then the subject 
should undergo an early termination due to lack of efficacy. 
Subjects will be encouraged to rescue only for moderate pain scores (NRS ≥ 4), however rescue 
may be requested at any time and medication will be provided when requested. 
9.2.3. 
Outpatient Analgesic Medications 
Once discharged from the inpatient unit, all study participants will be instructed to take a 
combination of over-the-counter (OTC) analgesics at an appropriate dose per medical judgment 
to manage any residual or breakthrough postsurgical pain. 
Outpatient period: after T96h discharge through D29/W4, if needed for pain management, the 
following oral OTC analgesics will be recommended for subjects to self-administer (note that 
these medications will not be provided by the sponsor):  
• A nonsteroidal anti-inflammatory drug (NSAID) (e.g., ibuprofen 200 mg prn up to qid 
[Advil® or Motrin®] or naproxen 220 mg prn up to tid [Aleve®]) or other NSAID per 
investigator discretion and  
• Acetaminophen 1000 mg prn up to tid or 650 mg up to qid (3g daily maximum limit) 
If a subject is still requiring opioid rescue in the 12h prior to discharge from the inpatient unit 
(i.e., from T84h on regardless of whether discharge is delayed), then prescribe no more than 9 
tablets of oxycodone 5 mg (1 PO tid prn) per investigator discretion for the initial outpatient 
period.  If refills are necessary, an unscheduled visit may be important to understand why there is 
continued pain, as persistent pain or pain exacerbations during this period may suggest the need 
to assess the surgical site.  If such a situation occurs, the Investigator should use clinical 
discretion on adequacy of analgesic treatment but capture this event as an AE and document any 
required treatments. 


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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. 
In the Pilot Stage, subjects in each cohort will be randomized to either the active medication or 
placebo.  Subsequently, the number of active treatment groups and sample size will be 
determined after the interim unblinded analysis of topline data from cohort #3 of the Pilot Stage. 
Once any subject number or randomization number is assigned, it cannot be reassigned to any 
other subject. This study will use manual randomization. 
Subjects may be rescreened if the screening window is exceeded due to scheduling issues.  
9.4. 
Blinding 
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.  Note that the placebo is identical in appearance to CA-008 once 
reconstituted. 
Under normal circumstances, the blind will not be broken until all participants have completed 
treatment. In case of emergency, and only if the information is required by the Investigator to 
ensure subject’s safety in managing a medical condition, the treatment may be unblinded at the 
site by using a code break module.  The code break module will be provided by the Sponsor or 
designee. If possible, the Investigator should contact the Sponsor prior to unblinding and after 
any actions have been taken. Whenever a treatment sequence is prematurely unblinded, the 
reason, date and time of the unblinding, and the individual who broke the blind must be 
documented. Individual code breaks will result in withdrawal of the participant from the study. 
It is assumed that the need to unblind a study subject’s treatment assignment will occur in the 
setting of an SAE, and therefore, all procedures for the reporting of a SAE must be followed. 
9.5. 
Prior and Concomitant Therapy 
All non-study medications, including prescription, over-the-counter, or herbal therapies, used by 
the subject will be documented for the 45 days prior to screening and throughout the study. The 


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Investigator will determine if the prior/concomitant medication(s) affect the subject’s eligibility 
to participate or continue to participate in the study.  
On a case-by-case basis, the Investigator is permitted to allow the use of some concomitant 
medications, for example, to treat an AE, if the Investigator determines that the medication will 
not affect the subject’s safety or study integrity. Wherever possible, the Investigator should 
obtain approval from the Medical Monitor prior to administering the medication.  
9.6. 
Study Restrictions 
In addition to the criteria described in Sections 8.2, 9.2, 9.5, and 10.1.2 the subject must agree to 
abide by the following study restrictions:  
Abstain from the following during the inpatient portion of the study: 
▪ consuming any alcohol 
▪ smoking or vaping (nicotine-containing or other substances)  
▪ illicit drug use or non-medical use of therapeutic drugs not allowed by the protocol 
▪ any foods containing capsaicin for 24 hours prior to PK blood draws 
Abstain from the following during the outpatient portion of the study: 
▪ Subjects will be asked to abstain from consuming more than 1 (women) or 2 drinks (men) per 
day of alcohol  
▪ Subjects will be asked to abstain from illicit drug use or non-medical use of therapeutic drugs  
▪ Subjects will be asked to abstain from taking prohibited medications  
9.7. 
Treatment Compliance  
Because all study medication is being administered by study personnel, no compliance 
procedures are necessary. Diversion will be monitored and recorded through rescue medication 
accountability. Any suspected or confirmed diversion will be documented and reported. 


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10. 
CONDUCT OF THE STUDY 
All study assessments will be performed at the visits and timepoints outlined in the Schedule of 
Assessments (Table 1); the following sections outline the detailed timing and procedures 
associated with the visits and assessments.  
10.1. 
Study Visits 
10.1.1. 
Screening Phase (Day -45 to Day -1):   
Subjects will be screened for participation at the study within 45 days of surgery/study drug 
administration. The following assessments will be completed: 
• 
Informed Consent 
• 
Inclusion / Exclusion evaluation 
• 
Demographics 
• 
Medical and surgical history 
• 
Prior/current medications 
• 
Complete Physical Exam (PE), including height and weight 
• 
Vital signs including temperature (Section 17.10 Appendix J) 
• 
Baseline neurosensory exam 
• 
Clinical laboratory tests (chemistry/coagulation, hematology, and urinalysis) (Section 
17.9 Appendix I) 
• 
Urine Drug Screening (UDS)  
• 
Alcohol breath/saliva test 
• 
Serum Pregnancy test (FCBP), if applicable 
• 
12-Lead Electrocardiograms (ECG)  
• 
KOOS Survey  
• 
Subject pain assessment training 
• 
Adverse Event (AE) assessment (record any current conditions as medical history) 
10.1.2. 
Surgery Phase: Day 1- Prior to surgery (baseline) up to the end of surgery   
10.1.2.1. Prior to Surgery (D-1 to D0) 
Subjects who meet the selection criteria at the Screening Visit and are eligible to participate in 
the study will be required to return to the study center for surgery within 45 days of screening. 
The following assessments will be performed: 
• 
Confirm informed consent 
• 
Review of Inclusion / Exclusion 


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• 
Review of medical and surgical history since screening 
• 
Review of prior and current concomitant medications 
• 
Interim targeted PE with inspection of the planned area of surgery (if not done at Screening 
visit) 
• 
Urine Pregnancy test (FCBP) if applicable 
• 
UDS  
• 
Alcohol breath/saliva test 
• 
Blood draws and urine collections for PK analyses 
• 
Vital signs and temperature 
• 
Subject pain training review (watch video) 
• 
Randomize to treatment after confirmation of continued eligibility 
10.1.2.2. Anesthesia and Surgery 
The surgery will be performed under general anesthesia with either supplemented by an adductor 
canal (AC) block AND an IPACK infiltration (Interspace between the Popliteal Artery and the 
Capsule of the posterior Knee between the femoral condyles).  Recent literature suggests the 
AC+IPACK approach is the new “best practice” to supplement anesthesia as part of an enhanced 
recovery after surgery (ERAS) for TKA (Cullom 2017, Sankineani 2018).   
Perform the AC+IPACK local anesthetic regional blocks under ultrasound guidance prior to the 
start of surgery.  The dose of IV fentanyl administered during surgery should be 100 to 300 mcg 
with adjustments per anesthesiologist discretion. 
• Using ropivacaine hydrochloride (RopiHCl)  
o AC block: 20 mL of 0.5% (100 mg)  
o IPACK infiltration: 20 mL of 0.2% (60 mg) 
A tourniquet will be used in all subjects. After exsanguination, but prior to surgical incision, 
perform surgical site infiltration with RopiHCl 0.2% 30 mL (100 mg).   
The total RopiHCl should not exceed 200 mg.  See Appendix M (Section 17.12) for guidance on 
RopiHCl dosing. 
10.1.3. 
Surgery Phase: Administration of Study Medication Into the Surgical Site 
Study treatment is to be administered intraoperatively as a single administration via “surgical 
site” infiltration.  The “surgical site” is defined as the area extending approximately 5 cm in all 
directions (lateral/medial/proximal/distal/deep) from the incision and osteotomy sites and 
surrounding tissues which may be affected by infiltration of the study treatment.   
Note that T0 is the time that the study treatment injection/instillation is completed.  
Pilot Stage: 


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Prior to hardware placement, 100 mL of study treatment should be infiltrated/instilled as follows: 
1. Infiltrate 15 mL divided equally throughout the posterior capsule  
With the leg in full extension, perform the following (working from top to bottom or using another 
standardized method per surgeon discretion) : 
2. Infiltrate 15 mL circumferentially around the distal femur  
3. Infiltrate a total of 30 mL divided equally into the medial and lateral gutters ensuring 
coverage of the periosteal borders 
4. Infiltrate 10 mL around the peripatellar region 
5. Infiltrate 10 mL divided equally medial and lateral to the tibial tubercle 
Following closure of the joint capsule, 
6. Instill 20 mL “intra-articularly” (lateral approach) and move the joint through full range of 
motion 
Second Stage: 
Instructions for study treatment infiltration/instillation will be designated in the protocol 
amendment to follow the Pilot Stage. 
10.1.4. 
Inpatient Phase: Time 0 (Post-Surgery) to Day 4 (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 96 hours. The schedule of 
assessments are as follows:  
• 
Subjects with inadequately controlled pain may request rescue at any time; however, subjects 
will be encouraged to receive rescue medication only with an NRS ≥ 4.   
• 
Pain intensity (assessed with NRS):  
o 
During the inpatient stay, beginning with the PACU admission and after the subject is 
awake: assess the NRS at rest at 0.5, 1, 2, 4, 6, 8, 12, 16, 20, and 24 hours, and every 4 
hours (if awake at time of assessment) until discharge from the inpatient unit.  Time 
windows: for T0.5 to T2 (±5 min) and from T4 onward (±15 min). 
o 
Pain scores may be skipped between the hours of midnight and 6 a.m., but the subject 
may not miss two consecutive assessments.  The T12, T24, T48, T72 and T96h 
assessments must be completed even if the subject is asleep at these times. 
o 
Pain intensity (NRS) will be completed at the time of rescue medication request (±15 
minutes).     
o 
During the inpatient stay, starting on postoperative day 1 (after T24): each morning on 
ambulation at 0800h (±2h) and each evening at 2000h (±2h) document the NRS after 
physical therapy or with partial or full weightbearing for transfers to/from bed or frank 
ambulation of approximately 10 yards.  Actual assessment times must be documented.  
These assessments are in addition to the time-specific NRS assessments at rest.  If 


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however, these twice daily assessments coincide with timed assessments of NRS at rest, 
then the time assessment at rest is used in place of the twice daily assessments. 
• 
Vital signs (heart rate [HR], blood pressure [BP], respiratory rate [RR]) and temperature are 
assessed together post-surgery at T1, T2, T4, T6, T12, and T24h, and every 8 hours thereafter 
until T96h.  Assessments between the hours of 00:00 and 06:00 may be skipped if the subject 
is sleeping; however, two consecutive assessments may not be skipped.  The allowable 
window is ±5 minutes for the first 4 hours post-surgery, and ±15 minutes for all other times. 
• 
Targeted Physical exam: 96 (±4) hours after the administration of study medication (prior to 
discharge from the unit).   
• 
ECG: 24 (±2) hours after the administration of study medication.  
• 
Surgical site assessment: 96 (±4) hours after the administration of study medication. If the 
investigator determines there are atypical wound healing or visible abnormal findings, a 
digital picture of the wound site should be performed. 
• 
Neurosensory testing of the surgical area: 96 (±4) hours after the administration of study 
medication.  
• KOOS Survey: T96h (±4h) prior to discharge from the unit 
• Clinical laboratory tests: T96h (±4h) prior to discharge from the unit. 
• 
Blood draw for PK analysis: The time points for whole blood collection will be at check-in/ 
baseline (up to 30 min prior to surgery), and T5min, T10 min, T15min, T30min, T45min, and 
T1, T1.5, T2, T2.5, T3, T4, T6, T8, T12, T16, T24, T30, T36 and T48h for a total of 20 
samples).   
• 
24h urine collection in two aliquots: end of surgery to T6h and T6h to T24h. 
• 
Subject completes Patient Global Evaluation (PGE) assessment and KOOS survey at T96h 
(±4) prior to discharge 
• 
Investigator completes Investigator Global Evaluation (IGE) assessment at T96 (±4) prior to 
discharge.  Note that the IGE may be performed by any investigator or sub-investigator. 
• 
Record rescue medication consumption and concomitant medications throughout the 
inpatient period. 
• 
Record AEs throughout the inpatient period (Section 17.11 Appendix K may be useful to the 
investigator for assessing systemic [general] AEs)  
After completing the assessments through T96h, the diary for at-home use will be reviewed and 
subjects will be discharged from the study center with diary to record pain assessments and pain 
medication at home.  Subjects will be provided routine standard of care for pain management 
after discharge from the study center.  Subjects will be instructed to return to the study center on 
Day 8 [±1 day] for follow-up assessments.  


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10.1.5. 
Outpatient Phase: Days 4 (after discharge) through 8: 
In their diary, subjects will assess their pain intensity at rest and after ambulation (of 
approximately 10 yards) once in the morning (08:00 ±4 hours), and once in the evening (20:00 
±4 hours) using the NRS (two separate scores “at rest” and after “ambulation”. Subjects will also 
record any medication they take to treat their pain.  
Subjects will return to the study center on Day 8 [±1 day] for the following assessments:  
• 
Subject home diary review (pain intensity and pain medication) 
• 
Pain Intensity assessment (NRS) 
• 
KOOS Survey on Day 8±1 
• 
Vital signs including temperature 
• 
Targeted PE 
• 
Surgical Site assessment (If the investigator determines there are atypical wound healing or 
visible abnormal findings, a digital picture of the wound site should be performed if the subject 
has consented to such a photo) 
• 
Neurosensory testing of the surgical area 
• 
Query the subject as to any rebound pain 
• 
Concomitant Medication Use/Concomitant Treatments 
• 
AE Assessment 
• 
PGE 
• 
IGE 
10.1.6. 
Outpatient Phase: Days 9 through 15: 
In their diary, subjects will assess their pain intensity at rest and after ambulation (of 
approximately 10 yards) once in the morning (08:00 ±4 hours), and once in the evening (20:00 
±4 hours) using the NRS (two separate scores “at rest” and after “ambulation”. Subjects will also 
record any medication they take to treat their pain.  
Subjects will return to the study center on Day 15 [±2 days] for the following assessments:  
• 
Subject home diary review (pain intensity and pain medication) 
• 
Pain Intensity assessment (NRS) 
• 
KOOS Survey 
• 
Vital signs including temperature 
• 
Targeted PE 
• 
Surgical Site assessment (If the investigator determines there are atypical wound healing or 
visible abnormal findings, a digital picture of the wound site should be performed if the subject 
has consented to such a photo) 
• 
Neurosensory testing of the surgical area 


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• 
Query the subject as to any rebound pain 
• 
Concomitant Medication Use/Concomitant Treatments 
• 
AE Assessment 
• 
PGE 
• 
IGE 
10.1.7. 
Outpatient Phase: Day 29 
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) 
• 
KOOS Survey 
• 
Vital signs 
• 
Targeted PE 
• 
Surgical Site assessment (If the investigator determines there are atypical wound healing or 
visible abnormal findings, a digital picture of the wound site should be performed if the subject 
has consented to such a photo) 
• 
Neurosensory testing of the surgical area 
• 
Knee x-ray of the operated site 
• 
Concomitant Medication Use/Concomitant Treatments 
• 
Query the subject as to any rebound pain 
• 
AE Assessment 
• 
PGE 
• 
IGE  
10.1.8. 
Outpatient Phase: Early Termination 
Subjects who elect to ET and are willing to perform study completion assessments will return to 
the study center at a convenient time after discontinuation, for the following assessments:  
• 
Subject home diary review (pain intensity and pain medication) 
• 
Pain Intensity assessment (NRS) 
• 
KOOS Survey 
• 
Vital signs including temperature 
• 
Targeted PE 
• 
Surgical Site assessment (If the investigator determines there are atypical wound healing or 
visible abnormal findings, a digital picture of the wound site should be performed if the subject 
has consented to such a photo) 
• 
Neurosensory testing of the surgical area 
• 
Knee x-ray of the operated site 


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• 
Concomitant Medication Use/Concomitant Treatments 
• 
Query the subject as to any rebound pain 
• 
AE Assessment 
• 
PGE 
• 
IGE  
If the subject has elected an early termination and is unwilling to come in to have the assessments 
performed, at least try to have them return to their surgeon for a wound assessment and x-ray. 
10.1.9. 
Outpatient Phase: Unscheduled Visit 
Note that unscheduled visits will be at the discretion of the Investigator but should include the 
following if performed prior to D15 visit:  
• 
Subject home diary review (pain intensity and pain medication) 
• 
Pain Intensity assessment (NRS) 
• 
KOOS Survey 
• 
Vital signs including temperature 
• 
Surgical Site assessment (If the investigator determines there are atypical wound healing or 
visible abnormal findings, a digital picture of the wound site should be performed) 
• 
Targeted Physical Exam 
• 
Neurosensory testing of the surgical area 
• 
Concomitant Medication Use/Concomitant Treatments 
• 
Query the subject as to any rebound pain 
• 
AE Assessment 
If after D15 visit, subjects will return for the following assessments:  
• 
Surgical Site assessment (If the investigator determines there are atypical wound healing or 
visible abnormal findings, a digital picture of the wound site should be performed) 
• 
Neurosensory testing of the surgical area 
• 
KOOS Survey 
• 
Concomitant Medication Use/Concomitant Treatments 
• 
Query the subject as to any rebound pain 
• 
AE assessment 
If after D29 visit, the investigator has clinical discretion on when subjects should return for follow 
up and what is performed at the visit.  The following are the minimum assessments:  
• 
Surgical Site assessment (If the investigator determines there are atypical wound healing or 
visible abnormal findings, a digital picture of the wound site should be performed) 
• 
Neurosensory testing of the surgical area 
• 
KOOS Survey 


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• 
Knee x-ray of the operated site to ensure proper healing.  Follow subject until resolution or 
stabilization. 
• 
Concomitant Medication Use/Concomitant Treatments 
• 
Query the subject as to any rebound pain 
• 
AE Assessment 
10.2. 
Subject Completion and Withdrawal 
10.2.1. 
Subject Completion 
A subject is considered to have completed the study once all end-of-study assessments are 
completed at D29 (or later if necessary), or at the last visit upon early termination of the study. 
10.2.2. 
Subject Withdrawal 
A subject is free to withdraw his/her consent and discontinue participation in the study at any time 
for any reason. A subject’s participation must therefore be terminated immediately upon his/her 
request, and the reason(s) for discontinuation appropriately documented. 
A subject may be discontinued from the study for any of the following reasons: 
▪ Safety reasons, including AEs or significant concomitant illness, injury, or urgent 
surgeries/procedures that would, in the judgment of the Investigator, affect assessments of 
clinical status to a significant extent, require discontinuation of study drug, or both 
▪ At the request of the Sponsor, regulatory agency, or Institutional Review Board (IRB) 
▪ Subject is lost to follow-up 
▪ Subject treatment allocation is unblinded (i.e., individual code break; Section 9.4) 
▪ Death of subject 
A subject may also be discontinued from the study, at the discretion of the Investigator and/or 
Sponsor, for any of the following reasons:  
▪ Subject refuses or is unable to adhere to the study protocol 
▪ Major protocol violation 
▪ Pregnancy 
▪ Use of unacceptable concomitant medication(s) 
▪ It is not considered in the best interest of the subject to continue 
▪ Administrative reasons (e.g., termination of enrollment or study) 
The Investigator must maintain a record of all subjects who discontinue from the study prior to 
completion; the reason(s) for study discontinuation will be documented. If a subject chooses to 
withdraw from the study, the Investigator should make a reasonable attempt to obtain and record 


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the reason(s) for withdrawal in as much detail as possible, although the subject is not obligated to 
provide such a reason.  
Subjects who elect to discontinue participation prior to D8 (W1) will be considered to have 
terminated as of the date of their election, however they will be asked to return to the site or their 
surgeon, if willing and at their convenience, to ensure adequate wound healing.  If a subject 
should refuse to complete early termination/Follow-up procedures or continued data collection, 
this information will be recorded. 
10.3. 
Study Procedures and Assessments 
10.3.1. 
Informed Consent 
The nature of the study and its risks and benefits will be explained to the subject by the 
Investigator or designated study personnel. The subject must voluntarily provide written 
informed consent on an ethics-approved informed consent form (ICF), prior to performing any 
study-related procedures. The subject’s source records must document that the consent process 
has been completed and that written informed consent has been obtained from the subject prior 
to the initiation of any study-specific procedures. Documentation that the subject was given 
adequate time to ask the Investigator (or designee) questions about their participation in the study 
and that a signed and dated copy of the ICF was provided to the subject should also be included 
in the medical records or clinical chart. 
10.3.2. 
Demographics 
The following demographics will be recorded: age (birthdate), sex, race, and ethnicity.  
10.3.3. 
Medical and Surgical History 
The complete medical and surgical history will include histories of acute, chronic, or infectious 
disease; surgical or oncologic histories; and any reported conditions affecting major body 
systems. All findings on medical history will be evaluated by the Investigator for clinical 
significance. 
10.3.4. 
Medication History  
All medications (prescription and non-prescription, herbal medications/natural health products, 
or investigational drugs) taken by the subjects during the 45 days prior to Screening will be 
recorded in the source documentation as medication history.  
10.3.5. 
Contraceptive Requirements 
Female subjects of childbearing potential must be using and willing to continue using medically 
acceptable contraception during the study unless they have a same sex partner.  Examples of 
medically acceptable forms of contraception include true abstinence, hormonal contraceptives 
(combined oral pill, patch or vaginal ring, intrauterine device or system, progestin implant or 


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injection), bilateral tubal ligation, or double-barrier methods (i.e., male condom in addition to a 
diaphragm or a contraceptive sponge).  
Female subjects of non-childbearing potential are not required to use contraception or undergo 
pregnancy tests; however, they must be surgically sterile (e.g., hysterectomy and/or bilateral 
oophorectomy or salpingo-oophorectomy, as determined by subject medical history) or 
congenitally sterile or must be post-menopausal. Post-menopausal is defined as being 
amenorrheic for at least one year without another cause. 
Male subjects, unless in a relationship with a same sex partner or a female partner who is of non-
childbearing potential (see above), must either be sterile (surgically or biologically) or commit to 
using double-barrier methods (i.e., male condom in addition to a diaphragm or a contraceptive 
sponge) during the study.   
10.3.6. 
Subject Pain Assessment Training 
Subjects will undergo study participation education on pain assessments and written testing 
procedures according to the Schedule of Study Procedures. 
10.3.7. 
Digital Photographs of the Surgical Site 
During the informed consent process, subjects will be asked if they are willing to allow digital 
photographs to be taken of the surgical site. This is optional, and their response will in no way 
affect their inclusion in the study. Their response will be included on the ICF.  
10.3.8. 
Numerical Rating Scale for Pain Intensity (NRS) 
The NRS is an 11-point scale with anchors 0 (no pain) and 10 (worst possible pain) (Section 17.2 
Appendix B).   
Subjects will report or record the intensity of their current pain at designated times during the 
study after administration of study treatment.  Subjects should be at rest for at least 5-10 minutes 
prior to completing NRS resting assessment and have sat or stood up from a recumbent position 
within the 5-10 minutes prior to completing NRS assessment after this change in position.   
10.3.9. 
Rebound Pain at the Surgical Site 
Subjects will be queried at each outpatient follow up visit as to whether they have noted any 
worsening pain (rebound pain) at the surgical site since the prior visit report (Section 17.3 
Appendix C). 
10.3.10. 
Knee Injury and Osteoarthritis Outcome Score (KOOS) 
Subjects will complete the KOOS survey at designated times during the study after 
administration of study treatment (Section 17.13 Appendix M).  The KOOS survey was 
developed in the 1990s as an instrument to assess the patient’s opinion about their knee and 


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associated problems (see http://www.koos.nu/).  Note that for purposes of this study, responses 
in the KOOS will not be considered or captured as spontaneous AEs. 
10.3.11. 
Patient Global Evaluation (PGE) 
Each subject will be asked to report their satisfaction with the study treatment for pain using a 4-
point categorical scale.  Each subject will be asked the following question:  
“How would you rate the study treatment that you have received for pain? Poor (0), Fair (1), 
Good (2), or Excellent (3)” (see Section 17.4 Appendix D). 
10.3.12. 
Investigator Global Evaluation (IGE) 
The investigator will report their satisfaction with the subject’s study treatment for pain using a 
4-point scale at designated times during the study after administration of study treatment.  A 
study investigator will be asked the following question:  
“How would you rate the study treatment that the patient received for pain? Poor (0), Fair (1), 
Good (2), or Excellent (3)” (see Section 17.5 AppendixEAppendix E). 
10.3.13. 
Rescue Medications 
The details of rescue medication (doses and times) will be recorded beginning from the end of 
surgery through 14 days after the end of surgery (D15 visit) or to Early Termination Visit if 
applicable.  Subjects will be instructed on the proper use and timing of rescue medication.   
Use Table 9 to calculate the oral morphine equivalent dose (MED) of various opioids. 
Table 9. Equianalgesic Conversion Table  
Opioid (Doses in mg) 
Conversion Factor to 
IV morphine 
Conversion Factor to PO 
morphine 
IV Fentanyl 
100 
 
IV Hydromorphone 
6 
 
IV Morphine 
1 
6* 
PO Hydrocodone 
 
1 
PO Morphine 
 
1 
PO Oxycodone 
 
1.5 
PO Tramadol 
 
0.1 
For any IV opioid, we will use a 2-step process to calculate its oral (PO) morphine 
equivalent dose (MED).   


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1. Convert its IV dose to IV morphine MED by multiplying by the conversion 
factor for IV equivalence.   
2. Once the IV morphine MED is calculated, convert to the PO morphine MED 
using the conversion factor for PO equivalence. 
For any PO opioid, use the conversion factor to calculate the PO MED. 
*Note that for non-tolerant patients, we are using the 6:1 conversion for IV to PO 
morphine. 
10.3.14. 
Clinical Laboratory Assessments  
All protocol-specified laboratory tests on blood and urine samples will be collected, processed, 
shipped and analyzed according to instructions from a selected central laboratory. The lab will 
generate laboratory reports and forward them to the clinical site in a timely manner. It is the 
responsibility of the Investigator to review and sign all lab reports expeditiously, 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. 
Additional laboratory samples may be taken at the discretion of the Investigator if the results of 
any tests fall outside reference ranges or clinical symptoms necessitate testing to ensure safety. 
Specific hematology, coagulation, biochemistry, and urinalysis assessments are listed in Table 
10. 


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Table 10. Clinical Laboratory Assessments 
Hematology 
Chemistry 
Urinalysis 
Hematocrit 
Hemoglobin 
Red blood cell (RBC) count  
Total and differential (absolute) 
white blood cell count 
Platelet count 
Sodium 
Potassium  
Calcium  
Chloride 
Glucose   
Creatinine 
BUN 
Albumin 
Tot Bili 
ALT 
AST 
GGT 
Alkaline phosphatase  
Color 
Turbidity 
pH 
Specific gravity 
Ketones 
Protein 
Glucose 
Bilirubin 
Occult blood / Nitrite 
Urobilinogen 
Leukocyte esterase 
Microscopic examination of 
sediment, only if urinalysis 
dipstick results are abnormal 
 
Coagulation 
Activated partial 
thromboplastin time (aPTT) 
Prothrombin time (PT) / 
International normalized ratio 
(INR) 
 
The clinical laboratory tests will be completed per the Schedule of Assessments.  In addition to 
the clinical laboratory tests, a serum pregnancy test will be performed at the Screening Visit and 
a urine pregnancy test will be performed prior to surgery for women of childbearing potential. 
ALT or AST > 3x ULN / Tot. Bili > 2 X ULN/ Alk Phos. >2X ULN will be considered an 
adverse event, as well as any other changes deemed clinically significant by the Investigator.  
10.3.15. 
Urine Drug Screen and Alcohol Test 
Urine drug screen and alcohol breath/saliva tests will be completed at screening and pre-
procedure. All subjects will be tested for drugs-of-abuse (e.g., amphetamines, barbiturates, 
benzodiazepines, cocaine, opiates, phencyclidine, tetrahydrocannabinol, methadone, 
methamphetamine, tricyclic anti-depressants, oxycodone and others). 
 
The drug and alcohol screens will be performed in-house at the Clinical Unit. If any of these tests 
are positive, the subject will not be allowed further participation in the trial. However, a positive 
test may be repeated at the discretion of the investigator.  
10.3.16. 
Vital Signs 
Vital signs will consist of BP, HR, and RR and temperature following a rest period. Vital signs 
will be assessed per the Schedule Assessments.   


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10.3.17. 
12-Lead Electrocardiogram (ECG) 
12-Lead ECGs will be performed per the Schedule of Assessments after the subject has been 
resting in a recumbent/supine position for at least 5 minutes. The ECG variables will include 
ventricular heart rate and the PR, QRS, QT and QTcF intervals. ECGs will be signed and dated 
by a medically-qualified individual to confirm review of the ECG and verify whether any 
abnormalities are clinically significant. In general, abnormal, clinically significant ECGs are 
expected to be associated with an item recorded in medical history (e.g., at Screening) or with an 
AE (if it occurred post study treatment).  Note that for QTc, clinically significant changes in 
ECG (using QTCf, should be <450 msec for male subjects / < 470 msec for female subjects.  
Clinically significant changes in ECG are: an increase of QTcF of 30msec or greater, as well as 
any other changes deemed by the Investigator as significant will be considered an AE. 
10.3.18. 
Physical Examination 
A complete PE including all major body systems (HEENT, neurologic, cardiovascular, respiratory, 
gastrointestinal, dermatologic and musculoskeletal systems) will be performed at Screening.  A 
focused interim or targeted PE will be performed pre-surgery and after surgery during the inpatient 
and outpatient periods (see Table 1).  
Body weight (kg), in indoor clothing, but without shoes, will be measured at Screening and 96 
hours.  Height in centimeters (cm) will be measured, and BMI will be calculated at Screening only. 
BMI shall be calculated as kg/m2.  The site should use NIH website BMI calculator (available at: 
http://www.nhlbi.nih.gov/health/educational/lose_wt/BMI/bmi-m.htm). 
10.3.19. 
Surgical Site Assessment  
The surgical site should be assessed per the Schedule of Assessments to determine if any site 
related AEs have occurred.   The investigator will evaluate their satisfaction with the healing of 
the wound during this Surgical Site assessment using an 11-point scale (0-10) where a score of 0 
is “Completely unsatisfied,” and a score of 10 is “Completely satisfied.” (Section 17.6 Appendix 
F).  Assessments will also be performed at each of the Follow-up visits or at the time of early 
discontinuation. When assessed on Day 29, if the Investigator observes insufficient wound or bone 
healing or to ensure an ongoing AE has resolved, the subject will be scheduled for a follow-up 
visit.  
If  there are skin reactions atypical for the type of surgery, e.g., more than expected erythema, 
drainage, bruising or hematoma, induration, swelling or other skin changes, they should be 
documented as AEs, graded for severity and followed regularly until resolution or establishment 
of a new baseline (the grading guide for atypical wound findings may be useful to the 
investigator: Section 17.7 Appendix G). 


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10.3.20. 
Neurosensory Testing 
Neurosensory testing of the skin surrounding the incision will be conducted per the Schedule of 
Events.  This evaluation will include the details described in Section 17.8 Appendix H.  
Numbness or other sensory changes at or near the incision need not be considered a neurologic 
AE since these could occur because of tissue trauma and inflammation from surgery. 
Sensory deficits or clinically significant persistent sensory change beyond the area proximal to 
the incision at time of discharge, such as allodynia or hyperalgesia, must be designated as a 
neurologic AE.  Subjects will be followed until there is full return to baseline for the 
neurosensory assessment or until there is a determination that it has reached a resolution or 
establishment of a new baseline 
10.3.21. 
Assessment of Adverse Events 
All AEs and SAEs will be documented and followed from the time the subject has signed the 
ICF until Day 29 or later as necessary. All SAEs and non-serious AEs will be documented and 
followed from the time of administration of study treatment until Day 29 or until resolution or 
establishment of a new baseline.  AEs that occur between Screening and the surgery should be 
considered medical history, and be added to the subject’s medical record, unless related to a 
study procedure. Serious AEs and AEs that have been designated as possibly related to study 
drug will be followed until resolution or stabilization. Further details on AEs, including 
definitions, elicitation, and reporting are provided in Section 11. 
10.3.22. 
Pharmacokinetic Assessments and Samples 
Details for the collection and processing of blood samples for measurement of PK (CA-008, 
Capsaicin, and CA-101) and urine collections are outlined in the Lab Manual. 
10.4. 
Safety, PK and Efficacy Endpoints 
10.4.1. 
Safety Endpoints 
Safety endpoints include the following: 
• Incidence of spontaneously reported TEAEs or SAEs 
• Clinical laboratory test results  
• Vital sign measurements 
• ECG results 
• PE findings  
• Surgical Site wound assessment findings 
• Neurosensory testing results 


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• Knee x-ray 
• Presence of rebound pain 
• Concomitant Medication Use/Concomitant Treatments 
10.4.2. 
Pharmacokinetic Endpoints 
Full details of pharmacokinetic endpoints will be described in a separate PK Analysis Plan. The 
time points for whole blood collection are outlined in the Schedule of Assessments.  Actual 
sampling times will be used to calculate plasma-derived PK parameters.  
10.4.3. 
Pilot Stage Efficacy Endpoints 
10.4.3.1. Primary Efficacy Endpoint 
Time-specific mean pain intensity scores at T96h for CA-008 vs. placebo. 
Note that pooled placebo for cohorts #2 and #3 will be used for the primary and key secondary 
efficacy assessments during the exploratory pilot stage.   
10.4.3.2. Key Secondary Efficacy Endpoints 
For the CA-008 vs. placebo comparison: 
• Weighted sum of pain intensity (SPI) assessments = Area Under the Curve (AUC) of the 
NRS current pain intensity scores from T0 to 96h at rest (AUC0 to 96h).  
• Percentage of subjects who do not require opioids (i.e., opioid free; OF) from T0 to T96: 
OF0 to 96h 
• Total opioid consumption (in daily oral morphine equivalents) = OC from T0 to T96h: OC0 
to 96h    
10.4.4. 
Stage 2 Efficacy Endpoints 
All analyses will compare each CA-008 dose group vs. the placebo group. 
10.4.4.1. Primary Efficacy Endpoint 
Weighted sum of pain intensity (SPI) assessments = Area Under the Curve (AUC) of the NRS 
current pain intensity scores from T0 to 96h at rest (AUC0 to 96h).    
10.4.4.2. Key Secondary Efficacy Endpoints 
• Percentage of subjects who do not require opioids (i.e., opioid free; OF) from T0 to T96: 
OF0 to 96h 
• Total opioid consumption (in daily oral morphine equivalents) = OC from T0 to T96h: 
OC0 to 96h  
• Using NRS at rest: AUC0 to W1 


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10.4.4.3. Other Endpoints 
• Using NRS at rest: AUC 0 to 24h, AUC 0 to 120h, AUC 6 to 96h, AUC24 to 96h, AUC96h to W1, 
AUC96h to W2  
• AUC 0 to 96h (ambulation), AUC 0 to W1 (ambulation), AUC24h to W1(ambulation), AUC96h to W2 (ambulation) 
• Time-specific mean NRS scores at T48, T72, T96, T120, T144 and T168h 
• OC24 to 48h, OC24 to 72h, OC24 to 96h 
• OF24 to 96h, OF96h to W1 and OF96h to W2 
• KOOS improvement from T96h to D8/W1, D15/W2 and D29/W4 
• TTFRafter T0 and TTFRafter T24h  
• The fraction of subjects who rescue at T6, T12, T24, T48, T72 and T96h 
• Analgesic consumption from T96h to W1 (AC96h to W1) and AC96h to W2 
• PGE comparing the %age of subjects reporting “poor” + “fair” vs. “good” + “excellent” 
responses, and the %age reporting each category of response at T96h, D8/W1, D15/W2 
and D29/W4 
• IGE comparing the %age of those reporting “poor” + “fair” vs. “good” + “excellent” 
responses, and the %age reporting each category at T96h, D8/W1, D15/W2 and D29/W4 
• Number and %age subjects with an AE of lack of efficacy (LOE) during the inpatient 
period: LOE0 to 96h 
• HCU96h to W2 and HCU96h to W4 
 


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11. 
ADVERSE EVENTS 
11.1. 
Adverse Events and Serious Adverse Events 
The following definitions, developed in accordance with the United States (US) Code of Federal 
Regulations (CFR) and the International Conference on Harmonization (ICH) Clinical Safety 
Data Management Guidance for Industry, E2A, will be used to identify AEs in this study. 
An AE is any untoward medical occurrence in a subject administered a pharmaceutical product 
that does not necessarily have a causal relationship with this treatment.  An AE can therefore be 
any unfavorable and unintended sign (e.g., including an abnormal laboratory finding), symptom, 
or increase in severity of a preexisting abnormality, temporally associated with the use of a 
medicinal (investigational) product, whether or not considered related to the medicinal 
(investigational) product. 
Since this is a study using a surgical pain model, findings that are “typical” for the surgery 
should not be captured as an AE.  Atypical or worse than typical findings should be captured as 
AEs. 
A “suspected adverse reaction” means any AE for which there is a reasonable possibility that the 
drug caused the event.  “Reasonable possibility” means there is evidence to suggest a causal 
relationship between the drug and the adverse event.   
11.1.1. 
Relationship to Study Treatment 
A qualified investigator must make the determination of relationship to the investigational 
product for each AE.  The Investigator should decide whether, in his or her medical judgment, 
there is a reasonable possibility that the event may have been caused by the study treatment.   
 
Causality 
Category 
Description 
Unlikely related 
A clinical event, including laboratory test abnormality, with a temporal 
relationship to study treatment administration which makes a causal 
relationship improbable or if other drugs, chemicals or underlying 
disease provide more plausible explanations.  
While temporal sequence may be an important factor in determining 
causality: i.e., whether the observed reaction or event began after the 
study treatment, it may well be that the surgery, anesthesia, a concurrent 
medical condition or concomitant medications administered during or 
after surgery were more likely than not to be responsible for the AE.  
The investigator should use clinical judgment to evaluate the evidence 
and determine whether there is a reasonable possibility that study 


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treatment actually caused the AE or whether based upon the evidence it 
is more likely that something else is responsible.  If the former, choose 
“possibly related” and if the latter, “unlikely related.”   
For the purpose of this protocol, the term “unlikely related” will be 
considered an AE not related to study treatment. 
Possibly related 
A clinical event, including laboratory test abnormality, with a temporal 
relationship to study treatment administration, which also may be 
explained by concurrent disease or other drugs or chemicals.  In such 
cases, if the investigator using clinical judgment is unable to rule out a 
reasonable possibility that study treatment was partly responsible, then 
choose “possibly related.”  
For the purpose of this protocol, an event that has possible relationship 
to study treatment will be defined as a “Suspected Adverse Drug 
Reaction”.  
Probably related 
A clinical event, including laboratory test abnormality, with a temporal 
relationship to study treatment administration, in which the investigator 
has determined that the event is unlikely to be attributed to other 
factors.   
For the purpose of this protocol, an event that has probable relationship 
to study treatment will be defined as an “Adverse Drug Reaction”. 
 
11.1.2. 
Adverse Event Reporting 
All AEs must be entered on the AE CRF, regardless of causality or severity. AEs include new 
AEs, worsening baseline conditions, clinically significant laboratory findings, disease-related 
signs and symptoms that were not present at baseline, and any events or findings that the 
Investigator feels are clinically significant. 
Disease-related signs and symptoms that are present at baseline should not be recorded as AEs 
unless they worsen in severity or increase in frequency. 
Information collected concerning AEs will include the following: 
▪ Name of the event 
▪ Onset date 
▪ Resolution date 
▪ Severity (i.e., mild, moderate, severe or potentially life-threatening) 
▪ Relationship to study treatment 
▪ Action and outcome 
▪ Seriousness of event 


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All SAEs will be documented and followed from the time the subject has signed the ICF until 
D29±2 after the completion of surgery. All SAEs and non-serious AEs will be documented and 
followed from the time of administration of study treatment until Day 29 or later if necessary. 
AEs that occur between Screening and the administration of study medication should be 
considered medical history and added to the subject’s medical record, unless the AE is due to a 
study-related procedure (such as phlebotomy), in which case it will be recorded as a non-
treatment emergent AE.  Serious AEs and AEs that have been designated as possibly related to 
study treatment will be followed until resolution or stabilization. 
11.1.3. 
Serious Adverse Event (SAE) 
An SAE or reaction is any adverse drug experience occurring at any dose that results in any of 
the following outcomes: 
▪ Death 
▪ Is life-threatening (at the time of the event) 
▪ Requires subject hospitalization or prolongation of existing hospitalization, 
▪ Results in persistent or significant disability/incapacity 
▪ Is a congenital anomaly/birth defect (in an offspring) 
▪ An Important medical event that may not result in death, be life-threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical judgment, 
the event may jeopardize the subject and/or may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition. 
All AEs requiring hospitalization or prolongation of a pre-existing hospitalization should be 
reported as SAEs unless they occur ≥ 14 days after the Day 29 visit, or 21 days after an early 
termination AND are not considered to be study treatment-related by the Investigator. 
Hospitalizations meeting the following criteria will not be reported as an SAE but must be 
recorded on the appropriate CRF: study specified hospitalization, short-term administrative 
hospitalization for procedures, tests or treatments of conditions that would not otherwise 
constitute an SAE, elective hospitalizations. 
11.1.3.1. Serious Adverse Event Reporting 
Serious AEs must be reported to the Sponsor or designee within 24 hours of knowledge of the 
event. All SAEs that occur while a subject is receiving study treatment and within 14 days 
following the study completion visit (or 21 days following an ET if applicable) are reportable 
within 24 hours. During this follow-up period beyond study completion or after an ET, only 
those SAEs considered to be possibly related to study treatment should be reported within 24 
hours. 


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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 CRO 
Medical Monitor or designee.  Calls related to SAEs should first be directed to the CRO 
Medical Monitor or designee.  
o CRO Medical Monitor: Jon Ruckle, MD 
o 24/7 Emergency contact: 808-349-9812 / (253) 448-8690 
o SAE Reporting email: MedicalMonitorCA-PS-203@Lotuscr.com  
▪ The Sponsor’s Medical Monitor is available for questions about safety-related issues or to 
request waivers to modify postoperative patient care: Mike A. Royal, MD JD MBA; 858-
204-1112 or mike@concentricanalgesics.com. 
▪ The initial report should include all information known at the time of the report (additional 
information can be reported as discovered). Do not delay the initial reporting to obtain 
resolution or follow-up information. 
▪ The site will enter into the electronic database (or fax, if the database cannot be accessed for 
any reason) an SAE report, or similar form, that includes the following information, as 
available: 
o Subject ID 
o Basic demographic information (age, gender, weight) 
o Outcomes attributed to the event (death, life-threatening hospitalization [new or 
prolonged], disability, congenital anomaly, required medical intervention to prevent 
permanent impairment/damage, etc.) 
o Onset date and severity of the event 
o Brief description of the event including frequency and severity of symptoms leading 
to diagnosis 
o List of relevant test results and laboratory data 
o Any other relevant history 
o Whether the study treatment was discontinued 
o Investigator’s assessment of causality 
The CRO Medical Monitor or another representative of the Sponsor may contact the Investigator 
to request additional information regarding the event or to confirm information. All SAEs will be 
entered on the AE CRF. The same nomenclature should be used on both the SAE report and the 
AE CRF.  The Investigator is responsible for the complete and timely reporting of all SAEs to 
the Sponsor (or designee), reporting pertinent follow-up information on the SAE, and notifying 
the appropriate IRB of the occurrence of and details surrounding the event. In the event there is a 
question as to whether the AE is serious, the event should be reported. 


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11.2. 
Severity Grading for AEs 
Grading the severity of AEs is per investigator discretion (the guidance reflected in Sections 
17.9, 17.10 and 17.11; Appendices I, J and K may be helpful).   Additionally, the following 
general guideline may be helpful: 
• Grade 1 (mild) = asymptomatic or mild symptoms requiring no treatment, only clinical or 
diagnostic observation 
• Grade 2 (moderate) = event or symptoms limit age-appropriate activities of daily living 
(ADLs) more than is expected from the surgery itself, requiring minimal treatment or 
local noninvasive intervention indicated.   
• Grade 3 (severe) = medically-significant but not immediately life-threatening, 
significantly limiting of self-care ADLs, requiring of medical treatment and may require 
hospitalization or prolongation of hospitalization.   
11.3. 
Pregnancy 
If a female subject becomes pregnant at any time during the study, the Investigator must notify 
the CRO Medical Monitor or designee within 48 hours of learning about the pregnancy. The 
Investigator will be required to follow the subject through the pregnancy term, and report to the 
CRO Medical Monitor or designee the course of the pregnancy, including perinatal or neonatal 
outcome. Information on the status of the mother and the child will be forwarded to the CRO 
Medical Monitor or designee. Any premature termination of the pregnancy will also be reported 
on this form. Although pregnancy occurring in a clinical study is not considered to be an SAE, 
any pregnancy complication or elective termination of a pregnancy for medical reasons will be 
recorded as an AE and will be followed as such. A spontaneous abortion is considered to be an 
SAE. 


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12. 
DATA QUALITY ASSURANCE 
This study will be conducted under Good Clinical Practice (GCP) and all applicable regulatory 
requirements. To ensure compliance, the Sponsor or designee may conduct a quality assurance 
audit, as outlined in Section 12.2.  
Actions to ensure the accuracy and reliability of data include the selection of qualified 
investigators and appropriate study centers; the review of protocol procedures with the 
Investigator and study personnel prior to study start; the design of suitable source documents 
with appropriate instructions for use (where applicable); the internal audit of source data 
according to GCP and internal procedures to ensure their accuracy, completeness, and 
verifiability; as well as the periodic site monitoring by the Sponsor. The Sponsor or designee will 
review source documents for accuracy and completeness during on-site monitoring visits and 
after their return to the Sponsor; any discrepancies will be resolved with the Investigator, as 
appropriate.  
Significant and/or repeated non-compliance will be investigated, and remedial action instituted 
when appropriate. Failure to comply with remedial actions may result in investigational site 
termination and regulatory authority notification. 
12.1. 
Data Collection  
Source documents include, but are not limited to, original documents, data and records such as 
hospital/medical records (including electronic health records), clinic charts, lab results, 
participant diaries, data recorded in automated instruments, microfilm or magnetic media, and 
pharmacy records, etc. This study will use electronic data capture (EDC). At a minimum, all data 
required by the protocol should have supporting source documentation for entries in the EDC 
system. 
All CRFs will be completed by the site staff prior to review by the Sponsor’s monitor or 
designated representative. The Sponsor’s monitor or designated representative will review all 
source records on-site and compare them to the data collected on the CRF.  All entries, 
corrections, and alterations will be made by the Investigator or other authorized study personnel. 
All data entries will be verified for accuracy and correctness by independent monitors. The 
electronic data capture system maintains a full audit trail.  
12.2. 
Study Auditing and Monitoring 
Monitoring of the study site (including, but not limited to, reviewing CRFs for accuracy and 
completeness) will be performed by the Sponsor’s designated monitor(s). The extent, nature, and 
frequency of on-site visits will be based on such considerations as the study objectives and/or 


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endpoints, the purpose of the study, study design complexity, and enrollment rate. By signing the 
protocol, the Investigator agrees that, within local regulatory restrictions and institutional and 
ethical considerations, authorized representatives of the Sponsor, a regulatory authority, and/or 
an IRB may visit the site to perform audits or inspections, including the drug storage area, study 
drug stocks, drug accountability records, participant charts and source documents, and other 
records related to study conduct. The purpose of the Sponsor audit or inspection is to 
systematically and independently examine all study-related activities and documents to 
determine whether the study-related activities were conducted, and data recorded, analyzed, and 
accurately reported according to the protocol, the site’s standard operating procedures, GCP 
guidelines of the ICH, and any applicable regulatory requirements. The Investigator should 
contact the Sponsor immediately if contacted by a regulatory agency regarding an inspection. 


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13. 
STATISTICAL METHODS AND DETERMINATION OF 
SAMPLE SIZE 
13.1. 
Statistical and Analytical Plans 
The sections of the Statistical Considerations describe the statistical methods to be used to 
analyze the efficacy and safety.  These methods may be revised and updated due to reasons such 
as regulatory requirements or need for further clarifications.  The final analysis will be 
documented in a formal Statistical Analysis Plan (SAP) that must be finalized before database 
lock.  The SAP will include details on how variables will be derived, how missing data will be 
handled, and how data will be presented as well as the details on statistical methods to be used 
for safety and efficacy analyses.  The final clinical study report will discuss deviations from the 
SAP, if any. 
13.2. 
Sample Size Justification 
Given the uncertainty in estimating a sample size for TKA surgery, the results from the Phase 2 
bunionectomy study and the Pilot Stage (cohorts #1 through #3) topline data from the current 
study will be used to determine active treatment doses and sample size for Stage 2 of this study. 
To this end, an interim unblinded analysis will be performed after the last subject has completed 
the D8/W1 visit (details may be found in the SAP).  Topline results will be generated and used 
for the subsequent protocol amendment plan wherein several CA-008 dose groups are planned 
compared to placebo in a prospective, randomized, parallel design for Stage 2 of the study. 
13.3. 
Analysis Populations 
The following analysis populations are planned for this study:  
• The Safety Population will include all subjects who received any part of a dose of study 
treatment.   
• The PK Population will include all subjects who receive a full dose of study treatment and 
complete all PK assessments. 
• The intent-to-treat (ITT) population will include all subjects as randomized to study 
treatment.   
Membership in analysis populations will be determined before unblinding.  
Subjects who elect to discontinue study participation (early termination or ET) after 
randomization but prior to receiving study treatment will be replaced.   
Subjects who elect to ET after receiving study treatment will not be replaced, however those who 
ET during the inpatient phase of the study, will be asked to continue with assessments through 


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T96h if they have not elected to withdraw from all aspects of study participation. 
13.4. 
Planned Analyses 
Unless otherwise indicated, all testing of statistical significance will be 2-sided, and a difference 
resulting in a P value of less than or equal to 0.05 will be considered statistically significant.  
Furthermore, the baseline will be the last assessment before the dosing of study medication.  
All inferential assessments will be 2-sided tests performed at the 0.05 alpha level unadjusted for 
multiple comparisons.  A hierarchical alpha testing strategy will be utilized to control for the 
overall experiment-wise alpha.  First the primary analysis will be performed at the 0.05 alpha 
level.  If the primary analysis is statistically significant, then a limited number of key secondary 
analyses will be analyzed in a pre-specified order and analyses will be considered as statistically 
significant only if the preceding test is statistically significant.  The order of the secondary 
analyses will be specified in the SAP and signed off prior to unblinding. 
Summary statistics will be provided for the variables described in the following sections. For 
continuous variables, these statistics will typically include the number of subjects, mean, 
standard deviation (SD), median, minimum, and maximum. For categorical variables, these 
statistics will typically include the number and percentage of subjects in each category. 
13.5. 
Study Subjects and Demographics 
13.5.1. 
Disposition and Withdrawals 
The numbers of subjects randomized, completing, and withdrawing, along with reasons for 
withdrawal, will be tabulated overall and by treatment group. The number of subjects in each 
analysis population will be reported. 
13.5.2. 
Protocol Deviations 
Major protocol deviations will be classified and documented before database lock and will be 
discussed in the CSR.  All protocol deviations, both minor and major, will be presented in a data 
listing. 
13.5.3. 
Demographics and Other Baseline Characteristics 
Demographic and baseline characteristics (including age, sex, race, weight, and height) will be 
summarized for each treatment group and for the overall population by descriptive statistics. 
Medical history and clinical laboratory tests will be listed. 
Prior and concomitant medications will be summarized by treatment group, by the number and 
percentage of subjects taking each medication, classified using World Health Organization Drug 
Dictionary Anatomical Therapeutic Chemical classes and preferred terms. 


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13.5.4. 
Exposure  
Since this is a single dose study, study drug administration will be summarized in terms of total 
exposure by cohort and treatment group. 
13.5.5. 
General Considerations 
All continuous study assessments will be summarized by treatment and time point (as applicable) 
using the descriptive statistics n, mean, SD, median, and range (minimum, and maximum).  
Categorical assessments will be summarized by treatment and time point (as applicable) using 
frequency counts and rates of occurrence (%).  Changes from baseline for continuous outcomes 
will be presented as their corresponding continuous measures for post-baseline visits.  All study 
data will be listed by treatment group, subject and time point.  
No preliminary rounding will be performed; rounding will only occur after the analysis.  Means 
and medians will be presented with one more decimal place than the precision of the data.  
Standard deviations will be presented with two more decimal places than the precision of the 
data.  Percentages will be presented with one decimal place.  A percentage of 0% or 100% will 
be reported as 0% or 100%, respectively.  Minimums and maximums will be presented with the 
same precision as the original data. 
All analyses will be performed using the SAS System® version 9.3 or higher. The domain 
(Study data tabulation Model [SDTM]) and analysis (Analysis Data Model [ADaM]) data sets 
will be taken as input to the SAS programs that generate the report-ready tables, figures and 
listings. The submission ready SDTM and ADaM data sets will be provided to the sponsor along 
with display deliveries. The specifications for the domain data sets and analysis data sets will be 
provided in a separate document. 
The following conventions will be used throughout the study analysis: 
• Time T0 is the time of completion of study treatment administration.  
• Day of surgery is defined as D0 
• Assessment visit times are defined by time T0/D0. 
• Baseline value is defined as the last valid measurement prior to beginning study treatment 
administration. 
• Change from baseline is defined as post-baseline value minus baseline value. 
• Duration of an AE will be computed in days for AEs lasting longer than 24 hours, and as 
hours for AEs lasting less than 24 hours.  Duration in hours will be calculated as the stop 
date/time of the event minus the start date/time.  Duration in days will be calculated by using 
stop date minus the start date +1 if AE occur on or after taking study medication.  If AE 
occur prior to the study medication, then the duration will be calculated by using stop date 
minus the start date.  If reported as ongoing at the time of database lock, the duration will be 
calculated using the date of the last visit or the last date of any AE for the subject in the 


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database, whichever is later.  Missing dates will be imputed as described in the Study’s 
Statistical Analysis Plan (SAP). 
• The number of days in the study is computed as: [Date of study completion or withdrawal 
minus the date of study drug administration (Day 1)] + 1.  
• If duplicate values are obtained at a given visit (e.g., repeated vital sign measurements), the 
last value will be used unless it is noted that the measurement was in error for that value. 
Values that compromise interpretation will not be used in summaries (e.g., values that were 
obtained post-dose will not be summarized as pre-dose values). 
13.5.6. 
Analysis of Efficacy Measures 
All efficacy endpoints (e.g., NRS scores), will be summarized over time by treatment using 
descriptive statistics including confidence intervals as appropriate. 
AUC calculations will be done using the standard trapezoidal rule  
AUC  =     ∑
(
𝑁𝑅𝑆𝑖+𝑁𝑅𝑆𝑖+1
2
)
𝑥
𝑖=0
∗ (𝑇𝑖+1 − 𝑇𝑖) 
Where:  NRSi = NRS at time i, and (Ti+1 – Ti) is the Time difference in minutes between time i 
and time i+1.  A similar calculation and handling of missing data will be performed for the NRS 
scores with position changes. 
Missing NRS will be handled as discussed in the Study’s SAP.   
The AUC analyses will be presented in a summary table with standard summary statistics for 
each dose cohort and placebo as well as active vs. placebo mean differences, standard errors, 
confidence intervals and comparison p-values as appropriate. Comparisons of individual dose 
cohorts for dose response may also be presented for certain secondary AUC endpoints. 
The AUC analyses will be presented in a summary table with standard summary statistics for 
each treatment group mean differences standard errors, confidence intervals and comparison p-
values as appropriate.   
Mean NRS scores over time (in-clinic and diary) will be graphed over time by treatment group.  
NRS over time by each subject may also be displayed graphically as warranted.  The individual 
NRS and the computed AUC variables will be listed for all individual subjects.   
In this study, subjects are permitted to take rescue medication for analgesia.  It is expected 
subjects randomized to placebo arm will take rescue medication more often.  During both 
inpatient and outpatient portions of the studies, the subjects will be instructed to record NRS 
immediately prior to taking rescue medication. 
For subjects who take rescue, the pre-rescue pain score will be used to impute scheduled 
assessments for 4 hours.  Intermittent missing pain scores (due to subject sleeping, etc.) will not 


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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. 
13.5.7. 
Handling of Dropouts or Missing Data 
All efforts will be made to minimize missing data.  These efforts will include the following: 
• Subjects are required to consent continuous data collection even after subjects 
discontinue the study medication; 
• Continue data collection after subjects taking rescue medication; 
• Establish robust efficacy data collection procedures. 
With the procedures above, it is expected that the missing would be minimal.  Missing at random 
is expected to be a reasonable assumption and the primary analyses are expected to be sufficient 
for this dose escalation study. Additional sensitivity analyses will be performed to support robust 
conclusions, if warranted and details are presented in a detailed SAP prior to database lock.  
For subjects who take rescue medication a windowed last pain score carried forward (wLOCF) 
will be used. The pre-rescue pain score will be used to impute scheduled assessments for 30 
minutes following the rescue use when IV fentanyl is used, 2 hours when IV hydromorphone is 
used, and 4 hours when PO oxycodone is used. Intermittent missing pain scores (due to subject 
sleeping, etc.) will not be imputed, and AUC will be calculated based on non-missing values. For 
subjects who drop out of the study prior to Day 15, scheduled assessments will first be imputed 
using the worst prior pain score carried forward (WOCF). As sensitivity analyses, the AUC will 
also be calculated where assessments after drop out will be imputed using LOCF, using the last 
scheduled non missing pain score prior to drop out, and the median scores for the remainder of 
the group continuing in the study, without imputation using actual data. 
For secondary continuous efficacy endpoints, similar methods as the primary analysis will be 
used.  For categorical endpoints, when assessments are imputed for data after a subject 
discontinues from the study, a WOCF method will be used. 
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 


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value imputation methods for subjects who drop out of the study may also be performed.  All 
imputation methods for pain intensity will be documented in the SAP. 
13.5.8. 
Analysis of Safety  
Safety analyses will be conducted using data from the Safety Population (as defined in 
Section 13.2).  
Safety will be assessed through treatment-emergent AEs (TEAEs); hematologic, biochemical, 
and urinalysis laboratory parameters; vital signs measurements; ECGs; physical exam, surgical 
site and neurosensory assessments.  
No formal statistical comparisons will be performed for safety endpoints. 
13.5.8.1. Adverse Events 
Adverse events will be coded by system organ class (SOC) and preferred term using the Medical 
Dictionary for Regulatory Activities (MedDRA) reporting system. Treatment-emergent AEs are 
defined as any of the following: 
▪ Non-serious AEs with onset on the date of treatment with the study drug through Day 29 or 
Early Termination, whichever occurs first;  
▪ Serious AEs with onset on the date of treatment with the study drug through 30 days after 
Day 29 or Early Termination, whichever occurs first; 
▪ AEs that start before the start of treatment but increase in severity or relationship at the time 
of or following the start of treatment through Day 29 or Early Termination, whichever occurs 
first. 
The number and percentage of subjects with TEAEs will be displayed for each treatment group 
by SOC and preferred term. Additionally, TEAEs will be tabulated for each treatment group by 
severity and by relationship to the study drug. A listing of SAEs will be provided if applicable. 
13.5.9. 
Clinical Laboratory Evaluations 
For continuous laboratory parameters, descriptive statistics will be presented for the value at 
each assessment time and for the changes from baseline by treatment group.  
Additionally, clinical laboratory parameters will be categorized as low, normal, or high 
according to laboratory range specifications 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. 


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13.5.10. 
Vital Signs and ECG 
Descriptive summaries (mean, SD, median, minimum, and maximum) of actual values and 
changes from Baseline will be calculated for vital signs and ECG.  Detailed description of the 
analysis will be included in the Study SAP. 
The incidence of abnormal ECG findings will be summarized for each visit.  
13.5.11. 
Physical Examination Findings 
Physical and Surgical Site examination data will be presented in the listings. Abnormal or 
clinically significant physical exam and surgical site findings will be recorded as AEs. 


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14. 
SITE AND INVESTIGATOR RESPONSIBILITIES 
Additional details may be outlined in the Clinical Study Agreement between the sponsor and the 
investigational site.  
14.1. 
Regulatory and Ethical Considerations 
14.1.1. 
Ethical Conduct of the Study 
The Investigator will conduct the study in accordance with GCP and all applicable regulations, 
including, where applicable, the Declaration of Helsinki. The study will also be carried out in 
keeping with applicable national and local laws and regulations. This may include an inspection 
by the Sponsor’s representatives and/or regulatory authority’s representatives at any time. 
14.1.2. 
Ethics Approval 
The investigational site’s IRB must meet all relevant regulatory requirements. The study protocol 
and ICF will be reviewed by the IRB prior to enrolling participants into the study; written 
approval from the committee must be received by the sponsor before drug will be released to the 
Investigator.  The Investigator is responsible for submitting all protocol or ICF changes and SAE 
reports to the IRB according to local procedures. At a minimum, all SAEs requiring an 
investigational new drug safety report must be immediately reported. 
In accordance with applicable local regulatory requirements, the Investigator may be obligated to 
provide periodic safety updates on the conduct of the study at his or her research site and 
notification of study closure to the IRB. Such periodic safety updates and notifications are the 
responsibility of the Investigator and not of the Sponsor. The Sponsor will be provided with 
copies of all notifications sent to the IRB. 
All relevant correspondence from the IRB will be forwarded by the respective study site to the 
Sponsor in a timely fashion. 
14.1.3. 
Subject Informed Consent 
The Investigator (or authorized designee) will ensure that the participant (or the participant’s 
legal representative) is given full and adequate oral and written information about the nature, 
purpose, potential and possible risks and benefits of the study. Each prospective subject will 
receive an IRB-approved ICF that summarizes the pertinent study information and will be given 
ample time to read the form and ask questions about the study. All information is to be provided 
in a language understandable to the participant and must not include any language that waives 
the participant’s legal rights. Prospective participants must also be informed of their right to 
withdraw consent without prejudice at any time during the study. If the participant chooses to 
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Significant changes to the protocol or product safety information may require a revision of the 
ICF, which must be reviewed and signed by all applicable study participants. 
The time that informed consent is obtained must be documented. The Investigator must maintain 
the original, signed ICF in the participant’s source documents. A copy of the signed ICF must be 
given to the study participant. 
14.2. 
Privacy and Confidentiality 
The Investigator is responsible for complying with applicable privacy regulations, per his or her 
jurisdiction. Only information identified in this protocol will be collected. The information 
collected will only be used for the purposes identified in this protocol. 
To ensure anonymity and to limit disclosure, participants will be assigned a unique identifier at 
their first assessment. This identifier will be cross-referenced in the participant’s chart. The 
identifier will not contain any potentially identifiable information. An identifier log will be 
maintained, linking each participant’s name to the corresponding identifier. This log will be 
stored at the research site in a secure location. 
The knowledge gained through this study is the property of the Sponsor. The Sponsor, 
representatives and affiliated companies of the Sponsor, the IRB, and regulatory agencies (such 
as the United States FDA) may inspect medical records related to the study to check the validity 
and accuracy of the data gathered in this study. Participant medical records (with participant’s 
initials and/or date of birth) may be copied. Confidentiality of participant records will be 
maintained except where release of information is required by law.  
The results of this study will be reported in such a manner that participants will not be 
identifiable in any way. Published reports or presentations will refer to grouped data or coded 
individual data and not to any identifiable individuals. Study reports sent to the Sponsor or drug 
regulatory agencies will not include participant names. 
By signing the ICF, the participant consents to the collection, access, use, and disclosure of his or 
her information as described in the ICF document. If a participant withdraws consent, some of 
the subject’s information may still be collected, used, and disclosed by those involved in this 
study, per applicable laws.  
By signing this protocol, the Investigator affirms that he or she will maintain in confidence 
information furnished to him or her by the Sponsor and will divulge such information to his or 
her respective IRB or IEC under an appropriate understanding of confidentiality with such board. 
All data will be considered the sole property of the Sponsor. Please refer to the Clinical Study 
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14.3. 
Study and Site Closure 
Upon completion of the study, all study data will be provided to the Sponsor following review of 
site study records for completeness, and data clarifications and resolutions. Accounting, 
reconciliation, and final disposition of used and unused study drugs, treatment codes, and 
emergency code break envelopes will be performed, as applicable. 
In addition, the Sponsor reserves the right to temporarily suspend or prematurely discontinue this 
study at any time and for any reason. If such action is taken, the Sponsor will discuss this with 
the Investigator (including the reasons for taking such action) at that time. The Sponsor will 
promptly inform any other investigators and/or institutions conducting the study, if the study is 
suspended or terminated for safety reasons and will inform the regulatory authorities of the 
suspension or termination of the study and the reason(s) for the action. If required by applicable 
regulations, the Investigator will inform the IRB promptly and provide the study participants 
with the reason for the suspension or termination. If the study is prematurely discontinued, all 
study data will be returned to the Sponsor.  
14.4. 
Regulatory Documents and Records Retention 
The Investigator is responsible for creating and/or maintaining all study documentation required 
by 21 CFR 50, 54, 56 and 312, ICH E6 section 8, as well as any other documentation defined in 
the protocol or Clinical Study Agreement. The Investigator must provide key documents to the 
Sponsor prior to the start of the study.  A complete list of required regulatory documents will be 
supplied by the Sponsor or its representative. 
Federal and local regulations require that the Investigator retain a copy of all regulatory 
documents and records that support the data for this study for whichever of the following is the 
longest period of time: 
▪ A period of 2 years following the final date of approval by the FDA or other regulatory 
agency of the study drug for the purposes that were the subject of the investigation; or 
▪ A period of 5 years following the date on which the results of the investigation were 
submitted to the FDA or other regulatory agency in support of, or as part of, an 
application for a research or marketing permit for the study drug for the purposes that 
were the subject of the investigation. 
The Sponsor will notify investigators once one of the above 2 timeframes has been satisfied. 
If the investigation does not result in the submission of the data in support of, or as part of, an 
application for a research or marketing permit, records must be retained for a period of 2 years 
following notification by the Sponsor that the entire clinical investigation (not merely the 
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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 
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15. 
INVESTIGATOR PROTOCOL AGREEMENT PAGE 
A Phase 2, Randomized, Double-blind, Placebo-Controlled Efficacy, 
Pharmacokinetics and Safety Study of CA-008 in Subjects Undergoing 
Total Knee Arthroplasty 
 
Version: 3.2 
Date: 19 February 2019 
 
I have read this protocol and I agree to conduct the study in accordance with the 
protocol and with all applicable government regulations and International 
Conference on Harmonisation/Good Clinical Practice guidances. 
 
Principal Investigator’s Name 
 
(please print or type) 
 
 
 
 
 
 
Principal Investigator’s Signature 
 
Date 
(DD-MMM-
YYYY) 
 


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16. 
REFERENCES 
1. Babbar S, Marier JF, Mouksassi MS et al. Pharmacokinetic analysis of capsaicin after 
topical administration of a high-concentration capsaicin patch to patients with peripheral 
neuropathic pain. Ther Drug Monit 2009; 31:502-10. 
2. Caterina MJ, Julius D. The vanilloid receptor: a molecular gateway to the pain pathway.  
Annu Rev Neurosci 2001 24:487-517. 
3. Cullom C, Weed JT. Anesthetic and analgesic management for outpatient knee 
arthroplasty. Curr Pain Headache Rep 
4. Dudley-Cash AI, Brennan TJ.  The effect of low concentration capsaicin infiltration on 
acute pain from incision.  Soc Neuroscience 2012, New Orleans. 
5. 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. 
6. Sankineani SR, Reddy ARC, Eachempati KK et al. Comparison of adductor canal block 
and IPACK block (interspace between the popliteal artery and the capsule of the posterior 
knee) with adductor canal block alone after total knee arthroplasty: a prospective control 
trial on pain and knee function in immediate postoperative period.  Eur J Orthop Surg 
Traumatol 2018; doi: 10.1007/s00590-018-2218-7 [Epub ahead of print] 
7. Suresh D, Srinivasan K. Tissue distribution & elimination of capsaicin, piperine & 
curcumin following oral intake in rats. Indian J Med Res 2010; 131:682-91. 
8. Surh YJ, Lee RC, Park KK et al. Chemoprotective effects of capsaicin and diallyl sulfide 
against mutagenesis or tumorigenesis by vinyl carbamate and N-nitrosodimethylamine.  
Carcinogenesis 1995; 16:2467-71. 
9. Tominaga, M., Caterina, M.J., Malmberg, A.B., Rosen, T.A., Gilbert, H., Skinner, K., 
Raumann, B.E., Basbaum, A.I., Julius, D., 1998. The cloned capsaicin receptor integrates 
multiple pain-producing stimuli. Neuron 21, 531–543. 
 
 
 
 
 
 


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17. 
APPENDICES 
17.1. 
Appendix A: American Society of Anesthesiologists Physical Status 
Classification System (ASA Class) 
 
*The addition of “E” denotes Emergency surgery: (An emergency is defined as existing when delay in 
treatment of the patient would lead to a significant increase in the threat to life or body part)  
 
Available at: https://www.asahq.org/resources/clinical-information/asa-physical-status-
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17.2. 
Appendix B: 0 to 10 Numerical Rating Scale of Pain Intensity (NRS) 
Pain Intensity - Numerical Rating Scale (NRS) 
On a scale of 0-10, please rate your pain by marking the appropriate box that best describes your 
pain NOW. 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No Pain 
 
 
 
 
 
 
 
 
Worst pain 
imaginable 
 
Subject Initials: __________ 
 
 
 


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17.3. 
Appendix C: Assessment of Rebound Pain at the Surgical Site 
(Rebound Pain) 
Rebound Pain 
Ask the subject the following question: “Have you noticed any increase in pain at the surgical site 
(rebound pain) since your last visit?” 
 
                                                       yes        no       
 
Subject Initials: __________ 
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17.4. 
Appendix D: Patient Global Evaluation [of Satisfaction with Study 
Treatment] (PGE) 
Patient Global Evaluation (PGE) 
Instructions to Subject:  Please respond to the question below. When completed, please initial 
at the bottom of the page. 
How would you rate your satisfaction with the study treatment that you received during 
surgery for postop pain? 
(Mark one box) 
 
 Excellent (3) 
 
 Good (2) 
 
 Fair (1) 
 
 Poor (0) 
Subject Initials: __________ 
 
 
 


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


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17.6. 
Appendix F: Surgical Site Assessment 
The investigator should grade the level of satisfaction with wound healing using this 0-10 scale 
with 0=completely unsatisfied and 10=completely satisfied. 
Post-Operative Surgical Site Assessment 
Instructions to Investigator: Please respond to the question below. When completed, please 
initial at the bottom of the page. 
On a scale of 0 to 10, please rate your clinical satisfaction with the wound healing.  
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Completely unsatisfied 
 
 
 
 
 
 
 
Completely satisfied 
 
Investigator Initials: __________ 
In the assessment of satisfaction with wound healing, it should be performed with what is 
typically observed for surgeries of this type in the investigator’s clinical opinion.  The surgical 
wound adverse event grading scale which follows may be helpful is there is an atypical or 
abnormal finding. 
 
 


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17.7. 
Appendix G: Surgical Wound Adverse Event Grading Guide  
The investigator may find the following table to be a useful guide for grading specific AEs using 
this 4-point categorical scale for common wound complications.  The investigator should use 
clinical discretion in determining whether the particular parameter is atypical or unusual 
compared to what is expected as a typical healing process. 
PARAMETER 
GRADE 
DESCRIPTION 
ERYTHEMA 
0 
NONE 
1 
VERY SLIGHT (BARELY PERCEPTIBLE) 
2 
SLIGHT (WELL DEFINED) 
3 
MODERATE  
4 
SEVERE (BEET REDNESS) TO SLIGHT ESCHAR 
FORMATION (INJURIES IN DEPTH) 
DRAINAGE 
0 
NONE 
1 
SEROUS 
2 
SEROSANGUINOUS 
3 
BLOODY 
4 
PURULENT 
EDEMA 
0 
NONE 
1 
VERY SLIGHT (BARELY PERCEPTIBLE) 
2 
SLIGHT (EDGES WELL DEFINED) 
3 
MODERATE (RAISED APPROXIMATELY 1 MM) 
4 
SEVERE (RAISED >1 MM AND BEYOND AREA OF 
EXPOSURE) 
INDURATION 
0 
NONE 
1 
MINIMAL 
2 
MILD (SPONGY TISSUE) 
3 
MODERATE (FIRM, WARM) 
4 
SEVERE (HARD, RED, HOT, CREPITUS) 
HEMATOMA 
0 
NONE 
1 
MINIMAL 
2 
MILD 
3 
MODERATE 
4 
SEVERE 
 


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17.8. 
Appendix H: Neurosensory Examination Form 
 
Neurosensory testing should be performed in an area approximately 3 to 5 cm above and 
below the surgical incision site in all 4 quadrants of the leg compared to the control site.  The 
instructions below may assist the investigator or designee in performing neurosensory 
testing. 
• Monofilament (von Frey) Testing: For this examination, the filament should initially be 
prestressed (4-6 perpendicular applications to the dorsum of the examiner’s first finger). 
The filament is then applied perpendicularly at the location to be assessed and briefly, 
(<1 second) with even pressure.  When the filament bends, the force of 10 grams has 
been applied.  The subject, whose eyes are closed, is asked to respond yes if he / she feels 
the filament.  Eight correct responses out of 10 applications is considered normal: one to 
seven correct responses indicate reduced sensation and no correct responses translates 
into absent sensation.     
• Testing for Allodynia: performed at the location to be assessed using a foam brush.  
Note that allodynia testing is best assessed by using the foam brush, and while it may be 
elicited using von Frey filament testing, document presence of allodynia only with brush 
stimulation.  For allodynia assessment the foam brush will be lightly stroked 3 times 
across the skin in the location to be assessed.  Subject will be asked to compare sensation 
to the control site just distal to the costal margin.  If the sensation is described as painful 
or very unpleasant then allodynia will be reported as present.  If sensation is slightly 


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unpleasant or mildly irritating compared to the control area then hyperaesthesia will be 
reported as present. If subject reports the stimulus as the same as the control area then 
sensation will be reported as normal. If sensation is less than the control area then 
sensation will be reported as reduced, and if sensation is not felt as all then it will be 
reported as absent.   
 
 


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17.9. 
Appendix I: Toxicity Grading Scale for Clinical Laboratory 
Abnormalities 
The following tables are excerpted from the Guidance for Industry: Toxicity Grading Scale 
for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical 
Trials.  The grading system can be “useful in defining a particular study’s stopping rules (e.g., a 
certain number of adverse events, as defined in the table, may call for stopping the study.)”   
The Guidance may be found in its entirety at: 
https://www.fda.gov/downloads/BiologicsBloodVaccines/ucm091977. 
For clinical laboratory values not covered in this Guidance, the Common Terminology Criteria 
for Adverse Events (CTCAE) v5.0 (November 27, 2017) may be useful as a reference.  CTCAE 
v5.0 and prior versions are available at 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  


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17.10. 
Appendix J: Toxicity Grading Scale for Clinical Vital Sign 
Abnormalities 
The following guidance is excerpted from the Common Terminology Criteria for Adverse Events 
(CTCAE) v5.0 (November 27, 2017) as a reference.  CTCAE v5.0 and prior versions are 
available at https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
The grading system can be “useful in defining a particular study’s stopping rules (e.g., a certain 
number of adverse events, as defined in the table, may call for stopping the study.)”   
 
These excerpts are from various sections within CTCAE v5.0: 
 
 
 
 


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17.11. 
Appendix K: Toxicity Grading Scale for Systemic (General) Adverse 
Events 
The following table is excerpted from the Guidance for Industry: Toxicity Grading Scale for 
Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials.  
The grading system can be “useful in defining a particular study’s stopping rules (e.g., a certain 
number of adverse events, as defined in the table, may call for stopping the study.)”   
The Guidance may be found in its entirety at: 
https://www.fda.gov/downloads/BiologicsBloodVaccines/ucm091977. 
The investigator may find this useful for grading common systemic (general) TEAEs reported 
after surgery. 
 
 
 


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17.12. 
Appendix L: Ropivacaine Dosage Recommendations 
 
 
 


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17.13. 
Appendix M: Knee Injury and Osteoarthritis Outcome Survey 
(KOOS) 
 
 
 


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KOOS FAQs 
Background information 
What is the KOOS? 
The Knee injury and Osteoarthritis Outcome Score (KOOS) is a patient-reported outcome measurement 
instrument, developed to assess the patient’s opinion about their knee and associated problems. The 
KOOS evaluates both short-term and long-term consequences of knee injury and also consequences of 
primary osteoarthritis (OA). It holds 42 items in five separately scored subscales: KOOS Pain, KOOS 
Symptoms, Function in daily living (KOOS ADL), Function in Sport and Recreation (KOOS Sport/Rec), 
and knee-related Quality of Life (KOOS QOL) (Roos and Lohmander 2003). 
In which populations can the KOOS be used? 
KOOS has been used in patients 13-79 years of age. 
KOOS is intended to be used for knee injury that can result in posttraumatic osteoarthritis (OA); i.e. knee 
ligament injury (ACL, posterior cruciate ligament [PCL], medial collateral ligament [MCL]), meniscal tears, 
knee cartilage lesions, knee OA, and osteochondritis dissecans, etc. 
KOOS is meant to be used over short and long time intervals; to assess changes from week to week 
induced by treatment (examples include: ligament reconstruction (ACL, PCL, MCL), meniscectomy, 
microfracture, osteochondral autografts, tibial osteotomy, total knee replacement (TKR), exercise (land-
based, aquatic-based), intra-articular sodium hyaluronate injection, pharmacologic therapy, and 
glucosamine supplementation) or over years due to the primary injury, post traumatic OA or primary OA 
(Roos and Lohmander 2003).  
How was the KOOS developed? 
KOOS was developed by Ewa Roos and co-authors in the 1990s as an instrument to assess the patient’s 
opinion about their knee and associated problems. Items were selected based on: (1) the Western Ontario 
and McMaster Universities Osteoarthritis Index (WOMAC), version 3.0; (2) a literature review; (3) an expert 
panel (patients referred to physical therapy for knee injuries, orthopedic surgeons, and physical therapists 
from Sweden and the US); and, (4) a pilot study of two questionnaires (one for symptoms of ACL injury, one 
for symptoms of OA) in individuals with posttraumatic OA. 
What are the KOOS subscales and what areas of health do they measure? 
The KOOS collects data on five knee-specific patient-centered outcomes: (1) KOOS Pain; (2) KOOS 
Symptoms: Other symptoms such as swelling, restricted range of motion and mechanical symptoms; 
(3) KOOS ADL: Disability on the level of daily activities; (4) KOOS Sport/Rec: Disability on a level 
physically more demanding than activities of daily living; (5) KOOS QOL: Quality of life, mental and social 
aspects such as awareness and lifestyle changes.  
In what settings is the KOOS responsive to change? 
KOOS’ responsiveness has been reported following surgical procedures including ACL reconstruction, 
meniscectomy, cartilage repair procedures, tibial osteotomy, total knee replacement as well as physical 
therapy, nutritional and pharmaceutical interventions. Following orthopedic surgery, including total knee 
replacement, KOOS QOL is usually as responsive, or more responsive, than KOOS Pain and KOOS ADL 
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What is the Minimal Detectable Change of the KOOS in different settings? 
The minimal detectable change (MDC) is dependent on the test-retest reliability of an instrument. The more 
reliable a measure is, the smaller the difference that can be detected longitudinally. The test-retest reliability 
is, in turn, dependent on factors such as patient characteristics and time between assessments. 
In studies of patients with knee injury, the MDC ranges for KOOS Pain were 6-6.1, for KOOS Symptoms: 5-
8.5, for KOOS ADL: 7-8, for KOOS Sport/Rec: 5.8-12, and for KOOS QOL: 7-7.2 (Collins, Misra et al. 
2011). 
In one study including patients with knee OA, the MDCs for KOOS Pain were 13.4, for KOOS Symptoms: 
15.5, for KOOS ADL: 15.4, for KOOS Sport/Rec: 19.6, and for KOOS QOL: 21.1 (Collins, Misra et al. 2011). 
What is the Minimal Clinically Important Change in the KOOS in different settings 
The minimal clinically important change (MIC) can be defined as the smallest change score needed for the 
effect to be considered clinically relevant (de Vet, Ostelo et al. 2007). MIC can be calculated in many 
different ways using anchor-based and distribution-based methods. Recent publications highlight that there 
is probably no such thing as one MIC for a specific patient-reported outcome measure, such as the KOOS. 
Instead MIC seems to be dependent on context factors including patient group, intervention, time to follow-
up, etc. Therefore, it is more probable that in the future, a range of MICs will be established for an 
instrument. Research is ongoing to establish the MIC for the KOOS in many different contexts. Until then, a 
MIC of 8-10 is considered appropriate for the KOOS (Roos and Lohmander 2003). For performing a sample 
size calculation, usually an SD of 15 can be used. However, the variation within the group to be studied will 
depend on the characteristics of the group. Usually elderly or more impaired groups have greater within-
group variation than younger or healthier groups. 
What is the Patient Acceptable Symptom State of the KOOS in different settings? 
The Patient Acceptable Symptom State (PASS) can be defined as the value beyond which the patients can 
consider them well. The PASS is an absolute value (not a change value) and can be used as a patient 
centered and clinically relevant treatment target (the proportion of patients reaching a satisfactory state) 
(Tubach, Ravaud et al. 2005). Similar to the MIC, research is ongoing within this area to establish PASS for 
KOOS when used in different contexts. 
KOOS administration 
Who answers the questionnaire? 
The KOOS is self-administered and completed by the patient. No interview or phone formats are available.  
How long does it take to complete the KOOS? 
The KOOS questionnaire takes about 10 minutes to fill out.  
How is the KOOS administered? 
The KOOS is self-explanatory and can be administered in the waiting room prior to a clinical visit or used in 
a postal mail survey. KOOS has not been validated for interview administration (Collins, Misra et al. 2011).  
KOOS Scores 


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How is the KOOS scored? 
The five patient-relevant subscales of KOOS are scored separately: KOOS Pain (9 items); KOOS 
Symptoms (7 items); KOOS ADL (17 items); KOOS Sport/Rec (5 items); KOOS QOL (4 items). A Likert 
scale is used and all items have five possible answer options scored from 0 (No Problems) to 4 (Extreme 
Problems) and each of the five scores is calculated as the sum of the items included. Scores are 
transformed to a 0–100 scale, with zero representing extreme knee problems and 100 representing no knee 
problems as is common in orthopaedic assessment scales and generic measures. Scores between 0 and 
100 represent the percentage of total possible score achieved. An aggregate total score is not calculated 
since it is regarded desirable to analyze and interpret the five dimensions separately. Please find more 
extensive instructions on score calculations in the scoring section of the KOOS User’s Guide. 
For statistical purposes, when used as the primary outcome in an RCT, a single score can be constructed. 
In this case, the five individual subscale scores should be secondary outcomes. Please see reference 
(Roos, Engelhart et al. 2011) for more information on this procedure. 
How are the KOOS scores interpreted? 
The score is a percentage score from 0 to 100, with 0 representing extreme problems and 100 representing 
no problems. This scoring direction, 100 indicating no problems, is common in orthopaedic instruments and 
generic measures like the SF-36. In measures developed by rheumatologists, like the WOMAC, 100 usually 
represents the worst possible result.  
How should the patient be instructed on scoring activities he/she is not able to perform? 
It is important to determine whether or not each subscale is relevant at the time point chosen, considering 
the specific study population. For example, difficulty with Sport/Rec function may not be relevant to assess 
2 weeks post-operatively. 
The following guideline for study staff is available: 
KOOS Pain and KOOS ADL subscales: If a subject avoids an activity (e.g., twisting/pivoting or going up or 
down stairs) due to doctor's orders or because the subject has chosen to avoid the activity, the subject 
should be instructed to choose “(4) Extreme” for those items. 
KOOS Sport/Rec subscale: The same as above. Also, if a subject does not normally engage in an activity 
(e.g., running or jumping), the subject should be instructed to leave the item blank. 
How do I handle missing items? 
Missing data: If a mark is placed outside a box, the closest box is chosen. If two boxes are marked, that 
which indicates the more severe problem is chosen. 
As long as at least 50% of the subscale items are answered for each subscale, a mean score can be 
calculated. If more than 50% of the subscale items are omitted, the response is considered invalid and no 
subscale score should be calculated. For KOOS Pain, this means that 5 items must be answered; for 
KOOS Symptoms, 4 items; for KOOS ADL, 9 items; for KOOS Sport/Rec, 3 items; and for KOOS QOL, 2 
items in order to calculate a subscale score. Subscale scores are independent and can be reported for any 
number of the individual subscales, i.e. if a particular subscale is not considered valid (for example, KOOS 
Sport/Rec 2 weeks after total knee replacement), the results from the other subscales can be reported at 
this time-point.  
NB: The excel Scoring sheet available for download does not automatically take the number of missing 
items into account.  
Can a total score be calculated? 
An aggregate total score is not calculated since it is regarded desirable to analyze and interpret the five 
dimensions separately. For statistical purposes, when used as the primary outcome in an RCT, a single 
score can be constructed. In this case, the five individual subscale scores should be secondary outcomes. 


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For more information on this procedure, see reference (Roos, Engelhart et al. 2011) or the FAQs section 
on statistics.  
How do I present my data? 
The results of the five subscales can be plotted as an outcome profile, preferably in a graph with scores 
from 0-100 on the y-axis and the five subscales on the x-axis (an example is presented in the KOOS User’s 
Guide, under the heading of KOOS Profile). The order of the subscales from left to right should be: KOOS 
Pain, KOOS Symptoms, KOOS ADL, KOOS Sport/Rec and KOOS QOL. This way profiles can be 
compared visually across studies. Changing this order makes visual comparison more difficult.  
How do I use KOOS as the primary outcome in an RCT? 
There are two ways to apply the KOOS as the primary outcome in an RCT. Either way, the primary 
endpoint should be specified a priori. You can either (1) choose the single subscale you consider is the 
most likely to measure the change from the intervention of interest, or you can (2) create a composite score, 
referred to as KOOS4 or KOOS5, depending on the number of subscales included in this composite 
score. Please note that this is very different from calculating a total score! Calculating an average score 
from subscale scores ensures similar weight from all subscales in the composite score. Calculating a total 
score is never recommended. In either case, all KOOS subscales should be included as secondary 
endpoints to enable clinical interpretation of the results. 
As examples, since exercise is aimed at improving physical function, it may be appropriate to apply the 
KOOS ADL subscale as the primary endpoint in an older group of OA patients, and the KOOS Sport/Rec 
subscale as the primary endpoint in a younger group of knee-injured patients in a trial of an exercise 
intervention. However, in pharmacological trials, the subscale KOOS Pain may be more appropriate as the 
primary endpoint since pharmacological agents often are supposed to relieve pain. When two different 
interventions are included (for example a surgical and a non-surgical) or when the intervention is supposed 
to affect more than one subscale to a similar degree, a composite score may be most appropriate as the 
primary outcome. Below, an example is given where KOOS4 was applied. You can also read more about 
“Single Subscale versus Overall score” and “Multiplicity” in the review by Roos et al (Roos, Engelhart et al. 
2011).  
References 
Ageberg, E., M. Forssblad, et al. (2010). "Sex differences in patient-reported outcomes after anterior cruciate ligament reconstruction: 
data from the Swedish knee ligament register." Am J Sports Med 38(7): 1334-1342. 
Beaton, D. E., C. Bombardier, et al. (2000). "Guidelines for the process of cross-cultural adaptation of self-report measures." Spine 
(Phila Pa 1976) 25(24): 3186-3191. 
Collins, N. J., D. Misra, et al. (2011). "Measures of knee function: International Knee Documentation Committee (IKDC) Subjective 
Knee Evaluation Form, Knee Injury and Osteoarthritis Outcome Score (KOOS), Knee Injury and Osteoarthritis Outcome Score 
Physical Function Short Form (KOOS-PS), Knee Outcome Survey Activities of Daily Living Scale (KOS-ADL), Lysholm Knee Scoring 
Scale, Oxford Knee Score (OKS), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), Activity Rating Scale 
(ARS), and Tegner Activity Score (TAS)." Arthritis care & research 63 Suppl 11: S208-228. 
Collins, N. J. and E. M. Roos (2012). "Patient-reported outcomes for total hip and knee arthroplasty: commonly used instruments and 
attributes of a "good" measure." Clinics in geriatric medicine 28(3): 367-394. 
de Vet, H. C., R. W. Ostelo, et al. (2007). "Minimally important change determined by a visual method integrating an anchor-based and 
a distribution-based approach." Quality of life research : an international journal of quality of life aspects of treatment, care and 
rehabilitation 16(1): 131-142. 
Flandry, F., J. P. Hunt, et al. (1991). "Analysis of subjective knee complaints using visual analog scales." Am J Sports Med 19(2): 112-
118. 
Frobell, R. B., E. M. Roos, et al. (2010). "A randomized trial of treatment for acute anterior cruciate ligament tears." The New England 
journal of medicine 363(4): 331-342. 
Frobell, R. B., E. Svensson, et al. (2008). "Self-reported activity level and knee function in amateur football players: the influence of 
age, gender, history of knee injury and level of competition." Knee Surg Sports Traumatol Arthrosc 16(7): 713-719. 
Gudbergsen, H., E. M. Bartels, et al. (2011). "Test-retest of computerized health status questionnaires frequently used in the 
monitoring of knee osteoarthritis: a randomized crossover trial." BMC musculoskeletal disorders 12: 190. 
Lequesne, M. G., C. Mery, et al. (1987). "Indexes of severity for osteoarthritis of the hip and knee. Validation--value in comparison with 
other assessment tests." Scand J Rheumatol Suppl 65: 85-89. 
Östenberg, A., E. M. Roos, et al. (2000). "Physical capacity in Female Soccer Players - Does Age Make a Difference?" Advances in 


Clinical Trial Protocol CA-PS-203 
              
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Version: 19 February 2019 
 
 
 
 
 
 
 
Page 121 of 124 
Physiotherapy 2(1): 39-48. 
Paradowski, P. T., S. Bergman, et al. (2006). "Knee complaints vary with age and gender in the adult population. Population-based 
reference data for the Knee injury and Osteoarthritis Outcome Score (KOOS)." BMC Musculoskelet Disord 7: 38. 
Roos, E., L. Engelhart, et al. (2011). "ICRS Recommendation Document: Patient-reported outcome instruments for use in patients with 
articular cartilage defects." Cartilage 2(2): 122-136. 
Roos, E. M., H. P. Roos, et al. (1999). "WOMAC Osteoarthritis Index--additional dimensions for use in subjects with post-traumatic 
osteoarthritis of the knee. Western Ontario and MacMaster Universities." Osteoarthritis and cartilage 7(2): 216-21. 
Roos, E. M. and L. S. Lohmander (2003). "Knee injury and Osteoarthritis Outcome Score (KOOS): from joint injury to osteoarthritis." 
Health Qual Life Outcomes 1: 64. 
Roos, E. M., H. P. Roos, et al. (1998). "Knee Injury and Osteoarthritis Outcome Score (KOOS)--development of a self-administered 
outcome measure." J Orthop Sports Phys Ther 28(2): 88-96. 
Roos, E. M. and S. Toksvig-Larsen (2003). "Knee injury and Osteoarthritis Outcome Score (KOOS) - validation and comparison to the 
WOMAC in total knee replacement." Health Qual Life Outcomes 1(1): 17. 
Salavati, M., B. Akhbari, et al. (2011). "Knee injury and Osteoarthritis Outcome Score (KOOS); reliability and validity in competitive 
athletes after anterior cruciate ligament reconstruction." Osteoarthritis and cartilage / OARS, Osteoarthritis Research Society 19(4): 
406-410. 
Tanner, S. M., K. N. Dainty, et al. (2007). "Knee-specific quality-of-life instruments: which ones measure symptoms and disabilities 
most important to patients?" Am J Sports Med 35(9): 1450-1458. 
Tubach, F., P. Ravaud, et al. (2005). "Evaluation of clinically relevant states in patient reported outcomes in knee and hip 
osteoarthritis: the patient acceptable symptom state." Ann Rheum Dis 64(1): 34-37. 
 
 
 


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KOOS Scoring 2012 
A change in how to manage missing items was introduced in 2012. Previously, 2 
missing items were allowed in each subscale. From 2012, at least 50% of the items 
should be responded to. The differences in subscale level are outlined in the following 
table: 
 
Number of items needed  
for calculation of  
subscale score (2012  
rule for missing items) 
Number of items needed  
for calculation of  
subscale score (1998 rule  
for missing items) 
Pain 
5 
7 
Symptoms 
4 
5 
ADL 
9 
15 
Sport/Rec 
3 
3 
QOL 
2 
2 
 
KOOS Scoring instructions 
Assign the following scores to the boxes: 
None 
Mild 
Moderate 
Severe 
Extreme 
 
 
 
 
 
0 
1 
2 
3 
4 
Each subscale score is calculated independently. Calculate the mean score of the 
individual items of each subscale and divide by 4 (the highest possible score for a 
single answer option). Traditionally in orthopedics, 100 indicates no problems and 0 
indicates extreme problems. The normalized score is transformed to meet this 
standard. 
Missing data: If a mark is placed outside a box, the closest box is chosen. If two 
boxes are marked, that which indicates the more severe problem is chosen. 
As long as at least 50% of the subscale items are answered for each subscale, a 
mean score can be calculated. If more than 50% of the subscale items are omitted, the 
response is considered invalid and no subscale score should be calculated. For the 
subscale Pain, this means that 5 items must be answered; for Symptoms, 4 items; for 
ADL, 9 items; for Sport/Rec, 3 items; and for QOL, 2 items must be answered in order 
to calculate a subscale score. Subscale scores are independent and can be reported 


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Page 123 of 124 
for any number of the individual subscales, i.e. if a particular subscale is not 
considered valid (for example, the subscale Sport/Rec 2 weeks after total knee 
replacement), the results from the other subscale can be reported at this time-point. 
KOOS Excel Scoring Files 
Excel spreadsheets with formulae to calculate the five subscale scores are available 
from www.koos.nu. If, for any reason, you prefer to use your own spreadsheets, the 
Excel formulae are given below. NB: The excel spreadsheet available from koos.nu 
does not take the number of missing items into account and will return a total subscale 
score regardless of missing items. 
Excel: When the raw data have been entered in the order the items occur in the KOOS 
questionnaires, these can be copied and pasted directly into an Excel spreadsheet to 
automatically calculate the five subscore scales. Please note that it has been assumed 
that the items in the subscale symptoms appear first in the questionnaire. 
KOOS Pain: 
=100-AVERAGE(I2:Q2)/4*100 
KOOS Symptoms: 
=100-AVERAGE(B2:H2)/4*100 
KOOS ADL: 
=100-AVERAGE(R2:AH2)/4*100 
KOOS Sport/Rec: 
=100-AVERAGE(AI2:AM2)/4*100 
KOOS QOL: 
=100-AVERAGE(AN2:AQ2)/4*100  
 
KOOS Manual Score Calculation 
The slightly updated version of the formulae (presented above and used from August 
2012 in the spreadsheets available from www.koos.nu) does not need any manual 
imputation: Apply the mean of the observed items within the subscale (e.g. KOOS 
Pain), divide by 4, and multiply by 100; when this number is then subtracted from 100, 
you have the KOOS subscale estimate for that particular cross-sectional assessment of 
the individual patient. For manual calculations, please use the formulae provided below 
for each subscale:  
 


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WOMAC - How to score from the KOOS  
Assign scores from 0 to 4 to the boxes as shown above. To get original WOMAC 
Scores, sum the item scores for each subscale. If you prefer  
percentage scores in accordance with the KOOS, use the formula provided below 
to convert the original WOMAC scores. 
Transformed scale = 100 - actual raw score x 100 maximum score 
WOMAC subscores 
Original score = sum of Maximum score the 
following items  
Pain 
P5-P9 
20 
Stiffness 
S6-S7 
8 
Function 
A1-A17 
68 
 
KOOS Profile 
To visualize differences in the five different KOOS subscores and change between 
different administrations of the KOOS (e.g. pre-treatment to post-treatment), KOOS 
Profiles can be plotted. The example from Nilsdotter et al. [17] shows KOOS profiles 
prior to and at 3 time points following total knee replacement (TKR). 
 

SAP_001.pdf: 
OFFICIAL TITLE:  
Statistical Analysis Plan 
A Phase 2,Randomized, Double-blind, Placebo-Controlled Efficacy, Pharmacokinetics and Safety Study of 
CA-008 in Subjects Undergoing Total Knee Arthroplasty 
 
NCT NUMBER: 
NCT03731364 
 
DOCUMENT DATE:  
24 April 2019 


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