Conditions: Postsurgical Pain
Allocation: RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 193
Healthy volunteers: no

Brief summary:
In the pilot (Part A) of this study, multiple doses of CA-008 (vocacapsaicin) were evaluated for safety, tolerability, and PK. Doses were then selected for the expanded part (Part B) of the study, where CA-008 was compared to placebo. Patients had serial assessments of safety, PK, and drug effect.

Detailed description:
Not provided

Arms:
arm 1: Single administration (0.3 mg/mL concentration) arm 2: Single administration (0.5 mg/mL concentration) arm 3: Single administration (0.75 mg/mL concentration) arm 4: Single administration

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

Protocol document:
Prot_000.pdf: 
OFFICIAL TITLE:  
A Two-Part, Phase 1/2, Randomized, Double-blind, Placebo-controlled, Adaptive Safety, 
Pharmacokinetics, and Preliminary Efficacy Study of CA-008 in Patients Undergoing Total Knee 
Arthroplasty  
 
NCT NUMBER: 
NCT04203537 
 
DOCUMENT DATE:  
22 April 2020  Amendment 1 


 
 
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Clinical Trial Protocol 
 
A Two-Part, Phase 1/2, Randomized, Double-blind, Placebo-Controlled, 
Adaptive Safety, Pharmacokinetics, and Preliminary Efficacy Study of 
CA-008 in Patients Undergoing Total Knee Arthroplasty 
 
Investigational Product: CA-008 by Injection/Instillation 
IND: 129114 
 
Concentric Analgesics, Inc. 
 
Original Protocol Date: 12 November 2019 
Amendment 1 Date: 22 April 2020 
 
 
 
 
 
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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SIGNATURE PAGE 
A Two-Part, Phase 1/2, Randomized, Double-blind, Placebo-Controlled, Adaptive Safety, 
Pharmacokinetics, and Preliminary Efficacy Study of CA-008 in Patients Undergoing Total 
Knee Arthroplasty 
 
Approved by: 
 
 
 
 
_____________________________________ 
_______________________ 
 
Nancy Wu 
 
Date 
 
Head of Clinical Operations 
 
 
Concentric Analgesics, Inc. 
 
 
Authored and Approved by: 
 
 
 
 
_____________________________________ 
_______________________ 
 
Sam Teichman, MD 
 
Date 
 
VP, Head of Clinical Development 
 
Concentric Analgesics, Inc. 
 


 
 
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1. 
KEY PERSONNEL CONTACT INFORMATION 
Sponsor 
Concentric Analgesics, Inc. (Concentric) 
Vanessa Huels 
Sr Clinical Trial Manager 
vhuels@concentricanalgesics.com 
415-481-1732 
Sam L. Teichman, M.D. 
VP, Head of Clinical Development 
steichman@concentricanalgesics.com 
925-437-2067 
 
CRO 
Lotus Clinical Research, LLC 
Primary 
Contact 
Nina Green 
Project Manager 
ngreen@lotuscr.com 
440-991-7469 
 
CRO Medical 
Monitors 
Primary: Jon L. Ruckle, MD, CPI 
MedicalMonitorCA-PS-208@Lotuscr.com 
808-349-9812 
Secondary: Royce Morrison, MD 
MedicalMonitorCA-PS-208@Lotuscr.com 
206-799-7386 


 
 
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Summary of Changes from CA-PS-208 protocol v1.0 to v2.0 
 
Substantive changes: 
 
1. Inclusion criterion #7 (Synopsis and Section 8.2.1): 
 
Expanded eligible body mass index from ≤ 36 kg/m2 to body mass index ≤ 42 kg/m2 
 
Rationale: Patients requiring total knee arthroplasty are often overweight or obese.  Obesity is not 
a contraindication to treatment with this locally-acting analgesic 
 
2. Clarified and added detail on study drug administration based on cases completed to date and 
surgeon input (Section 10.1.3) 
 
Rationale: As per protocol Section 10.1.3, “Modifications to the total study drug dose, volume, 
drug concentration, and allocation for subsequent patients may occur based on information from 
prior patients.”  No changes were made to total dose, volume or concentration.  Additional detail 
and instruction were provided for the locations of study drug delivery based on input and 
experience from Part A of the study and surgeon input. 
 
Other changes: 
 
Clarifications and Additions: 
 
 
• Removed background information that is no longer verifiable (Section 5.1) 
• Added information on recently completed toxicological study (Section 5.2) 
• Reworded study objectives for clarity (Synopsis, Section 6.1.1 and Section 6.1.2) 
• Clarified Exclusion Criterion #3 (Synopsis and Section 8.2.2) concerning allergy or 
contraindication to study components 
• Clarified Exclusion Criterion #5 (Synopsis and Section 8.2.2) concerning maximum acceptable 
prophylactic dose of aspirin 
• Clarified Exclusion Criterion #7 (Synopsis, Section 8.2.2 and Section 10.3.16) to define more 
clearly a disqualifying positive urine drug screen 
• Resolved ambiguities of timing of certain drug administration. The original protocol has two 
different instructions due to a typo. All patients enrolled have received the correct dosing.  
(Synopsis and Section 9.2.1 10.1.3) 
• Clarified protocol deviation criterion for rescue medication use (Section 9.2.2) 
• Clarified timing of pre-rescue NRS in relation to rescue medication (Section 9.2.3) 
• Clarified that all opioid rescue medication is to be included in total opioid consumption 
(Section 9.2.3) 
• Added detail on type of local anesthetic to be used (Synopsis and Section 10.1.2.2) 
• Added detail on post-incision local anesthetic delivery (Section 10.1.2.2) 
• Noted that tourniquet use is as per institutional guidelines and is not required (Section 10.1.2.2) 
• Clarified definition of surgical site (Section 10.1.3) 
• Clarified timing of study assessments (Section 10.1.4) 


 
 
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• Clarified appropriate staff who can perform assessment (Synopsis and Section 10.1.4) 
• Revised description of complete physical examination to match standard being used in CRF 
(Section 10.3.19) 
• Clarified definition of post-menopausal FSH level (Section 10.3.5) 
• Added clarity on NRS pain score recording to specify knee surgical site (Synopsis, Section 
10.3.8 and Appendix F) 
• Clarified requirement for knee X-ray study procedure (Synopsis and Section 10.4.1) 
• Clarified definition of non-opioid analgesic consumption endpoint (Synopsis and Section 
10.4.3.2)  
• Corrected the definition of mITT population (Synopsis and Section 13.2) 
• Added definition of major protocol deviation (Section 13.4.2) 
• Corrected formula for Area Under the Curve (AUC) (Section 13.4.6) 
• Added information on exploratory efficacy analyses from the SAP (Section 13.4.6) 
 
Administrative: 
 
• Updated study contact personnel and information  
• Corrected typographical errors in directions for study drug administration (Synopsis and 
Section 10.1.3) 
• Added reference to Statistical Analysis Plan for detail on statistical considerations and 
exploratory efficacy endpoints (Synopsis, Section 10.4.3.2 and Section 13.1) 
 
 


 
 
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2. 
PROTOCOL SYNOPSIS 
Sponsor:  
Concentric Analgesics, Inc. (Concentric) 
101 California Street, Suite 1210 
San Francisco, CA 94111 
CRO: 
Lotus Clinical Research, LLC 
Protocol Number: 
CA-PS-208 
IND# 
129114 
Study Title: 
A Two-Part, Phase 1/2, Randomized, Double-blind, Placebo-Controlled, Adaptive 
Safety, Pharmacokinetics, and Preliminary Efficacy Study of CA-008 in Patients 
Undergoing Total Knee Arthroplasty 
Study Treatment 
CA-008 and placebo 
Planned Study 
Center(s): 
Part A: 
1 US site 
Part B: 
Up to 3 US sites 
Indication: 
Acute postsurgical pain 
Sample Size: 
Part A: 
• 
Cohort #1: total N = 8 (randomized 3:1 active to placebo), no more than 
4 patients dosed per week  
• 
Cohort #2: total N = 8 (randomized 3:1 active to placebo), no more than 
4 patients dosed per week 
After review of cohort study data, a cohort may be expanded to N = 16.  One (1) or 
2 additional cohorts may be added with N = 8 or 16 in each cohort, using the same 
3:1 randomization ratio.  The total sample size in Part A is thus 16-64 patients. 
Part B: 
In Part B, a total of 150-300 patients will be randomized in 3-4 parallel arms (with 
50-100 patients in each arm). The number of patients to be enrolled in Part B will not 
exceed 300. 
Population: 
Adults 18 to 80 years of age, inclusive, who are planning to undergo an elective 
unilateral total knee arthroplasty (replacement) (TKA) and who otherwise meet 
eligibility criteria may be considered for enrollment into the study. 
Study Duration: 
Approximately 76 days per patient from screening to Day 29 (D29) + 2 days (however, 
this could be longer to follow any adverse event (AE) to resolution or to establishment 
of a new baseline). 
Overall Study 
Design: 
This is a two-part, Phase 1/2, randomized, double-blind, placebo-controlled study.  In 
Part A, 2 or more exploratory sequential dose-escalation cohorts will be evaluated, 
each with administration of a single dose of CA-008 or placebo infiltrated/instilled 


 
 
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during surgery in patients undergoing TKA.  
In Part B, 2 or 3 active dose levels of CA-008 will be evaluated compared to placebo in 
a randomized, double-blind, parallel-group design.  
For each patient, the study will be conducted in two periods: 
• 
Inpatient period which continues from check-in on Day 1 (D1) until discharge 
(4 days or 96 hours [h] following surgery [T96 + 4 h], [D5]).   
• 
Outpatient period which begins on discharge from the inpatient unit through 
follow up visits to D29 + 2 days.  Note that additional follow up visits may 
occur at any time or even after D29 to follow AEs to resolution or to establish 
a new baseline. 
During the inpatient period, patients will undergo TKA including study drug treatment 
(CA-008 or placebo) followed by serial assessments of safety, pharmacokinetic (PK), 
and drug effect, in particular focusing on reported pain and need for analgesia.  During 
the outpatient period, patients will have serial assessments of safety and drug effect.  
Safety and drug effect assessments will focus on reported pain and need for analgesia. 
Study Objectives: 
Part A: 
Primary Objective: 
• 
Evaluate the safety and tolerability of a single intraoperative administration of 
either CA-008 or placebo in patients undergoing an elective TKA.  
Secondary Objectives: 
• 
Evaluate the PK profile of a single intraoperative administration of CA-008 in 
patients undergoing an elective TKA. 
• 
Evaluate, preliminarily, the activity of CA-008 on reported pain, opioid 
consumption, and patient-reported outcomes (PROs).  
• 
Determine the dose(s) for testing in Part B. 
Part B: 
Primary Objective: 
• 
Evaluate, during a specified post-operative time interval, the efficacy of 2 or 
3 selected doses of CA-008 on reported pain in patients undergoing an elective 
TKA. 
Secondary Objectives: 
• 
Evaluate the efficacy of 2 or 3 selected doses of CA-008 on reported pain in 
patients undergoing an elective TKA during additional specified post-operative 
time intervals. 
• 
Evaluate the effect of CA-008 on opioid consumption. 
• 
Evaluate the effect of CA-008 on PROs. 
• 
Evaluate, preliminarily, the effect of CA-008 on performance-based outcome 
measures (PBOMs), including knee range of motion (ROM). 
• 
Evaluate the safety and tolerability of CA-008 or placebo in patients 


 
 
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undergoing an elective TKA. 
• 
Evaluate the PK profile of a single intraoperative administration of CA-008 in 
patients undergoing an elective TKA.  
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 and 
Perioperative 
Care:  
The surgery will be performed under spinal anesthesia (isobaric bupivacaine 0.5%, 
[preservative-free] 12-15 mg and fentanyl 25 mcg) with adequate supplemental 
sedation, typically with midazolam (up to 5 mg), fentanyl (up to 100 mcg) and 
propofol infusion, but anesthesia and sedation will be per institutional guidelines.  
If the patient appears to have an inadequate level of anesthesia from the spinal 
anesthetic (“failed spinal anesthetic”), the patient should receive a general anesthetic 
with either an inhaled anesthetic or propofol infusion with or without nitrous oxide 
(N20).  
In addition, patients will receive ropivacaine hydrochloride (RopiHCl) delivered as 
follows: 
• 
Prior to start of surgery under ultrasound guidance: 
o Femoral nerve block: RopiHCl 0.5%, 12 mL (60 mg)  
o IPACK infiltration:  RopiHCl 0.2%, 20 mL (40 mg) 
• 
Immediately after surgical incision:  
o Periarticular infiltration: RopiHCl 0.2%, 50 mL (100 mg).  
The total RopiHCl should not exceed 200 mg.  See Section 17.5, Appendix E for 
guidance on RopiHCl dosing.  
Note: IPACK = Interspace between the Popliteal Artery and the Capsule of the 
posterior Knee between the femoral condyles) 
Standard anesthetic and perioperative care will be provided per institutional guidelines.  
This will typically include (but not be limited to) steps to ensure preservation of 
intraoperative normothermia (including the use of preoperative and intraoperative 
forced-air warming) and deep venous thrombosis prophylaxis. 


 
 
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Dose Groups: 
Part A: 
1. Sequential Cohort #1: total N = 8 patients randomized 3:1 CA-008 36 mg in 
120 mL (0.3 mg/mL) or placebo 120 mL 
2. Sequential Cohort #2: total N = 8 patients randomized 3:1 CA-008 60 mg in 
120 mL (0.5 mg/mL) or placebo 120 mL 
3. Additional sequential cohorts may receive doses between 15-90 mg or placebo 
using the same 3:1 randomization ratio 
Part B: 
4. The doses of active drug to be administered in Part B will be in the range of 
15-90 mg and will not exceed the maximum dose administered safely in Part A.  
Doses will be selected based on safety and tolerability data from Part A and from 
prior studies of CA-008. 
Injection of Study 
Treatment: 
The initial total study drug volume administered per patient will be 120 mL.  This 
initial 120 mL of study treatment administered per patient in the first study cohort will 
be delivered during the surgical procedure in 3 divided aliquots.  The initial allocation 
will be: (a) a total of 15 mL into the cut surfaces divided into aliquots following each 
osteotomy; (b) 30 mL prior to hardware placement; (c) 60 mL after hardware 
placement and (d) 15 mL following closure of the joint capsule.   
Modifications to the total study drug dose, volume, drug concentration, and allocation 
for subsequent patients may occur based on information from prior patients. 
Intraoperative 
Analgesia: 
Within 15 minutes prior to the end of surgery, administer the following: 
• 
IV hydromorphone, 1 mg 
• 
IV ketorolac, 30 mg  
Dose adjustments may be made per surgeon’s/anesthesiologist’s discretion to 
accommodate the patient’s age and health status. 
• 
IV acetaminophen, 1g   
After these have been administered, no additional non-opioid analgesics are to be 
administered during the inpatient phase (through T96). 
If a patient had an inadequate level of anesthesia from the spinal anesthetic and 
received a general anesthetic, the patient should receive IV hydromorphone, 1 mg, 
within 30 minutes of anesthesia induction and up to 1 mg of IV hydromorphone within 
15 minutes of end of surgery.  
Patients who develop clinically significant hemodynamic instability or other anesthesia 
complication prior to study drug administration should not receive study drug; in Part 
A, these patients will be replaced.  Replacement patients will be assigned the same 
treatment as the original patient.  A ‘replacement’ randomization list matching that of 
the main list will be created to facilitate this process. 
Postsurgical Care: After surgery, patients will be transferred to the post-anesthesia care unit (PACU) 
where patients will be monitored for at least 90 minutes during which time pain 


 
 
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assessments can begin once the patient is awake.  T0 is the time of admission into the 
PACU (as recorded in notes by the PACU nurse). 
Patients will use the 0 to 10 numerical rating scale (NRS) to report their current pain 
intensity multiple times per day during the remainder of the inpatient part of the study.  
Scheduled times for serial pain assessments are outlined in the protocol below.  Rescue 
medication will be administered at these times only upon request based on the currently 
reported pain score. 
If the patient reports pain spontaneously and requests analgesia at an unscheduled time 
(i.e., PRN), an NRS should be used to record the pain present at that time.  This 
unscheduled NRS must be recorded just prior to administration of any PRN analgesia, 
i.e., within 5 minutes prior to any PRN IV analgesic treatment and within 15 minutes 
prior to any PRN oral analgesic treatment.  NRS scores for PRN pain medication will 
not replace the recording of scheduled NRS scores. 
Medication for moderate to severe pain (NRS ≥ 4) will be administered upon request as 
follows: 
• 
From T0 to T25 minutes: 
o IV fentanyl 50 mcg, Q 5 minutes for pain NRS > 4 
• 
From T26 minutes to PACU discharge: 
o IV hydromorphone 0.5 mg, Q 10 minutes for pain NRS > 4 
After discharge from the PACU, patients are followed through T96 (± 4 h) as inpatients 
in the inpatient unit where safety and activity/efficacy evaluations will be performed.  
Patients will be required to meet standard criteria for discharge to outpatient status.  
Patients will continue to be monitored as outpatients after discharge from the inpatient 
unit through D29 + 2 days 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 T24:  
o Administer IV hydromorphone 0.5 mg, Q15 minutes PRN pain NRS ≥ 4. 
• 
After T24:  
o Administer PO oxycodone 10 mg, Q 4 h PRN pain NRS 5-10. 
o Only PO oxycodone may be used as rescue.  If a patient still requires IV 
opioid rescue after T24, then the patient will revert to IV analgesia 
management per institutional guidelines.  These patients will still also be 
followed for NRS, safety, and other assessments.  
Patients will be encouraged to use rescue medication only for moderate-to-severe pain 
(NRS 5-10); however, rescue with oxycodone, 10 mg PO may be requested at any time 
(i.e., even when NRS < 5) and medication will be provided when requested.   
NRS scores recorded for PRN pain medication will not replace the recording of 
scheduled NRS scores.  However, if PRN rescue medication has recently been 
administered and persistent pain is reported in a scheduled NRS record prior to rescue 
medication taking effect, a second dose of rescue medication should not be 
administered. 


 
 
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Analgesia during 
the Outpatient 
Period: 
 
Following discharge from the hospital through the D15 visit, pain will be managed 
with the following regimen only:   
• 
Scheduled medication: 
o Celecoxib, 100 mg PO BID (unless contraindicated) 
• 
Rescue medications (for pain as needed):  
o Acetaminophen, 650 mg PO Q 6 h for mild pain (i.e., NRS < 5) (unless 
contraindicated) 
o Acetaminophen, 325 mg/Oxycodone, 5 mg (Percocet) – 1 or 2 tablets PO 
Q 4-6 h for moderate-severe pain (i.e., NRS 5-10).  Discharge patient with 
20 tablets.  Use of this rescue medication [time, dose] must be recorded in 
the diary.  Pre-rescue medication NRS for opioids will also be recorded in 
the diary. 
Note:   
• 
Instruct patients to use acetaminophen as the initial option for treating pain.  
 
Document the number of tablets prescribed and also document any additional 
prescriptions required if the patient’s pain continues to be an issue requiring additional 
opioid medication. 
Following D15, pain will be managed per institutional guidelines and standards of care.  
Pain medication use will be recorded as a concomitant medication from D15 through 
D29. 
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 visit occurs, the 
Investigator should use clinical discretion regarding the adequacy of analgesic 
treatment, capture this occurrence as an AE, and document any required treatments. 
Inclusion 
Criteria: 
In order to participate, patients must meet all inclusion criteria:  
1. Plan to undergo an elective primary unilateral TKA under spinal anesthesia 
with sedation, without collateral procedure or additional surgeries. 
2. Appropriate candidate for spinal anesthesia, including no contraindications, no 
anatomical constraints. 
3. Adults 18-80 years of age, inclusive. 
4. American Society of Anesthesiology (ASA) physical Class 1, 2, or 3 at the 
time of randomization (Section 17.2, Appendix B). 
5. If a male, 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. 
6. 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; 


 
 
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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 (as 
documented by history and FSH level), 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. 
7. Have a body mass index ≤ 42 kg/m2. 
8. Be willing and able to sign the informed consent form (ICF) approved by an 
Institutional Review Board (IRB). 
9. Be willing and able to complete study procedures and pain scales and to return 
for outpatient follow up visits as required. 
10. Be willing and able to avoid foods containing capsaicin for 24 hours prior to 
surgery. 
Exclusion 
Criteria: 
If any of the following exclusion criteria apply, a patient may not participate in 
the study:  
1. In the opinion of the Investigator, the patient has: 
a. 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. moderate to severe chronic neuropathic pain or signs of central sensitization; 
c. active skin disease or other clinically significant abnormality at the anticipated 
site of surgery that could interfere with the planned surgery. 
2. The patient is tolerant to opioids (opioid-tolerant) defined as someone who has 
been receiving or has received chronic opioid therapy (use within the 2 weeks prior 
to surgery and duration of use > 4 weeks) greater than 15 mg of oral morphine 
equivalents per day for greater than 3 out of 7 days per week over a one-month 
period within 6 months of screening. 
3. The patient has a known allergy (or contraindication) to any of the following: chili 
peppers, capsaicin or the components of CA-008, ropivacaine hydrochloride (HCl), 
ketorolac, acetaminophen, fentanyl, hydromorphone, morphine, oxycodone, or 
celecoxib. 
4. As determined by the Investigator (with input from the study’s medical monitor if 
requested by the Investigator), the patient has a history or clinical manifestation of 
significant medical, neuropsychiatric, or other condition, including a clinically 
significant existing arrhythmia, left bundle branch block or abnormal 


 
 
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electrocardiogram (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. 
5. Use of the following disallowed medications: 
a. Within 1 day prior to surgery and throughout the inpatient period, taking or 
using any capsaicin-containing products, such as dietary supplements or over-
the-counter (OTC) preparations, including topical formulations, and 
prescription medications. 
b. Within the 7 days prior to surgery, 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.    
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 patient is taking centrally- and/or peripherally-acting analgesic 
medications, such as acetaminophen, NSAIDs, tramadol, or opioids, for 
knee-related pain, the patient may participate in the study if not opioid-
tolerant (defined above) and the patient is willing to discontinue these 
medications 3 days prior to surgery.  Note that (a) baby aspirin (81 
mg/day) for cardiovascular prophylaxis or (b) regular or enteric-coated 
aspirin (up to 325 mg given up to twice daily) for venous thrombo-
embolism prophylaxis is allowed during the study. 
c. Within the 7 days prior to the planned surgery and throughout the study, 
taking (a) antiarrhythmics (except beta-blockers and digoxin); (b) warfarin or 
other anticoagulants (see exception below); (c) lithium; or (d) 
aminoglycosides or other antibiotics for an infection (except for ophthalmic 
use).  
d. Within the 14 days prior to surgery, 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). 
e. Taking 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. 
6. In the opinion of the Investigator, within the past year, the patient has 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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7. The patient has a disqualifying positive urine drug screen or alcohol breath/saliva 
test during screening or check-in (See Section 10.3.16).   
8. The patient has previously participated in a clinical study with CA-008. 
9. The patient has participated in another clinical trial or used an investigational 
product within 30 days or 5 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: 
1. Screening D −45 to Day Prior to Surgery: Patients undergo screening during 
this period. All screening assessments (including informed consent form [ICF]) 
must be completed at least 1 day prior to surgery.  
2.  Site Unit Admission D1: Day of surgery, patients will be randomized and 
baseline evaluations will be performed prior to surgery.  Day 1 includes the 
day before surgery if check-in occurs at that time. 
3. Surgery D1: TKA procedure is performed; study treatment is administered 
prior to wound closure.  PK sample collection is to be done per 
protocol-specified time points through 24 h following the last study treatment 
instillation. 
4. Post-surgery T0 to T96: T0 is the time of admission into the PACU (as 
recorded in notes by the PACU nurse).  Patient remains in the PACU and then 
in the inpatient unit for study assessments.  Discharge to outpatient status after 
T96 (± 4 h) assessments with follow up instructions, particularly on diary 
completion. 
5. Follow Up D8 + 1 day: clinic visit for study assessments. 
6. Follow Up D15 + 2 days: clinic visit for study assessments. 
7. Follow Up D29 + 2 days: clinic visit for study assessments and study 
completion visit, unless additional follow up for wound healing is needed. 
8. If needed, Unscheduled Visits or Follow Up after D29: Clinic visit as 
needed for any ongoing safety issue occurring between scheduled visits or 
continuing after the D29 visit. 
9. Early Termination (ET): For patients who terminate early, an ET visit will be 
required. 
Monitored 
Parameters: 
• 
Treatment-emergent AEs (TEAEs) 
• 
Medical history (MHx) 
• 
Physical examination (PE) findings, particularly neurosensory findings at the site 
of incision and the skin proximal and distal to the incision 
• 
Surgical site assessment for wound healing, including a digital photograph if the 
patient has consented 
• 
Neurosensory testing near the surgical site 
• 
Clinical laboratory testing (standard chemistry, CBC, coagulation, urinalysis), drug 
and alcohol testing, pregnancy testing 


 
 
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• 
X-ray of the knee, only if any evidence of abnormalities in bone healing 
• 
12-lead ECGs 
• 
Blood draws for pharmacokinetics (PK) 
• 
NRS scores assessing rest pain and evoked pain at the knee surgical site 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 worsening (rebound) pain at the surgical site   
• 
Knee injury and Osteoarthritis Outcome Score (KOOS)  
• 
Knee Range of Motion (ROM) (using goniometry: active flexion and extension, 
passive flexion and extension) (Section 17.10, Appendix J) 
• 
Ability to walk > 100 ft (> 30 m) with only the aid of a walker during twice-daily 
inpatient physical therapy sessions (or assessed by site staff) 
• 
Performance-based functional outcome measures (PBOMs):  
o Timed Up and Go (TUG) (Section 17.13, Appendix M)  
o Sit to Stand Test (Section 17.11, Appendix K) 
o Walking Speed Test (Section 17.12, Appendix L) 
• 
Total postsurgical opioid consumption converted to an oral morphine equivalent 
dose (OME) 
• 
Patient Reported Outcomes Measurement Information System (PROMIS) 10 
Global Health questionnaire, V1.1 (Section 17.9, Appendix I) 
Safety Endpoints:  
1. Incidence of spontaneously reported TEAEs or serious AEs (SAEs) from study 
medication administration through D29 or later if necessary:  
o TEAEs are defined as AEs occurring post study medication administration 
o AEs recorded from the time the ICF is signed up to study medication 
administration will be recorded in medical history. 
o Note: A PK sample should be collected during the in-patient phase of the 
study as part of the evaluation of any SAE or severe TEAE.   
2. PE: full PE at screening (without a breast, genital, or rectal examination).  
Interim targeted PE on D1 prior to surgery (can be done on the day before 
surgery if check-in occurs then), T96, and as an outpatient on D8, D15, and 
D29 (later if necessary). 
3. Vital signs (heart rate [HR], blood pressure [BP], respiratory rate [RR]) at 
screening, D1 prior to surgery, post-surgery T2, T6, T12, and T24, and every 8 
hours thereafter until T96, and as an outpatient on D8, D15, and D29 or later if 
necessary.  Assess temperature on D1 prior to surgery.  Temperature will be 
recorded daily along with vital signs per site SOPs at 2, 6, 12, 24, and every 
8 hours thereafter until discharge from the inpatient facility (if awake at the 
time of assessment between hours of midnight and 6:00 AM).   


 
 
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4. Surgical site assessments at T96 prior to discharge from the inpatient unit and 
then as an outpatient on D8, D15, and D29 (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. 
5. Neurosensory testing near the incision (compared to a similar site on the 
opposite leg) will be performed at Screening visit, T96 (prior to discharge from 
the inpatient unit) and then as an outpatient on D8, D15, and D29. 
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.  Patients 
will be followed until there is a return to baseline or establishment of a new 
baseline. 
6. X-ray of the operated knee at D29 and later only if any evidence of 
abnormalities in bone healing until resolution or stabilization 
7. Query patients as to whether they have experienced any worsening (rebound) 
pain at the surgical site at D8, D15, and D29. 
8. 12-lead ECGs, and standard clinical laboratory tests 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 12-lead ECG at screening and T24 (± 2 h) 
o Hematology/Coagulation at screening and T96 (± 4 h): 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 (± 4 h) to include at least the 
following: alanine aminotransferase (ALT) and aspartate aminotransferase 
(AST), total bilirubin (Tot. Bili), 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 (± 4 h): including macroscopic analysis 
and, if indicated, microscopic analysis.  
o Note: Safety laboratory assessments may be collected, as appropriate, as 
part of the evaluation of an SAE or severe TEAE. 


 
 
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Activity/Efficacy 
Parameter 
Assessments:  
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 patient is awake.  T0 is the time of admission into the 
PACU (as recorded in notes by the PACU nurse).  If the patient is able to 
provide responses, obtain NRS scores at T0 plus 1 hour (T1), T0 plus 2 hours 
(T2, etc.), T4, T6, T8, T12, T16, T20, T24, and every 4 hours thereafter (if 
awake at time of assessment) until discharge from the inpatient unit.  Time 
windows: ± 5 minutes for T1 and T2; ± 15 minutes for T4 onward.  Scheduled 
NRS scores must be recorded regardless of timing of pre-rescue medication 
NRS scores and administration of rescue medication.  The actual time of all 
NRS scores must be recorded, i.e., not the nominal time. 
• 
During the inpatient stay, evoked NRS twice daily after physical therapy (most 
preferred) or ambulation for approximately 10 yards (preferred) or transfers 
to/from bed or wheelchair.  Obtain these NRS scores after morning physical 
therapy or ambulation at 10:00 AM (± 1 h) and after afternoon physical therapy 
or ambulation at 4:00 PM (± 1 h). 
• 
During the inpatient stay, pain scores may be skipped between the hours of 
midnight and 6:00 AM, but the patient may not miss two consecutive 
assessments.  The T12, T24, T48, T72, and T96 assessments must be completed 
even if the patient must be awakened at these times. 
• 
During the inpatient stay, an additional NRS assessment must be obtained 
within 5 minutes prior to IV rescue medication administration and within 
15 minutes prior to oral rescue medication administration. 
• 
During the outpatient period (after T96 and through D15), instruct the patient to 
document their NRS scores twice daily at 11:00 AM (± 1 h) and 7:00 PM 
(± 1 h) at rest and during 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.  Instruct the patient to: 
o Obtain the morning NRS assessment;  
o 
Obtain the evening NRS assessment;  
o 
Opioid and non-opioid rescue medication (dose, date, time) must be 
recorded in the diary through D15, including a pre-rescue NRS score. 
2. Daily opioid consumption (specific drug, dose, date, time) will be recorded during 
the inpatient and outpatient periods (through D15) to allow calculation of total opioid 
consumption (OC) and daily opioid (rescue medication) consumption in OMEs.  
• 
Document daily use of opioid analgesia during the outpatient period through D15.  
1. 
Document each opioid prescription provided to the patient and the number of 
and type of tablets provided to the patient. 
3. Ability to walk > 100 ft (> 30 m) with only the aid of a walker during twice-daily 
inpatient physical therapy sessions (or assessed by site staff) on D3, D4, and D5 to 
allow assessment of discharge readiness.  
4. KOOS survey at Screening, T96, D8, D15, and D29. 


 
 
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5. PROMIS 10 Global Health questionnaire at Screening, D15, and D29. 
6. Knee ROM at Screening, T48 (± 4 h), T96 (± 4 h)/Discharge, D8, D15, and D29. 
7. PBOMs: (Sit to Stand Test, Walking Speed Test, TUG) at T96 (± 4 h)/Discharge, 
D15, and D29. 
Efficacy 
Endpoints  
 
Part A: There are no efficacy endpoints for Part A 
Part B: 
Primary efficacy endpoint:  
• 
Area under the curve (AUC) of the rest NRS from T12 to T96 (AUC12-96).  AUC is 
the weighted sum of current pain intensity (SPI) assessments for a specified time 
interval. 
Key secondary efficacy endpoints:  
• 
Evoked pain NRS: AUC12–96 
• 
Percentage of patients who do not require opioids (i.e., opioid-free or OF) from 
T24 to T96: OF24-96 
• 
Total opioid consumption (in daily OME) = OC from T12 to T96: OC12-96 
• 
NRS at rest and evoked NRS from T12 to D8: AUC12-D8 
Exploratory efficacy endpoints for Part B:  
• 
Using rest NRS: AUC0-24, AUC0-96, AUC6-96, AUC24-96, AUC96-D8, and AUC96-D15; 
• 
Using evoked NRS: AUC0-96 (ambulation), AUC0-D8 (ambulation), AUC24-D8(ambulation), and 
AUC96-D15 (ambulation); 
• 
Time-specific mean NRS scores at T48, T72, T96, T120, T144, and T168; 
• 
OC0-96, OC24-48, OC24-72, OC24-96, OC24-D8, and OC24-D15; 
• 
OF0-96, OF24-D15, OF96-D8, and OF96-D15; 
• 
Additional exploratory and sensitivity analyses rest/evoked NRS AUC, OC, and 
OF during different intervals may be undertaken: 
• 
Knee ROM: mean and proportion of patients with > 90° and proportion of patients 
with > 115° active flexion at T48 (± 4 h), T96 (± 4 h)/Discharge, D8, D15, and 
D29. 
• 
KOOS improvement from Screening to D8, D15, and D29; and from T96 to D8, 
D15, and D29; 
• 
Improvement in PBOMs (Sit to Stand, Walking Speed Test, TUG) at T96 
(± 4 h)/Discharge, D15, and D29; 
• 
The proportion of patients who rescue T0-T6, T6-T12, T12-T24, T24-T48, T48-
T72, and T72-T96; 
• 
Total non-opioid analgesic consumption (AC), ie, rescue acetaminophen use for 
the indicated time intervals: AC96-D8 and AC96-D15; 
• 
PROMIS 10 Global Health questionnaire score improvement from Screening to 
D15 and to D29; 
• 
Number and percentage patients with an AE of lack of efficacy (LOE) during the 
inpatient period: LOE0-96. 


 
 
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• 
Discharge readiness at T48 (± 4 h), T72 (± 4 h), and T96 (± 4 h)/Discharge as 
assessed by the earliest presence of all three of the following: (i) Adequate 
analgesia (defined as median rest NRS < 4 during an 8-hour period); (ii) 
independence from intravenous opioids during an 8-hour period; and (iii) ability to 
ambulate > 100 ft (> 30 m) with only the aid of a walker during a physical therapy 
session. 
Note: Details on additional or alternative exploratory efficacy endpoints are provided 
in the study Statistical Analysis Plan (SAP).  The SAP will supersede the protocol with 
respect to the analyses specified, although the primary and key secondary efficacy 
endpoints described in the protocol will remain unchanged. 
 
PK Endpoints: 
Part A: 
PK sample collection will be performed on all patients.  The time points for whole 
blood collection will be at pre-dose (from check-in and up to 30 minutes before the 
start of surgery), and at pharmacokinetic time (PKT) 0.167 h (10 min), 0.25 h (15 min), 
0.5 h (30 min), 0.75 h (45 min), and at 1, 1.5, 2, 3, 4, 6, 8, 12, 16, and 24 hours after the 
last study treatment instillation (total of 15 samples).  
Part B: 
PK sample collection will be performed at one site. The time points for whole blood 
collection will be at pre-dose (from check-in and up to 30 minutes before the start of 
surgery), and at PKT 0.167 h (10 min), 0.25 h (15 min), 0.5 h (30 min), 0.75 h 
(45 min), and at 1, 1.5, 2, 3, 4, 6, 8, 12, 16, and 24 hours after the last study treatment 
instillation (total of 15 samples).  At least 12 of the 15 samples should be collected in 
each of these patients.  The number of patients will depend on the number of dose 
levels being tested, but approximately15 patients per dose level are planned. 
Actual sampling times will be used to calculate plasma-derived PK parameters.   
Plasma concentration for CA-008 and key metabolite(s) (including capsaicin and 
CA-101) at PK sampling times will be summarized using descriptive statistics, 
including mean, SD, median, minimum and maximum values, coefficient of variation 
(CV%), and geometric mean and geometric coefficient of variation (geoCV%).  PK 
parameters include (but are not limited to) maximum observed plasma drug 
concentration (Cmax), time to maximum plasma drug concentration (Tmax), half-life, and 
area under the plasma concentration-time curve (AUC0-last and AUC0-∞). 
The PK will be documented in the PK Analysis Plan. 
Note: A PK sample should be collected during the in-patient phase of the study as part 
of the evaluation of any SAE or severe TEAE. 
Stopping Rules: 
Study enrollment will be paused if patients experience intolerable “related” TEAEs, as 
outlined below. 
1 or more patients with any grade 4 “related” TEAE in any of the categories shown 
in Table 7, Section 7.4 
2 or more patients with the same grade 3 “related” TEAE in any of the categories 


 
 
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shown in Table 7, Section 7.4 
2 or more patients with the same grade 3 or 4 “related” TEAE shown in 
Appendix A (Section 17.1) or found in the in the toxicity grading scale cited 
therein.  
“Related” includes possibly, probably, and definitely related causality assessments. 
In Part A, should a stopping rule be triggered, the Sponsor’s medical monitor, the CRO 
medical monitor, and the relevant Principal Investigator (PI) will review the blinded 
data to determine whether or not it is appropriate to resume enrollment with the same 
or a modified dose.  Unblinding of an individual treatment assignment may be required 
to complete this safety assessment. 
In Part B, should a stopping rule be triggered, the Sponsor’s medical monitor, the CRO 
medical monitor, the relevant PI, and an independent medical monitor will review the 
blinded data to determine whether or not it is appropriate to resume enrollment, modify 
the study or stop the study.  The independent medical monitor will have the authority 
to unblind the treatment assignment for the affected patients as part of the safety 
review.   
The study will be stopped if a safety signal is detected that indicates an unacceptable 
risk to study participants. 
Sample Size 
Justification: 
In Part A, no formal statistical hypothesis testing will be performed.  The sample size 
of 8 initial patients per dose level, with the potential for expansion to 16 patients, has 
been selected based on prior clinical trial experience with CA-008 and is considered 
sufficient for exploration of tolerability and safety parameters, establishment of a PK 
profile, and preliminary assessment of the efficacy of CA-008 in postoperative 
analgesia. 
In Part B, a total of 150-300 patients will be randomized in 3-4 parallel arms with 
50-100 patients in each arm.  The number of patients to be enrolled in Part B will not 
exceed 300.  Assuming a t-test for the difference in 2 independent means, a sample size 
of approximately 50 patients per group would provide approximately 85% power to 
detect an effect size (Cohen’s d) of 0.6 at a two-sided level of significance, alpha, of 
0.05 in the primary efficacy endpoint NRS AUC12-96.  Enrollment is currently planned 
at 55 patients per arm to allow for patients whose data are not eligible for inclusion in 
the final analysis.  In this scenario, it is anticipated that, in Part B, 3 active dose levels 
– 60 mg, 36 mg, and 15 mg – are to be tested versus placebo, yielding 4 trial arms and 
a resulting total sample size of 220 patients.  Alternative assumptions concerning the 
anticipated effect size lead to a different number of patients per group.  The actual 
doses, number of active arms (2 or 3), and sample size to be tested in Part B will be 
determined at the end of Part A based on information in the protocol and Statistical 
Analysis Plan.   
Study 
Populations: 
The following 5 analysis populations are planned for this study:  
1 
Safety Population consists of all patients who received any part of a dose of study 
treatment.  (Note this must include anyone who terminates early for lack of 


 
 
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efficacy). 
2 
PK Population consists of all patients who received a full dose of study treatment 
and completed at least one PK assessment. 
3 
Modified Intent-to-treat (mITT) Population consists of all patients who received 
any dose of study treatment.  
4 
Per Protocol (PP) Population consists of all patients who received a full dose of 
study treatment and have evaluable NRS pain assessments at least through T96 
(± 4 h)/Discharge 
5 
Study Completers consists of all patients who received a full dose of study 
treatment and completed the entire study period through D29 + 2 days. 
Patients who discontinue study participation before or after randomization but prior to 
receiving study treatment will be replaced.   
Patients who are withdrawn or who elect to withdraw after receiving study treatment 
will not be replaced. Those who withdraw during the inpatient phase of the study, will 
be asked to continue with assessments through T96 if they have not elected to 
withdraw from all aspects of study participation (see Section 10.2).  Patients who elect 
to discontinue participation on or prior to D8 will be considered to have terminated as 
of the date of their election; however, they will be asked to return to the site one time to 
ensure that adequate wound healing has occurred (see Section 10.2). 
Statistical 
Considerations:  
 
In general, descriptive statistics for continuous variables will include n, mean, standard 
deviation (SD), standard error of mean (SEM), (if appropriate), median, minimum, and 
maximum.  Categorical variables will be described by number and percentage.  
All safety assessments and baseline characteristics will be summarized using the Safety 
Population.  All safety summaries will be grouped by the actual treatment received.  
Data from all patients receiving placebo will be combined for summaries.  
Safety and tolerability will be evaluated by examining the occurrence of AEs, 
including TEAEs.  AEs leading to discontinuation from the study, AEs related to study 
treatment, and AEs by severity will be summarized by treatment group.   
Actual values 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.  Abnormal values will be determined and 
flagged in the listings.  Laboratory shift tables displaying the change (number of 
patients) 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.  
Efficacy, PK, and other assessments will be summarized using appropriate descriptive 
statistics.  A detailed methodology for the statistical analyses of the data collected in 
this study will be documented in a statistical analysis plan (SAP) which will be signed 
prior to the database lock. 


 
 
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Table 1. Schedule of Assessments – Part A and Part B 
Study Period 
Screening 
Inpatient 
Follow-Up Clinic Visits 
Unscheduled 
Visit1 
Early 
Termination19 
Day of 
Surgery 
Surgery 
Post-
Surgery 
T24 
T48 
T72 
T96 ± 
4 h 
Study Day 
D −45 to 
Day Prior 
to Surgery 
D1 
(prior to 
surgery) 
D1 
D1 
D2 
D3 
D4 
D5 
D8 + 
1 day 
D15 + 
2 days 
D29 + 
2 days 
Assessment 
Informed Consent 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Screening Medical and 
Surgical History 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Screens for alcohol/drugs of 
abuse 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Patient Pain Assessment 
Training 
X2 
X2 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test  
(or FSH if post-menopausal) 
X3 
(serum) 
X3 
(urine) 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs (supine) 
X 
X 
 
X4 
X4 
X4 
X4 
X4 
X 
X 
X 
X 
X19 
Temperature (oral) 
X 
X 
 
X4 
X4 
X4 
X4 
X4 
X 
X 
X 
X 
X19 
Physical Examination 
X5 
X5 
 
 
 
 
 
X5 
X5 
X5 
X5 
X5 
X5,19 
12-Lead ECG 
X 
 
 
 
X6 
 
 
 
 
 
 
 
 
Enroll/Randomize 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Surgery 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Study treatment 
Infiltration/instillation 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Admission to PACU 
 
 
 
T0 
 
 
 
 
 
 
 
 
 
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 
Concomitant Medication 
Assessment 
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 


 
 
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Study Period 
Screening 
Inpatient 
Follow-Up Clinic Visits 
Unscheduled 
Visit1 
Early 
Termination19 
Day of 
Surgery 
Surgery 
Post-
Surgery 
T24 
T48 
T72 
T96 ± 
4 h 
Study Day 
D −45 to 
Day Prior 
to Surgery 
D1 
(prior to 
surgery) 
D1 
D1 
D2 
D3 
D4 
D5 
D8 + 
1 day 
D15 + 
2 days 
D29 + 
2 days 
Assessment 
Patient home diary record 
(NRS) 
 
 
 
 
 
 
 
X11 
X11 
X11 
 
 
X11,19 
Paper/Electronic Diary 
(review, distribution and/or 
collection) 
 
 
 
 
 
 
 
X12 
X12 
X12,13 
 
 
X13 
Patient home diary 
(analgesic consumption) 
 
 
 
 
 
 
 
X 
X 
X13 
 
 
X 
Prescription for outpatient 
opioid rescue  
 
 
 
 
 
 
 
X14 
 
 
 
 
 
PROMIS 10 Global Health 
questionnaire 
X 
 
 
 
 
 
 
 
 
X 
X 
 
 
KOOS Survey 
X 
 
 
 
 
 
 
X 
X 
X 
X 
 
X 
Knee ROM 
X 
 
 
 
 
X 
 
X 
X 
X 
X 
 
X 
Ability to walk > 100 ft 
(> 30 m) 
 
 
 
 
 
BID 
BID 
BID 
 
 
 
 
 
PBOMs15 
 
 
 
 
 
 
 
X 
 
X 
X 
 
 
Blood draw for PK analysis 
 
X16,17 
 
X16 
X16 
 
 
 
 
 
 
 
 
Worsening (rebound) pain 
 
 
 
 
 
 
 
 
X18 
X18 
X18 
 
X18 
Knee x-ray 
 
 
 
 
 
 
 
 
 
 
X20 
 
X20 
1 
Unscheduled visits may occur at any time and assessments are to be completed at the Investigator’s discretion. 
2 
Pain assessment training with test during screening; re-watch 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 after T0 at 2, 6, 12, 24, and every 8 hours thereafter (if awake at time of assessment between the hours of 12:00 AM and 6:00 AM) 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, and a physical examination to capture changes after Surgery, at T96 (± 4 hours), but prior to discharge from the inpatient unit, 
and D8, D15, and D29 or if the patient terminates early, at that time if allowed.  Body weight (kg), in indoor clothing, but without shoes, will be measured at Screening and at T96.  Height (cm) 
will be measured and body mass index (BMI) will be calculated at Screening only. 
6 
Post-Surgery ECG should be performed at T24 (± 2 hours). 
7 
Surgical Site assessment: T96 (± 4 hours, but prior to discharge from the inpatient unit) and D8, 15, and 29. 
8 
Neurosensory Exam of the area proximal to the surgical incision approximately 3 cm from the incision at Screening visit, T96 (± 4 hours, but prior to discharge from the inpatient unit) and D8, 
D15, and D29 or if the patient terminates early, at that time if allowed. 


 
 
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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 T96 is 
± 4 hours). 
10 
During the inpatient stay, NRS at rest beginning with the PACU admission (T0) may be assessed once the patient is awake. If the patient is able to provide responses, obtain NRS scores T0 plus 
1 hour (T1), T0 plus 2 hours (T2, etc.), T4, T6, T8, T12, T16, T20, T24, and every 4 hours (if awake at time of assessment) until discharge from the inpatient unit. Time windows: for T1 to T2 (± 
5 min) and from T4 onward (± 15 min).  Scheduled NRS scores must be recorded regardless of timing of pre-rescue medication NRS scores and administration of rescue medication.  The actual 
time of all NRS scores must be recorded, i.e., not the nominal time.  During the inpatient stay, evoked NRS twice daily after physical therapy (most preferred) or ambulation for approximately 10 
yards (preferred) or transfers to/from bed or wheelchair.  Obtain these NRS scores after morning physical therapy or ambulation at 10:00 AM (± 1 h) and after afternoon physical therapy or 
ambulation at 4:00 PM (± 1 h).  During the inpatient stay, pain scores may be skipped between the hours of midnight and 6:00 AM, but the patient may not miss two consecutive assessments.  
The T12, T24, T48, T72, and T96 assessments must be completed even if the patient must be awakened at these times.  During the inpatient stay, an additional NRS assessment must be obtained 
within 5 minutes prior to IV rescue medication administration and within 15 minutes prior to oral rescue medication administration.  During the outpatient period, (after T96 and through D15), 
instruct the patient to document their NRS scores twice daily at 11:00 AM (± 1 h) and 7:00 PM (± 1 h) at rest and during 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.  Instruct the patient to: 
• 
Obtain the morning NRS assessment; 
• 
Obtain the evening NRS assessment; 
• Opioid and non-opioid rescue medication (dose, date, time) must be recorded in the diary through D15, including a pre-rescue NRS score. 
11 
The patient is expected to document NRS pain scores at rest and on ambulation 2 ×/day through D15 (at the times and qualifications noted above).   
12 
The diary and instructions are provided to the patient prior to discharge (T96).  At each subsequent visit, review Patient Diary instructions with patient and collect the patient’s NRS scores and 
other study-related assessments. 
13 
Collect Patient Diary Data.  
14 
Patients will be given a prescription for 20 tablets of acetaminophen 325 mg/oxycodone 5 mg (Percocet) one or two tablets PO Q 4-6 h PRN moderate-severe pain (i.e., NRS 5 – 10).   
15 
PBOMs: Sit to Stand Test, Walking Speed Test, TUG. 
16 
Collect blood samples for PK.  The time points for whole blood collection will be at pre-dose (from check-in and up to 30 minutes before the start of surgery), and at PKT 0.167 (10 min), 0.25 
(15 min), 0.5 (30 min), 0.75 (45 min), and at 1, 1.5, 2, 3, 4, 6, 8, 12, 16, and T24 after last study treatment instillation (total of 15 samples). There will be a ± 2-minute window allowed for the 10- 
to 15-minute collections, a ± 5-minute window allowed for collections at 30 minutes through 4 hours, and a ± 15-minute window for collections after 4 hours.  In the event of an AE, an 
unscheduled PK draw will be performed. 
17 
Patients must abstain from foods containing capsaicin for T24 prior to surgery. 
18 
Assess for presence of worsening (rebound) pain at the surgical site (yes/no response). 
19 
If the patient terminates early, complete all procedures listed, as appropriate.  The following assessments are done only if the Early Termination occurs prior to the D15 visit: Patients home diary 
review, vital signs, and targeted physical examination. 
20 
X-ray of the operated knee on D29 and later only if any evidence of abnormal bone healing until resolution or stabilization.  Also perform this at early termination if patient gives consent. 


 
 
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3. 
TABLE OF CONTENTS 
1. 
Key Personnel Contact Information ................................................................................... 3 
2. 
Protocol Synopsis .................................................................................................................. 6 
3. 
Table of Contents ................................................................................................................ 25 
4. 
List of Abbreviations and Definition of Terms ................................................................ 28 
5. 
Introduction ......................................................................................................................... 32 
5.1. 
Background .............................................................................................................................. 32 
5.2. 
CA-008 Product Introduction ................................................................................................. 33 
5.3. 
Previous Human Experience .................................................................................................. 33 
5.4. 
Study Rationale ........................................................................................................................ 42 
5.5. 
Dose Rationale ......................................................................................................................... 43 
6. 
Study Objectives.................................................................................................................. 44 
6.1. 
Primary Objectives .................................................................................................................. 44 
6.2. 
Secondary Objectives .............................................................................................................. 44 
7. 
Investigational Plan ............................................................................................................ 45 
7.1. 
Overall Study Design and Plan ............................................................................................... 45 
7.2. 
Duration of Participation ........................................................................................................ 45 
7.3. 
Dose Escalation and Cohort Expansion ................................................................................. 45 
7.4. 
Study Stopping Rules .............................................................................................................. 46 
8. 
Selection of Study Population ............................................................................................ 48 
8.1. 
Study Population ..................................................................................................................... 48 
8.2. 
Eligibility Criteria ................................................................................................................... 48 
9. 
Study Treatments ................................................................................................................ 52 
9.1. 
Study Treatment ...................................................................................................................... 52 
9.2. 
Other Interventions ................................................................................................................. 53 
9.3. 
Method of Assigning Patients to Treatment Groups ............................................................ 56 
9.4. 
Blinding .................................................................................................................................... 56 
9.5. 
Prior and Concomitant Therapy ............................................................................................ 57 
9.6. 
Study Restrictions .................................................................................................................... 57 
9.7. 
Treatment Compliance............................................................................................................ 58 
10. 
Conduct of the study ....................................................................................................... 59 
10.1. 
Study Visits ............................................................................................................................... 59 
10.2. 
Patient Completion and Withdrawal ..................................................................................... 71 
10.3. 
Study Procedures and Assessments ....................................................................................... 72 
10.4. 
Safety, Tolerability, Pharmacokinetic (PK), and Efficacy Endpoints ................................ 80 
11. 
Adverse Events ................................................................................................................ 82 
11.1. 
Adverse Events and Serious Adverse Events ........................................................................ 82 
12. 
Data Quality Assurance .................................................................................................. 88 
12.1. 
Data Collection ......................................................................................................................... 88 


 
 
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12.2. 
Study Auditing and Monitoring ............................................................................................. 88 
13. 
Statistical Methods .......................................................................................................... 90 
13.1. 
Sample Size Justification......................................................................................................... 90 
13.2. 
Analysis Populations ............................................................................................................... 90 
13.3. 
Planned Analyses ..................................................................................................................... 91 
13.4. 
Study Patients and Demographics ......................................................................................... 92 
14. 
Site and Investigator Responsibilities ........................................................................... 97 
14.1. 
Regulatory and Ethical Considerations ................................................................................. 97 
14.2. 
Privacy and Confidentiality .................................................................................................... 98 
14.3. 
Study and Site Closure ............................................................................................................ 99 
14.4. 
Regulatory Documents and Records Retention .................................................................... 99 
14.5. 
Delegation of Responsibilities and Adequate Resources .................................................... 100 
14.6. 
Protocol Amendments ........................................................................................................... 100 
14.7. 
Financial Disclosure .............................................................................................................. 100 
15. 
Investigator Protocol Agreement Page ....................................................................... 101 
16. 
References ...................................................................................................................... 102 
17. 
Appendices ..................................................................................................................... 103 
17.1. 
Appendix A: Toxicity Grading Scale for Systemic (General) Adverse Events ................ 103 
17.2. 
Appendix B: American Society of Anesthesiologists Physical Status Classification System 
(ASA Class) ......................................................................................................................................... 104 
17.3. 
Appendix C: Toxicity Grading Scale for Clinical Vital Sign Abnormalities ................... 105 
17.4. 
Appendix D: Toxicity Grading Scale for Clinical Laboratory Abnormalities ................. 107 
17.5. 
Appendix E: Ropivacaine Dosage Recommendations ........................................................ 110 
17.6. 
Appendix F: 0 to 10 Numerical Rating Scale of Pain Intensity (NRS) ............................. 111 
17.7. 
Appendix G: Assessment of Worsening (Rebound) Pain at the Surgical Site ................. 112 
17.8. 
Appendix H: Knee Injury and Osteoarthritis Outcome Survey (KOOS) ........................ 113 
17.9. 
Appendix I: PROMIS 10 GLOBAL Health Questionnaire ............................................... 125 
17.10. 
Appendix J: Knee ROM Procedure ................................................................................ 127 
17.11. 
Appendix K: Sit to Stand Test (30-Second Chair Stand) Assessment .......................... 128 
17.12. 
Appendix L: Walking Speed Test .................................................................................... 129 
17.13. 
Appendix M: TUG Test .................................................................................................... 130 
17.14. 
Appendix N: Surgical Site Assessment ............................................................................ 131 
17.15. 
Appendix O: Surgical Wound Adverse Event Grading Guide ..................................... 132 
17.16. 
Appendix P: Neurosensory Examination Form ............................................................. 133 
 


 
 
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LIST OF TABLES 
Table 1. 
Schedule of Assessments – Part A and Part B ...................................................... 22 
Table 2. 
Overall Summary of Adverse Events (CA-PS-201) ............................................. 35 
Table 3. 
Summary of TEAEs by MedDRA SOC/PT (CA-PS-201) ................................... 35 
Table 4. 
Overall Summary of TEAEs – (CA-PS-203) ........................................................ 40 
Table 5. 
Summary of Serious Adverse Events – (CA-PS-203)........................................... 40 
Table 6. 
Summary of TEAEs by MedDRA SOC/PT (CA-PS-203) ................................... 41 
Table 7.  
Study Stopping Rules .............................................................................................. 47 
Table 8. 
Clinical Laboratory Assessments .......................................................................... 77 
 


 
 
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4. 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Term 
AC 
Analgesic consumption 
ADaM 
Analysis Data Model 
AE 
Adverse event 
ALK 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
aPTT 
Activated partial thromboplastin time 
ASA 
American Society of Anesthesiologists 
AST 
Aspartate aminotransferase 
AUC 
Area Under the Curve 
AUC0-∞ 
Area Under the Curve from time 0 to infinity  
AUC0-last 
Area Under the Curve from time 0 to the last PK sample collection time 
BID 
Bis in die (twice daily) 
BMI 
Body mass index 
BP 
Blood Pressure 
BUN 
Blood urea nitrogen 
CA-008 
Investigational product 
CA-101 
Cyclic urea 
CBC 
Complete blood count 
CFR 
Code of Federal Regulations 
cm 
Centimeter 
Cmax 
Maximum observed plasma drug concentration 
CNS 
Central nervous system 
CRF / eCRF 
Case Report Form (may include electronic data capture systems or paper forms) 
CRO 
Contract research organization 
CS 
Clinically significant 
CSA 
Clinical Study Agreement 
CV% 
Coefficient of variation  
D# or D-# 
Day # (study days after surgery), Day # prior to surgery 
DVT 
Deep Venous Thrombosis 
ECG 
Electrocardiogram 
EDC 
Electronic data capture 
ET 
Early Termination 
FCBP 
Female of childbearing potential 
FDA 
Food and Drug Administration 
FIH 
First-In-Human 


 
 
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Abbreviation 
Term 
FSH 
Follicle stimulating hormone 
G 
Gram 
GCP 
Good Clinical Practice 
geoCV% 
Geometric coefficient of variation 
GGT 
Gamma-glutamyl transferase 
GLP 
Good Laboratory Practice 
h or HRS 
Hour(s) 
HCl 
Hydrochloride 
HCU 
Health care utilization 
HEENT 
Head, Eye, Ear, Nose and Throat 
HR 
Heart rate 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Institutional Ethics Committee 
INR 
International Normalized Ratio 
IPACK 
Interspace between the Popliteal Artery and the Capsule of the posterior Knee 
IRB 
Institutional Review Board 
IV 
Intravenous 
kg 
Kilogram 
KOOS 
Knee Injury and Osteoarthritis Outcome Score 
LOCF 
Last pain score carried forward 
LOE 
Lack of efficacy 
m 
Meter 
mcg or µ 
Microgram 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
MHx 
Medical history 
min 
Minutes 
mITT 
Modified Intent-to-treat 
mL 
Milliliter 
ms 
Millisecond 
NCS 
Not clinically significant 
NIH 
National Institute of Health 
NRS 
Numeric Rating Scale of Pain Intensity 
NSAID 
Nonsteroidal anti-inflammatory drug 
OC 
Opioid consumption in morphine equivalent dose 


 
 
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Abbreviation 
Term 
OF 
Opioid free 
OME 
Oral morphine equivalent 
OTC 
Over-the-counter 
PACU 
Post-anesthesia care unit 
PBOM 
Performance-based functional outcome measure 
PE 
Physical examination 
PHN 
Postherpetic neuralgia 
PI 
Principal Investigator 
PKT 
Pharmacokinetic time 
PK 
Pharmacokinetic[s] 
PO 
Per os (oral) 
PRN 
Pro re nata (as needed) 
PRO 
Patient-reported outcome 
PROMIS 
Patient Reported Outcomes Measurement Information System 
PT 
Prothrombin time 
QID 
Quater in die (four times daily) 
RBC 
Red blood cell 
RopiHCl 
Ropivacaine hydrochloride 
ROM 
Range of motion 
RR 
Respiratory rate 
SAE 
Serious adverse event  
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SDTM 
Study data tabulation model 
SEM 
Standard error of mean 
SNRIs 
Serotonin-norepinephrine reuptake inhibitors 
SOC 
System Organ Class 
SPI 
Sum of pain intensity 
SSRIs 
Selective serotonin reuptake inhibitors 
T# 
Time in hours since arrival in the PACU (T0 equals time of admission into the PACU) 
t½  
Elimination half-life 
TEAEs 
Treatment emergent adverse event[s] 
THC 
Tetrahydrocannabinol 
TID 
Ter in die (three times daily) 
TKA 
Total knee arthroplasty 
TKR 
Total knee replacement 


 
 
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Abbreviation 
Term 
Tmax 
Time to maximum plasma drug concentration 
Tot. Bili 
Total bilirubin 
TRPV1 
Transient receptor potential vanilloid-1 
TUG 
Timed Up and Go 
UDS 
Urine drug screen[ing] 
ULN 
Upper limit of normal 
US 
United States 
V 
Volume of distribution 
W# 
Week # visit after surgery 
wLOCF 
windowed last pain score carried forward 
WOCF 
worst prior pain score carried forward 


 
 
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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 T96 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. 
In order 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/).   


 
 
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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 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 have been determined in multiple clinical trials conducted to date.  
In Concentric GLP toxicological study no. CA-NC-008-TOX-019-CR, single-dose subcutaneous 
administration of CA-008 HCl was well-tolerated when administered to male and female 
anesthetized dogs at dose levels up to 3.24 mg/kg CA-008 HCl (3.00 mg/kg CA-008 free 
base; Human Equivalent Dose [HED] of approximately 100 mg for a 60 kg patient).  Test article 
was formulated in 0.5 mM citrate, 0.4 mg/mL mannitol in saline for injection, with a final pH of 
approximately 3.7 to 3.8.  This study supports clinical doses up to 100 mg of CA-008 (free base), 
with concentrations up to 2.00 mg/mL CA-008 (free base).  
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 over-the-counter (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 


 
 
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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 40 patients undergoing a unilateral transpositional first metatarsal osteotomy for correction of 
hallux valgus deformity, more commonly known as a bunionectomy.  This study also evaluated 
pharmacokinetic (PK) and preliminary efficacy assessment of CA-008 to inform future studies in 
our clinical development plan.  This study was originally designed to look at 4 different doses of 
CA-008 (0.5 mg, 1 mg, 2 mg, and 3 mg), however based upon the relatively benign adverse 
event (AE) profile, the Data Management Committee gave the go-ahead for a 5th cohort (4.2 mg) 
to be added.  The safety, efficacy and PK results for the Phase 1 bunionectomy study are shown 
in the current Investigators’ Brochure.   
Additionally, a follow-on Phase 2 bunionectomy study (CA-PS-201) was completed with 
147 patients enrolled and randomized to one of 3 active doses: 0.05 mg/mL (0.7 mg, N = 36), 
0.15 mg/mL (2.1 mg, N = 36) and 0.3 mg/mL (4.2 mg, N = 37) vs. placebo (N = 38) in a 1:1:1:1 
randomization, respectively.  Based upon topline results, the highest dose of 4.2 mg was 
statistically significantly superior to placebo for the primary efficacy endpoint of Pain AUC0-96 
(p = 0.005) and key secondary efficacy endpoints: Pain AUC 0 to Week 1 (AUC0-W1) 
(p = 0.036); mean opioid consumption (reduced by 50%, p < 0.002); and percent of patients who 
were opioid free (OF) from 0-96 (26% vs. 5% for placebo; p = 0.039).   
Low but measurable levels of CA-008 were documented in the systemic circulation for a few 
hours following study drug instillation with a Tmax of ~15 minutes.  CA-008 was safe and 
well-tolerated at all doses.  There were no treatment-emergent adverse events (TEAE) leading to 
patient discontinuation and no pattern of TEAEs that suggested a drug-related safety concern.  
There were no serious adverse events (SAEs) reported.  Table 2 and Table 3 show the summary 
of safety for the study based upon summary tables and patient listings.   


 
 
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Table 2. Overall Summary of Adverse Events (CA-PS-201) 
 
 
Table 3. Summary of TEAEs by MedDRA SOC/PT (CA-PS-201) 
No. of Subjects 
Total N=147 
n (%) 
CA-008 
Placebo 
(Standard of care 
alone) 
N=37 
n (%) 
System Organ Class 
                    Preferred Term 
0.7 mg (0.05 
mg/mL) 
N=36 
n (%) 
2.1 mg (0.15 
mg/mL) 
N=36 
n (%) 
4.2 mg (0.3 
mg/mL) 
N=38 
n (%) 
No. of TEAEs 
287 
69 
82 
76 
60 
No. of Subjects with any TEAE1 
106 (72.1) 
27 (75.0) 
28 (77.8) 
26 (68.4) 
25 (67.6) 
Cardiac disorders 
6 (4.1) 
1 (2.8) 
2 (5.6) 
3 (7.9) 
0 
Angina pectoris 
1 (0.7) 
1 (2.8) 
0 
0 
0 
Bradycardia 
2 (1.4) 
0 
1 (2.8) 
1 (2.6) 
0 
Sinus tachycardia 
1 (0.7) 
0 
1 (2.8) 
0 
0 
Tachycardia 
2 (1.4) 
0 
0 
2 (5.3) 
0 
Eye disorders 
1 (0.7) 
0 
1 (2.8) 
0 
0 
Eye haematoma 
1 (0.7) 
0 
1 (2.8) 
0 
0 
Gastrointestinal disorders 
41 (27.9) 
8 (22.2) 
10 (27.8) 
10 (26.3) 
13 (35.1) 
Abdominal pain 
1 (0.7) 
0 
0 
0 
1 (2.7) 
Abdominal pain upper 
1 (0.7) 
1 (2.8) 
0 
0 
0 
Constipation 
10 (6.8) 
3 (8.3) 
2 (5.6) 
1 (2.6) 
4 (10.8) 
Diarrhoea 
1 (0.7) 
0 
1 (2.8) 
0 
0 
Dyspepsia 
1 (0.7) 
0 
1 (2.8) 
0 
0 
Flatulence 
1 (0.7) 
0 
0 
1 (2.6) 
0 
Nausea 
29 (19.7) 
6 (16.7) 
7 (19.4) 
7 (18.4) 
9 (24.3) 
Paraesthesia oral 
1 (0.7) 
0 
0 
0 
1 (2.7) 
Stomatitis 
1 (0.7) 
1 (2.8) 
0 
0 
0 
Vomiting 
12 (8.2) 
1 (2.8) 
4 (11.1) 
3 (7.9) 
4 (10.8) 
General disorders and 
administration site conditions 
20 (13.6) 
6 (16.7) 
3 (8.3) 
5 (13.2) 
6 (16.2) 
Administration site warmth 
2 (1.4) 
1 (2.8) 
0 
1 (2.6) 
0 
Application site pain 
1 (0.7) 
0 
0 
0 
1 (2.7) 
Application site rash 
1 (0.7) 
0 
0 
1 (2.6) 
0 


 
 
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Table 3. Summary of TEAEs by MedDRA SOC/PT (CA-PS-201) 
No. of Subjects 
Total N=147 
n (%) 
CA-008 
Placebo 
(Standard of care 
alone) 
N=37 
n (%) 
System Organ Class 
                    Preferred Term 
0.7 mg (0.05 
mg/mL) 
N=36 
n (%) 
2.1 mg (0.15 
mg/mL) 
N=36 
n (%) 
4.2 mg (0.3 
mg/mL) 
N=38 
n (%) 
Chills 
1 (0.7) 
0 
0 
0 
1 (2.7) 
Feeling hot 
6 (4.1) 
1 (2.8) 
2 (5.6) 
1 (2.6) 
2 (5.4) 
Impaired healing 
1 (0.7) 
1 (2.8) 
0 
0 
0 
Infusion site oedema 
6 (4.1) 
3 (8.3) 
0 
1 (2.6) 
2 (5.4) 
Infusion site pain 
3 (2.0) 
1 (2.8) 
1 (2.8) 
0 
1 (2.7) 
Oedema peripheral 
2 (1.4) 
0 
0 
2 (5.3) 
0 
Pain 
4 (2.7) 
1 (2.8) 
1 (2.8) 
1 (2.6) 
1 (2.7) 
Infections and infestations 
9 (6.1) 
0 
5 (13.9) 
3 (7.9) 
1 (2.7) 
Cellulitis 
3 (2.0) 
0 
1 (2.8) 
1 (2.6) 
1 (2.7) 
Pharyngitis 
1 (0.7) 
0 
1 (2.8) 
0 
0 
Post procedural cellulitis 
1 (0.7) 
0 
1 (2.8) 
0 
0 
Post procedural infection 
1 (0.7) 
0 
1 (2.8) 
0 
0 
Postoperative wound infection 
3 (2.0) 
0 
1 (2.8) 
1 (2.6) 
1 (2.7) 
Tooth infection 
1 (0.7) 
0 
0 
1 (2.6) 
0 
Injury, poisoning and procedural 
complications 
18 (12.2) 
3 (8.3) 
5 (13.9) 
3 (7.9) 
7 (18.9) 
Foot fracture 
1 (0.7) 
0 
0 
0 
1 (2.7) 
Incision site erythema 
1 (0.7) 
0 
0 
0 
1 (2.7) 
Incision site haematoma 
2 (1.4) 
1 (2.8) 
1 (2.8) 
0 
0 
Scar 
1 (0.7) 
1 (2.8) 
0 
0 
0 
Wound 
1 (0.7) 
0 
0 
1 (2.6) 
0 
Wound dehiscence 
15 (10.2) 
2 (5.6) 
5 (13.9) 
3 (7.9) 
5 (13.5) 
Investigations 
7 (4.8) 
2 (5.6) 
2 (5.6) 
3 (7.9) 
0 
Alanine aminotransferase 
increased 
3 (2.0) 
0 
0 
3 (7.9) 
0 
Aspartate aminotransferase 
increased 
3 (2.0) 
0 
0 
3 (7.9) 
0 
Blood glucose increased 
1 (0.7) 
0 
1 (2.8) 
0 
0 
Blood pressure increased 
2 (1.4) 
2 (5.6) 
0 
0 
0 
Body temperature increased 
1 (0.7) 
0 
1 (2.8) 
0 
0 
Gamma-glutamyltransferase 
increased 
1 (0.7) 
0 
0 
1 (2.6) 
0 
Metabolism and nutrition 
disorders 
3 (2.0) 
0 
1 (2.8) 
2 (5.3) 
0 
Decreased appetite 
3 (2.0) 
0 
1 (2.8) 
2 (5.3) 
0 
Musculoskeletal and connective 
tissue disorders 
17 (11.6) 
7 (19.4) 
5 (13.9) 
4 (10.5) 
1 (2.7) 
Arthralgia 
2 (1.4) 
1 (2.8) 
1 (2.8) 
0 
0 
Back pain 
4 (2.7) 
2 (5.6) 
0 
2 (5.3) 
0 
Joint stiffness 
1 (0.7) 
0 
1 (2.8) 
0 
0 
Limb discomfort 
2 (1.4) 
2 (5.6) 
0 
0 
0 
Muscle spasms 
3 (2.0) 
0 
3 (8.3) 
0 
0 
Muscle twitching 
1 (0.7) 
1 (2.8) 
0 
0 
0 
Musculoskeletal pain 
1 (0.7) 
0 
0 
1 (2.6) 
0 
Musculoskeletal stiffness 
1 (0.7) 
0 
1 (2.8) 
0 
0 
Neck pain 
1 (0.7) 
0 
0 
1 (2.6) 
0 
Pain in extremity 
4 (2.7) 
1 (2.8) 
0 
2 (5.3) 
1 (2.7) 
Nervous system disorders 
53 (36.1) 
17 (47.2) 
14 (38.9) 
14 (36.8) 
8 (21.6) 
Burning sensation 
4 (2.7) 
2 (5.6) 
0 
2 (5.3) 
0 
Dizziness 
12 (8.2) 
4 (11.1) 
5 (13.9) 
1 (2.6) 
2 (5.4) 
Headache 
28 (19.0) 
7 (19.4) 
8 (22.2) 
7 (18.4) 
6 (16.2) 
Hyperaesthesia 
2 (1.4) 
1 (2.8) 
0 
1 (2.6) 
0 


 
 
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Table 3. Summary of TEAEs by MedDRA SOC/PT (CA-PS-201) 
No. of Subjects 
Total N=147 
n (%) 
CA-008 
Placebo 
(Standard of care 
alone) 
N=37 
n (%) 
System Organ Class 
                    Preferred Term 
0.7 mg (0.05 
mg/mL) 
N=36 
n (%) 
2.1 mg (0.15 
mg/mL) 
N=36 
n (%) 
4.2 mg (0.3 
mg/mL) 
N=38 
n (%) 
Hypoaesthesia 
2 (1.4) 
0 
1 (2.8) 
1 (2.6) 
0 
Paraesthesia 
3 (2.0) 
1 (2.8) 
0 
1 (2.6) 
1 (2.7) 
Presyncope 
1 (0.7) 
1 (2.8) 
0 
0 
0 
Somnolence 
6 (4.1) 
2 (5.6) 
0 
2 (5.3) 
2 (5.4) 
Syncope 
1 (0.7) 
0 
1 (2.8) 
0 
0 
Psychiatric disorders 
1 (0.7) 
0 
0 
0 
1 (2.7) 
Depressed mood 
1 (0.7) 
0 
0 
0 
1 (2.7) 
Renal and urinary disorders 
4 (2.7) 
0 
4 (11.1) 
0 
0 
Polyuria 
4 (2.7) 
0 
4 (11.1) 
0 
0 
Urge incontinence 
1 (0.7) 
0 
1 (2.8) 
0 
0 
Reproductive system and breast 
disorders 
1 (0.7) 
0 
0 
1 (2.6) 
0 
Vaginal haemorrhage 
1 (0.7) 
0 
0 
1 (2.6) 
0 
Respiratory, thoracic and 
mediastinal disorders 
6 (4.1) 
3 (8.3) 
0 
3 (7.9) 
0 
Dysphonia 
1 (0.7) 
1 (2.8) 
0 
0 
0 
Hypoxia 
4 (2.7) 
2 (5.6) 
0 
2 (5.3) 
0 
Rhinorrhoea 
1 (0.7) 
0 
0 
1 (2.6) 
0 
Skin and subcutaneous tissue 
disorders 
13 (8.8) 
2 (5.6) 
4 (11.1) 
1 (2.6) 
6 (16.2) 
Dermatitis 
1 (0.7) 
0 
1 (2.8) 
0 
0 
Dry skin 
1 (0.7) 
0 
0 
1 (2.6) 
0 
Hyperhidrosis 
4 (2.7) 
2 (5.6) 
0 
0 
2 (5.4) 
Petechiae 
1 (0.7) 
0 
1 (2.8) 
0 
0 
Pruritus 
3 (2.0) 
0 
1 (2.8) 
0 
2 (5.4) 
Rash 
2 (1.4) 
0 
0 
0 
2 (5.4) 
Rash erythematous 
1 (0.7) 
0 
1 (2.8) 
0 
0 
Skin maceration 
3 (2.0) 
0 
1 (2.8) 
0 
2 (5.4) 
Surgical and medical procedures 
1 (0.7) 
1 (2.8) 
0 
0 
0 
Wound drainage 
1 (0.7) 
1 (2.8) 
0 
0 
0 
Vascular disorders 
9 (6.1) 
2 (5.6) 
3 (8.3) 
4 (10.5) 
0 
Deep vein thrombosis 
1 (0.7) 
0 
1 (2.8) 
0 
0 
Diastolic hypotension 
1 (0.7) 
1 (2.8) 
0 
0 
0 
Hot flush 
2 (1.4) 
0 
0 
2 (5.3) 
0 
Hypertension 
2 (1.4) 
0 
0 
2 (5.3) 
0 
Hypotension 
2 (1.4) 
0 
2 (5.6) 
0 
0 
Thrombophlebitis 
1 (0.7) 
1 (2.8) 
0 
0 
0 


 
 
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Table 3. Summary of TEAEs by MedDRA SOC/PT (CA-PS-201) 
No. of Subjects 
Total N=147 
n (%) 
CA-008 
Placebo 
(Standard of care 
alone) 
N=37 
n (%) 
System Organ Class 
                    Preferred Term 
0.7 mg (0.05 
mg/mL) 
N=36 
n (%) 
2.1 mg (0.15 
mg/mL) 
N=36 
n (%) 
4.2 mg (0.3 
mg/mL) 
N=38 
n (%) 


 
 
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Table 3. Summary of TEAEs by MedDRA SOC/PT (CA-PS-201) 
No. of Subjects 
Total N=147 
n (%) 
CA-008 
Placebo 
(Standard of care 
alone) 
N=37 
n (%) 
System Organ Class 
                    Preferred Term 
0.7 mg (0.05 
mg/mL) 
N=36 
n (%) 
2.1 mg (0.15 
mg/mL) 
N=36 
n (%) 
4.2 mg (0.3 
mg/mL) 
N=38 
n (%) 
Source: Table 14.3.1.2 
 
A Phase 2, single-ascending dose study was completed in patients undergoing total knee 
arthroplasty (TKA) (CA-PS-203).  A total of 54 patients received one of three active doses of 
CA-008: 5 mg as 0.05 mg/mL (N = 9), 10 mg as 0.1 mg/mL (N = 13), 15 mg as 0.15 mg/mL 
(N = 12) or placebo (N = 20).  All doses of CA-008 were safe and well-tolerated (Table 4 and 
Table 6).  Four SAEs occurred in 3 patients and all were considered unrelated to study drug: 
perforated ulcer in one patient, cerebrovascular accident and seizure in one patient, and deep 
venous thrombosis in one patient (Table 5).  No effect on pain relief was detected due to the 
small sample size and low doses of study drug administered.   
 


 
 
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Table 4. Overall Summary of TEAEs – (CA-PS-203) 
 
Total Events / N of Subjects with Any Event, n (%) 
 
Total 
N=54 
Cohort 1 
Cohorts 2 and 3 
 
CA-008 
5 mg 
N=9 
Placebo 
N=9 
CA-008 
10 mg 
N=13 
CA-008 
15 mg 
N=12 
Pooled 
Placebo 
N=11 
No. of TEAEs / 
172/ 
35/ 
28/ 
36/ 
46/ 
27/ 
No. of Subjects with any TEAE1 
45 (83.3) 
7 (77.8) 
7 (77.8) 
12 (92.3) 
10 (83.3) 
9 (81.8) 
N of Treatment Related AEs/ 
11/ 
1/ 
3/ 
1/ 
1/ 
5/ 
N of Subjects with Any Related 
TEAE2 
8 (14.8) 
1 (11.1) 
3 (33.3) 
1 (7.7) 
1 (8.3) 
2 (18.2) 
N of Severe TEAEs/ 
1/ 
0/ 
0/ 
0/ 
0/ 
1/ 
N of Subjects with Any Severe 
TEAE 
1 (1.9) 
0 
0 
0 
0 
1 (9.1) 
N of SAEs/ 
4/ 
1/ 
0/ 
0/ 
2/ 
1/ 
N of Subjects with Any SAE 
3 (5.6) 
1 (11.1) 
0 
0 
1 (8.3) 
1 (9.1) 
N of TEAEs Leading to 
Discontinuation/ 
2/ 
0/ 
0/ 
0/ 
2/ 
0/ 
N of Subjects with TEAEs 
Leading to Discontinuation 
1 (1.9%) 
0 
0 
0 
1 (8.3) 
0 
1 A TEAE is defined as any new AE or an existing AE that worsens in severity during or after study drug administration. 
2 Treatment related TEAEs are defined as TEAEs with relationship to probably or possibly related. 
Source: Table 14.3.1 
 
 
Table 5. Summary of Serious Adverse Events – (CA-PS-203) 
 
Total Events / N of Subjects with Any Event, n (%) 
 
Total 
N=54 
Cohort 1 
Cohorts 2 and 3 
System Organ Class 
                     Preferred Term 
CA-008 
5 mg 
N=9 
Placebo 
N=9 
CA-008 
10 mg 
N=13 
CA-008 
15 mg 
N=12 
Pooled 
Placebo 
N=11 
No. of Subjects with any SAE 
3 (5.6) 
1 (11.1) 
0 
0 
1 (8.3) 
1 (9.1) 
General disorders and 
administration site conditions 
1 (1.9) 
0 
0 
0 
0 
1 (9.1) 
Perforated ulcer 
1 (1.9) 
0 
0 
0 
0 
1 (9.1) 
Nervous system disorders 
1 (1.9) 
0 
0 
0 
1 (8.3) 
0 
Cerebrovascular accident 
1 (1.9) 
0 
0 
0 
1 (8.3) 
0 
Seizure 
1 (1.9) 
0 
0 
0 
1 (8.3) 
0 
Vascular disorders 
1 (1.9) 
1 (11.1) 
0 
0 
0 
0 
Deep vein thrombosis 
1 (1.9) 
1 (11.1) 
0 
0 
0 
0 
Source: Table 14.3.1.3 
 
 
 
 


 
 
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Table 6. Summary of TEAEs by MedDRA SOC/PT (CA-PS-203) 
 
Total Events / N of Subjects with Any Event, n (%) 
 
Total 
N=54 
Cohort 1 
Cohorts 2 and 3 
System Organ Class 
    Preferred Term 
CA-008 
5 mg 
N=9 
Placebo 
N=9 
CA-008 
10 mg 
N=13 
CA-008 
15 mg 
N=12 
Pooled 
Placebo 
N=11 
No. of Subjects with any TEAE 
45 (83.3) 
7 (77.8) 
7 (77.8) 
12 (92.3) 
10 (83.3) 
9 (81.8) 
Cardiac disorders 
16 (29.6) 
5 (55.6) 
0 
2 (15.4) 
3 (25.0) 
6 (54.5) 
Sinus tachycardia 
16 (29.6) 
5 (55.6) 
0 
2 (15.4) 
3 (25.0) 
6 (54.5) 
Gastrointestinal disorders 
30 (55.6) 
5 (55.6) 
5 (55.6) 
8 (61.5) 
8 (66.7) 
4 (36.4) 
Abdominal distension 
1 (1.9) 
0 
1 (11.1) 
0 
0 
0 
Constipation 
8 (14.8) 
2 (22.2) 
3 (33.3) 
0 
3 (25.0) 
0 
Dyspepsia 
2 (3.7) 
0 
0 
2 (15.4) 
0 
0 
Nausea 
27 (50.0) 
5 (55.6) 
5 (55.6) 
8 (61.5) 
5 (41.7) 
4 (36.4) 
Vomiting 
12 (22.2) 
1 (11.1) 
0 
4 (30.8) 
5 (41.7) 
2 (18.2) 
General disorders and 
administration site conditions 
17 (31.5) 
4 (44.4) 
3 (33.3) 
4 (30.8) 
2 (16.7) 
4 (36.4) 
Application site pain 
2 (3.7) 
0 
2 (22.2) 
0 
0 
0 
Instillation site induration 
1 (1.9) 
1 (11.1) 
0 
0 
0 
0 
Oedema peripheral 
3 (5.6) 
1 (11.1) 
0 
0 
1 (8.3) 
1 (9.1) 
Perforated ulcer 
1 (1.9) 
0 
0 
0 
0 
1 (9.1) 
Peripheral swelling 
1 (1.9) 
0 
0 
0 
0 
1 (9.1) 
Pyrexia 
12 (22.2) 
3 (33.3) 
2 (22.2) 
4 (30.8) 
2 (16.7) 
1 (9.1) 
Infections and infestations 
4 (7.4) 
2 (22.2) 
1 (11.1) 
0 
1 (8.3) 
0 
Respiratory tract infection 
1 (1.9) 
1 (11.1) 
0 
0 
0 
0 
Upper respiratory tract infection 
1 (1.9) 
0 
1 (11.1) 
0 
0 
0 
Urinary tract infection 
3 (5.6) 
1 (11.1) 
1 (11.1) 
0 
1 (8.3) 
0 
Injury, poisoning and procedural 
complications 
13 (24.1) 
2 (22.2) 
3 (33.3) 
2 (15.4) 
3 (25.0) 
3 (27.3) 
Contusion 
3 (5.6) 
1 (11.1) 
0 
0 
2 (16.7) 
0 
Deep vein thrombosis 
postoperative 
1 (1.9) 
0 
0 
1 (7.7) 
0 
0 
Incision site vesicles 
1 (1.9) 
0 
0 
0 
0 
1 (9.1) 
Lumbar vertebral fracture 
1 (1.9) 
0 
0 
0 
1 (8.3) 
0 
Post procedural haematoma 
4 (7.4) 
1 (11.1) 
2 (22.2) 
0 
0 
1 (9.1) 
Post procedural haemorrhage 
2 (3.7) 
1 (11.1) 
0 
0 
0 
1 (9.1) 
Post procedural oedema 
3 (5.6) 
1 (11.1) 
1 (11.1) 
1 (7.7) 
0 
0 
Postoperative wound complication 
3 (5.6) 
1 (11.1) 
1 (11.1) 
0 
1 (8.3) 
0 
Procedural pain 
2 (3.7) 
0 
0 
0 
1 (8.3) 
1 (9.1) 
Wound secretion 
1 (1.9) 
1 (11.1) 
0 
0 
0 
0 
Investigations 
1 (1.9) 
0 
0 
0 
1 (8.3) 
0 
Electrocardiogram QT prolonged 
1 (1.9) 
0 
0 
0 
1 (8.3) 
0 
Musculoskeletal and connective 
tissue disorders 
9 (16.7) 
1 (11.1) 
1 (11.1) 
3 (23.1) 
2 (16.7) 
2 (18.2) 
Arthralgia 
4 (7.4) 
0 
1 (11.1) 
1 (7.7) 
1 (8.3) 
1 (9.1) 
Back pain 
1 (1.9) 
0 
0 
0 
0 
1 (9.1) 
Groin pain 
3 (5.6) 
1 (11.1) 
0 
2 (15.4) 
0 
0 
Pain in extremity 
1 (1.9) 
0 
0 
0 
1 (8.3) 
0 
Nervous system disorders 
7 (13.0) 
2 (22.2) 
1 (11.1) 
2 (15.4) 
2 (16.7) 
0 
Allodynia 
1 (1.9) 
0 
1 (11.1) 
0 
0 
0 
Cerebrovascular accident 
1 (1.9) 
0 
0 
0 
1 (8.3) 
0 
Dizziness 
4 (7.4) 
1 (11.1) 
0 
1 (7.7) 
2 (16.7) 
0 
Dysarthria 
1 (1.9) 
0 
0 
0 
1 (8.3) 
0 
Headache 
1 (1.9) 
1 (11.1) 
0 
0 
0 
0 
Paraesthesia 
1 (1.9) 
1 (11.1) 
0 
0 
0 
0 


 
 
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Table 6. Summary of TEAEs by MedDRA SOC/PT (CA-PS-203) 
 
Total Events / N of Subjects with Any Event, n (%) 
 
Total 
N=54 
Cohort 1 
Cohorts 2 and 3 
System Organ Class 
    Preferred Term 
CA-008 
5 mg 
N=9 
Placebo 
N=9 
CA-008 
10 mg 
N=13 
CA-008 
15 mg 
N=12 
Pooled 
Placebo 
N=11 
Seizure 
1 (1.9) 
0 
0 
0 
1 (8.3) 
0 
Tremor 
1 (1.9) 
0 
0 
1 (7.7) 
0 
0 
Psychiatric disorders 
1 (1.9) 
0 
0 
1 (7.7) 
0 
0 
Anxiety 
1 (1.9) 
0 
0 
1 (7.7) 
0 
0 
Renal and urinary disorders 
2 (3.7) 
0 
1 (11.1) 
0 
1 (8.3) 
0 
Pollakiuria 
1 (1.9) 
0 
1 (11.1) 
0 
0 
0 
Urinary retention 
1 (1.9) 
0 
0 
0 
1 (8.3) 
0 
Respiratory, thoracic and 
mediastinal disorders 
2 (3.7) 
0 
0 
1 (7.7) 
1 (8.3) 
0 
Hiccups 
1 (1.9) 
0 
0 
1 (7.7) 
0 
0 
Respiratory depression 
1 (1.9) 
0 
0 
0 
1 (8.3) 
0 
Skin and subcutaneous tissue 
disorders 
9 (16.7) 
0 
3 (33.3) 
2 (15.4) 
3 (25.0) 
1 (9.1) 
Blister 
1 (1.9) 
0 
0 
0 
1 (8.3) 
0 
Erythema 
1 (1.9) 
0 
0 
0 
0 
1 (9.1) 
Hyperhidrosis 
1 (1.9) 
0 
1 (11.1) 
0 
0 
0 
Pruritus 
2 (3.7) 
0 
1 (11.1) 
1 (7.7) 
0 
0 
Pruritus generalised 
3 (5.6) 
0 
1 (11.1) 
0 
2 (16.7) 
0 
Rash 
2 (3.7) 
0 
1 (11.1) 
1 (7.7) 
0 
0 
Surgical and medical procedures 
1 (1.9) 
0 
0 
0 
0 
1 (9.1) 
Post procedural drainage 
1 (1.9) 
0 
0 
0 
0 
1 (9.1) 
Vascular disorders 
15 (27.8) 
2 (22.2) 
2 (22.2) 
4 (30.8) 
5 (41.7) 
2 (18.2) 
Deep vein thrombosis 
1 (1.9) 
1 (11.1) 
0 
0 
0 
0 
Hot flush 
1 (1.9) 
0 
1 (11.1) 
0 
0 
0 
Hypertension 
8 (14.8) 
0 
0 
2 (15.4) 
4 (33.3) 
2 (18.2) 
Hypotension 
6 (11.1) 
1 (11.1) 
1 (11.1) 
2 (15.4) 
2 (16.7) 
0 
Source: Table 14.3.1.1 
 
 
An additional Phase 2, single-ascending dose study was completed in patients undergoing 
complete abdominoplasty (CA-PS-204).  A total of 54 patients received one of three active doses 
of CA-008: 5 mg as 0.05 mg/mL (N = 9), 10 mg as 0.1 mg/mL (N = 13), 15 mg as 0.15 mg/mL 
(N = 12) or placebo (N = 20).  All doses of CA-008 were safe and well-tolerated.  Four SAEs 
occurred in 4 patients and all were considered unrelated to study drug: post-procedural 
hemorrhage in two patients, spontaneous abortion in one patient, and deep venous thrombosis in 
one patient.  No effect on pain relief was detected due to the small sample size and low doses of 
study drug administered. 
5.4. 
Study Rationale 
CA-008 is being investigated as a potential therapy for treatment of pain following surgery.   


 
 
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5.5. 
Dose Rationale 
5.5.1. 
Selection of Doses 
The safety of CA-008 was established in relevant animal models and supported by two clinical 
studies after bunionectomy (CA-PS-2017-101 and CA-PS-201) with doses up to 4.2 mg 
(concentration 0.3 mg/mL) and clinical studies after total knee arthroplasty (CA-PS-203) and 
total abdominoplasty (CA-PS-204) with doses up to 15 mg (concentration 0.15 mg/mL), as well 
as knowledge from prior human studies with an injectable formulation of capsaicin.  Taken 
together, the characterization of the pharmacology, pharmacokinetics, and toxicology profiles 
and the anticipated benefits as well as the potential risks are considered appropriate to support 
the intended initial dose of 36 mg CA-008 (concentration 0.3 mg/mL), and if well-tolerated, 
followed by 60 mg (concentration 0.5 mg/mL) in this total knee arthroplasty 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. 
Primary Objectives  
For Part A: 
• Evaluate the safety and tolerability of a single intraoperative administration of 
CA-008 or placebo in patients undergoing an elective TKA.   
For Part B: 
• 
Evaluate, during a specified post-operative time interval, the efficacy of 2 or 
3 selected doses of CA-008 on reported pain in patients undergoing an elective TKA. 
6.2. 
Secondary Objectives 
For Part A: 
• Evaluate the PK profile of a single intraoperative administration of CA-008 in 
patients undergoing an elective TKA.  
• Evaluate, preliminarily, the activity of CA-008 on reported pain, opioid consumption, 
and PROs (PBOMs and ROM). 
• Determine of the dose(s) for testing in Part B. 
For Part B: 
• Evaluate, during additional specified post-operative time intervals, the efficacy of 
2 or 3 selected doses of CA-008 on reported pain in patients undergoing an elective 
TKA. 
• Evaluate the effect of CA-008 on opioid consumption.  
• Evaluate the effect of CA-008 on patient-reported outcomes (PROs). 
• Evaluate, preliminarily, the effect of CA-008 on performance-based outcome 
measures (PBOMs), including knee range of motion (ROM). 
• Evaluate the safety and tolerability of CA-008 or placebo in patients undergoing an 
elective TKA. 
• Evaluate the PK profile of a single intraoperative administration of CA-008 in 
patients undergoing an elective TKA. 


 
 
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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design and Plan 
This is a two-part, Phase 1/2, randomized, double-blind, placebo-controlled study.  In Part A, 
2 or more exploratory sequential dose-escalation cohorts will be evaluated, each with 
administration of a single dose of CA-008 or placebo infiltrated/instilled during surgery in 
patients undergoing TKA.  
In Part B, 2 or 3 active dose levels of CA-008 will be evaluated compared to placebo in a 
randomized, double-blind, parallel-group design.  
For each patient, the study will be conducted in two periods: 
• Inpatient period, which continues from check-in on Day 1 (D1) until discharge (4 days or 
96 hours [h] following surgery [T96 ± 4 h], [D5]).   
• Outpatient period, which begins on discharge from the inpatient unit through follow up 
visits to D29 + 2 days.  Note that additional follow up visits may occur at any time or 
even after D29 to follow AEs to resolution or to establish a new baseline. 
During the inpatient period, patients will undergo TKA including study drug treatment (CA-008 
or placebo) followed by serial assessments of safety, PK, and drug effect, in particular focusing 
on reported pain and need for analgesia.  During the outpatient period, patients will have serial 
assessments of safety and drug effect.  Safety and drug effect assessments will focus on reported 
pain and need for analgesia. 
7.2. 
Duration of Participation 
Each patient is expected to be in the study approximately 76 days from screening to 
D29 + 2 days visit (however, this could be longer to follow any AE for resolution or 
establishment of a new baseline). 
7.3. 
Dose Escalation and Cohort Expansion 
In general, during Part A, dose escalation will be permitted if there have been no adverse effects 
on wound healing and no intolerable systemic side effects.  During Part A, dose escalation, dose 
reduction, or cohort expansion decisions will be made by the Sponsor’s medical monitor, the 
CRO’s medical monitor, and a relevant Principal Investigator (PI).  This will be based on review 
of at least the following safety data: 
• In-patient (i.e., through 96 h) safety and tolerability data from all 8 initial patients in a 
current cohort, including vital signs, physical examination, neurosensory examination, 
surgery site assessment, laboratory assessments, and adverse events; 


 
 
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• D8 ambulatory visit safety and tolerability data from at least 4 of the initial 8 patients in 
the current cohort, including vital signs, physical examination, neurosensory 
examination, surgery site assessment, and adverse events; 
• D15 ambulatory visit safety and tolerability data from all patients in any previously 
completed cohort, including vital signs, physical examination, neurosensory examination, 
surgery site assessment, and adverse events. 
Also, please note that cohorts in Part A will be randomized 3:1 active to placebo in a blocked 
randomization of 4 patients so that the first 4 patients will include 3 patients receiving active 
drug and 1 patient receiving placebo. 
7.4. 
Study Stopping Rules 
Study enrollment will be paused if patients experience intolerable “related” TEAEs, (shown in 
Table 7) as defined below: 
• 1 or more patients with any grade 4 “related” TEAE in any of the categories  
• 2 or more patients with the same grade 3 “related” TEAE in any of the categories  
• 2 or more patients with the same grade 3 or 4 “related” TEAE shown in Section 17.1, 
Appendix A or found in the in the toxicity grading scale cited therein. 
“Related” includes possibly, probably, and definitely related causality assessments. 
Refer to Table 7 below for descriptions/definitions of AE severity grading.   
In Part A, should a stopping rule be triggered, the Sponsor’s medical monitor, the CRO medical 
monitor, and the relevant PI will review the blinded data to determine whether or not it is 
appropriate to resume enrollment with the same or a modified dose.  Unblinding of an individual 
treatment assignment may be required to complete this safety assessment. 
In Part B, should a stopping rule be triggered, the Sponsor’s medical monitor, the CRO medical 
monitor, the relevant PI, and an independent medical monitor will review the blinded data to 
determine whether or not it is appropriate to resume enrollment, modify the study, or stop the 
study.  The independent medical monitor will have the authority to unblind the treatment 
assignment for the affected patients as part of the safety review.   
The study will be stopped if a safety signal is detected that indicates an unacceptable risk to 
study participants. 


 
 
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Table 7.  
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 intravenous (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, 18-80 years of age inclusive, who are planning to 
undergo an elective unilateral TKA. 
8.1.1. 
Number of Participants 
Part A: 
• Cohort #1: N = 8 (randomized 3:1 CA-008 to placebo), no more than 4 patients dosed per 
week 
• Cohort #2: N = 8 (randomized 3:1 CA-008 to placebo), no more than 4 patients dosed per 
week 
After review of cohort study data, a cohort may be expanded to N = 16. One (1) or 2 additional 
cohorts may be added with N = 8 or 16, in each cohort, using the same 3:1 randomization ratio.  
The total sample size in Part A is thus 16-64 patients. 
Part B: 
In Part B, a total of 150-300 patients will be randomized in 3-4 parallel arms  (with 
50-100 patients in each arm).  The number of patients to be enrolled in Part B will not exceed 
300. 
8.2. 
Eligibility Criteria 
8.2.1. 
Inclusion Criteria 
Patients must meet all of the following criteria to be considered eligible to participate in the study: 
1. Plan to undergo an elective primary unilateral TKA under spinal anesthesia with sedation, 
without collateral procedure or additional surgeries; 
2. Appropriate candidate for spinal anesthesia, including no contraindications, no anatomical 
constraints;  
3. Adults 18-80 years of age, inclusive; 
4. American Society of Anesthesiology (ASA) physical Class 1, 2, or 3 at the time of 
randomization (Section 17.2, Appendix B); 
5. If a male, 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; 
6. 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 (as documented by 
history and FSH level), 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. 
7. Have a body mass index ≤ 42 kg/m2; 
8. Be willing and able to sign the informed consent form (ICF) approved by an Institutional 
Review Board (IRB); 
9. Be willing and able to complete study procedures and pain scales and to return for outpatient 
follow up visits as required. 
10. Be willing and able to avoid foods containing capsaicin for 24 hours prior to surgery. 
8.2.2. 
Exclusion Criteria 
Patients will not be eligible to participate in this study if any one of the following exclusion 
criteria are met: 
1. In the opinion of the Investigator, the patient has:  
a. 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. moderate to severe chronic neuropathic pain or signs of central sensitization;  
c. active skin disease or other clinically significant abnormality at the anticipated 
site of surgery that could interfere with the planned surgery. 
2. The patient is tolerant to opioids (opioid-tolerant) defined as someone who has been 
receiving or has received chronic opioid therapy (use within the 2 weeks prior to surgery and 
duration of use > 4 weeks) greater than 15 mg of oral morphine equivalents per day for 
greater than 3 out of 7 days per week over a one-month period within 6 months of screening. 
3. The patient has a known allergy (or contraindication) to any of the following: chili peppers, 
capsaicin or the components of CA-008, ropivacaine HCl, ketorolac, acetaminophen, 
fentanyl, hydromorphone, morphine, oxycodone, or celecoxib; 
4. As determined by the Investigator (with input from the study’s medical monitor if requested 
by the Investigator), the patient has 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, 


 
 
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or known bleeding abnormality that could preclude or impair study participation or interfere 
with study assessments; 
5. Use of the following disallowed medications: 
o Within 1 day prior to surgery and throughout the inpatient period, taking or using any 
capsaicin-containing products, such as dietary supplements or OTC preparations, 
including topical formulations, and prescription medications; 
o Within the 7 days prior to surgery, 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;   
▪ 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.  
▪ If the patient is taking centrally- and/or peripherally-acting analgesic 
medications, such as acetaminophen, NSAIDs, tramadol, or opioids, for 
knee-related pain, the patient may participate in the study if not opioid-tolerant 
(defined above) and the patient is willing to discontinue these medications 
3 days prior to surgery.  Note that (a) baby aspirin (81 mg/day) for 
cardiovascular prophylaxis or (b) regular or enteric-coated aspirin (up to 325 mg 
given up to twice daily) for venous thrombo-embolism prophylaxis is allowed 
during the study. 
o Within the 7 days prior to the planned surgery and throughout the study, taking (a) 
antiarrhythmic drugs (except beta-blockers and digoxin); (b) warfarin or other 
anticoagulants (see exception below); (c) lithium; or (d) aminoglycosides or other 
antibiotics for an infection (except for ophthalmic use); 
o Within the 14 days prior to surgery, 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); 
o Taking 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. 
6. In the opinion of the Investigator, within the past year, the patient has 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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7. The patient has a disqualifying positive urine drug screen or alcohol breath/saliva test during 
screening or check-in;  
8. The patient has previously participated in a clinical study with CA-008; 
9. The patient has participated in another clinical trial or used an investigational product within 
30 days or 5 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 
CA-008 for injection, 15 mg per vial, is a white lyophilized powder.  On the day of use the 
appropriate number of vials will be reconstituted in sterile saline to a total volume of 120 mL. 
The placebo comparator is identical in appearance to the reconstituted CA-008 solution. 
The proposed initial doses of CA-008 to be evaluated in Part A are:  
• Cohort #1: CA-008 36 mg in 120 mL (0.3 mg/mL) or placebo in 120 mL 
• Cohort #2: CA-008 60 mg in 120 mL (0.5 mg/mL) or placebo in 120 mL 
• Additional sequential cohorts may receive doses between 15-90 mg or placebo 
• Modifications to the total study drug dose, volume, drug concentration, and allocation for 
subsequent patients may occur based on information from prior patients.  
The doses of CA-008 to be administered in Part B will be in the range of 15-90 mg and will not 
exceed the maximum dose administered safely in Part A.  Doses will be selected based on safety 
and tolerability data from Part A and from prior studies of CA-008. 
An unblinded pharmacist or designee may use unblinded vials identified as to contents to prepare 
the study treatment solutions.  The anesthesia and surgical team and study site personnel will be 
blinded as to study treatment; details will be presented in the Unblinding Plan and/or the 
Pharmacy Manual. 
9.1.3. 
Study Treatment Storage 
Study treatments will be stored at 5°C (2°C to 8°C) until the day of surgery.  All study treatments 
should be stored in a secured area and in accordance with the product labeling and all applicable 
laws, regulations, and local/institutional requirements.  A description of storage conditions for all 
investigational products will be provided in the Pharmacy Manual. 


 
 
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9.1.4. 
Study Treatment Accountability 
All study treatment will be transported, received, stored, and handled strictly in accordance with 
the container or product label, the instructions provided to the research site, and applicable 
regulations.  Detailed drug accountability records must be maintained, including the dates 
shipments are received, the quantity of material received, the dates dispensed, and the running 
inventory.  All unused supplies will be checked against the drug accountability records during 
the study and/or at the end of the study. Unused supplies will be returned to the Sponsor’s drug 
supply vendor at the end of the trial.  
Only eligible patients 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 patients.  
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.  
9.2. 
Other Interventions 
9.2.1. 
Inpatient Analgesia  
During the surgery, ensure that each patient has received at least 100 mcg of intravenous (IV) 
fentanyl with adjustments above this dose per anesthesiologist’s discretion. 
Within 15 minutes prior to the end of surgery, administer the following: 
• 
IV hydromorphone, 1 mg 
• 
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 patient’s age and health status. 
• 
IV acetaminophen, 1 g (Ofirmev®, Mallinckrodt Pharmaceuticals 2018) full prescribing 
information at http://ofirmev.com/.  
After these non-opioids have been administered, no additional non-opioid analgesics are to be 
administered during the inpatient phase (through T96).  
If a patient had an inadequate level of anesthesia from the spinal anesthetic and received a 
general anesthetic, the patient should receive IV hydromorphone, 1 mg, within 30 minutes of 
anesthesia induction and up to 1 mg of IV hydromorphone within 15 minutes of the end of 
surgery. 
Patients who develop clinically significant hemodynamic instability or other anesthesia 
complication prior to study drug administration should not receive study drug; in Part A, these 


 
 
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patients will be replaced.  Replacement patients will be assigned the same treatment as the 
original patient.  A ‘replacement’ randomization list matching that of the main list will be created 
to facilitate this process. 
9.2.2. 
Inpatient Rescue Medications 
After surgery, patients will be transferred to the post-anesthesia care unit (PACU) where patients 
will be monitored for at least 90 minutes during which time pain assessments can begin once the 
patient is awake.  T0 is the time of admission into the PACU (as recorded in notes by the PACU 
nurse).   
Patients will use the 0 to 10 numerical rating scale (NRS) to report their current pain intensity 
multiple times per day during the remainder of the inpatient part of the study.  Scheduled times 
for serial pain assessments are outlined in the protocol below.  Rescue medication will be 
administered at these times only upon request based on the currently reported pain score. 
If the patient reports pain spontaneously and requests analgesia at an unscheduled time (i.e., 
PRN), an NRS should be used to record the pain present at that time.  This unscheduled NRS 
must be recorded just prior to administration of any PRN analgesia, i.e., within 5 minutes prior to 
any PRN IV analgesic treatment and within 15 minutes prior to any PRN oral analgesic 
treatment.  NRS scores for PRN pain medication will not replace the recording of scheduled 
NRS scores. 
Medication for moderate to severe pain (NRS ≥ 4) will be administered upon request as follows: 
• From T0 to T25 minutes: 
o IV fentanyl 50 mcg, Q 5 minutes for pain NRS > 4 
• From T26 minutes to PACU discharge: 
o IV hydromorphone 0.5 mg, Q 10 minutes for pain NRS > 4 
After discharge from the PACU, patients are followed through T96 (± 4 h) as inpatients in the 
inpatient unit where safety and activity/efficacy evaluations will be performed.   
From the time of PACU discharge through T24: 
• Administer IV hydromorphone, 0.5 mg Q15 minutes PRN pain NRS ≥ 4 as reported by 
patients. 
After T24: 
• Administer PO oxycodone, 10 mg Q4 h PRN pain NRS 5-10.   
• Only PO oxycodone may be used as rescue.  If a patient still requires IV opioid rescue 
after T24, then the patient will revert to IV analgesia management per institutional 
guidelines.  These patients will still also be followed for NRS, safety, and other 
assessments.  
Patients will be encouraged to use rescue medication only for moderate-to-severe pain scores 


 
 
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(NRS 5-10); however, rescue with oxycodone 10 mg PO may be requested at any time (i.e., even 
when NRS < 5) and medication will be provided when requested.  
Note: Since rescue medication may be taken at any time, it will not be considered a protocol 
deviation during the inpatient or outpatient periods if a patient takes a rescue medication more 
frequently than the protocol prescribing interval, eg, if oxycodone is prescribed as 10 mg PO 
Q4h PRN pain, it is not a protocol deviation if a dose is taken fewer than 4 hours following a 
prior dose.  This will be recorded in the rescue medication list and/or in the diary. 
NRS scores recorded for PRN pain medication will not replace the recording of scheduled NRS 
scores.  However, if PRN rescue medication has recently been administered and persistent pain is 
reported in a scheduled NRS prior to rescue medication taking effect, a second dose of rescue 
medication should not be administered. 
Patients will be required to meet standard criteria for discharge to outpatient status.  Patients will 
continue to be monitored as outpatients after discharge from the inpatient unit through D29 + 
2 days for various safety and efficacy assessments, and later if necessary, for safety follow-up. 
9.2.3. 
Outpatient Analgesic Medications 
Following discharge from the hospital through the D15 visit, pain will be managed with the 
following regimen only:   
• Scheduled medication: 
o 
Celecoxib 100 mg PO BID (unless contraindicated) 
• Rescue medications (for pain as needed):  
o 
Acetaminophen 650 mg PO Q6 hours for mild pain (i.e., NRS < 5) (unless 
contraindicated) 
o 
Acetaminophen 325 mg/Oxycodone 5 mg (Percocet) – 1 or 2 tablets PO Q 4-6 h 
for moderate-severe pain (i.e., NRS 5-10).  Discharge patient with 20 tablets.  Use 
of this rescue medication [time, dose] must be recorded in the diary.  Pre-rescue 
medication NRS for opioids will also be recorded in the diary.  The timing of the 
pre-rescue NRS will be assumed to be the same as the timing of the pre-rescue 
medication. 
Note: 
• Instruct patients to use acetaminophen as the initial option for treating pain.  
• If opioids other than oxycodone are taken for rescue medication, eg, hydrocodone, they 
will be recorded in the diary and included in the total amount of opioid rescue 
medication. 
Document the number of tablets prescribed and also document any additional prescriptions 
required if the patient’s pain continues to be an issue requiring additional opioid medication. 


 
 
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Following D15, pain will be managed per institutional guidelines and standards of care.  Pain 
medication use will be recorded as a concomitant medication from D15 through D29. 
The use of these and/or other medications to treat pain will be documented in the patient diary 
through the D15 visit. 
Note: All medications taken during the outpatient period through the D29 visit will be 
documented as concomitant medications. 
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 visit occurs, the Investigator 
should use clinical discretion regarding the adequacy of analgesic treatment, capture this 
occurrence as an AE, and document any required treatments. 
9.3. 
Method of Assigning Patients to Treatment Groups 
Randomization will be used to avoid bias in the assignment of patients to treatments, to increase 
the likelihood that known and unknown patient attributes (e.g., demographics, baseline 
characteristics) are evenly balanced across treatment groups, and to enhance the validity of 
statistical comparisons across treatment groups.  
Patients who have provided written informed consent will be assigned a unique number in the 
screening process.  This number will be used to identify the patient throughout the study. 
Patients in each cohort in Part A will be randomized in a ratio of 3:1, active to placebo, in a 
blocked randomization of 4 patients so that the first 4 patients will include 3 patients 
receiving active drug and 1 patient receiving placebo.  After review of cohort study data, a cohort 
may be expanded to N = 16. One (1) or 2 additional cohorts may be added with N = 8 or 16, 
using the same 3:1 randomization ratio.   
In Part B, a blocked randomization for each site will be used with a block size that is three times 
the number of study arms, e.g., if there are 4 treatment arms, the block size will be 12 patients.  
Treatment assignments will be determined by a computer-generated randomization schedule. 
Once any patient number or randomization number is assigned, it cannot be reassigned to any 
other patient.  
Patients may be rescreened if the screening window is exceeded due to scheduling issues.  
9.4. 
Blinding 
In order to reduce the potential for bias in the study, treatment group assignments will be 
double-blinded during the study.  The patient, investigational site personnel with the exception of 
the unblinded pharmacist, Sponsor, and Sponsor designees directly involved in the conduct 
and/or monitoring of this study will not be aware of patients’ treatment group assignments.  Note 
that the placebo is identical in appearance to CA-008. 


 
 
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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 patient’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 assignment is prematurely unblinded, the 
reason, date and time of the unblinding, and the individual who broke the blind must be 
documented.  
It is assumed that the need to unblind a study patient’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, OTC, or herbal therapies, used by the patient 
will be documented for the 30 days prior to screening (prior medications), during screening, and 
throughout the study (concomitant medications).  The Investigator will determine if the 
prior/concomitant medication(s) affect the patient’s eligibility to participate or continue to 
participate in the study.  
The use of benzodiazepines and the non-benzodiazepines (eszopiclone, ramelteon, zaleplon, and 
zolpidem) are permitted to treat insomnia during the post-operative period. 
Within the 7 days prior to the planned surgery, and throughout the study, antibiotics for an 
infection are permitted for ophthalmic use or for treatment or prophylaxis of post-operative 
surgical site infections.  At the Investigator’s discretion, agents intended for deep venous 
thrombosis (DVT) prophylaxis after the surgery is allowed. 
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 patient’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 patient must agree to 
abide by the following study restrictions:  
Abstain from the following during the inpatient portion of the study: 
1. Consuming any alcohol 
2. Smoking or vaping (nicotine-containing or other substances)  
3. Illicit drug use or non-medical use of therapeutic drugs not allowed by the protocol 


 
 
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4. Any foods containing capsaicin for 24 hours prior to PK blood draws 
Abstain from the following during the outpatient portion of the study: 
• 
Patients will be asked to abstain from consuming more than 1 (women) or 2 drinks (men) per 
day of alcohol  
• 
Patients will be asked to abstain from illicit drug use or non-medical use of therapeutic drugs  
• 
Patients will be asked to abstain from taking prohibited medications  
9.7. 
Treatment Compliance  
Because all study medication is being administered by study personnel, no patient compliance 
procedures are necessary.  Potential diversion of controlled opioid medication 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 Prior to Surgery):   
Patients will be screened for participation at the study within 45 days of surgery/study drug 
administration.  The following assessments will be completed at least 1 day prior to surgery: 
• 
Informed consent; 
• 
Inclusion/exclusion criteria evaluation; 
• 
Demographics; 
• 
Medical and surgical history; 
• 
Prior/current medications; 
• 
Complete physical examination (PE) (without a breast, genital, or rectal examination), 
including height and weight; 
• 
Vital signs - heart rate (HR), blood pressure (BP), respiratory rate (RR) in the supine 
position, and temperature (oral) (Section 17.3, Appendix C); 
• 
Baseline neurosensory exam; 
• 
Clinical laboratory tests (Section 17.4, Appendix D): 
▪ Hematology/Coagulation: 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). 
▪ Blood Chemistry: including alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), total bilirubin (Tot. Bili), gamma-glutamyl 
transferase (GGT), albumin, blood urea nitrogen (BUN), creatinine, 
alkaline phosphatase (ALK), sodium, potassium, calcium, chloride, and 
glucose. 
▪ Urinalysis: including macroscopic analysis and, if indicated, microscopic 
analysis. 
• 
Urine drug screening (UDS);  
• 
Alcohol breath/saliva test; 
• 
Serum pregnancy test (FCBP), βhCG test at screening, if applicable;  


 
 
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• 
FSH (if post-menopausal only); 
• 
12-lead electrocardiogram (ECG); 
• 
KOOS survey (Section 10.3.10);  
• 
Patient Reported Outcomes Measurement Information System (PROMIS) 10 Global 
Health questionnaire (Section 10.3.11); 
• 
Knee Range of Motion (ROM) (Section 10.3.12); 
• 
Patient pain assessment training; 
• 
AE assessment (record any current conditions as medical history); 
• 
Patients will be asked to abstain from foods containing capsaicin for 24 hours prior to 
their surgery. 
10.1.2. 
Surgery Phase: Admission to Unit for Surgery (Baseline) to End of Surgery 
10.1.2.1. Admission to Site Unit (D1) Prior to Surgery 
Patients 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 will be performed on D1 prior to surgery: 
• 
Confirm informed consent; 
• 
Review of inclusion/exclusion criteria; 
• 
Review medical and surgical history since screening; 
• 
Review prior and current concomitant medications; 
• 
Interim targeted PE with inspection of the planned area of surgery; 
• 
Urine pregnancy test (FCBP), if applicable, (unless post-menopausal status confirmed by 
FSH), usually to be done within 24 hours prior to surgery; 
• 
UDS;  
• 
Alcohol breath/saliva test; 
• 
Blood draws for PK analyses; 
• 
Vital signs - HR, BP, RR (supine), and temperature (oral); 
• 
Patient to watch pain training video; 
• 
Randomize the patient to treatment after confirmation of patient’s continued eligibility; 
• 
AE assessment (record any current conditions as medical history). 
10.1.2.2. Anesthesia and Surgery (D1) 
The surgery will be performed under spinal anesthesia (isobaric bupivacaine [preservative-free] 
0.5% 12-15 mg, and fentanyl 25 mcg) with adequate supplemental sedation, typically with 


 
 
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midazolam (up to 5 mg), fentanyl (up to 100 mcg), and propofol infusion, but anesthesia and 
sedation will be per institutional guidelines.   
If the patient appears to have an inadequate level of anesthesia from the spinal anesthetic (“failed 
spinal anesthetic”), the patient should receive a general anesthetic with either an inhaled 
anesthetic or propofol infusion with or without nitrous oxide (N20).   
In addition, patients will receive ropivacaine hydrochloride (RopiHCl) delivered as follows: 
• Prior to start of surgery under ultrasound guidance: 
o Femoral nerve block: RopiHCl 0.5%, 12 mL (60 mg)  
o IPACK infiltration:  RopiHCl 0.2%, 20 mL (40 mg) 
And 
• Immediately after surgical incision:  
o Periarticular infiltration: RopiHCl 0.2%, 50 mL (100 mg)   
o Periarticular infiltration is to be performed using a 22-gauge needle as follows: 
- After the surgical incision and prior to the arthrotomy, infiltrate 25 mL of RopiHCl 
into the tissue adjacent to and along the planned arthrotomy incision site. 
- After the arthrotomy and after the initial dissection but prior to bony resection/cuts, 
infiltrate 25 mL of RopiHCl into the residual soft tissue envelope of the distal femur 
and proximal tibia that has been surgically debrided (eg, the fat pad, subperiosteal 
dissection, synovium, etc). 
Note regarding periarticular infiltration:  In general, the intent is to deliver local anesthetic into 
the surgical site “on the way in” (upon adequate exposure of and prior to incision of target 
tissues).   Conversely, study drug (active or placebo) will be administered to target tissues “on 
the way out” (at the time of device implantation and surgical closure). 
The total RopiHCl should not exceed 200 mg.  See Section 17.5, Appendix E for guidance on 
RopiHCl dosing.  
Note: IPACK = Interspace between the Popliteal Artery and the Capsule of the posterior Knee 
between the femoral condyles) 
Standard anesthetic and perioperative care will be provided per institutional guidelines.  This will 
typically include (but not be limited to) steps to ensure preservation of intraoperative 
normothermia (including the use of preoperative and intraoperative forced-air warming) and 
deep venous thrombosis prophylaxis. 
As per institutional guidelines, a pneumatic tourniquet is inflated prior to incision and deflated at 
the conclusion of the surgery.  The time of tourniquet placement and removal will be 
documented.  


 
 
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For failed spinal anesthetic (either inability to place or inadequate level), patient may receive 
general anesthesia that includes additional intraoperative analgesics as described in Section 9.2.1. 
10.1.3. 
Surgery Phase: Administration of Study Medication Into the Surgical Site 
The initial total study drug volume administered per patient will be 120 mL.  This initial 120 mL 
of study treatment administered per patient in the first study cohort will be delivered during the 
surgical procedure in 4 divided aliquots.  The initial allocation will be:  
(a) a total of 15 mL onto the cut surfaces following each osteotomy;  
(b) 30 mL prior to hardware placement;  
(c) 60 mL following hardware placement; and 
(d) 15 mL following closure of the joint capsule.   
Modifications to the total study drug dose, volume, drug concentration, and allocation for 
subsequent patients may occur based on information from prior patients.  Minor variability may 
occur due to implementation by different surgeons and to anatomical differences.  
Study treatment is to be administered intraoperatively as a single administration via “surgical 
site” infiltration/instillation prior to wound closure.  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.  The “surgical site” will include all tissue 
traumatized by the surgical procedure, ie, tissue that has been dissected, cut, electrocauterized 
(bovied), or sutured, etc.  
Record start and end time of study treatment instillation.  Syringe numbers correspond to 
instructions provided in the pharmacy manual. 
A total volume of 15 mL will be instilled on cut bone surfaces.  Study treatment will be instilled 
on the cut surfaces (cortical and cancellous bone) immediately after each osteotomy using a 
syringe with a soft catheter (eg, Angiocath). The initial allocation of volume of study treatment 
for each osteotomy site will be: 
Syringe #1: Femur bone: Instill ~8 mL in two aliquots separated by >1-2 minutes 
Syringe #2: Tibia bone: Instill ~5 mL in two aliquots separated by >1-2 minutes 
Syringe #3: Patella bone: Instill ~2 mL in two aliquots separated by >1-2 minutes 
Note:  Instillation of study treatment at each osteotomy site to be divided into two equal 
portions with administration separated by >1-2 minutes (e.g., for femur, instill 4 mL, repeat 
after >1–2 minutes). 
Note: The technique for all tissue infiltration described below should include multiple, small-
volume micro-injections along the course of each needle track.  The intent is to distribute the 
study drug widely across the nerve endings in the surgical site where TRPV1 receptor targets are 


 
 
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located  not in isolated deep depot injections along nerves. Study drug is designed for field block 
rather than conduction block  
Prior to hardware placement, 30 mL of study treatment will be infiltrated using a control syringe 
with a 22-gauge needle as follows: 
Infiltrate periosteum of distal femur: 
Syringe #4: Femoral periosteum area (20 mL):  
These three infiltration sites are optimally accessed with the syringe held in front of the joint 
and the needle angled proximally (cephalad).  The injections can be made from within the 
joint. 
- Infiltrate ~7-8 mL into periosteum of lateral half of distal femur (lateral femoral 
periosteum) AND 
- Infiltrate ~7-8 mL into periosteum of medial half of distal femur (medial femoral 
periosteum) AND 
- Infiltrate ~5 mL into the meniscectomy site and along the remnant edge of the coronary 
(meniscotibial) ligament 
Note:  Use multiple small-volume injections delivered slowly. Infiltration should cause a 
wheal to form under the periosteal tissue and there should be minimal extravasation of the 
injection fluid into the joint. 
Syringe #5: Posterior capsule area (10 mL):  
- Infiltrate 10 mL into the posterior aspect of the capsule  
Note: Use multiple small injections across the back of the knee.  Do not plunge into the 
midline or laterally near the peroneal nerve.   
After the implants have been placed, with the leg in full extension, 60 mL of study treatment will 
be infiltrated as follows (working from top to bottom, clockwise or using another standardized 
method per surgeon discretion): 
Syringe #6: Distal femur area: Infiltrate ~15 mL into the deep tissue of the distal femur, 
i.e., capsule and other soft tissue that can be associated with postoperative pain  
Infiltrate a total of ~30 mL divided equally into the medial and lateral gutter areas ensuring 
coverage of the periosteal borders 
Infiltrate a total of ~30 mL divided equally into the medial and lateral gutter areas ensuring 
coverage of the periosteal borders: 
Syringe #7: Medial gutter area (15 mL) 
Syringe #8: Lateral gutter area (15 mL) 


 
 
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Note: The gutter area is to include (a) any tissue that has been traumatized by the surgery, 
i.e., that has been cut, sutured, electrocauterized (bovied), dissected, etc, and (b) the deeper 
contiguous tissues that have not been directly traumatized by the surgical procedure. 
Syringe #9: Peripatellar area: Infiltrate ~5 mL around the peripatellar region 
Syringe #10: Tibial tubercle area: Infiltrate ~10 mL divided equally medial and lateral to 
the tibial tubercle 
Note: Syringes #7-10 are intended to include any tissue that has been traumatized by the 
surgery.  This would include the arthrotomy "edges," retinaculum, etc. 
Note: Place the needle to the desired depth and inject as the needle is being withdrawn.  
Aspirate when needed or in areas of concern.  Aim to deliver as much of the liquid into the 
tissue as possible. 
Following closure of the joint capsule, 
Syringe #11: Intra-Articular (“Capsule”): Instill ~15 mL “intra-articularly” (lateral 
approach) and move the joint through full range of motion. 
10.1.4. 
Post-surgery: T0 (Admission into the PACU) to D5 (Discharge) 
Following surgery, patients will be transferred to the PACU where they will undergo an 
assessment of safety and efficacy over the next 96 (± 4) hours.  T0 is the time of admission into 
the PACU (as recorded in notes by the PACU nurse).  The schedule of assessments is as follows:  
• 
Patients with inadequately controlled pain may request rescue at any time during T0 to 
D5; however, patients will be encouraged to receive rescue medication only with an NRS 
≥ 4.   
• 
Pain intensity (assessed with NRS):  
• 
During the inpatient stay, NRS at rest beginning with the PACU admission may 
be assessed once the patient is awake.  T0 is the time of admission into the PACU 
(as recorded in notes by the PACU nurse).  If the patient is able to provide 
responses, obtain NRS scores at T0 plus 1 hour (T1), T0 plus 2 hours (T2, etc.), 
T4, T6, T8, T12, T16, T20, T24, and every 4 hours thereafter (if awake at time of 
assessment) until discharge from the inpatient unit.  Time windows: ± 5 minutes 
for T1 and T2; ± 15 minutes for T4 onward.  Scheduled NRS scores must be 
recorded regardless of timing of pre-rescue medication NRS scores and 
administration of rescue medication.  The actual time of all NRS scores must be 
recorded, i.e., not the nominal time. 
• 
During the inpatient stay, evoked NRS twice daily after physical therapy (most 
preferred) or ambulation for approximately 10 yards (preferred) or transfers 
to/from bed or wheelchair.  Obtain these NRS scores after morning physical 


 
 
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therapy or ambulation at 10:00 AM (± 1 h) and after afternoon physical therapy or 
ambulation at 4:00 PM (± 1 h). 
• 
During the inpatient stay, pain scores may be skipped between the hours of 
midnight and 6:00 AM, but the patient may not miss two consecutive 
assessments.  The T12, T24, T48, T72, and T96 assessments must be completed 
even if the patient must be awakened at these times. 
• 
During the inpatient stay, an additional NRS assessment must be obtained within 
5 minutes prior to IV rescue medication administration and within 15 minutes 
prior to oral rescue medication administration. 
• 
Vital signs - HR, BP, RR (supine), and temperature (oral) - are assessed together post-
surgery at T2, T6, T12, and T24, and every 8 hours thereafter until T96.  Assessments 
between the hours of 12:00 AM and 6:00 AM may be skipped if the patient 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 PE: T96 (± 4 h) (prior to discharge from the inpatient unit).   
• 
12-lead ECG: T24 (± 2 h).  
• 
Surgical site assessment: T96 (± 4 h) prior to discharge from the inpatient unit. If the 
Investigator determines 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 (Section 17.15, 
Appendix O).  A digital photograph of the wound site should be taken (Section 17.14, 
Appendix N). 
• 
Neurosensory testing of the surgical area near the incision (compared to a similar site on 
the opposite leg): T96 (± 4 h) prior to discharge from the inpatient unit. 
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.  Patients will be followed 
until there is a return to baseline or establishment of a new baseline.  
• KOOS Survey: T96 (± 4 h) prior to discharge from the inpatient unit (Section 10.3.10). 
• Knee ROM at T48 (± 4 h) and Discharge (T96) (Section 10.3.12). 
• Ability to walk >100 ft (> 30 m) with only the aid of a walker during twice-daily 
inpatient physical therapy sessions (or assessed by site staff) on D3, D4, and D5 to allow 
assessment of discharge readiness. 


 
 
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• Performance-based functional outcome measures (PBOMs) at T96 (± 4 h) 
(Section 10.3.13):  
1. 
Sit to Stand Test (also known as 30-Second Chair Stand) Assessment 
(Section 17.11, Appendix K); 
2. 
Walking Speed Test (Section 17.12, Appendix L);  
3. 
TUG Test (Section 17.13, Appendix M). 
• Clinical laboratory tests T96 (± 4 h) prior to discharge from the inpatient unit:  
o 
Hematology/Coagulation: hemoglobin, hematocrit, white blood cell count with 
differential, red blood cell count, platelet count, aPTT, and PT or INR. 
o 
Blood Chemistry: including ALT, AST, Tot. Bili, GGT, albumin, BUN, 
creatinine, ALK, sodium, potassium, calcium, chloride, and glucose. 
o 
Urinalysis: including macroscopic analysis and, if indicated, microscopic 
analysis. 
• 
Blood draw for PK analysis: The time points for whole blood collection will be at pre-
dose (from check-in and up to 30 minutes before the start of surgery), and 
pharmacokinetic time (PKT) 0.167 h (10 min), 0.25 h (15 min), 0.5 h (30 min), 0.75 h 
(45 min), and at 1, 1.5, 2, 3, 4, 6, 8, 12, 16, and 24 hours after the last study treatment 
instillation (total of 15 samples).  In the event of an AE, an unscheduled PK draw will be 
performed.  
• 
Total post-surgical opioid consumption converted to an oral morphine equivalent dose (OME). 
• 
Record rescue medication consumption and concomitant medications throughout the 
inpatient period. 
• 
Record AEs throughout the inpatient period (Section 17.1, Appendix A may be useful to the 
Investigator for assessing systemic [general] AEs).  
After completing the assessments through T96, the diary for at-home use will be reviewed and 
patients will be discharged from the study center with the diary to record pain assessments and 
pain medication at home.  Patients will be provided routine standard of care for pain 
management after discharge from the study center.   
Patients will be given a prescription for 20 tablets of acetaminophen 325 mg/oxycodone 5 mg 
(Percocet) one or two tablets PO Q 4-6 h PRN moderate-severe pain (i.e., NRS 5 – 10).  
Document the number of tablets prescribed and also document any additional prescriptions 
required if the patient’s pain continues to be an issue requiring additional opioid medication. 
Patients will be instructed to return to the study center on D8 (+ 1 day) for follow-up 
assessments.  


 
 
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10.1.5. 
Outpatient Phase: D5 (after Discharge) through D8 
After discharge at T96 (± 4 h) and through D8, patients will assess their pain intensity in their 
diary.  
• 
Instruct patients to document their NRS scores twice daily at 11:00 AM (± 1 h) and 
7:00 PM (± 1 h) at rest and during 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.  Instruct patients to: 
o Obtain the morning NRS assessment; 
o Obtain the evening NRS assessment; 
o Opioid and non-opioid rescue medication (dose, date, time) must be recorded 
through D15. 
Patients will return to the study center on D8 (+ 1 day) for the following assessments:  
• 
Patient home diary review (pain intensity [NRS score] and pain medication); 
• 
Vital signs - HR, BP, RR (supine), and temperature (oral); 
• 
Targeted PE; 
• 
Surgical site assessment: If the Investigator determines 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 (Section 17.15, Appendix O). A digital photograph of the wound site should 
be taken (Section 17.14, Appendix N); 
• 
Neurosensory testing of the surgical area near the incision (compared to a similar site on 
the opposite leg):  
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.  Patients will be followed 
until there is a return to baseline or establishment of a new baseline. 
• 
Query the patient as to whether they have experienced any worsening (rebound) pain at 
the surgical site (Section 10.3.9); 
• 
KOOS Survey on D8 (+ 1 day) (Section 10.3.10); 
• 
Knee ROM (D8) (Section 10.3.12); 
• 
Concomitant medication use/concomitant treatments; 
• 
AE assessment. 


 
 
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10.1.6. 
Outpatient Phase: D9 through D15 
From D9 through D15, patients will assess their pain intensity in their diary.  
• 
Instruct the patient to document their NRS scores twice daily at 11:00 AM (± 1 h) and 
7:00 PM (± 1 h) at rest and during 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; 
o Obtain the evening NRS assessment; 
o Opioid and non-opioid rescue medication (dose, date, time) must be recorded 
through D15. 
Patients will return to the study center on D15 (+ 2 days) for the following assessments:  
• 
Patient home diary review (pain intensity [NRS score] and pain medication) and 
collection (Section 10.3.8); 
• 
Vital signs - HR, BP, RR - (supine), and temperature (oral); 
• 
Targeted PE; 
• 
Surgical Site assessment: If the Investigator determines 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 (Section 17.15, Appendix O).  A digital photograph of the wound site 
should be taken (Section 17.14, Appendix N); 
• 
Neurosensory testing of the surgical area near the incision (compared to a similar site on 
the opposite leg): 
a. 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. 
b. 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.  Patients will be followed 
until there is a return to baseline or establishment of a new baseline. 
• 
Query the patient as to whether they have experienced any worsening (rebound) pain at 
the surgical site (Section 10.3.9); 
• 
KOOS Survey (Section 10.3.10); 
• 
PROMIS 10 Global Health questionnaire (Section 10.3.11); 
• 
Knee ROM (Section 10.3.12); 
• 
PBOMs: (Section 10.3.13):  
1. 
Sit to Stand Test Assessment (Section 17.11, Appendix K); 
2. 
Walking Speed Test (Section 17.12, Appendix L);  


 
 
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3. 
TUG Test (Section 17.13, Appendix M). 
• 
Concomitant medication use/concomitant treatments; 
• 
AE assessment. 
10.1.7. 
Outpatient Phase: D29 
Patients will return to the study center on D29 (+ 2 days), or at the time of discontinuation, for 
the following assessments:  
• 
Vital signs - HR, BP, RR - (supine), and temperature (oral); 
• 
Targeted PE; 
• 
Surgical site assessment: If the Investigator determines 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 (Section 17.15, Appendix O). A digital photograph of the wound site should 
be taken (Section 17.14, Appendix N); 
• 
Neurosensory testing of the surgical area near the incision (compared to a similar site on 
the opposite leg):  
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.  Patients will be followed 
until there is a return to baseline or establishment of a new baseline. 
• 
Query the patient as to whether they have experienced any worsening (rebound) pain at 
the surgical site (Section 10.3.9); 
• 
KOOS survey (Section 10.3.10); 
• 
PROMIS 10 Global Health questionnaire (Section 10.3.11); 
• 
Knee ROM (Section 10.3.12); 
• 
PBOMs: (Section 10.3.13):  
4. 
Sit to Stand Test Assessment (Section 17.11, Appendix K); 
5. 
Walking Speed Test (Section 17.12, Appendix L);  
6. 
TUG Test (Section 17.13, Appendix M). 
• 
X-ray of the operated knee (and later if any evidence of abnormalities in bone healing 
until resolution or stabilization); 
• 
Concomitant medication use/concomitant treatments; 
• 
AE assessment.  


 
 
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10.1.8. 
Early Termination 
If prior to D15 visit, patients will return for the following assessments: 
• 
Patient home diary review (pain intensity [NRS] and pain medication) (Section 10.3.8); 
• 
Vital signs - HR, BP, RR - (supine), and temperature (oral); 
• Targeted physical examination; 
• Surgical site assessment (If the Investigator determines there are atypical wound healing 
or visible abnormal findings, a digital photograph of the wound site should be taken) 
(Section 17.14, Appendix N); 
• 
Neurosensory testing of the surgical area (Section 10.3.21); 
• Query the patient as to whether they have experienced any worsening (rebound) pain at 
the surgical site (Section 10.3.9); 
• 
KOOS survey (Section 10.3.10); 
• PROMIS 10 Global Health questionnaire (Section 10.3.11) 
• Concomitant medication use/concomitant treatments; 
• AE assessment. 
If after D15 visit, patients will return for the following assessments:  
• Surgical site assessment (If the Investigator determines there are atypical wound healing 
or visible abnormal findings, a digital photograph of the wound site should be taken) 
(Section 17.14, Appendix N); 
• Neurosensory testing of the surgical area (Section 10.3.21); 
• Query the patient as to whether they have experienced any worsening (rebound) pain at 
the surgical site (Section 10.3.9); 
• KOOS survey (Section 10.3.10); 
• PROMIS 10 Global Health questionnaire (Section 10.3.11); 
• Concomitant medication use/concomitant treatments; 
• AE assessment. 
If after D29 visit, the Investigator has clinical discretion as to what assessments are to be 
completed 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 photograph of the wound site should be taken) 
(Section 17.14, Appendix N); 
• Neurosensory testing of the surgical area (Section 10.3.21); 
• Query the patient as to whether they have experienced any worsening (rebound) pain at 
the surgical site (Section 10.3.9); 
• KOOS survey (Section 10.3.10); 


 
 
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• PROMIS 10 Global Health questionnaire (Section 10.3.11); 
• X-ray of the operated knee to ensure proper healing.  Follow patient until resolution or 
stabilization; 
• Concomitant medication use/concomitant treatments; 
• AE assessment. 
10.1.9. 
Unscheduled Visit 
Unscheduled visits may occur at any time and assessments are to be completed at the 
Investigator’s discretion based on the reason for the visit and entered into the EDC.  At a 
minimum, the following should be performed: 
• 
Vital signs - HR, BP, RR - (supine), and temperature (oral); 
• 
Targeted PE; 
• 
Surgical site assessment: If the Investigator determines there are atypical wound healing or 
visible abnormal findings, a digital photograph of the wound site should be taken 
(Section 17.14, Appendix N); 
• 
Neurosensory testing of the surgical area (Section 10.3.21); 
• 
Concomitant medication use/concomitant treatments; 
• 
AE assessment. 
10.2. 
Patient Completion and Withdrawal 
10.2.1. 
Patient Completion 
A patient 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. 
Patient Withdrawal 
If a patient still requires IV opioid rescue after T24, then the patient will be withdrawn from 
activity/efficacy assessments but continue serial NRS and safety assessments and revert to IV 
analgesia management per standard-of-care.  These patients will still be followed for pain and 
safety assessments. 
A patient is free to withdraw his/her consent and discontinue participation in the study at any 
time for any reason.  A patient’s participation must therefore be terminated immediately upon 
his/her request, and the reason(s) for discontinuation appropriately documented.  Patients who 
elect to discontinue participation prior to D8 will be considered to have terminated as of the date 
of their election. 
The degree to which a patient withdraws can vary, and efforts will be made to collect important 
safety data whenever feasible and if the patient agrees.  Patients can: 


 
 
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1. Withdraw from activity/efficacy assessments but agree to participate in all study safety 
assessments; 
2. Withdraw from activity/efficacy assessments but agree to participate in limited study 
safety assessments; 
3. Withdraw from study activity/efficacy and safety assessments.  In this case, patients 
should still return for a surgical follow-up assessment of wound healing. 
A patient may be discontinued from the study for any of the following reasons: 
4. 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; 
5. At the request of the Sponsor, regulatory agency, or Institutional Review Board (IRB); 
6. Patient is lost to follow-up; 
7. Patient treatment allocation is unblinded (i.e., individual code break; Section 9.4); 
8. Death of patient. 
A patient may also be discontinued from the study, at the discretion of the Investigator and/or 
Sponsor, for any of the following reasons:  
9. Patient refuses or is unable to adhere to the study protocol; 
10. Major protocol violation; 
11. Pregnancy; 
12. Use of unacceptable concomitant medication(s); 
13. It is not considered in the best interest of the patient to continue; 
14. Administrative reasons (e.g., termination of enrollment or study). 
The Investigator must maintain a record of all patients who discontinue from the study prior to 
completion; the reason(s) for study discontinuation will be documented. If a patient chooses to 
withdraw from the study, the Investigator should make a reasonable attempt to obtain and record 
the reason(s) for withdrawal in as much detail as possible, although the patient is not obligated to 
provide such a reason.  
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 patient by the 
Investigator or designated study personnel. The patient must voluntarily provide written 
informed consent on an IRB-approved informed consent form (ICF), prior to performing any 
study-related procedures. The patient’s source records must document that the consent process 
has been completed and that written informed consent has been obtained from the patient prior to 
the initiation of any study-specific procedures. Documentation that the patient was given 
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and that a signed and dated copy of the ICF was provided to the patient should also be included 
in the medical records or clinical chart. 
10.3.2. 
Demographics 
The following demographic data 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 impact on 
study eligibility. 
10.3.4. 
Medication History  
All medications (prescription and non-prescription, herbal medications/natural health products, 
or investigational drugs) taken by the patients during the 30 days prior to Screening will be 
recorded in the source documentation as medication history.  
10.3.5. 
Contraceptive Requirements 
Female patients of childbearing potential must be using and willing to continue using medically 
acceptable contraception during the study.  Examples of medically acceptable forms of 
contraception include true abstinence, hormonal contraceptives (combined oral pill, patch or 
vaginal ring, intrauterine device or system, progestin implant or injection), bilateral tubal 
ligation, or double-barrier methods (i.e., male condom in addition to a diaphragm or a 
contraceptive sponge).  
Female patients 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 patient 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 with an FSH > 40 mIU/mL confirmed 
during screening (or FSH above the relevant laboratory value for post-menopausal status). 
Male patients, unless in a relationship with 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 study 
participation.   
10.3.6. 
Patient Pain Assessment Training 
Patients will undergo study participation education on pain assessments and written testing 
procedures according to the Schedule of Study Procedures. 


 
 
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10.3.7. 
Digital Photographs of the Surgical Site 
During the informed consent process, patients 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 17.6, Appendix F).   
Patients will report or record the intensity of their current pain at the knee surgical site at 
designated times during the study after administration of study treatment.  Patients should be at 
rest for at least 5-10 minutes prior to completing NRS resting assessment. 
• During the inpatient stay, NRS at rest beginning with the PACU admission may be assessed 
once the patient is awake.  T0 is the time of admission into the PACU (as recorded in notes 
by the PACU nurse).  If the patient is able to provide responses, obtain NRS scores at T0 plus 
1 hour (T1), T0 plus 2 hours (T2, etc.), T4, T6, T8, T12, T16, T20, T24, and every 4 hours 
thereafter (if awake at time of assessment) until discharge from the inpatient unit.  Time 
windows: ± 5 minutes for T1 and T2; ± 15 minutes for T4 onward.  Scheduled NRS scores 
must be recorded regardless of timing of pre-rescue medication NRS scores and 
administration of rescue medication.  The actual time of all NRS scores must be recorded, 
i.e., not the nominal time. 
• During the inpatient stay, evoked NRS twice daily after physical therapy (most preferred) or 
ambulation for approximately 10 yards (preferred) or transfers to/from bed or wheelchair.  
Obtain these NRS scores after morning physical therapy or ambulation at 10:00 AM (± 1 h) 
and after afternoon physical therapy or ambulation at 4:00 PM (± 1 h). 
• During the inpatient stay, pain scores may be skipped between the hours of 12:00 AM and 
6:00 AM, but the patient may not miss two consecutive assessments.  The T12, T24, T48, 
T72, and T96 assessments must be completed even if the patient must be awakened at these 
times. 
• During the inpatient stay, an additional NRS assessment must be obtained within 5 minutes 
prior to IV rescue medication administration and within 15 minutes prior to oral rescue 
medication administration. 
• During the outpatient period (after T96 and through D15), instruct the patient to document 
their NRS scores twice daily at 11:00 AM (± 1 h) and 7:00 PM (± 1 h) at rest and during 
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; 
o Obtain the evening NRS assessment; 


 
 
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o Opioid and non-opioid rescue medication (dose, date, time) must be recorded in the 
diary through D15, including a pre-rescue NRS score. 
10.3.9. 
Worsening (Rebound) Pain at the Surgical Site 
Patients 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 17.7, 
Appendix G). 
10.3.10. 
Knee Injury and Osteoarthritis Outcome Score (KOOS) 
Patients will complete the KOOS survey at designated times during the study and after 
administration of study treatment (at Screening, T96, D8, D15, and D29) (Section 17.8, 
Appendix H).  The KOOS survey was developed in the 1990s as an instrument to assess the 
patient’s opinion about their knee and 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. 
PROMIS 10 Global Health Questionnaire 
Patients will complete the PROMIS 10 Global Health questionnaire at Screening, D15, and D29 
(Section 17.9, Appendix I). 
10.3.12. 
Knee Range of Motion (ROM) 
Patients will have their Knee ROM tested using a goniometer at Screening, T48 (± 4 h), 
T96/Discharge, D8, D15, and D29 (Section 17.10, Appendix J). 
10.3.13. 
Performance-Based Objective Measures (PBOMs) 
Patients will undergo PBOMs at T96 (± 4 h)/Discharge, D15, and D29.  These measures include: 
1. 
Sit to Stand Test Assessment (Section 17.11, Appendix K); 
2. 
Walking Speed Test (Section 17.12, Appendix L);  
3. 
TUG Test (Section 17.13, Appendix M). 
10.3.14. 
Rescue Medications 
The details of rescue analgesic medication (specific drugs, doses, dates, and times) will be 
recorded during the inpatient period beginning from the end of surgery through the outpatient 
period to D15 (+ 2 days) visit or to the Early Termination Visit, if applicable.  Patients will be 
instructed on the proper use and timing of rescue medication. 
The statistician will use a standard conversion table of OMEs to calculate the oral morphine 
equivalent dose of various opioids (see the Statistical Analysis Plan [SAP] for further details). 
Total opioid consumption (OC) and daily opioid (rescue medication) consumption in OMEs will 
be calculated during the inpatient period and up to the D15 visit.   


 
 
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• 
Document daily use of OTC analgesics (and oxycodone if prescribed) during the 
outpatient period through D15.   
• 
Document each opioid prescription provided to the patient and the number of and type of 
tablets provided to the patient.  
10.3.15. 
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 
laboratory 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 laboratory reports 
expeditiously to document appropriate safety monitoring of study patients.  The Investigator 
should sign and date each laboratory report concurrent with her or his review.  The Investigator 
should exercise medical and scientific judgment in deciding whether abnormal laboratory values 
are clinically significant or not and should indicate the clinical significance of each 
abnormal/flagged value by noting “NCS” (not clinically significant) or “CS” (clinically 
significant).  All clinically significant values will be recorded in the eCRF and followed until 
resolution.  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 8. 


 
 
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Table 8. 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) 
 
Endocrinology 
FSH, as appropriate 
 
The clinical laboratory tests will be completed per the Schedule of Assessments (Table 1).  In 
addition to the clinical laboratory tests, a serum pregnancy test (βhCG) will be performed at the 
Screening Visit and a urine pregnancy test will be performed prior to surgery for females of 
childbearing potential.  
ALT or AST > 3 × ULN, Tot. Bili > 2 × ULN, and Alk Phos > 2 × ULN will be considered an 
adverse event, as well as any other changes deemed clinically significant by the Investigator.  
10.3.16. 
Urine Drug Screen and Alcohol Test 
Urine drug screen and alcohol breath/saliva tests will be completed at screening and pre-
procedure.  All patients will be tested for drugs-of-abuse (e.g., amphetamines, barbiturates, 
benzodiazepines, cocaine, opiates, phencyclidine, tetrahydrocannabinol (THC), methadone, 
methamphetamine, tricyclic anti-depressants, oxycodone, and others). 
The drug and alcohol screens will be performed in-house at the inpatient unit.  If any of these 
tests are positive, except as indicated below, the patient will not be allowed further participation 
in the trial.  However, a positive test may be repeated at the discretion of the Investigator.   
In the case of a urine drug screen at screening that is positive for THC, if the patient is willing to 
abstain from use or consumption of THC-containing products from 3 days prior to surgery until 


 
 
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the Day 15 visit, they may be allowed to participate in the study.  In this case, a urine drug screen 
positive for THC at check-in will not exclude the patient. 
If other positive urine drug screen results can be explained by a current prescription or 
acceptable over-the-counter medication (that doesn’t otherwise exclude the patient as determined 
by the investigator), then the patient may continue to participate in the study 
10.3.17. 
Vital Signs 
Vital signs (supine) will consist of HR, BP, RR, and temperature (oral) following a rest period. 
Vital signs will be assessed per the Schedule Assessments (Table 1).  One missed scheduled 
assessment of vital signs will not be considered a protocol deviation.  Two missed assessments of 
vital signs in a row is a protocol deviation. 
10.3.18. 
12-Lead Electrocardiogram (ECG) 
All 12-lead ECGs will be performed per the Schedule of Assessments (Table 1) after the patient 
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 QTcF, clinically significant prolongation 
of QTcF should be > 450 ms for male patients and > 470 ms for female patients or an increase of 
QTcF of 30 ms or greater (compared to the pre surgical ECG), as well as any other changes 
deemed by the Investigator as significant.  Clinically significant changes in ECG will be 
considered an AE. 
10.3.19. 
Physical Examination 
A complete PE including all major body systems (general appearance, HEENT, neck, 
neurologic, cardiovascular, lungs, abdomen, skin, extremities, genitourinary, lymph nodes, 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 T96.  
Height in centimeters (cm) will be measured, and body mass index (BMI) will be calculated at 
Screening only.  BMI shall be calculated as kg/m2.  The site should use the NIH website BMI 
calculator (available at: http://www.nhlbi.nih.gov/health/educational/lose_wt/BMI/bmi-m.htm). 
10.3.20. 
Surgical Site Assessment  
The surgical site should be assessed per the Schedule of Assessments (Table 1) 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 


 
 
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score of 0 is “Completely unsatisfied,” and a score of 10 is “Completely satisfied” 
(Section 17.14, Appendix N).  Assessments will also be performed at each of the follow-up visits 
or at the time of early discontinuation.  Insufficient wound healing that is clinically significant 
should be recorded as an AE.  When assessed on D29, if the Investigator observes insufficient 
wound or bone healing or to ensure an ongoing AE has resolved, the patient 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 17.15, Appendix O). 
10.3.21. 
Neurosensory Testing 
Neurosensory testing of the skin surrounding the incision (compared to a similar site on the 
opposite leg) will be conducted per the Schedule of Assessments (Table 1).  This evaluation will 
include the details described in Section 17.16, Appendix P.   
• 
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.  Patients 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. 
10.3.22. 
Assessment of Adverse Events 
All AEs and SAEs will be documented and followed from the time the patient has signed the ICF 
until D29 or later as necessary.  All SAEs and non-serious AEs will be documented and followed 
from the time of administration of study treatment until D29 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 patient’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. 
10.3.23. 
Pharmacokinetic Assessments and Samples 
Details for the collection and processing of blood samples for measurement of PK (CA-008, 
capsaicin, and CA-101) are outlined in the Laboratory Manual. 


 
 
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Part A: 
PK sample collection will be performed on all patients.  The time points for whole blood 
collection will be at pre-dose (from check-in and up to 30 minutes before the start of surgery), 
and at PKT 0.167 h (10 min), 0.25 h (15 min), 0.5 h (30 min), 0.75 h (45 min), and at 1, 1.5, 2, 3, 
4, 6, 8, 12, 16, and 24 hours after the last study treatment instillation (total of 15 samples).  
Part B: 
PK sample collection will be performed at one site.  The time points for whole blood collection 
will be at pre-dose (from check-in and up to 30 minutes before the start of surgery), and at PKT 
0.167 h (10 min), 0.25 h (15 min), 0.5 h (30 min), 0.75 h (45 min), and at 1, 1.5, 2, 3, 4, 6, 8, 12, 
16, and 24 hours after the last study treatment instillation (total of 15 samples).  At least 12 of the 
15 samples should be collected in each of these patients.  The number of patients will depend on 
the number of dose levels being tested but approximately 15 patients per dose level are planned. 
10.4. 
Safety, Tolerability, Pharmacokinetic (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; 
• Knee x-ray (only if any evidence of abnormalities in bone healing); 
• Presence of worsening (rebound) pain; 
• Concomitant medication use/concomitant treatments. 
10.4.2. 
Pharmacokinetic (PK) Endpoints 
Full details of pharmacokinetics will be described in a separate PK Analysis Plan. The time 
points for whole blood collection are outlined in the Schedule of Assessments (Table 1).   
Part A: 
PK sample collection will be performed on all patients.  The time points for whole blood 
collection will be at pre-dose (from check-in and up to 30 minutes before the start of surgery), 


 
 
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and at PKT 0.167 h (10 min), 0.25 h (15 min), 0.5 h (30 min), 0.75 h (45 min), and at 1, 1.5, 2, 3, 
4, 6, 8, 12, 16, and 24 hours after the last study treatment instillation (total of 15 samples).  
Part B: 
PK sample collection will be performed at one site.  The time points for whole blood collection 
will be at pre-dose (from check-in and up to 30 minutes before the start of surgery), and at PKT 
0.167 h (10 min), 0.25 h (15 min), 0.5 h (30 min), 0.75 h (45 min), and at 1, 1.5, 2, 3, 4, 6, 8, 12, 
16, and 24 hours after the last study treatment instillation (total of 15 samples).  At least 12 of the 
15 samples should be collected in each of these patients.  The number of patients will depend on 
the number of dose levels being tested but approximately 15 patients per dose level are planned. 
Actual sampling times will be used to calculate plasma-derived PK parameters.  
Plasma concentration for CA-008 and key metabolite(s) (including capsaicin and CA-101) at PK 
sampling times will be summarized using descriptive statistics, including mean, SD, median, 
minimum and maximum values, and coefficient of variation (CV%), geometric mean and 
geometric coefficient of variation (geoCV%).  PK parameters include (but are not limited to) 
maximum observed plasma drug concentration (Cmax), Tmax, half-life, and areas under the plasma 
concentration-time curve (AUC0-last and AUC0-∞).  
Note: A PK sample should be collected during the in-patient phase of the study as part of the 
evaluation of any SAE or severe TEAE. 
10.4.3. 
Efficacy Endpoints 
10.4.3.1. Efficacy Endpoints for Part A 
There are no efficacy endpoints for Part A. 
10.4.3.2. Efficacy Endpoints for Part B  
The primary efficacy endpoint for Part B: 
• NRS AUC at rest from T12 to T96 (AUC12-96).  NRS AUC is the weighted sum of current 
pain intensity (SPI) assessments for a specified time interval. 
Key secondary efficacy endpoints:  
• Evoked pain NRS: AUC12 – 96 
• Percentage of patients who do not require opioids (i.e., opioid-free or OF) from T24 to 
T96: OF24-96 
• Total opioid consumption (in daily OME) = OC from T12 to T96: OC12-96 
• NRS at rest and evoked NRS from T12 to D8: AUC12-D8 
Exploratory efficacy endpoints for Part B are: 
• Using rest NRS: AUC0-24, AUC0-96, AUC6-96, AUC24-96, AUC96-D8, and AUC96-D15; 


 
 
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• Using evoked NRS: AUC0-96 (ambulation), AUC0-D8 (ambulation), AUC24-D8 (ambulation), and 
AUC96-D15 (ambulation); 
• Time-specific mean NRS scores at T48, T72, T96, T120, T144, and T168; 
• OC0-96, OC24-48, OC24-72, OC24-96, OC24-D8, and OC24-D15; 
• OF0-96, OF24-D15, OF96-D8, and OF96-D15; 
• Additional exploratory and sensitivity analyses rest/evoked NRS AUC, OC, and OF 
during different intervals may be undertaken; 
• Knee ROM: mean and proportion of patient s with > 90° and proportion of patients with 
> 115° active flexion at T48 (± 4 h), T96 (± 4 h)/Discharge, D8, D15, and D29; 
• KOOS improvement from Screening to D8, D15, and D29; and from T96 to D8, D15, 
and D29; 
• Improvement in PBOMs (Sit to Stand, Walking Speed Test, TUG) at T96 
(± 4 h)/Discharge, D15, and D29 
• The proportion of patients who rescue T0-T6, T6-T12, T12-T24, T24-T48, T48-T72, and 
T72-T96; 
• Total non-opioid analgesic consumption (AC), ie, rescue acetaminophen use for the 
specified intervals: AC96-D8 and AC96-D15; 
• PROMIS 10 Global Health questionnaire score improvement from Screening to D15 and 
to D29; 
• Number and percentage patients with an AE of lack of efficacy (LOE) during the 
inpatient period: LOE0-96. 
• Discharge readiness at T48 (± 4 h), T72 (± 4 h) and T96 (± 4 h)/Discharge as assessed by 
the earliest presence of all three of the following: (i) Adequate analgesia (defined as 
median rest NRS < 4 during an 8-hour period); (ii) independence from intravenous 
opioids during an 8-hour period; and (iii) ability to ambulate >100 ft (> 30 m) with only 
the aid of a walker during a physical therapy session. 
Note: Details on additional or alternative exploratory efficacy endpoints are provided in the 
study Statistical Analysis Plan (SAP).  The SAP will supersede the protocol with respect to the 
analyses specified, although the primary and key secondary efficacy endpoints described in the 
protocol will remain unchanged. 
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. 


 
 
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An AE is any untoward medical occurrence in a patient 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 
Not Related 
Temporal relationship to study treatment administration is missing or 
implausible, or there is an evident other cause. 
Unlikely related 
A clinical event, including laboratory test abnormality, with a temporal 
relationship to study treatment administration which makes a causal 
relationship improbable or if other drugs, chemicals or underlying 
disease provide more plausible explanations.  
While temporal sequence may be an important factor in determining 
causality: i.e., whether the observed reaction or event began after the 
study treatment, it may well be that the surgery, anesthesia, a concurrent 
medical condition or concomitant medications administered during or 
after surgery were more likely than not to be responsible for the AE.  
The Investigator should use clinical judgment to evaluate the evidence 
and determine whether there is a reasonable possibility that study 
treatment actually caused the AE or whether based upon the evidence it 
is more likely that something else is responsible.  If the former, choose 
“possibly related” and if the latter, “unlikely related.”   
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 


 
 
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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, or severe) 
• Relationship to study treatment 
• Action and outcome 
• Seriousness of event 
All SAEs will be documented and followed from the time the patient has signed the ICF until 
D29 + 2 days after the completion of surgery.  All SAEs and non-serious AEs will be 
documented and followed from the time of administration of study treatment until D29 or later if 
necessary. AEs that occur between Screening and the administration of study medication should 
be considered medical history and added to the patient’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. 


 
 
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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 patient 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 patient 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 D29 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 patient is receiving study treatment and within 14 days 
following the study completion visit (or 21 days following an early termination [ET] if 
applicable) are reportable within 24 hours. During this follow-up period beyond study 
completion or after an ET, only those SAEs considered to be possibly related to study treatment 
should be reported within 24 hours. 
The procedure for reporting an SAE is as follows: 
• 
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.  
• 
The Sponsor’s Medical Monitor is available for questions about safety-related issues or to 
request waivers to modify post-operative patient care.  
• 
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. 


 
 
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• 
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 Patient 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. 
11.2. 
Severity Grading for AEs 
Grading the severity of AEs is per Investigator discretion (the guidance reflected in 
Sections 17.4, 17.3 and 17.1; Appendices I, J, and K, respectively, 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.  
• 
Grade 4 (potentially life-threatening).  


 
 
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11.3. 
Pregnancy 
If a female patient 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 patient 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.  In order 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, laboratory 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 eCRFs 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 recorded on the eCRF.  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 EDC 
system maintains a full audit trail.  
12.2. 
Study Auditing and Monitoring 
Monitoring of the study site (including, but not limited to, reviewing eCRFs for accuracy and 
completeness) will be performed by the Sponsor’s designated monitor(s).  The extent, nature, 
and frequency of on-site visits will be based on such considerations as the study objectives 
and/or endpoints, the purpose of the study, study design complexity, and enrollment rate.  By 


 
 
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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  
The statistical methods to be employed in assessing the safety and efficacy CA-008 in patients 
undergoing TKA in accordance with this Phase 1/2 study protocol are outlined below.  Detailed 
descriptions of all summaries and analyses to be performed, including all secondary efficacy 
analyses and all safety analyses, will be provided in a statistical analysis plan (SAP) that will be 
finalized prior to database lock.  The SAP will supersede the protocol with respect to the 
analyses specified.  
13.1. 
Sample Size Justification 
In Part A, no formal statistical hypothesis testing will be performed.  The sample size of 8 initial 
patients per dose level, with the potential for expansion to 16 patients, has been selected based on 
prior clinical trial experience with CA-008 and is considered sufficient for exploration of 
tolerability and safety parameters, establishment of a PK profile, and preliminary assessment of 
the efficacy of CA-008 in postoperative analgesia. 
In Part B, a total of 150-300 patients will be randomized in 3-4 parallel arms with 
50-100 patients in each arm.  The number of patients to be enrolled in Part B will not exceed 
300. Assuming a t-test for the difference in 2 independent means, a sample size of approximately 
50 patients per group would provide approximately 85% power to detect an effect size (Cohen’s 
d) of 0.6 at a two-sided level of significance, alpha, of 0.05 in the primary efficacy endpoint NRS 
AUC12-96.  Enrollment is currently planned at 55 patients per arm to allow for patients whose 
data are not eligible for inclusion in the final analysis.  In this scenario, it is anticipated that, in 
Part B, 3 active dose levels – 60 mg, 36 mg, and 15 mg – are to be tested versus placebo, 
yielding 4 trial arms and a resulting total sample size of 220 patients.  Alternative assumptions 
concerning the anticipated effect size lead to a different number of patients per group.  The 
actual doses, number of active arms (2 or 3), and sample size to be tested in Part B will be 
determined at the end of Part A based on information in the protocol and SAP. The SAP will 
update and supersede the protocol with respect to the sample size, though the total number of 
patients enrolled will not change. 
Note: If activity and efficacy assessments from Part A remain blinded, then the patients enrolled 
in Part A can be pooled with patients treated with the same dose of active drug or placebo from 
Part B during the efficacy analysis. 
13.2. 
Analysis Populations 
The following 5 analysis populations are planned for this study:  
1 
Safety Population consists of all patients who received any part of a dose of study 
treatment.  (Note this must include anyone who terminates early for lack of efficacy). 


 
 
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2 
PK Population consists of all patients who received a full dose of study treatment and 
completed at least one PK assessment. 
3 
Modified Intent-to-treat (mITT) Population consists of all patients who received any dose 
of study treatment.   
4 
Per Protocol (PP) Population consists of all patients who received a full dose of study 
treatment and have evaluable NRS pain assessments at least through T96 (± 4 
h)/Discharge. 
5 
Study Completers consists of all patients who received a full dose of study treatment and 
completed the entire study period through D29 + 2 days. 
Note: If activity and efficacy assessments from Part A remain blinded, then the patients enrolled 
in Part A can be pooled with patients treated with the same dose of active drug or placebo from 
Part B during the efficacy analysis. 
Membership in analysis populations will be determined before treatment assignments are 
unblinded for planned data analyses.  
Patients in Part A who discontinue study participation before or after randomization but prior to 
receiving study treatment will be replaced.   
Patients who are withdrawn or elect to withdraw after receiving study treatment will not be 
replaced.  Those patients who withdraw during the inpatient phase of the study, will be asked to 
continue with assessments through T96 if they have not elected to withdraw from all aspects of 
study participation (see Section 10.2).  Patients who elect to discontinue participation on or prior 
to D8 will be considered to have terminated as of the date of their election to discontinue; 
however, they will be asked to return to the study site one time to ensure that adequate wound 
healing has occurred (see Section 10.2). 
13.3. 
Planned Analyses 
The final data analysis will be performed after all patients have either completed or have been 
discontinued from the study.  The study will be unblinded after patient membership in each of 
the various analysis populations has been determined at a blinded data review meeting and upon 
confirmation of database lock. 
Any deviations from the analyses presented in the SAP will be detailed in the clinical study 
report. 
All efficacy data will be summarized and analyzed using the mITT and PP populations unless 
otherwise noted.  Safety data will be summarized using the Safety population. 
All data recorded in the study database will be included in data listings.  Any spurious or 
erroneous data will be queried and followed up until satisfactorily resolved; if not resolvable, the 
data will be set to missing. 


 
 
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Summary statistics—number of patients (n), mean, standard deviation (SD), median, minimum, 
and maximum—will be presented for continuous variables.  Frequencies and percentages will be 
presented for categorical variables.  Unless otherwise noted, percentages will be calculated using 
the total number of patients in the appropriate population and/or subgroup and per treatment 
group, where applicable.  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, patient, and time point.  
Statistical testing including p-values and confidence intervals (CIs) will be presented as 
described in each section below.  Tests of statistical significance will be 2-sided at the 0.05 level 
of significance.  Because preliminary assessments of efficacy are the focus of efficacy analyses, 
no adjustments in the level of significance will be made for multiple comparison tests.  
13.4. 
Study Patients and Demographics 
13.4.1. 
Disposition and Withdrawals 
The numbers of patients randomized, completing, and withdrawing, along with reasons for 
withdrawal, will be tabulated overall and by treatment group.  The number of patients in each 
analysis population will be reported. 
13.4.2. 
Protocol Deviations 
Protocol deviations will be adjudicated and classified as major or minor during a blinded data 
review performed by the Sponsor and Medical Monitor prior to database lock and will be 
presented in a data listing.  In general, major protocol deviations are deviations from the study 
protocol that may significantly impact the completeness, accuracy, and/or reliability of the study 
data or that may significantly affect a subject's rights, safety, or well-being.  Major protocol 
deviations will be discussed in the CSR.   
13.4.3. 
Demographics and Other Baseline Characteristics 
Demographic and baseline characteristics (including age, sex, race, weight, and height) will be 
summarized for each treatment group and for the overall population by descriptive statistics.  
Medical history and clinical laboratory tests will be listed. 
Prior and concomitant medications will be summarized by treatment group, by the number and 
percentage of patients taking each medication, classified using World Health Organization Drug 
Dictionary Anatomical Therapeutic Chemical classes and preferred terms. 
13.4.4. 
Exposure  
Since this is a single dose study, study drug administration will be summarized in terms of total 
exposure by cohort and treatment group. 


 
 
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13.4.5. 
General Considerations 
All analyses will be performed using SAS® version 9.3 or higher.  The Clinical Data Interchange 
Standards Consortium (CDISC) SDTM (Study Data Tabulation Model) domain data sets and the 
ADaM (Analysis Data Model) analysis data sets employed in generating the tables, figures, and 
listings (TFLs) specified in the SAP will be provided to the Sponsor along with the generated 
TFLs.  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 for efficacy measures is the time of admission into the PACU and will be 
designated by T0.  
• The timing of PK assessments is based on the time since the end of the study drug 
treatment infiltration or instillation. 
• Day of surgery/study drug administration is defined as D1. 
• Elapsed assessment visit times are defined by time elapsed from T0 or D1. 
• The baseline value of any parameter is defined as the last valid measurement of that 
parameter prior to the beginning of study treatment administration. 
• The change from baseline value of a parameter is defined as the post-baseline value 
minus the 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.  Missing dates will be imputed as described in 
the SAP. 
13.4.6. 
Analysis of Efficacy Measures 
All efficacy endpoints using NRS scores will be summarized over time by cohort and treatment 
using descriptive statistics including confidence intervals as appropriate. 
There are no efficacy endpoints for Part A. 
In Part B, the primary efficacy endpoint is the area under the curve (AUC) for NRS at rest versus 
time from T12 to T96 (AUC12-96). NRS AUC is the weighted SPI assessments for a specified 
time interval. 
AUC calculations will be done using the standard trapezoidal rule:  
 
AUC𝑇1−𝑇2 = ∑
NRS𝑖−1 + NRS𝑖
2
𝑛
𝑖=1
(𝑡𝑖−𝑡𝑖−1) 
 
Where NRS𝑖 = NRS at time i, n is the number of minutes between T1 and T2, and (𝑡𝑖−𝑡𝑖−1) 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. 


 
 
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Missing NRS values will be handled as discussed in the 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. 
Mean NRS scores over time (in-clinic and diary) will be graphed over time by treatment group.  
NRS over time by each patient may also be displayed graphically as warranted.  The individual 
NRS and the computed AUC values will be listed for all individual patients.   
In this study, patients are permitted to take rescue medication for analgesia.  It is anticipated that 
patients randomized to placebo will take rescue medication more often than patients on active 
treatment.  During both inpatient and outpatient portions of the studies, a pre-rescue NRS should 
be recorded just prior to taking rescue medication, i.e., reflecting the pain level triggering the 
need for rescue analgesia. 
For patients who take rescue medication a windowed last pain score carried forward (wLOCF) 
will be used in the calculation of the NRS AUC.  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 patient sleeping, etc.) will not be imputed, and AUC will be 
calculated based on non-missing values.  
Sensitivity analyses of the primary efficacy variable using additional methods of imputation for 
rescue medication may also be performed.  Exploratory analyses of the primary efficacy variable 
using alternative methods may also be performed, e.g., mixed effects modeling and Silverman 
Rank Analysis.  In addition, exploratory analyses of combined active vs. placebo and high-dose 
active vs low-dose active may be performed.  Information is provided in the SAP. 
For secondary continuous efficacy endpoints based on the NRS scores, similar methods as the 
primary analysis will be used.   
Note: If activity and efficacy assessments from Part A remain blinded, then the patients enrolled 
in Part A can be pooled with patients treated with the same dose of active drug or placebo from 
Part B during the efficacy analysis. 
13.4.7. 
Handling of Dropouts or Missing Data 
All efforts will be made to minimize missing data.  These efforts will include the following: 
• Data will be collected regardless of study status or rescue use unless patient withdraws 
consent or is lost to follow up; 
• Continue data collection after patients take rescue medication. 


 
 
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With the procedures above, it is expected that the missing data would be minimal and random.  
Additional sensitivity analyses may be performed to assess the robustness of analysis 
conclusions, if warranted; details will be presented in the SAP.  
For patients who drop out of the study prior to D15 due to LOE or AEs, scheduled assessments 
may be imputed using worst prior pain score carried forward.  For patients who drop out of the 
study prior to D15, scheduled NRS assessments will first be imputed using the worst prior pain 
score carried forward (WOCF).  
As sensitivity analyses, the NRS AUC may also be calculated where, for each patient, 
assessments after dropout will be imputed by: (1) using LOCF; (2) using the last scheduled non-
missing NRS prior to drop out; (3) the median NRS of the patients continuing in the study who 
are from the same treatment group as the dropout patients; and (4) without imputation of missing 
data.   
For categorical endpoints, when assessments are to be imputed for data after a patient 
discontinues from the study, a WOCF method or Worst Case will be used (e.g., for the 
PROMIS 10 Global, imputed value would be ‘Poor’).  Sensitivity analyses using additional 
methods of imputation may be performed.  
All imputation methods for pain intensity will be documented in the SAP. 
13.4.8. 
Analysis of Safety  
Analysis of safety will be performed for the Safety population (as defined in Section 13.2).  
All safety summaries will be grouped by the actual treatment received.  Data from all patients 
receiving  placebo will be combined for summaries.  
Actual values and change from baseline clinical laboratory measures, vital signs, ECGs, physical 
examination, surgical site, and neurosensory assessments will be assessed and summarized by 
treatment group.   
No formal statistical comparisons will be performed for safety endpoints. 
13.4.8.1. 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 D29 or 
Early Termination, whichever occurs first;  
• Serious AEs with onset on the date of treatment with the study drug through 30 days after 
D29 or Early Termination, whichever occurs first; 


 
 
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• AEs that start before the start of treatment but increase in severity or relationship at the time 
of or following the start of treatment through D29 or Early Termination, whichever occurs 
first. 
Safety and tolerability will be evaluated by examining the occurrence of AEs, including TEAEs.  
AEs leading to discontinuation from the study, AEs related to study treatment, and AEs by the 
maximum severity will be summarized by treatment group.  The number and percentage of 
patients with TEAEs will be displayed for each treatment group by SOC and preferred term.  
Additionally, TEAEs will be tabulated for each treatment group by severity and by relationship 
to the study drug.  A listing of SAEs will be provided, if applicable. 
13.4.9. 
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.  Laboratory shift tables displaying the change 
(number of patients) relative to the normal range from baseline to each study visit will also be 
presented by treatment for each test.   
Laboratory values that are outside the normal range will also be flagged in the data listings, 
along with corresponding normal ranges. 
13.4.10. 
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 ECGs.  A detailed description of 
these analyses will be included in the SAP. 
The incidence of abnormal ECG findings will be summarized for each visit.  
13.4.11. 
Physical Examination Findings 
Physical examination and surgical site examination data will be presented in the listings. 
Abnormal or clinically significant physical examination and surgical site examination 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. 
Patient 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 patient will 
receive an IRB-approved ICF that summarizes the pertinent study information and will be given 
ample time to read the form and ask questions about the study.  All information is to be provided 
in a language understandable to the participant and must not include any language that waives 
the participant’s legal rights.  Prospective participants must also be informed of their right to 
withdraw consent without prejudice at any time during the study.  If the participant chooses to 
participate, he/she must sign the ICF before any study-related procedures are performed.  


 
 
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Significant changes to the protocol or product safety information may require a revision of the 
ICF, which must be reviewed and signed by all applicable study participants. 
The time that informed consent is obtained must be documented.  The Investigator must maintain 
the original, signed ICF in the participant’s source documents.  A copy of the signed ICF must be 
given to the study participant. 
14.2. 
Privacy and Confidentiality 
The Investigator is responsible for complying with applicable privacy regulations, per his or her 
jurisdiction. Only information identified in this protocol will be collected.  The information 
collected will only be used for the purposes identified in this protocol. 
To ensure anonymity and to limit disclosure, participants will be assigned a unique identifier at 
their first assessment.  This identifier will be cross-referenced in the participant’s chart.  The 
identifier will not contain any potentially identifiable information.  An identifier log will be 
maintained, linking each participant’s name to the corresponding identifier.  This log will be 
stored at the research site in a secure location. 
The knowledge gained through this study is the property of the Sponsor.  The Sponsor, 
representatives and affiliated companies of the Sponsor, the IRB, and regulatory agencies (such 
as the United States FDA) may inspect medical records related to the study to check the validity 
and accuracy of the data gathered in this study.  Participant medical records (with participant’s 
initials and/or date of birth) may be copied.  Confidentiality of participant records will be 
maintained except where release of information is required by law.  
The results of this study will be reported in such a manner that participants will not be 
identifiable in any way.  Published reports or presentations will refer to grouped data or coded 
individual data and not to any identifiable individuals.  Study reports sent to the Sponsor or drug 
regulatory agencies will not include participant names. 
By signing the ICF, the participant consents to the collection, access, use, and disclosure of his or 
her information as described in the ICF document.  If a participant withdraws consent, some of 
the patient’s information may still be collected, used, and disclosed by those involved in this 
study, per applicable laws.  
By signing this protocol, the Investigator affirms that he or she will maintain in confidence 
information furnished to him or her by the Sponsor and will divulge such information to his or 
her respective IRB or IEC under an appropriate understanding of confidentiality with such board.  
All data will be considered the sole property of the Sponsor.  Please refer to the Clinical Study 
Agreement for details. 


 
 
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14.3. 
Study and Site Closure 
Upon completion of the study, all study data will be provided to the Sponsor following review of 
site study records for completeness, and data clarifications and resolutions.  Accounting, 
reconciliation, and final disposition of used and unused study drugs, treatment codes, and 
emergency code break envelopes will be performed, as applicable. 
In addition, the Sponsor reserves the right to temporarily suspend or prematurely discontinue this 
study at any time and for any reason.  If such action is taken, the Sponsor will discuss this with 
the Investigator (including the reasons for taking such action) at that time.  The Sponsor will 
promptly inform any other Investigators and/or institutions conducting the study, if the study is 
suspended or terminated for safety reasons and will inform the regulatory authorities of the 
suspension or termination of the study and the reason(s) for the action.  If required by applicable 
regulations, the Investigator will inform the IRB promptly and provide the study participants 
with the reason for the suspension or termination.  If the study is prematurely discontinued, all 
study data will be returned to the Sponsor.  
14.4. 
Regulatory Documents and Records Retention 
The Investigator is responsible for creating and/or maintaining all study documentation required 
by 21 CFR 50, 54, 56 and 312, ICH E6 section 8, as well as any other documentation defined in 
the protocol or Clinical Study Agreement.  The Investigator must provide key documents to the 
Sponsor prior to the start of the study.  A complete list of required regulatory documents will be 
supplied by the Sponsor or its representative. 
Federal and local regulations require that the Investigator retain a copy of all regulatory 
documents and records that support the data for this study for whichever of the following is the 
longest period of time: 
• A period of 2 years following the final date of approval by the FDA or other regulatory 
agency of the study drug for the purposes that were the patient 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 patient of the investigation. 
The Sponsor will notify Investigators once one of the above 2 timeframes has been satisfied. 
If the investigation does not result in the submission of the data in support of, or as part of, an 
application for a research or marketing permit, records must be retained for a period of 2 years 
following notification by the Sponsor that the entire clinical investigation (not merely the 
Investigator’s portion) is completed, terminated, or discontinued or 2 years following withdrawal 


 
 
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of the Investigational New Drug application/Clinical Trial Authorization or request for 
marketing approval (New Drug Application/Marketing Authorization Application).  
If the Investigator retires, relocates, or for other reasons withdraws from the responsibility of 
keeping the study records, custody must be transferred to a person who will accept the 
responsibility.  The Sponsor must be notified in writing of the name and address of the new 
custodian. Study records should not be destroyed without consultation with the Sponsor. 
14.5. 
Delegation of Responsibilities and Adequate Resources 
The Investigator should have adequate time to conduct the study properly and should have an 
adequate number of qualified staff to assist with the conduct of the study.  
The term “Investigator” used throughout this protocol refers to the principal Investigator and/or 
qualified sub-Investigators.  However, the Investigator may delegate responsibilities to other 
investigational site personnel.  The Investigator shall delegate tasks only to individuals qualified 
by education, training and experience to perform the delegated tasks.  The Investigator shall have 
direct oversight of all delegated activities and shall document delegation of responsibilities.  The 
Investigator is responsible for ensuring all delegated staff has been properly trained on the 
protocol and their assigned study responsibilities.  A delegation log identifying all delegated 
duties and the individual to whom they have been delegated will be maintained at the 
investigational site.  
14.6. 
Protocol Amendments 
Approval of a protocol amendment by the Investigator’s IRB must be obtained before 
implementation of the protocol amendment, unless a change is necessary to eliminate an 
apparent immediate hazard to the participant or when the change involves logistical or 
administrative aspects of the study.  The protocol amendment must be signed and dated by both 
the Sponsor and the Investigator.  The Sponsor or designee will submit protocol amendments to 
the appropriate regulatory authorities, if required. 
14.7. 
Financial Disclosure 
Clinical Investigators are required to provide financial disclosure information for the submission 
of certification or disclosure statements required under 21 CFR § 54. As defined in 21 CFR § 
54.2, a clinical Investigator is a listed or identified Investigator or sub-Investigator who is 
directly involved in the treatment or evaluation of research participants.  The term also includes 
the spouse and each dependent child of the Investigator.  In addition, Investigators must 
promptly update financial disclosure information if any relevant changes occur during the course 
of the investigation and for 1 year following completion of the study. 


 
 
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15. 
INVESTIGATOR PROTOCOL AGREEMENT PAGE 
A Two-Part Phase 1/2, Randomized, Double-blind, Placebo-Controlled, Adaptive 
Safety, Pharmacokinetics, and Preliminary Efficacy Study of CA-008 in Patients 
Undergoing Total Knee Arthroplasty 
 
Version: 2.0 
Date: 22 April 2020 
 
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 guidelines. 
 
Principal Investigator’s 
Name 
  
(please print or type) 
  
 
 
 
 
 
 
 
Principal Investigator’s Signature 
 
Date  
 
 


 
 
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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. Hartrick CT, Pestano C, Carlson N, Hartrick S.  Capsaicin instillation for post-operative 
pain following total knee arthroplasty: a preliminary report of a randomized, double-
blind, parallel-group, placebo-controlled, multicentre trial. Clin Drug Investig. 2011 Dec 
1;31(12):877-82. 
4. Suresh D, Srinivasan K. Tissue distribution & elimination of capsaicin, piperine & 
curcumin following oral intake in rats. Indian J Med Res. 2010;131:682-91. 
5. Surh YJ, Lee RC, Park KK, et al. Chemoprotective effects of capsaicin and diallyl sulfide 
against mutagenesis or tumorigenesis by vinyl carbamate and N-nitrosodimethylamine.  
Carcinogenesis 1995;16:2467-71. 
6. Tominaga M, Caterina MJ, Malmberg AB, Rosen TA, Gilbert H, Skinner K, Raumann 
BE, Basbaum AI, Julius D. The cloned capsaicin receptor integrates multiple pain-
producing stimuli. Neuron 21, 1998;531-43. 


 
 
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17. 
APPENDICES 
17.1. 
Appendix A: 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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17.2. 
Appendix B: American Society of Anesthesiologists Physical Status 
Classification System (ASA Class) 
 
*The addition of “E” denotes Emergency surgery: (An emergency is defined as existing when delay in treatment of 
the patient would lead to a significant increase in the threat to life or body part)  
 
Available at: https://www.asahq.org/resources/clinical-information/asa-physical-status-
classification-system 
 


 
 
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17.3. 
Appendix C: 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.)”   
 
 


 
 
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These excerpts are from various sections within CTCAE v5.0: 
 
 
 
 
 
 
 
 
 
 


 
 
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17.4. 
Appendix D: 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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17.5. 
Appendix E: Ropivacaine Dosage Recommendations 
 
 
 
 


 
 
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17.6. 
Appendix F: 0 to 10 Numerical Rating Scale of Pain Intensity (NRS) 
The NRS score is to be used to rate the pain at the knee surgical site.   
 
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 
 
Patient Initials: __________ 
 
 
 


 
 
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17.7. 
Appendix G: Assessment of Worsening (Rebound) Pain at the 
Surgical Site  
Worsening (Rebound) Pain 
Ask the patient the following question: “Have you noticed any increase in pain at the surgical site 
(worsening pain) since your last visit?” 
 
                                                     ð  yes      ð  no       
 
Patient Initials: __________ 
 
Rebound pain may also be characterized as worsening pain at the surgical site. 
 
 


 
 
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17.8. 
Appendix H: 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 
(Collins and Roos 2012). 


 
 
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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).  
 


 
 
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KOOS Scores 
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 patient avoids an activity (e.g., twisting/pivoting or going up or 
down stairs) due to doctor's orders or because the patient has chosen to avoid the activity, the patient 
should be instructed to choose “(4) Extreme” for those items. 
KOOS Sport/Rec subscale: The same as above. Also, if a patient does not normally engage in an activity 
(e.g., running or jumping), the patient 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.  
 


 
 
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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. 
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) Patientive 
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 patientive 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. 


 
 
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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 
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 patients 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 
for any number of the individual subscales, i.e. if a particular subscale is not 


 
 
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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:  
 


 
 
CA-PS-208 
 
 
Amendment 1 
 
22 April 2020 
Page 124 of 134 
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). 
 
 


 
 
CA-PS-208 
 
 
Amendment 1 
 
22 April 2020 
Page 125 of 134 
17.9. 
Appendix I: PROMIS 10 GLOBAL Health Questionnaire 
 


 
 
CA-PS-208 
 
 
Amendment 1 
 
22 April 2020 
Page 126 of 134 
 
PROMIS v.1.1 - Global 
 
Page 2 of 2 
 
 


 
 
CA-PS-208 
 
 
Amendment 1 
 
22 April 2020 
Page 127 of 134 
17.10. 
Appendix J: Knee ROM Procedure 
 
Goniometry Procedure for Knee Flexion and Extension 
• Position joint in zero position and stabilize proximal joint component. 
• For passive ROM, staff will move joint to end of range of motion (to assess quality of 
movement). 
• 
For active ROM, patient will move joint to end of range of motion (to assess quality of 
movement). 
• Determine end-feel at point where measurement will be taken (at the end of available 
range of motion). 
• Identify and palpate bony landmarks. 
• Align goniometer with bony landmarks while holding joint at end of range. 
• Read the goniometer. 
• Record measurement. 
 


 
 
CA-PS-208 
 
 
Amendment 1 
 
22 April 2020 
Page 128 of 134 
17.11. 
Appendix K: Sit to Stand Test (30-Second Chair Stand) Assessment 
 


 
 
CA-PS-208 
 
 
Amendment 1 
 
22 April 2020 
Page 129 of 134 
17.12. 
Appendix L: Walking Speed Test 
 
Walking Speed Test (or Gait Speed)  
 
Test Protocol: Measure and mark a standard distance, e.g. 5 meters (16.4 feet).   
Then measure and mark 5 feet before the start, and 5 feet after the end. 
Put cones at the starting line and the finish line. 
 
 
5 feet 
 
 
5 Meters (16.4 feet) 
 
 
5 feet 
 
 
 Starting line 
 
 
 begin timing                                             stop timing → 
 
 
Finish line → 
 
Gait Speed = distance / time    e.g.,  5 meters / __ sec. 
 
Instructions: “Walk at a comfortable pace”.   
 
Have the person perform 3 repetitions and calculate the average time.   
 
Participant’s performance:   
_________ seconds 
 
Calculated gait speed (distance/time): _________ m/sec 
 
e.g. the person takes 8.5 seconds to walk 5 meters → 5/8.5 = 0.6 m/sec  
 
Quick estimates: 10 sec = 0.5 m/s, 7 sec = 0.7 m/s, 5 sec = 1.0 m/s,  
4 sec = 1.25 m/s, 3 sec = 1.7 m/s  
 
Adapted from:  
https://geriatrictoolkit.missouri.edu › Gait-Speed 
 


 
 
CA-PS-208 
 
 
Amendment 1 
 
22 April 2020 
Page 130 of 134 
17.13. 
Appendix M: TUG Test 
 


 
 
CA-PS-208 
 
 
Amendment 1 
 
22 April 2020 
Page 131 of 134 
17.14. 
Appendix N: 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. 
 
 


 
 
CA-PS-208 
 
 
Amendment 1 
 
22 April 2020 
Page 132 of 134 
17.15. 
Appendix O: 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 
 


 
 
CA-PS-208 
 
 
Amendment 1 
 
22 April 2020 
Page 133 of 134 
17.16. 
Appendix P: Neurosensory Examination Form 
Was the neurosensory exam completed?  
___ Yes 
 ___ No 
Date of Assessment 
______________ 
Time of Assessment ___: ___ 
 
 
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. 
• Visual Examination of Surgical Site: For this examination, report any findings 
observed during visual inspection of the surgical site. 
• Light Touch Testing: For this examination, using the tip of your finger or a piece of 
cotton, briefly touch rather than stroke the patient’s skin at the location to be assessed.  
Ask the patient to close their eyes and indicate when the touch is felt. 
• 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 patient, 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.  Patient will be asked to compare sensation 
Caudad to Wound 
Visual Exam of the surgical site   ___ Normal ___ Abnormal, describe: _______________ 
Light Touch  
 
 
___ Normal ___Reduced ___ Absent 
Von Frey Stimulation 
 
___Normal ___ Reduced ___ Absent 
Brush Stimulation 
 
___ Normal ___ Reduced ___ Absent ___ Pain (Allodynia) 
Cephalad to Wound 
Visual Exam of the surgical site ___ Normal ___ Abnormal, describe: _______________ 
Light Touch  
 
 
___ Normal ___Reduced ___Absent 
Von Frey Stimulation 
 
___Normal ___ Reduced ___Absent 
Brush Stimulation 
 
___ Normal ___ Reduced ___ Absent ___ Pain (Allodynia) 


 
 
CA-PS-208 
 
 
Amendment 1 
 
22 April 2020 
Page 134 of 134 
to the control site just distal to the costal margin.  If the sensation is described as painful 
or very unpleasant then allodynia will be reported as present.  If sensation is slightly 
unpleasant or mildly irritating compared to the control area, then hyperaesthesia will be 
reported as present. If patient 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.   
 

SAP_001.pdf: 
OFFICIAL TITLE:  
STATISTICAL ANALYSIS PLAN 
A Two-Part, Phase 1/2, Randomized, Double-blind, Placebo-controlled, Adaptive Safety, 
Pharmacokinetics, and Preliminary Efficacy Study of CA-008 in Patients Undergoing Total Knee 
Arthroplasty 
 
NCT NUMBER: 
NCT04203537 
 
DOCUMENT DATE:  
12 Nov 2020 


Sponsor: Concentric Analgesics, Inc. 
 
Statistical Analysis Plan  
Protocol Number: CA-PS-208 
 
Date: 12NOV2020 
 
CONFIDENTIAL 
 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN  
 
A Two-Part, Phase 1/2, Randomized, Double-blind, Placebo-controlled, Adaptive 
Safety, Pharmacokinetics, and Preliminary Efficacy Study of CA-008 in Patients 
Undergoing Total Knee Arthroplasty 
 
Protocol Number:  CA-PS-208 
Protocol Version Amendment 1 (22APR2020) 
 
SPONSORED BY 
Concentric Analgesics, Inc. 
 
PREPARED BY 
Lotus Clinical Research®, LLC 
100 W California Blvd, Unit 25 
Pasadena, CA 91105 
626-397-2390 office 
info@LotusCR.com 
www.LotusCR.com 
 
This document is confidential and proprietary to Concentric Analgesics, Inc.  Acceptance of this document 
constitutes agreement by the recipient that no unpublished information contained herein will be reproduced, 
published, or otherwise disclosed without the prior written approval of Concentric Analgesics, Inc., except that this 
document may be disclosed to appropriate Institutional Review Boards under the condition that they keep the 
information confidential. 
 
DocuSign Envelope ID: BD9C7D20-3069-4B0B-8682-8AE9172DFD77


Sponsor: Concentric Analgesics, Inc. 
Statistical Analysis Plan  
Protocol Number: CA-PS-208 
Date: 12NOV2020 
 
CONFIDENTIAL 
 Page 2 of 64 
 
DOCUMENT VERSION CONTROL 
Version Number 
Date 
Comments/Changes 
V1.0 
21Jun2020 
SAP  
V2.0 
07Oct2020 
Update SAP After blinded TLFs 
review  
V3.0 
12Nov2020 
Update the definition of  Per-
Protocol analysis population prior 
to DBL/unblinding 
 
 
 
 
DocuSign Envelope ID: BD9C7D20-3069-4B0B-8682-8AE9172DFD77


Sponsor: Concentric Analgesics, Inc. 
Statistical Analysis Plan  
Protocol Number: CA-PS-208 
Date: 12NOV2020 
 
CONFIDENTIAL 
 Page 3 of 64 
APPROVALS 
Author: 
 
 
__________________________________  
 
 
________________ 
 
Leonid Zeitlin  
 
 
 
 
 
 
Date 
 
Biostatistician 
 
Quartesian LLC 
 
 
Reviewed: 
 
 
__________________________________  
 
 
________________ 
 
Song Liou 
 
 
 
 
 
 
 
Date 
 
Senior Biostatistician 
 
Lotus Clinical Research®, LLC 
 
 
Approved: 
 
 
__________________________________  
 
 
________________ 
 
Sam Teichman, MD  
 
 
 
 
 
Date 
 
VP, Head of Clinical Development 
 
Concentric Analgesics, Inc. 
 
 
 
 
 
__________________________________  
 
 
________________ 
 
Henry C. Foehl, PhD  
 
 
 
 
 
Date 
 
Consultant to Concentric Analgesics, Inc. 
 
Foehl Statistics & Analytics LLC 
 
 
 
DocuSign Envelope ID: BD9C7D20-3069-4B0B-8682-8AE9172DFD77
12-Nov-20
13-Nov-20
12-Nov-20
12-Nov-20


Sponsor: Concentric Analgesics, Inc. 
Statistical Analysis Plan  
Protocol Number: CA-PS-208 
Date: 12NOV2020 
 
CONFIDENTIAL 
 Page 4 of 64 
 
TABLE OF CONTENTS 
 
1. 
PURPOSE OF THE ANALYSES ..................................................................................... 9 
2. 
PROTOCOL SUMMARY ............................................................................................... 10 
2.1 
Study Objectives ................................................................................................ 10 
2.1.1 
Part A of the Study ............................................................................................. 10 
2.1.2 
Part B of the Study ............................................................................................. 10 
2.2 
Overall Study Design and Plan .......................................................................... 11 
2.2.1 
Study Assessment Schedule ............................................................................. 12 
2.2.2 
Study Population ................................................................................................ 12 
2.2.3 
Treatment Regimens ......................................................................................... 12 
2.2.4 
Treatment Group Assignments or Randomization .............................................. 17 
2.2.5 
Sample Size Determination ................................................................................ 17 
3. 
GENERAL ANALYSIS AND REPORTING CONVENTIONS .......................................... 19 
4. 
ANALYSIS POPULATIONS ........................................................................................... 21 
4.1 
Analysis Populations .......................................................................................... 21 
4.2 
Disposition of Patients ....................................................................................... 21 
4.3 
Protocol Deviations ............................................................................................ 22 
5. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ................................. 23 
5.1 
Demographics and Baseline Characteristics ...................................................... 23 
5.2 
Medical History .................................................................................................. 23 
6. 
MEASUREMENTS OF TREATMENT EXPOSURE AND COMPLIANCE ...................... 24 
7. 
EFFICACY EVALUATION ............................................................................................. 25 
7.1 
Handling of Dropouts or Missing Data ................................................................ 25 
7.2 
Efficacy Endpoints ............................................................................................. 25 
7.2.1 
Primary Efficacy Endpoint .................................................................................. 25 
7.2.2 
Key Secondary Efficacy Endpoints .................................................................... 25 
7.2.3 
Exploratory Efficacy Endpoints........................................................................... 25 
7.3 
Derivation of Efficacy Endpoints ......................................................................... 26 
7.3.1 
NRS Measurements ........................................................................................... 26 
7.3.2 
Handling of NRS Scores Post Rescue Medication Use ...................................... 27 
7.3.3 
Imputation of Missing NRS Scores ..................................................................... 29 
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Sponsor: Concentric Analgesics, Inc. 
Statistical Analysis Plan  
Protocol Number: CA-PS-208 
Date: 12NOV2020 
 
CONFIDENTIAL 
 Page 5 of 64 
7.3.4 
NRS AUC .......................................................................................................... 29 
7.3.5 
Total Opioid Consumption .................................................................................. 30 
7.3.6 
Total Non-opioid Analgesic Consumption .......................................................... 31 
7.3.7 
Knee Range of Motion (ROM) ............................................................................ 31 
7.3.8 
KOOS Questionnaire ......................................................................................... 31 
7.3.9 
Performance-based Outcome Measures (PBOMs). ........................................... 31 
7.3.10 PROMIS 10 Global Health Questionnaire Score ................................................ 32 
7.3.11 AE of Lack of Efficacy ........................................................................................ 32 
7.3.12 Discharge Readiness ......................................................................................... 32 
7.4 
Analysis Methods ............................................................................................... 32 
7.4.1 
General Considerations ..................................................................................... 32 
7.4.2 
Pooling of Data .................................................................................................. 33 
7.4.3 
Primary Efficacy Endpoint .................................................................................. 33 
7.4.4 
Other AUC Endpoints, Total Opioid Consumption, and Total Non-
opioid Analgesic Consumption Endpoints .......................................................... 36 
7.4.5 
Time to Cessation of Opioid Use ........................................................................ 37 
7.4.6 
Percentage of Patients Who Are Opioid-free ...................................................... 37 
7.4.7 
Time-specific Mean Rest NRS Scores ............................................................... 37 
7.4.8 
Knee Range of Motion (ROM) ............................................................................ 38 
7.4.9 
KOOS Questionnaire ......................................................................................... 39 
7.4.10 Performance-Based Outcome Measure (PBOM). .............................................. 39 
7.4.11 PROMIS 10 Global Health Questionnaire Scores .............................................. 39 
7.4.12 Time to Discharge Readiness ............................................................................ 40 
7.4.13 Other Binary Endpoints ...................................................................................... 40 
8. 
SAFETY EVALUATION ................................................................................................. 41 
8.1 
Overview of Safety Analysis Methods ................................................................ 41 
8.2 
Adverse Events .................................................................................................. 41 
8.2.1 
Adverse Event Summaries ................................................................................. 43 
8.2.2 
Deaths, Serious Adverse Events, Adverse Events leading to 
Withdrawal ......................................................................................................... 43 
8.3 
Clinical Laboratory Test Results ......................................................................... 44 
8.4 
Drugs of Abuse and Alcohol Screens, Pregnancy Test ...................................... 44 
8.5 
Vital Signs .......................................................................................................... 45 
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Sponsor: Concentric Analgesics, Inc. 
Statistical Analysis Plan  
Protocol Number: CA-PS-208 
Date: 12NOV2020 
 
CONFIDENTIAL 
 Page 6 of 64 
8.6 
ECG ................................................................................................................... 45 
8.7 
Physical Examination ......................................................................................... 45 
8.8 
Surgical Site Assessments ................................................................................. 46 
8.9 
Neurosensory Test ............................................................................................. 46 
8.10 
X-ray of the Operated Knee ............................................................................... 46 
8.11 
Presence of Rebound (or Worsening) Pain ........................................................ 47 
8.12 
Prior and Concomitant Medications ................................................................... 47 
8.13 
Patient Pain Assessment Training and Surgery Details...................................... 47 
9. 
PHARMACOKINETIC EVALUATION ............................................................................ 48 
10. 
OTHER ANALYSES ...................................................................................................... 49 
11. 
DEVIATIONS FROM THE SAP ..................................................................................... 50 
12. 
CHANGES IN CONDUCT OR PLANNED ANALYSES FROM THE 
PROTOCOL .................................................................................................................. 51 
13. 
EXAMPLE SAS CODE .................................................................................................. 52 
14. 
REFERENCES .............................................................................................................. 54 
15. 
APPENDICES ............................................................................................................... 55 
15.1 
Scoring of KOOS Questionnaire ........................................................................ 55 
15.2 
Scoring of PROMIS 10 Questionnaire ................................................................ 55 
15.3 
Planned Tables, Figures, and Listings ............................................................... 57 
15.3.1 Tables ................................................................................................................ 57 
15.3.2 Figures ............................................................................................................... 61 
15.3.3 Listings .............................................................................................................. 62 
16. 
DOCUMENT HISTORY ................................................................................................. 64 
 
 
 
LIST OF IN-TEXT TABLES 
Table 1. 
Schedule of Assessments – Part A and Part B .............................. 13 
 
 
 
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Sponsor: Concentric Analgesics, Inc. 
Statistical Analysis Plan  
Protocol Number: CA-PS-208 
Date: 12NOV2020 
 
CONFIDENTIAL 
 Page 7 of 64 
LIST OF ABBREVIATIONS 
AC 
Analgesic Consumption 
ADaM 
Analysis Data Model 
ADL 
Actives of Daily Living 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
ANOVA 
Analysis of Variance 
ATC 
Anatomical Therapeutic Chemical 
AUC 
Area Under the Curve 
BMI 
Body Mass Index 
CI 
Confidence Interval 
CMH 
Cochran-Mantel-Haenszel 
CRO 
Clinical Research Organization 
CSR 
Clinical Study Report 
 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
ET 
Early Termination 
FDA 
Food and Drug Administration 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization  
IV 
Intravenous 
KOOS 
Knee injury and Osteoarthritis Outcome Score 
LOCF 
Last Observation Carried Forward 
LOE 
Lack of Efficacy 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified Intent-to-treat 
NRS 
Numerical Rating Scale for Pain Intensity  
DocuSign Envelope ID: BD9C7D20-3069-4B0B-8682-8AE9172DFD77


Sponsor: Concentric Analgesics, Inc. 
Statistical Analysis Plan  
Protocol Number: CA-PS-208 
Date: 12NOV2020 
 
CONFIDENTIAL 
 Page 8 of 64 
OC 
Opioid Consumption in oral morphine equivalents (Sec 7.3.6) 
OF 
Opioid-free  
OME 
Oral Morphine Equivalent  
PACU 
Post-anesthesia Care Unit 
PBOM 
Performance-based Outcome Measure 
PE 
Physical Examination 
PI 
Principal Investigator 
PK 
Pharmacokinetic 
PO 
Per Os (orally) 
PP 
Per Protocol 
PRO 
Patient-reported Outcome 
PT 
Preferred Term 
QOL 
Quality of Life 
ROM 
Range of Motion 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SDTM 
Standard Data Table Model 
SE 
Standard Error 
SOC 
System Organ Class 
TEAE 
Treatment Emergent Adverse Event 
TFLs 
Tables, figures, and listings 
TKA 
Total Knee Arthroplasty 
WHO  
World Health Organization 
wLOCF 
Windowed Last Observation Carried Forward 
 
 
 
DocuSign Envelope ID: BD9C7D20-3069-4B0B-8682-8AE9172DFD77


Sponsor: Concentric Analgesics, Inc. 
Statistical Analysis Plan  
Protocol Number: CA-PS-208 
Date: 12NOV2020 
 
CONFIDENTIAL 
 Page 9 of 64 
1. PURPOSE OF THE ANALYSES 
This statistical analysis plan (SAP) is based on protocol number CA-PS-208 Amendment 1 
(22APR2020) from Concentric Analgesics, Inc.  
This SAP is written with due consideration of the recommendations outlined in the most recent 
International Conference on Harmonisation (ICH) Efficacy Guideline E9, Statistical Principles for 
Clinical Trials, and the most recent ICH Efficacy Guideline E3, Structure and Content of Clinical 
Study Reports. 
Presented in this SAP are the details of the specific statistical methods that will be employed in 
the summary and analysis of data from study CA-PS-208. 
 
 
DocuSign Envelope ID: BD9C7D20-3069-4B0B-8682-8AE9172DFD77


Sponsor: Concentric Analgesics, Inc. 
Statistical Analysis Plan  
Protocol Number: CA-PS-208 
Date: 12NOV2020 
 
CONFIDENTIAL 
 Page 10 of 64 
2. PROTOCOL SUMMARY 
This is a two-part, Phase 1/2 study in patients undergoing total knee arthroplasty (TKA); in each 
part, patients receive, in randomized, double-blind fashion, administration of a single dose of 
CA-008 or placebo infiltrated/instilled during surgery.  In Part A, 3 exploratory sequential dose-
escalation cohorts will be evaluated; in Part B, 2 active dose levels of CA-008 will be evaluated 
compared to placebo in a parallel-group design. 
2.1 
Study Objectives 
2.1.1 Part A of the Study 
2.1.1.1 Primary Objective 
• 
Evaluate the safety and tolerability of a single intraoperative administration of either 
CA-008 or placebo in patients undergoing an elective TKA. 
2.1.1.2 Secondary Objectives 
• 
Evaluate the pharmacokinetic (PK) profile of a single intraoperative administration of 
CA-008 in patients undergoing an elective TKA. 
• 
Evaluate, preliminarily, the effect of CA-008 with respect to patients’ self-reported pain, 
opioid consumption (OC), patient-reported outcomes (PROs), performance-based 
outcome measures (PBOMs), and range of motion (ROM). 
• 
Determine the dose(s) for testing in Part B. 
2.1.2 Part B of the Study  
2.1.2.1 Primary Objective 
• 
Evaluate, during a specified post-operative time interval, the efficacy of 2 selected doses 
of CA-008 with respect to self-reported pain in patients undergoing an elective TKA. 
2.1.2.2 Secondary Objectives 
• 
Evaluate, during specified additional post-operative time intervals, the efficacy of 3 
selected doses of CA-008 with respect to self-reported pain in patients undergoing an 
elective TKA. 
• 
Evaluate the effect of CA-008 on opioid consumption. 
DocuSign Envelope ID: BD9C7D20-3069-4B0B-8682-8AE9172DFD77


Sponsor: Concentric Analgesics, Inc. 
Statistical Analysis Plan  
Protocol Number: CA-PS-208 
Date: 12NOV2020 
 
CONFIDENTIAL 
 Page 11 of 64 
• 
Evaluate the effect of CA-008 on PROs. 
• 
Evaluate, preliminarily, the effect of CA-008 on PBOMs and ROM. 
• 
Evaluate the safety and tolerability of CA-008 or placebo in patients undergoing an 
elective TKA. 
• 
Evaluate the PK profile of a single intraoperative administration of CA-008 in patients 
undergoing an elective TKA. 
2.2 
Overall Study Design and Plan 
In Part A, of this two-part, Phase 1/2 study, 3 exploratory sequential dose-escalation cohorts will 
be evaluated, each with administration of a single dose of CA-008 or placebo infiltrated/instilled 
during surgery in patients undergoing TKA.   
During Part A, patients were randomized in a 3:1 ratio, active to placebo.  Dose escalation, dose 
reduction, or cohort expansion decisions were made by the Sponsor’s medical monitor, the 
CRO’s medical monitor, and a designated Principal Investigator (PI) after reviewing blinded 
safety data.   
In Part B, 2 active dose levels (36 mg and 60 mg) of CA-008 will be evaluated compared to 
placebo in a randomized, double-blind, parallel-group design.  
For each patient, the study was to be conducted in two periods: 
• 
Inpatient period, which continues from check-in on Day 1 (D1) until discharge (4 days or 
96 hours [h] following surgery [T96 ± 4 h], [D5]). 
• 
Outpatient period, which begins on discharge from the inpatient unit through follow up 
visits to D29 + 2 days.  Note that additional follow up visits may occur at any time or 
even after D29 to follow AEs to resolution or to establish a new baseline. 
During the inpatient period, patients undergo TKA and administration of study drug (CA-008 or 
placebo) followed by serial assessments of safety, PK, and drug effect, in particular focusing on 
patients’ self-reported pain using a numeric rating scale (NRS) for pain intensity and patients’ 
self-expressed need for analgesia.  During the outpatient period, serial assessments of safety 
and drug effect are performed; safety and drug effect assessments focus on patients’ self-
reported pain and need for analgesia. 
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Sponsor: Concentric Analgesics, Inc. 
Statistical Analysis Plan  
Protocol Number: CA-PS-208 
Date: 12NOV2020 
 
CONFIDENTIAL 
 Page 12 of 64 
Each patient is expected to be in the study for approximately 76 days from screening to the D29 
+ 2 days visit; this period could be longer to permit following any AE to resolution or the 
establishment of a new baseline.  
As per the protocol, after the 3rd cohort of Part A was enrolled, a safety review was conducted 
by site investigators, the medical monitor of the CRO, and the sponsor’s medical monitor.  Part 
A included 3 cohorts with dose levels 36 mg (0.3 mg/mL), 60 mg (0.5 mg/mL), and 90 mg (0.75 
mg/mL) of CA-0008 or placebo.   
Also, as per the protocol, a decision was made to progress to Part B of the study.  Part B will 
include 3 parallel, blinded arms: 36 mg of CA-008 (0.3 mg/mL), 60 mg (0.5 mg/mL) of CA-008, 
and placebo. Up to 201 patients will be randomized to Part B in a 1:1:1 ratio with ~67 patients in 
each arm.  See Section 2.2.5 below for sample size considerations. 
2.2.1 Study Assessment Schedule 
The Schedule of Assessments is presented in Table 1 below.  Note: Time 0 (T0) is further 
defined for analyses in Section 3. 
2.2.2 Study Population 
The study population consists of adults, aged 18-80 years old inclusive, who are planning to 
undergo an elective unilateral TKA and meet the eligibility criteria described in Sections 8.2.1 
and 8.2.2 of the study protocol. 
2.2.3 Treatment Regimens 
Part A:   
Cohort #1: CA-008 36 mg vs. placebo in 120 mL of vehicle (0.3 mg/mL) 
Cohort #2: CA-008 60 mg vs. placebo in 120 mL of vehicle (0.5 mg/mL) 
Cohort #3: CA-008 90 mg vs. placebo in 120 mL of vehicle (0.75 mg/mL) 
Part B: 
Doses were selected based on safety and tolerability data from Part A and from prior studies of 
CA-008.  The selected doses are: 
Arm #1: CA-008 36 mg in 120 mL of vehicle (0.3 mg/mL) 
Arm #2: CA-008 60 mg in 120 mL of vehicle (0.5 mg/mL) 
Arm #3: Placebo (120 mL of vehicle) 
 
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Table 1. Schedule of Assessments – Part A and Part B 
Study Period 
Screening 
Inpatient 
Follow-Up Clinic Visits 
Unscheduled 
Visit1 
Early 
Termination19 
Day of 
Surgery 
Surgery 
Post-
Surgery 
T24 
T48 
T72 
T96 
± 4 h 
Study Day 
D -45 to 
Day Prior 
to 
Surgery 
D1 
(prior to 
surgery) 
D1 
D1 
D2 
D3 
D4 
D5 
D8 + 
1 day 
D15 + 
2 
days 
D29 + 
2 
days 
Assessment 
Informed Consent 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Screening Medical and 
Surgical History 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Screens for 
alcohol/drugs of abuse 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Patient Pain Assessment 
Training 
X2 
X2 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test  
(or FSH if post-
menopausal) 
X3 
(serum) 
X3 
(urine) 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs (supine) 
X 
X 
 
X4 
X4 
X4 
X4 
X4 
X 
X 
X 
X 
X 
Temperature (oral) 
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 
 
 
 
 
 
 
 
 
Enroll/Randomize 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Surgery 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Study treatment 
 
 
X 
 
 
 
 
 
 
 
 
 
 
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Statistical Analysis Plan  
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Date: 12NOV2020 
CONFIDENTIAL 
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Study Period 
Screening 
Inpatient 
Follow-Up Clinic Visits 
Unscheduled 
Visit1 
Early 
Termination19 
Day of 
Surgery 
Surgery 
Post-
Surgery 
T24 
T48 
T72 
T96 
± 4 h 
Study Day 
D -45 to 
Day Prior 
to 
Surgery 
D1 
(prior to 
surgery) 
D1 
D1 
D2 
D3 
D4 
D5 
D8 + 
1 day 
D15 + 
2 
days 
D29 + 
2 
days 
Assessment 
Infiltration/instillation 
Admission to PACU 
 
 
 
T0nrs 
 
 
 
 
 
 
 
 
 
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 
Concomitant Medication 
Assessment 
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 
Patient home diary 
record (NRS) 
 
 
 
 
 
 
 
X11 
X11 
X11 
 
 
X11 
Paper/Electronic Diary 
(review, distribution 
and/or collection) 
 
 
 
 
 
 
 
X12 
X12 
X12,13 
 
 
X13 
Patient home diary 
(analgesic consumption) 
 
 
 
 
 
 
 
X 
X 
X13 
 
 
X 
Prescription for 
outpatient opioid rescue 
 
 
 
 
 
 
 
X14 
 
 
 
 
 
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Date: 12NOV2020 
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Study Period 
Screening 
Inpatient 
Follow-Up Clinic Visits 
Unscheduled 
Visit1 
Early 
Termination19 
Day of 
Surgery 
Surgery 
Post-
Surgery 
T24 
T48 
T72 
T96 
± 4 h 
Study Day 
D -45 to 
Day Prior 
to 
Surgery 
D1 
(prior to 
surgery) 
D1 
D1 
D2 
D3 
D4 
D5 
D8 + 
1 day 
D15 + 
2 
days 
D29 + 
2 
days 
Assessment 
if needed 
PROMIS 10 Global 
questionnaire 
X 
 
 
 
 
 
 
 
 
X 
X 
 
 
KOOS Survey 
X 
 
 
 
 
 
 
X 
X 
X 
X 
 
X 
Knee ROM 
X 
 
 
 
 
 
X 
X 
X 
X 
X 
 
X 
Ability to walk > 100 ft 
(> 30 m) 
 
 
 
 
 
X 
X 
X 
 
 
 
 
 
PBOMs15 
 
 
 
 
 
 
 
X 
 
X 
X 
 
 
Blood draw for PK 
analysis 
 
X16,17 
 
X16 
X16 
 
 
 
 
 
 
 
 
Worsening (rebound) 
pain 
 
 
 
 
 
 
 
 
X18 
X18 
X18 
 
X18 
Knee x-ray 
 
 
 
 
 
 
 
 
 
 
X20 
 
X20 
1 
Unscheduled visits may occur at any time and assessments are to be completed at the Investigator’s discretion. 
2 
Pain assessment training with test during screening; re-watch 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 after T0 at 2, 6, 12, 24, and every 8 hours thereafter (if awake at time of assessment between the hours of 12:00 AM and 6:00 
AM) 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, and a physical examination to capture changes after Surgery, at 96 hours (± 4 hours) after T0, but 
prior to discharge, and D8, D15, and D29 after T0 or if the patient terminates early, at that time if allowed.  Body weight (kg), in indoor clothing, but without shoes, will be 
measured at Screening and at T96 hours.  Height (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 T0. 
7 
Surgical Site assessment: 96 hours (± 4 hours after T0 but prior to discharge from the inpatient unit) and D8, 15, and 29. 
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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 D8, 
D15, and D29 after T0 or if the patient 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 T96 is ± 4 hours). 
10 
During the inpatient stay, NRS at rest beginning with the PACU admission (T0nrs) may be assessed once the patient is awake. If the patient is able to provide responses, obtain 
NRS scores at T0nrs, T0nrs plus 1 hour (T1), T0nrs plus 2 hours (T2, etc.), T4, T6, T8, T12, T16, T20, T24, and every 4 hours (if awake at time of assessment) until discharge from the 
inpatient unit. Time windows: for T1 to T2 (± 5 min) and from T4 onward (± 15 min).  Scheduled NRS scores must be recorded regardless of timing of pre-rescue medication NRS 
scores and administration of rescue medication.  The actual time of all NRS scores must be recorded, i.e., not the nominal time.  During the inpatient stay, evoked NRS twice 
daily after physical therapy (most preferred) or ambulation for approximately 10 yards (preferred) or transfers to/from bed or wheelchair.  Obtain these NRS scores after 
morning physical therapy or ambulation at 10:00 AM (± 1 h) and after afternoon physical therapy or ambulation at 4:00 PM (± 1 h).  During the inpatient stay, pain scores may 
be skipped between the hours of midnight and 6:00 AM, but the patient may not miss two consecutive assessments.  The T12, T24, T48, T72, and T96 assessments must be 
completed even if the patient must be awakened at these times.  During the inpatient stay, an additional NRS assessment must be obtained within 5 minutes prior to IV rescue 
medication administration and within 15 minutes prior to oral rescue medication administration.  During the outpatient period, (after T96 and through D15), instruct the 
patient to document their NRS scores twice daily at 11:00 AM (± 4 h) and 7:00 PM (± 4 h) at rest and during 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.  Instruct the patient to: 
• 
Obtain the morning NRS assessment prior to taking any pain medication or at least 2 hours after taking any pain medication. 
• 
Obtain the evening NRS assessment at least 2 hours after taking any pain medication. 
• 
Opioid and non-opioid rescue medication (dose, date, time) must be recorded in the diary through D15, including a pre-rescue NRS score. 
11 
The patient is expected to document NRS pain scores at rest and on ambulation 2 ×/day through D15 (at the times and qualifications noted above).   
12 
The diary and instructions are provided to the patient prior to discharge (T96).  At each subsequent visit, review Patient Diary instructions with patient and collect the patient’s 
NRS scores and other study-related assessments. 
13 
Collect Patient Diary Data.  
14 
If the patient continues to require opioids during the 12 hours prior to discharge (any time from T84 h onward), then write a prescription for no more than 9 tablets of 
acetaminophen 325 mg/oxycodone 5 mg (Percocet) one or two tablets PO Q 4-6 h PRN per Investigator discretion.   
15 
PBOMs: Sit to Stand Test, Walking Speed Test, TUG. 
16 
Collect blood samples for PK.  The time points for whole blood collection will be at pre-dose (from check-in and up to 30 minutes before the start of surgery), and at PKT 0.167 
(10 min), 0.25 (15 min), 0.5 (30 min), 0.75 (45 min), and at 1, 1.5, 2, 3, 4, 6, 8, 12, 16, and 24 hours after last study treatment instillation (total of 15 samples). There will be a ± 
2-minute window allowed for the 10- to 15-minute collections, a ± 5-minute window allowed for collections at 30 minutes through 4 hours, and a ± 15-minute window for 
collections after 4 hours.  In the event of an AE, an unscheduled PK draw will be performed. 
17 
Patients must abstain from foods containing capsaicin for 24 hours prior to surgery. 
18 
Assess for presence of worsening (rebound) pain at the surgical site (yes/no response). 
19 
If the patient terminates early, complete all procedures listed, as appropriate. 
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 patient gives 
consent. 
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2.2.4 Treatment Group Assignments or Randomization 
In Part A of the study, 3 exploratory, sequential, dose-escalation cohorts were evaluated.  For 
each cohort, patients meeting the enrollment criteria were randomly allocated to receive either 
active drug or placebo in a 3:1 ratio using a block size of 4.  Eight patients were randomized in 
each cohort with no more than 4 patients dosed per week.  The total sample size in Part A was 
24 patients.  
In Part B, a block randomization for each site is used with a block size of 9 patients.  
Treatment assignments are determined by a computer-generated randomization schedule.  
Once any patient number or randomization number is assigned, it cannot be reassigned to any 
other patient. 
2.2.5 Sample Size Determination 
In Part A, no formal statistical hypothesis testing will be performed.  The sample size of 8 initial 
patients per dose level was selected based on prior clinical trial experience with CA-008 and 
considered sufficient for exploration of tolerability and safety parameters, establishment of a PK 
profile, and preliminary assessment of the efficacy of CA-008 in postoperative analgesia. 
In Part B, assuming a t-test for the difference in 2 independent means, a sample of 62 
patients per group would provide approximately 80% power to detect a treatment difference 
equivalent to an effect size (Cohen’s d) of 0.45 at a 1-sided level of significance, alpha, of 
0.05 in the primary efficacy endpoint, which is the area under the NRS versus time curve, 
NRS AUC12-96.  Because this is a proof-of-concept study, in which a decrease in mean NRS 
AUC12-96 for active treatment compared to placebo is postulated, a 1-sided test is specified for 
the sample size estimate. 
Assuming that for each of the 3 study arms (36 mg, 60 mg, and placebo) in the final primary 
endpoint efficacy analysis, an additional 5 patients per study arm should be enrolled to account 
for dropouts or unevaluable patients, the target sample size per study arm in Part B is 67 
patients, resulting in a total target sample size for the final efficacy analysis of 201 patients. 
Since it is intended that data for Part A will remain blinded until Part B is unblinded, data 
collected for both Part A and Part B patients will be pooled for final analyses as appropriate.  
Anticipating that pooling of Part A and Part B data will occur for the final efficacy analysis, and 
that the data for 6 patients from each of cohorts 1 and 2 of Part A that received active drug and 
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6 patients overall from cohorts 1, 2 and 3 that received placebo will be available for pooling, the 
target enrollment for Part B may be reduced to 183 patients, if warranted. 
 
 
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3. GENERAL ANALYSIS AND REPORTING CONVENTIONS 
General analysis and reporting conventions to be employed for study CA-PS-208 data are 
described below.  If departures from these conventions are appropriate, details will be 
presented in the relevant sections of this SAP. 
Continuous variables will be summarized by treatment group and time point (as applicable) 
using descriptive statistics: number of patients (n); mean; standard deviation (SD); median; and 
range (minimum and maximum).  Categorical variables will be summarized by treatment group 
and time point (as applicable) using frequency counts (n) and rates of occurrence (%).  
Changes from baseline for continuous variables will be presented as their corresponding 
continuous measures for post-baseline visits as applicable.  All study data will be listed by 
treatment group, patient, and time point (as applicable).  
Unless specified otherwise, in the analysis of categorical variables, the denominator for 
percentages will be the number of patients in the appropriate analysis population and treatment 
group who have a non-missing value of the categorical variable. 
No preliminary rounding of numeric data values will be performed; rounding will only occur after 
the completion of an analysis when data or calculation results are to be displayed.  Means and 
medians will be presented to one more decimal place than the number of decimal places 
recorded in the data.  Standard deviations will be presented to two more decimal places than 
the number of decimal places recorded in the data.  Percentages will be presented to one 
decimal place.  A percentage of 100 calculated to any number of decimal places will be reported 
as 100%; a percentage of 0 calculated to any number of decimal places will be reported as 0.  
Minimums and maximums will be presented with the same number of decimal places as the 
original data. 
Statistical testing including p-values and confidence intervals (CIs) will be presented as 
described in each section below.  Tests of statistical significance will be 1-sided or 2-sided at 
the 0.05 level of significance depending on the endpoint being tested, as specified below.  In 
particular, a 1-sided test of significance is specified for the primary analysis of the primary 
endpoint, NRS AUC12-96, because this is a proof-of-concept study in which a decrease in mean 
NRS AUC12-96 for active treatment compared to placebo is postulated. 
Because preliminary assessments of efficacy are the focus of efficacy analyses, no adjustments 
in the level of significance will be made for multiple comparison tests. 
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All analyses will be performed using SAS® version 9.3 or higher. The domain (Study data 
tabulation Model [SDTM]) and analysis (Analysis Data Model [ADaM]) data sets will be source 
of input to the SAS programs that generate the submission-ready tables, figures, and listings 
(TFLs). Submission-ready SDTM and ADaM data sets, define files, reviewer’s guide, and Open 
CDISC reports will be provided to the sponsor in addition to the TFLs.  
The following conventions will be used in the study analysis as needed for calculations: 
• 
Time 0 for safety assessments (T0) is the start time of study drug administration. 
• 
Time 0 for efficacy assessments (T0nrs) is the time of admission into the post-anesthesia 
care unit (PACU). 
• 
Time 0 for PK assessments (T0pk) is the stop time of study drug administration. 
• 
Day of surgery/study drug administration is defined as Day 1. 
• 
Elapsed assessment visit times are defined by time elapsed from the corresponding 
Time 0 (T0, T0nrs, or T0pk) or D1. 
• 
The baseline value of any parameter is defined as the most recent valid measurement of 
that parameter prior to the beginning of Time 0 (T0, T0nrs, or T0pk). 
• 
The change from baseline value of a parameter is defined as the post-baseline value 
minus the baseline value. 
• 
Duration of an AE will be computed in days for AEs lasting 24 or more hours, and as 
hours for AEs lasting less than 24 hours.  
 
 
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4. ANALYSIS POPULATIONS 
4.1 
Analysis Populations 
The following analysis populations will be used in this study:  
• 
Safety Population—consists of all patients who received any part of a dose of study 
treatment.  Patients in the Safety Population will be analyzed as treated. 
• 
PK Population—consists of all patients who received a full dose of study treatment and 
completed at least one PK assessment. Patients in the PK Population will be analyzed 
as treated. 
• 
Modified Intent-to-treat (mITT) Population—consists of all patients who were randomized 
and received any dose of study treatment.  Patients in the mITT Population will be 
analyzed as randomized. 
• 
Per Protocol (PP) Population—consists of all patients who received a full dose of study 
treatment and have evaluable NRS pain assessments at the T12, T24, T48, T72, and 
T96 timepoints and no two consecutive missing assessments among the other 
scheduled timepoints prior to T96.  Missing scheduled assessments after the T96 
timepoint will not exclude patients from the PP population.  Patients included in the PP 
Population must not have any major protocol deviations. Patients in the PP Population 
will be analyzed as treated. 
• 
Study Completers—consists of all patients in the mITT population who completed the 
entire study period through D29 + 2 days, whether or not they have complete sets of 
NRS scores. 
Analysis populations will be determined before the study data are unblinded for analysis.  
Efficacy analyses will be performed using the mITT and PP populations as detailed below.  
Safety analyses will be performed using the Safety population.  PK analyses will be performed 
using the PK population.  
4.2 
Disposition of Patients 
All patients and the analysis populations for which they qualify for inclusion will be presented in 
the listings.  Patients who are screened and who fail screening or withdraw consent prior to 
randomization or are randomized but not treated will be presented in a listing and included in 
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the patient disposition summary table.  Patients who are randomized, patients who are included 
in each study population, patients who are treated, patients who complete the study, and 
patients who withdraw early from the study and the reason for withdrawal, will be included by 
study part and by treatment group and overall in the patient disposition summary table. 
4.3 
Protocol Deviations 
Deviations from the study protocol will be categorized as deviations from protocol-specified 
requirements regarding: informed consent procedures; inclusion/exclusion criteria; study 
medication; prohibited medications; study procedures; study drug assignment/treatment; visit or 
assessment time windows; missed visits or assessments; and, other.  All protocol deviations will 
be captured on the electronic case report forms (eCRFs) and/or documented in site specific logs 
throughout the study.  Deviations will be categorized as described above and classified as major 
or minor by the Sponsor and the medical monitor after database lock but before the unbinding of 
study data for analysis.  Major protocol deviations will be discussed in the clinical study report 
(CSR).  In general, major protocol deviations are deviations from the study protocol that may 
significantly impact the completeness, accuracy, and/or reliability of the study data or that may 
significantly affect a patient's rights, safety, or well-being.  The number of patients with protocol 
deviations, both minor and major, will be presented for the Safety population in a data listing 
and will be summarized by category of deviation and major/minor classification. 
NOTE: In March 2020, the FDA issued guidance on the conduct of clinical trials during the 
COVID-19 pandemic to assure the safety of trial participants and to maintain study compliance 
with GCP.  The FDA provided information on alternative methods to complete serial, non-
invasive study assessments that allow compliance with local shelter-in-place considerations, 
e.g., phone contact or virtual visit using video chat/conferencing. 
Unavoidable protocol deviations involving study procedure scheduling delays, early or missed 
visits and missing information will result due to the COVID-19 situation.  In general, if a study 
procedure is completed, it will not be considered a protocol deviation, even if it is completed 
remotely, out-of-window, or using alternative methods.  If a procedure cannot be completed and 
results in missing data, it will be considered a protocol deviation.   
 
 
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5. DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
5.1 
Demographics and Baseline Characteristics 
Demographic variables include age, sex, race, and ethnicity.  Baseline characteristics include 
height (cm), weight (kg), and body mass index (BMI; kg/m2).  Demographic variables and 
baseline characteristics will be summarized overall and by treatment group for the Safety 
population.  
5.2 
Medical History 
Medical history will include acute, chronic, or infectious disease history; surgical or oncologic 
history; and any reported conditions affecting major body systems.  Medical events that occur 
prior to the study procedure (i.e., initiation of any surgery or anesthesia-related procedure) will 
be categorized as medical history.  All findings in a patient’s medical history will be evaluated by 
the Investigator for their potential effect on a patient’s eligibility for study participation.  Medical 
history will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) version 
22.1 and presented for the Safety population in a summary table of the number and percentage 
of occurrences, within treatment groups and overall, by System Organ Class (SOC) and 
Preferred Term (PT).  Patients will only be counted once for each SOC and PT. 
Medical histories will also be presented in a by-patient listing.  
 
 
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6. MEASUREMENTS OF TREATMENT EXPOSURE AND COMPLIANCE 
Because study medication is administered as a single dose at the study center by trained study 
personnel, patient compliance with respect to study medication administration will not be 
calculated.  A by-patient listing of study drug administration and exposure data will be provided.  
Individual instances of incomplete or problematic study medication delivery will be noted as 
protocol deviations. 
Descriptive statistics (n, mean, standard deviation, median, minimum, and maximum) for the 
volume (mL) of study drug administered will be presented for the Safety population in a 
summary table by treatment group, overall active treatment group, and overall. 
 
 
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7. EFFICACY EVALUATION 
The analysis of the primary endpoint and key secondary endpoints will be performed for the 
mITT and PP populations. The analysis of the exploratory efficacy endpoints will be performed 
for the mITT population only. 
7.1 
Handling of Dropouts or Missing Data 
Imputation of missing data, where appropriate, will be performed as indicated in this SAP for a 
given analysis; in particular, imputation of missing NRS scores is discussed in detail in section 
7.3.3.  Any spurious or erroneous data will be queried and followed up until satisfactorily 
resolved; if not resolvable, the data will be set to missing.  Study procedures have been 
designed to minimize opportunities for data not to be captured as planned, hence missing data 
will be considered to be missing at random.  
7.2 
Efficacy Endpoints 
7.2.1 Primary Efficacy Endpoint 
• 
Rest NRS AUC from T12 to T96: AUC12-96 
7.2.2 Key Secondary Efficacy Endpoints 
• 
Evoked NRS AUC from T12 to T96: AUC12-96 (ambulation) 
• 
Patient does not require opioids, i.e., patient is opioid-free (OF), from T24 to T96: OF24-96 
• 
Total opioid consumption (OC), in oral morphine equivalent (OME) dose, from T12 to 
T96: OC12-96 
• 
Rest NRS AUC from T12 to D8: AUC12-D8 
• 
Evoked NRS AUC from T12 to D8: AUC12-D8 (ambulation) 
7.2.3 Exploratory Efficacy Endpoints 
• 
Rest NRS AUC for the indicated time intervals: AUC0-24, AUC0-96, AUC6-96, AUC24-96, 
AUC96-D8, and AUC96-D15 
• 
Evoked NRS AUC for the indicated time intervals: AUC0-96 (ambulation), AUC0-D8 (ambulation), 
AUC24-D8 (ambulation), and AUC96-D15 (ambulation) 
• 
Rest NRS scores at T48, T72, T96, T120, T144, and T168 
• 
Total opioid consumption (OC), in oral morphine equivalent (OME) dose, for the 
indicated time intervals: OC0-96, OC24-48, OC24-72, OC24-96, OC24-D8, and OC24-D15 
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Date: 12NOV2010 
 
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• 
Patient does not require opioids, i.e., patient is opioid-free (OF), for the indicated time 
intervals: OF0-96, OF24-96, OF24-D15, OF96-D8, and OF96-D15 
• 
Time to cessation of opioid use 
• 
Knee ROM at T48 (± 4 h), T96 (± 4 h)/Discharge, D8, D15, and D29: active and passive 
flexion; active and passive extension 
• 
Change in KOOS score from Screening to D8, D15, and D29 
• 
Change in KOOS score from T96 to D8, D15, and D29 
• 
PBOM scores (Sit to Stand, Walking Speed Test, TUG) at T96 (± 4 h)/Discharge, D15, 
and D29 
• 
Patient required rescue medication for the indicated time intervals: T0nrs -T6, T6-T12, 
T12-T24, T24-T48, T48-T72, and T72-T96 
• 
Total non-opioid analgesic consumption (AC), i.e., rescue acetaminophen use for the 
indicated time intervals: AC96-D8 and AC96-D15 
• 
Change in PROMIS 10 Global Health questionnaire score from Screening to D15 and 
D29 
• 
Patient experienced an AE of lack of efficacy (LOE) during the inpatient period: LOE0-96 
• 
Discharge readiness at T24 (± 4 h), T48 (± 4 h), T72 (± 4 h), and T96 (± 4 h)/Discharge 
• 
Time to first occurrence of discharge readiness 
7.3 
Derivation of Efficacy Endpoints 
7.3.1 NRS Measurements 
At designated times during the study following the administration of study treatment, patients 
were to have reported or recorded their pain intensity at the time of assessment as follows: 
• 
During the inpatient stay, beginning at PACU admission, NRS at was to have been 
assessed once the patient was awake.  T0nrs is the time of admission into the PACU.  If 
the patient was able to provide responses, NRS scores were to be obtained at T0nrs plus 
1 hour (T1), T0nrs plus 2 hours (T2, etc.), T4, T6, T8, T12, T16, T20, T24, and every 
4 hours thereafter (if the patient was awake at the scheduled time of assessment) until 
discharge from the inpatient unit.  Time windows: ± 5 minutes for T1 and T2; ± 15 
minutes for T4 onward.  Scheduled NRS scores were to be recorded regardless of 
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timing of pre-rescue medication NRS scores and administration of rescue medication.  
The actual time, not the nominal time, of all NRS scores was to be recorded. 
• 
During the inpatient stay, evoked NRS twice daily was to be recorded after physical 
therapy (most preferred) or ambulation for approximately 10 yards (preferred) or 
transfers to/from bed or wheelchair.  These NRS scores were to be obtained after 
morning physical therapy or ambulation at 10:00 AM (± 1 h) and after afternoon physical 
therapy or ambulation at 4:00 PM (± 1 h). 
• 
During the inpatient stay, pain scores may have been skipped between the hours of 
12:00 AM and 6:00 AM, but the patient was not to have missed two consecutive 
assessments.  The T12, T24, T48, T72, and T96 assessments were to have been 
completed even if the patient had to be awakened at those times. 
• 
During the inpatient stay, an additional NRS assessment was to have been obtained 
within 5 minutes prior to IV rescue medication administration and within 15 minutes prior 
to oral rescue medication administration. 
• 
During the outpatient period (after T96, and through D15), patients were to be instructed 
to document their NRS scores twice daily at 11:00 AM (± 1 h) and 7:00 PM (± 1 h) at rest 
and during ambulation (e.g., with the use of a walker or a cane) for approximately 
10 yards.  Note that the actual time of these assessments was to have been 
documented in the diary whenever possible.  Patients were also to have been instructed 
to record pre-rescue NRS scores. 
7.3.2 Handling of NRS Scores Post Rescue Medication Use 
When rescue medication was used, any scheduled rest NRS assessment is censored if the 
assessment was taken within:  
• 
30 minutes after the start of IV fentanyl; 
• 
2 hours after the start of IV hydromorphone (from T0-T24); 
• 
4 hours after the administration of PO opioids.  
If other opioid rescue medications are used, other censoring intervals will be documented, e.g., 
3 hours after the start of IV morphine.  In the special case of the use of IV hydromorphone after 
T24 (defined as an adverse event of lack of efficacy), scheduled rest NRS assessments will be 
censored for 8 hours after the start of dosing.  Censored NRS assessments will be replaced by 
imputed values in summaries, derivations, and analyses as described below. 
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For patients who take rescue medication a ‘windowed’ last NRS score carried forward (wLOCF) 
will be used in the calculation of the rest NRS AUC.  Specifically, the most recent NRS score 
obtained prior to the administration of rescue medication, whether that score is the pre-rescue 
NRS assessment or a scheduled NRS assessment, will be used to impute an NRS score to 
replace the censored values (whether extant or missing) of all scheduled rest NRS assessments 
occurring during the censoring window, i.e., all scheduled rest NRS assessments for 30 minutes 
following rescue use when IV fentanyl is used, for 2 hours when IV hydromorphone is used, and 
for 4 hours when PO oxycodone is used. 
If a patient requested rescue medication at the time of a scheduled rest NRS assessment, the 
scheduled rest NRS assessment was also to be recorded as the pre-rescue NRS assessment.   
If a patient requests rescue medication within a wLOCF imputation time window, and additional 
rescue medication is administered prior to the end of that time window, the imputation window 
clock resets to 0 at the time of administration of the newly requested rescue medication and the 
imputation time window associated with that rescue medication begins; censored values during 
this new censoring window will be imputed using the pre-rescue NRS score obtained in 
response to the latest request for rescue medication or the most recent imputed NRS value if 
the pre-rescue NRS score is missing.  
In case a rescue medication administration time is not recoded in the rescue medication eCRF, 
but the time of the most recent pre-rescue NRS assessment occurring prior to the administration 
of rescue medication is recorded, that time shall be assumed to be the rescue medication 
administration time.  Conversely, if the most recent pre-rescue NRS assessment is recorded in 
the rescue medication eCRF, but the time is missing, the time will be assumed to be the time 
the rescue medication was administered.  Note, for the outpatient period, the time of pre-rescue 
NRS assessments is not captured in the diary.  The time of the pre-rescue NRS assessment will 
be assumed to be the time when the rescue medication was administered. 
If a patient’s pre-rescue NRS assessment is missing, then the mean of the patient’s non-missing 
pre-rescue NRS scores occurring prior to the missing score will be used to impute values for 
censored NRS scores during the ensuing wLOCF imputation time window.  If the patient has no 
non-missing pre-rescue NRS scores prior to the missing score, then the mean value of all study 
patients’ pre-rescue NRS scores occurring within the first 48 hours of entry into the PACU will 
be used to impute values for censored NRS scores during the ensuing wLOCF imputation time 
window. 
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Evoked NRS assessments occur twice daily at 10:00 AM (± 1 h) and 4:00 PM (± 1 h).  If an 
evoked NRS assessment is scheduled to occur during a wLOCF imputation time window, the 
evoked NRS score will not be censored and will not be replaced with an imputed value.  
7.3.3 Imputation of Missing NRS Scores 
For the primary analysis of the primary endpoint, intermittent missing NRS assessment scores 
(due to a patient sleeping, etc.) will not be imputed and AUCs will be calculated using the 
available NRS assessments, unless the missing NRS assessment is a rest NRS assessment 
occurring during a rescue medication imputation period, in which case the imputed value will be 
used. 
For a patient who dropped out of the study prior to D15 (the last day when NRS assessments 
were to be collected), the following algorithm will be used to impute NRS assessment scores for 
use in NRS AUC calculations that include time points after the patient’s date of discontinuation: 
• 
The score for scheduled rest NRS assessments after the date of discontinuation will be 
imputed using the most recent rest NRS score recorded prior to the patient’s date of 
discontinuation, i.e., LOCF.  If no rest NRS assessments exist prior to the patient’s date 
of discontinuation, all AUC calculations for that patient will be set to missing. 
• 
The score for scheduled evoked NRS assessments after the date of discontinuation will 
be imputed using the most recent evoked NRS score recorded on or prior to the patient’s 
date of discontinuation.  If no evoked NRS assessments exist on or prior to the date of 
discontinuation, the AUC calculation will be set to missing. 
Note that the replacement via imputation of a censored post-rescue NRS assessment (as 
described in section 7.3.2) must be performed prior to the selection of imputed values as 
described in this section. 
7.3.4 NRS AUC 
AUC calculations will be done using the standard trapezoidal rule:  
AUC𝑇1−𝑇2 = ∑
NRS𝑖−1 + NRS𝑖
2
𝑛
𝑖=1
(𝑡𝑖−𝑡𝑖−1) 
Where NRSi = NRS at time i, n is the number of hours between T1 and T2, and (ti − ti−1) is the 
time difference in hours between actual collection time i and actual collection time i − 1. 
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NRS assessment scores, whether rest or evoked, from all available eCRFs, including “Pain 
Intensity Assessment (NRS),” “Morning/Night Pain Intensity Assessment (NRS)—Inpatient,” 
“Morning/Night Pain Intensity Assessment (NRS)—Outpatient,” and “Rescue Medications” will 
be used in AUC calculations as appropriate for a specific computation.  For an AUC covering a 
particular time interval, e.g., from time Tn1 to time Tn2, all uncensored NRS assessments 
recorded from the start of the protocol-allowed window for time Tn1, up to the end of the 
protocol-allowed window for time Tn2, will be used; censored values will be replaced as 
described in sections 7.3.2.  For example, for AUC12-96, all uncensored NRS scores recorded 
from 12 hours minus 15 minutes to 96 hours plus 15 minutes relative to T0nrs (time of admission 
to the PACU) will be used. 
If the first NRS assessment, or the last NRS assessment, for the time interval specified for an 
AUC calculation is not recorded (i.e., no assessments occurred within the protocol-specified 
windows for these timepoints) then, if the score from an adjacent scheduled NRS assessment of 
the same type (rest or evoked) is recorded, the recorded score at the adjacent time will be used 
to impute the missing NRS score; if both an earlier and a later adjacent score are extant, then 
the higher of these two scores will be used for imputing the missing score.  If the first two or last 
two consecutively scheduled NRS scores of the same type (rest or evoked) for the time interval 
specified for an AUC calculation are not recorded, then the AUC calculation will be set to 
missing. 
7.3.5 Total Opioid Consumption 
Opioids taken as rescue medication will be converted into oral morphine equivalents (OME) 
using the conversion factors in Nielsen 2016.  Opioid use is recorded on the rescue medication 
eCRF from the end of surgery through T96/Discharge and following discharge either in the 
electronic or paper diary until the Day 15 (D15) visit or the Early Termination (ET) visit.  
Following discharge to outpatient status, opioid use recorded in the patient paper diary is 
transferred to the eCRF at subsequent clinic visits and electronic diary data is integrated into the 
study database directly.   
The total opioid consumption (OC) for each patient will be calculated as the sum of the OMEs of 
all of the medications taken during a specified interval.  For example, if a patient takes 5 OME of 
hydromorphone on Day 1, 5 OME of hydromorphone and 10 OME of oxycodone on Day 2, then 
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the total OC for Day 1 is 5 OME, and the total OC for Day 2 is 15 OME; the total OC for Days 1 
and 2 is 20 OME.  Patients that take no opioids in a day will have a total OC of zero for that day. 
Total OC will be determined for the following time periods: T12 to T96, T0nrs to T96, T24 to T48, 
T24 to T72, T24 to T96, T24 to D8, and T24 to D15. 
7.3.6 Total Non-opioid Analgesic Consumption 
Non-opioid analgesic use is recorded similarly to opioid rescue medication use (Section 7.3.5). 
Total non-opioid analgesic consumption (AC), i.e., total milligrams of rescue acetaminophen 
(including the acetaminophen component of Percocet) taken during the specified time intervals 
by each patient will be calculated for the following time periods: AC96-D8 and AC96-D15.  
7.3.7 Knee Range of Motion (ROM) 
Knee ROM will be assessed at Screening, T48, T96, D8, D15, and D29.  Angles of maximum 
knee flexion and extension will be recorded under passive motion (staff will flex or extend the 
knee joint to the end of the range of motion) and active motion (patient will flex or extend the 
knee joint to the end of the range of motion). 
7.3.8 KOOS Questionnaire 
The KOOS questionnaire will be administered at Screening, T96 (D5), D8, D15, and D29.  The 
following subscale scores will be calculated: 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).  Details of the scoring algorithm are provided in Appendix 15.1. 
7.3.9 Performance-based Outcome Measures (PBOMs). 
PBOMs will be assessed at T96 (D5), D15, and D29.  The following data will be collected: 
• 
Sit to Stand test: the number of times the patient is able to stand up and sit back down 
again in 30 seconds will be recorded. 
• 
Walking Speed Test: the walking speed (m/sec) over a distance of 5 meters will be 
recorded 
• 
Timed Up and Go (TUG) test: the time in seconds the patient took to perform the test will 
be recoded. 
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7.3.10 PROMIS 10 Global Health Questionnaire Score 
The PROMIS 10 questionnaire, version 1.1, was to be administered at Screening, D15, and 
D29. Global Physical Health and Global Mental Health scores will be calculated.  Details of the 
scoring algorithm are provided in Appendix 15.2. 
7.3.11 AE of Lack of Efficacy  
An AE of lack of efficacy will be defined as any AE coded using the Medical Dictionary for 
Regulatory Activities (MedDRA) with a preferred term (PT) of “drug ineffective.”  Patients who 
require IV opioid rescue medication after T24 will be considered to have an AE of lack of 
efficacy but will continue in the study. 
7.3.12 Discharge Readiness  
Each patient’s data will be assessed for the 8-hour intervals that end daily at 7:00 a.m., 3:00 
p.m., and 11:00 p.m., starting at 7:00 a.m. the morning after entry into the PACU (T0nrs) through 
T96 (± 4 h)/Discharge.  The elapsed time from T0nrs to the end time of any of the above 
specified 8-hour periods during which all three of the following criteria are simultaneously 
present in that 8-hour time period (i.e., a satisfied criterion’s presence in a prior 8-hour time 
period does not count, with the exception noted below), will be designated as a time point at 
which a patient is ready for discharge:  
• 
adequate analgesia, defined as median rest NRS < 4 (where rest NRS refers to 
recorded, not imputed, rest NRS scores within the 8-hour period); 
• 
independence from intravenous opioids; 
• 
ability to ambulate > 100 ft (> 30 m) with only the aid of a walker during a physical 
therapy session. 
Note: Because daily physical therapy sessions are scheduled at 10:00 AM (± 1 h) and 4:00 PM 
(± 1 h), the ‘ability to ambulate’ discharge criterion may not be fully evaluable during the 11:00 
PM to 7:00 AM 8-hour time periods.  For the 7:00 a.m. assessment of discharge readiness, the 
evaluation of the ability to ambulate from the prior 8-hr period (i.e., the period from 3:00 p.m. 
until 11:00 p.m. on the day before) will be used.   
7.4 
Analysis Methods 
7.4.1 General Considerations 
The final data analysis will be performed after all patients have either completed or have been 
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discontinued from the study, all data cleaning has been completed, and the study database has 
been locked.  The study will be unblinded after patient membership in each of the various 
analysis populations has been determined at a blinded data review meeting and upon 
confirmation of database lock. 
Any deviations from the analyses specified in this SAP will be detailed in the clinical study 
report. 
All data collected in the clinical database will be included in the data listings. 
Statistical testing including p-values and confidence intervals (CIs) will be presented as 
described in each section below.  The Type I error rate (alpha) for the primary analysis of the 
primary efficacy endpoint, primary endpoint sensitivity analyses, and key secondary efficacy 
endpoint analyses is 0.05 (one-sided).  For all other analyses, the Type I error rate is two-sided 
at the 0.05 level of significance.  Where appropriate, a significance level in the interval 0.05 < p 
< 0.10 will be considered as evidence of a trend. 
For this proof-of-concept study, no adjustment of the level of significance will be made for 
multiple testing. 
Because the 90 mg treatment group occurred only in Part A, and includes only 6 patients who 
received active treatment, inferential analyses for the 90 mg group will not be undertaken; only 
descriptive statistics will be provided for the 90 mg treatment group. 
See Section 13 for example SAS code for the analyses described in the following subsections. 
7.4.2 Pooling of Data 
The efficacy and safety data from Parts A and B of study CA-PS-208 will be pooled by treatment 
group, for the placebo, 30 mg, and 60 mg treatment groups, prior to performing analyses. 
7.4.3 Primary Efficacy Endpoint 
7.4.3.1 Primary Efficacy Endpoint Hypothesis 
The null hypothesis associated with the primary efficacy endpoint is that the mean rest NRS 
AUC12-96 does not differ between active treatment and placebo, tested against the alternative 
hypothesis that the mean rest NRS AUC12-96 is smaller for at least one active treatment 
compared to placebo. 
7.4.3.2 Primary Analysis of the Primary Efficacy Endpoint 
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The primary analysis of the primary efficacy endpoint will be performed for the mITT Population 
using a one-way analysis of variance (ANOVA) with a fixed effect for treatment.  The analysis 
result will be reported as the difference in Least Squares (LS) means, active minus placebo, for 
rest NRS AUC12-96, with the 90% confidence interval for the difference and the corresponding 
statistical p-value for the one-sided significance test.   
Should the ANOVA assumptions of normality of rest NRS AUC12-96 values, normality of 
residuals, or homogeneity of variances be significantly violated, the primary analysis may be 
repeated after suitable transformation of the data or the analysis may be replaced with a non-
parametric analysis. 
7.4.3.3 Primary Efficacy Endpoint Sensitivity Analyses 
In order to assess the sensitivity of the primary analysis of the primary endpoint to the censoring 
and imputation scheme specified for calculating the primary endpoint rest NRS AUC12-96 value 
following rescue medication administration, the primary analysis of the primary endpoint will be 
repeated in the mITT population in two ways: 
• 
No post rescue medication administration censoring and imputation is performed; the 
rest NRS AUC12-96 calculation will employ all scheduled rest NRS scores and pre-rescue 
rest NRS scores available in the interval T12 to T96. 
• 
No post rescue medication administration censoring and imputation is performed; the 
rest NRS AUC12-96 calculation will employ all available scheduled rest NRS scores only. 
7.4.3.4 Exploratory Analyses of the Primary Endpoint 
For the primary efficacy endpoint, two exploratory analyses will be performed as to explore 
different methods of accounting for the effect of rescue medication use in the primary analysis.  
Censoring of rest NRS scores post rescue medication use as described in Section 7.3.2 will not 
be included in these analyses. 
• 
Silverman Rank Analysis: Rank patients in the combined treatment groups according to 
their NRS AUC12-96 values; when ties occur, assign each of the tied observations the 
average of the ranks the tied observations would have if there were no ties.  Perform the 
above steps for total opioid use OME values.  Each rest NRS AUC12-96 rank and each 
total opioid use OME rank will be expressed as a percentage difference from the mean 
rank for that variable in the overall study population and plotted.  The integrated ranks of 
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the active treatment and placebo groups will be compared using the Kruskal-Wallis test 
(non-parametric ANOVA).  (See Silverman 1993.) 
• 
Analysis of Covariance (ANCOVA): The primary analysis of the primary efficacy 
endpoint will be revised with the addition of the patient’s Total Opioid Consumption as a 
covariate in the model as well as the treatment by Total Opioid Consumption interaction.  
The interaction term will be omitted from the model if not significant at the 0.1 level. 
7.4.3.5 Primary Efficacy Endpoint-related Tables, Figures, and Listings 
The primary endpoint analysis results will be presented in a summary and analysis table.  The 
number of patients (n) included in the analysis, mean (SD) of rest NRS AUC12-96, LS mean of 
rest NRS AUC12-96 and its standard error (SE) will be presented for all treatment groups.  The 
difference in LS mean from placebo for the 36 mg and 60 mg treatment groups, the 90% 
confidence interval (CI) for the difference in LS means, and the corresponding p-value for the 
difference will be presented by treatment group (36 mg and 60 mg).  Contrasts generated for 
the primary endpoint analysis for tests of active combined (36 mg and 60 mg groups combined) 
versus placebo and the 60 mg group versus the 36 mg group will also be presented. 
The output of the Kruskal-Wallis ANOVA for the Silverman rank analysis will be presented in a 
summary and analysis table.  A plot of the Silverman analysis summed percentage differences 
(for rest NRS and total opioid consumption OEM) over all treatment groups (placebo, 36 mg, 
and 60 mg) versus mean overall rank will be presented in a figure. 
NRS values by time point, and computed AUC values by type, will be presented in patient 
listings by treatment group.  Imputed NRS values will be flagged in the listing. 
. In order to visualize the effect of censoring scheduled rest NRS scores due to the 
administration of rescue medication, three figures will be provided: 
• 
A plot of mean scheduled rest NRS scores by nominal time point, where in calculating 
the mean, wherever a subject has a scheduled rest NRS score falling within a censoring 
interval due to the administration of rescue medication, the observed rest NRS score is 
replaced by the imputed score for that subject at that nominal time point (i.e., the wLOCF 
value is imputed at that nominal time point), and the mean is then calculated over all 
such NRS scores for each nominal time point. Missing due to early drop out are not 
imputed.  
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• 
A plot of mean scheduled rest NRS scores by nominal time point, where in calculating 
the mean post-dropout results are imputed with LOCF, but post-rescue results are not 
imputed. 
• 
A plot of the mean observed scheduled rest NRS scores with no imputation due to 
rescue medication use or post-dropout. 
Each figure will display the plot of NRS score by time for each treatment group (placebo, 36 mg, 
and 60 mg) and the regions corresponding to rest NRS AUC12-96 will be indicated on the plot. 
These figures will be provided for both the mITT and PP populations. The corresponding table 
with descriptive summaries at each time point will also be produced for each figure.  
Similar figures (with or without post-dropout LOCF imputations) and the corresponding tables 
will be created for evoked NRS. 
Plots of NRS values over time may be displayed in figures, by patient, as warranted. 
7.4.4 Other AUC Endpoints, Total Opioid Consumption, and Total Non-opioid Analgesic 
Consumption Endpoints 
Other AUC-based endpoints, total opioid consumption endpoints, and total non-opioid analgesic 
consumption endpoints will be analyzed using the same ANOVA approach employed in the 
primary analysis of the primary endpoint. 
 
7.4.4.1 Other AUC Endpoints and Total Opioid Consumption Endpoints and Related TFLs 
ANOVA output for other AUC-based endpoints, total opioid consumption endpoints, and total 
non-opioid analgesic consumption endpoints will be presented in tables analogous to those 
presented for the primary endpoint analysis. 
Figures will be provided displaying plots analogous to those specified for the primary endpoint 
for mean rest NRS values and mean evoked NRS values; regions corresponding to AUC for the 
relevant time periods will be indicated on the plots.  
A figure displaying total opioid consumption OEM values for each treatment group (placebo, 36 
mg, and 60 mg) in a bar chart will be provided.  A similar figure for total non-opioid analgesic 
consumption will also be provided.    
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7.4.5 Time to Cessation of Opioid Use 
The time in hours from T0nrs to the last recorded use of opioid analgesics through D15 will be 
analyzed using time to event analysis.  The mean and median time to cessation of opioid use 
and their 95% CIs will be presented by treatment group (placebo, 36 mg, and 60 mg) with log-
rank p-values for the difference in cessation time estimates between treatment groups (36 mg 
and 60 mg) and placebo.  Plots of time to cessation of opioid use will also be provided, by 
treatment group.   
7.4.6 Percentage of Patients Who Are Opioid-free 
The number and percentage of patients who are opioid-free (yes/no) from T0nrs to T96 (OF0-96), 
will be presented in an analysis table, by treatment group (placebo, 36 mg, and 60 mg), 
excluding the 90 mg treatment group.  A Cochran-Mantel-Haenszel (CMH) test will be used to 
test the null hypothesis of no difference between each active treatment group and placebo in the 
proportion of opioid-free patients in the mITT population from T0nrs to T96; the analysis will be 
repeated for the following time intervals: OF24-D15, OF96-D8, and OF96-D15.  Each of the OF 
analyses will be repeated for the PP population. For OF24-96 (one of the key secondary 
endpoints), one-sided Fisher's exact test will be used instead of the two-sided CMH test. 
Treatment versus placebo odds ratios with 95% CI, the difference in proportions (active 
treatment minus placebo) with 95% CI, and CMH p-values for the comparisons of active 
treatment versus placebo will be presented in the analysis table. 
7.4.7 Time-specific Mean Rest NRS Scores 
The mean rest NRS scores at T48, T72, T96, T120, T144, and T168 will be summarized 
descriptively by time point and treatment group and presented in a summary table. 
For this analysis, post-rescue assessments will be imputed as described in section 7.3.2.  
However, post-dropout missing NRS scores (described in section 7.3.3) will not be imputed. 
The difference in mean rest NRS scores between treatment groups at T48, T72, T96, T120, 
T144, and T168 will be will be analyzed in the mITT population using a linear mixed-effects 
model repeated measures ANOVA with fixed effects for treatment, time point, and the 
interaction of treatment and time point.  The Kenward-Roger method for computing the 
denominator degrees of freedom will be used.  An unstructured covariance matrix will be 
assumed; if convergence issues are experienced with this matrix type, then Toeplitz, first-order 
auto-regressive, and compound symmetry types will be tried in order and the first matrix to 
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result in successful convergence will be used.  Least Squares (LS) means, with 95% confidence 
intervals and the corresponding statistical p-value, will be presented for each time point for the 
difference between each active treatment group (36 mg and 60 mg) and placebo.  The analysis 
will be repeated for the PP population.  
In addition, a plot of mean NRS scores versus nominal time point, by treatment group, will be 
presented in a figure. 
7.4.8 Knee Range of Motion (ROM) 
Knee ROM scores collected at Screening, T48, T96, D8, D15, and D29, and their changes from 
Screening, will be summarized descriptively at each nominal time point, by treatment group; 
changes from T48 to T96, D8, D15, and D29 will also be summarized. 
The change from baseline and change from T48 in each (both passive and active flexion or 
extension) ROM score will be analyzed in the mITT population using a linear mixed-effects 
model with fixed effects for treatment, time point, baseline value as covariate, and the 
interaction of treatment and time point.  The Kenward-Roger method for computing the 
denominator degrees of freedom will be used and the covariance structure will be selected in 
the same way as described in section 7.4.7.  For each treatment group (placebo, 36 mg, and 60 
mg), the change from baseline mean (SD), LS mean (SE), and difference in LS mean from 
placebo with 95% CI and the corresponding statistical p-value, will be presented for each time 
point and treatment group; the analysis will be repeated for the PP population. 
In addition, the number and percentage of patients with > 90° and with > 115° active flexion and 
passive flexion, and the number and percentage of patients with < 0o, 10° to 0°, 20° to > 10°, 
and > 20° active extension and passive extension, will be presented in an analysis table by time 
point and treatment group. 
A Cochran-Mantel-Haenszel (CMH) test will be used to test the null hypothesis of no difference 
between each active treatment group (36 mg and 60 mg) and placebo in the proportion of 
patients with the given ranges of motion in the mITT population at the specified time points; the 
analysis will be repeated for the PP population. 
Treatment versus placebo odds ratios with 95% CI, the difference in proportions (active 
treatment minus placebo) with 95% CI, and CMH p-values for the comparisons of active 
treatment versus placebo will be presented in the analysis table. 
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7.4.9 KOOS Questionnaire 
KOOS questionnaire subscale scores calculated for Screening, T96 (D5), D8, D15, and D29, 
and their changes from Screening, will be summarized descriptively at each nominal time point, 
by treatment group; changes from T96 (D5) to D8, D15, and D29 will also be summarized.  The 
following subscale scores will be calculated: 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). 
The change from Screening to each subsequent time point, and the change from T96 (D5) to 
each subsequent time point, in each subscale score will be analyzed in the mITT population 
using a linear mixed-effects model with fixed effects for treatment, time point, the interaction of 
treatment and time point, and the corresponding baseline value as covariate, similar to the 
model in section 7.4.8.  For each treatment group (placebo, 36 mg, and 60 mg), the change 
from baseline mean (SD), LS mean (SE), and difference in LS mean from placebo with 95% CI 
and the corresponding statistical p-value, will be presented, by subscale, for each time point and 
treatment group; the analysis will be repeated for the PP population.  
7.4.10 Performance-Based Outcome Measure (PBOM). 
The results of PBOM measurements at T96 (± 4 h)/Discharge, D15, and D29 will be 
summarized descriptively by time point and treatment group and presented in separate 
summary tables for each of the PBOMs—sit to stand, walking speed, timed up and go (TUG). 
The difference in mean PBOM score between treatment groups at T96 (± 4 h)/Discharge, D15, 
and D29 will be analyzed in the mITT population using a linear mixed-effects model repeated 
measures ANOVA with fixed effects for treatment, time point, and the interaction of treatment 
and time point, similar to the model in section 7.4.8.  Least Squares (LS) means, with 95% 
confidence intervals and the corresponding statistical p-value, will be presented for each time 
point for the difference between each active treatment group (36 mg and 60 mg) and placebo.  
The analysis will be repeated for the PP population. 
7.4.11 PROMIS 10 Global Health Questionnaire Scores 
The PROMIS 10 questionnaire Global Physical Health and Global Mental Health subscale 
scores (see Appendix 51.2) at Screening (baseline), D15, and D29 and their changes from 
baseline will be summarized descriptively by timepoint and treatment group for each subscale. 
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The change from baseline in each subscale score will be analyzed in the mITT population using 
a linear mixed-effects model with fixed effects for treatment, time point, the interaction of 
treatment and time point, and the corresponding baseline value, similar to the model in section 
7.4.8.  For each treatment group (placebo, 36 mg, and 60 mg), the change from baseline mean 
(SD), LS mean (SE), and difference in LS mean from placebo with 95% CI and the 
corresponding statistical p-value, will be presented, by subscale, for each time point and 
treatment group; the analysis will be repeated for the PP population. 
7.4.12 Time to Discharge Readiness 
A time to event analysis will be provided to determine, for each treatment group (placebo, 
36 mg, and 60 mg), Kaplan–Meier estimates of the cumulative percentages of patients meeting 
all three discharge criteria at each time point and subsequent time points, i.e., for each patient, 
the time point, among T24 (± 4 h), T48 (± 4 h), T72 (± 4 h), and T96 (± 4 h)/Discharge, at which 
the patient meets all three discharge criteria at that time point and all subsequent time points 
(meaning no subsequent reversion to not ready for discharge status).  A time to event plot of 
cumulative percentage of patients, within each treatment group, versus time will be provided. 
7.4.13 Other Binary Endpoints 
For the following binary endpoints, the number and percentage of patients achieving the 
endpoint will be presented in an analysis table by timepoint (if applicable) and treatment group 
(placebo, 36 mg, and 60 mg), excluding the 90 mg treatment group: 
• 
use of rescue medication in time periods T0nrs-T6, T6-T12, T12-T24, T24-T48, T48-T72, 
and T72-T96; 
• 
patient experienced an AE of lack of efficacy (LOE) during the in-patient portion of the 
study, LOE0-96; 
• 
discharge readiness at T24 (± 4 h), T48 (± 4 h), T72 (± 4 h), and T96 (± 4 h)/Discharge. 
For each endpoint, a Cochran-Mantel-Haenszel (CMH) test will be used to test the null 
hypothesis of no difference between each active treatment group and placebo in the proportion 
of patients who met the endpoint in the mITT population for the relevant time period, where 
applicable; the analysis will be repeated for the PP population. 
Treatment versus placebo odds ratios with 95% CI, the difference in proportions (active 
treatment minus placebo) with 95% CI, and CMH p-values for the comparisons of active  
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treatment versus placebo will be presented in the analysis table. 
8. SAFETY EVALUATION 
8.1 
Overview of Safety Analysis Methods 
Analysis of safety will be performed for the Safety population. 
All safety summaries will be grouped by the actual treatment received.  Data from all patients 
receiving vehicle placebo will be combined for summaries. 
Actual values and change from baseline clinical laboratory measures, vital signs, ECGs, 
physical examination, surgical site, and neurosensory assessments will be assessed and 
summarized by treatment group. 
No formal statistical comparisons will be performed for safety endpoints.  
Safety outcomes include: 
• 
Incidence TEAEs or SAEs 
• 
Clinical laboratory test results 
• 
Vital sign measurements 
• 
ECG results 
• 
PE findings  
• 
Surgical site wound assessment findings 
• 
Neurosensory testing results 
• 
Knee x-ray (if performed) 
• 
Presence of worsening (rebound) pain 
• 
Concomitant medication use/concomitant treatments 
8.2 
Adverse Events 
All AEs are documented and followed from the time the patient signed the informed consent 
form (ICF) until Day 29 or later as necessary.  AEs will be coded by system organ class (SOC) 
and preferred term (PT) using the Medical Dictionary for Regulatory Activities (MedDRA Version 
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22.1) reporting system.  All coding will be reviewed prior to database lock.  All recorded AEs will 
be listed, but only TEAEs will be summarized. 
Treatment-emergent AEs are defined as any of the following:  
• 
Non-serious AEs with onset on the date of treatment with the study drug through Day 29 
or Early Termination 
• 
Serious AEs with onset on the date of treatment with the study drug through 30 days 
after Day 29 or 30 days after Early Termination 
• 
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  
In case an AE start date is partial, when comparing this date to the date of treatment, the latest 
possible date consistent with the known portion of the date will be imputed.  However, when 
comparing the start date to the Day 29/Early Termination date, the earliest possible date 
consistent with the known portion of the date will be imputed. 
For evaluation of causal relatedness to treatment, the categories are probably related, possibly 
related, unlikely related, and not related.  For categorization in the summary tables, AEs 
designated as probably or possibly related will be considered to be related. 
For the evaluation of event severity, the criteria are mild, moderate, severe, life-threatening, and 
fatal. 
Safety summaries will include the incidence of treatment emergent adverse events (TEAEs).  
AEs recorded on the CRF which began prior to treatment with study drug will not be included in 
the summary tables but will be included in the AE data listings.  TEAEs will be evaluated for 
severity and causality.  All TEAE summaries will be based on the number of patients 
experiencing an event, not the number of AEs experienced.  For example, if a patient reports 
the same AE on three separate occasions that patient will be counted only once for that 
preferred term.  Patients reporting more than one AE in a SOC will be counted only once in the 
SOC total. 
AEs and serious adverse events (SAEs) will be summarized separately and presented by 
treatment group.  The number and percentage of patients experiencing any event, and the 
number of events, will be presented.  Only TEAEs will be included in the summaries.  Non-
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treatment emergent events will be included in the patient listings and flagged, but they will not 
be included in the AE summaries. 
Summaries classifying AEs according to severity (i.e., mild, moderate, severe, or missing 
severity) and relationship to study drug (i.e., probably related, possibly related, unlikely related, 
not related, or relationship is missing) will be presented.  If a patient experiences the same AE 
at more than one severity or with more than one relationship to study drug, the most severe 
rating or the stronger causal relationship to study drug will be given precedence.  Any missing 
severity, causality, or outcome will not be imputed and will be classified as unknown. 
The denominator used for calculation of the safety summary percentages will be the number of 
patients in the Safety Population in the appropriate group.  AEs will be summarized for any 
exposure to study treatment by treatment group. 
8.2.1 Adverse Event Summaries 
The following AE summaries will be provided: 
• 
A summary of the number and percentage of patients reporting any TEAE, death, at 
least one severe TEAE, at least one serious TEAE, at least one TEAE possibly related 
to study drug, at least one TEAE leading to withdrawal from study drug, by treatment 
group. 
• 
A summary of the number and percentage of patients reporting a TEAE by treatment 
group, system organ class, and preferred term. 
• 
A summary of the number and percentage of patients reporting a TEAE by treatment 
group, system organ class, preferred term, and maximum severity (for each patient and 
each TEAE, the maximum reported severity recorded will be attributed and used in the 
summary). 
• 
A summary of the number and percentage of patients reporting a TEAE by treatment 
group, system organ class, preferred term, and relationship to study drug (the worst 
relationship to study drug will be attributed and used in the summary). 
8.2.2 Deaths, Serious Adverse Events, Adverse Events leading to Withdrawal 
The following summaries will be provided: 
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• 
A summary of the number and percentage of patients reporting a serious TEAE by 
treatment group, system organ class, and preferred term. 
• 
A summary of the number and percentage of patients reporting a serious TEAE by 
treatment group, system organ class, preferred term, and relationship to study drug. 
• 
A summary of the number and percentage of patients reporting a TEAE leading to 
discontinuation of study drug by treatment group, system organ class, and preferred 
term. 
• 
A summary of the number and percentage of patients with a SAE outcome of death by 
treatment group and preferred term. 
8.3 
Clinical Laboratory Test Results 
Clinical laboratory tests (chemistry, hematology/coagulation, and urinalysis) will be collected at 
screening and before discharge from the inpatient unit (T96).  All results will be presented in 
listings by patient and treatment group. 
For continuous laboratory parameters, descriptive statistics will be presented for the value at 
each assessment time and for the changes from baseline by visit and treatment group. Values 
reported as “< xx” or “> xx” (where xx is a number) will be treated as xx for the purposes of 
these summaries. 
Additionally, clinical laboratory parameters will be categorized as low, normal, or high according 
to laboratory range specifications.  Laboratory shift tables displaying the change (number and 
percentage of patients) relative to the normal range from baseline to the T96 timepoint will also 
be presented by treatment group for each test.   
Laboratory values that are outside the normal range will also be flagged in the data listings, 
along with corresponding normal ranges. 
8.4 
Drugs of Abuse and Alcohol Screens, Pregnancy Test 
Pregnancy tests (for female patients of childbearing potential), urine drug screens, and alcohol 
(breath or saliva) tests will be performed at screening and on D1 pre-surgery.  
Results will be presented in listings by patient.  Each test result will be recorded as “negative” or 
“positive”. 
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8.5 
Vital Signs 
Vital signs including blood pressure (systolic and diastolic; mmHg), heart rate (beats per 
minute), respiration rate (breaths per minute), and temperature (°C) will be assessed after T0 at 
2, 6, 12, 24, and every 8 hours thereafter (if awake at time of assessment between the hours of 
12:00 AM and 6:00 AM) until discharge from the inpatient unit (a patient 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 a ± 15-minute window is allowed. 
Body weight (kg), in indoor clothing, but without shoes, was to be measured at Screening and at 
T96.  Height (cm) was to be measured at screening only.  Body mass index (BMI) will be 
calculated for the Screening visit only. 
Vital signs (including weight) and their changes from baseline will be summarized descriptively 
by timepoint and treatment group. 
8.6 
ECG 
ECG will be performed at Screening and 24 hours (± 2 hours) after study medication 
administration.  Overall interpretation (Normal, Abnormal Not Clinically Significant, or Abnormal 
Clinically Significant) is recorded in the eCRF. 
Number and percentage of patients with each interpretation will be summarized by timepoint 
and treatment group. 
8.7 
Physical Examination  
A complete physical examination including all major body systems was to be performed at 
Screening.  In addition, a targeted physical examination was to be performed prior to surgery, 
then a physical examination to capture changes after surgery, at T96 (± 4 hours), but prior to 
discharge from the inpatient unit, and D8, D15, and D29 or at the time a patient terminates 
early, if permitted.   
Abnormal or clinically significant physical examination results recorded as AEs.  Physical 
examination results will be presented in a listing by patient and treatment group.  
 
 
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8.8 
Surgical Site Assessments 
Surgical sites were to be assessed at 96 hours (prior to discharge from the PACU) and then at 
the D8, D15, and D29 visits.  The investigator was to have evaluated wound healing 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.  Any clinically significant wound healing 
issues are captured as AEs and followed until resolution. 
All data will be presented in listings by patient and treatment group.  The surgical site 
assessment score will be summarized descriptively by treatment group and time point 
8.9 
Neurosensory Test 
Neurosensory testing near the incision (compared to a similar site on the opposite leg) was to 
be performed at screening, T96h (prior to discharge from the unit), and then at the D8, D15, and 
D29 visits. 
Two sides of the wound were to be examined: cephalad (upper) and caudad (lower).  For each 
side, the following assessments were to be recorded: 
• 
Visual Examination of the Surgical Site (Normal or Abnormal) 
• 
Light Touch (Normal, Reduced, or Absent) 
• 
Von Frey Stimulation (Normal, Reduced, or Absent) 
• 
Brush Stimulation (Normal, Reduced, Absent, or Pain [Allodynia]) 
The neurosensory assessment results will be listed and the number and percentage of patients 
with each response will be summarized by treatment group, time point, wound side (cephalad or 
caudad), and assessment. 
8.10 X-ray of the Operated Knee 
X-ray of the operated knee was to be performed on Day 29 (or Early Termination, if possible) 
and later in case of any evidence of abnormal bone healing until resolution or stabilization.   
Results of x-ray of the operated knee will not be entered into the study database.  The date and 
time the x-ray was performed will be presented in a listing by patient and treatment group.  
 
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8.11 Presence of Rebound (or Worsening) Pain 
Patients were to report whether they have noted any worsening pain (rebound pain) at the 
surgical site since the prior visit at visits D8, D15, and D29. 
The number and percentage of patients with rebound pain will be presented in a summary table 
by treatment and time point. 
8.12 Prior and Concomitant Medications 
Prior medications/therapies are those that stop prior to the start of the study drug administration.  
Any medication/therapy that stops at or after this time or ongoing is considered concomitant 
medication/therapy.  Prior and concomitant medications are collected for the 30 days prior to 
screening and throughout the study.  Prior and concomitant medications will be coded using 
World Health Organization Drug Dictionary Anatomical Therapeutic Chemical (WHO/ATC) 
classification index version Sep 1, 2019.  The number and percentage of patients who take 
concomitant medications will be summarized by the drug class (the highest available ATC level) 
and preferred term, overall and by treatment group for the safety population.  All medications 
and non-medical therapies captured in eCRFs will be presented by patient in listings by 
treatment group. 
8.13 Patient Pain Assessment Training and Surgery Details 
Pain assessment training was to be provided to patients during screening.  Patients were to re-
watch the video prior to surgery.  Patient pain assessment training and surgery details were to 
be documented in eCRFs and will be presented by patient in listings by treatment group. 
 
 
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9. PHARMACOKINETIC EVALUATION 
The time points for pharmacokinetic (PK) whole blood collections were to be at pre-dose (from 
check-in and up to 30 minutes before the start of surgery), and at pharmacokinetic time (PKT) 
0.167 (10 min), 0.25 (15 min), 0.5 (30 min), 0.75 (45 min), and at 1, 1.5, 2, 3, 4, 6, 8, 12, 16, and 
24 hours after the last study treatment instillation (total of 15 samples).  There was to be a ± 2-
minute window allowed for the 10-minute and 15-minute collections, a ± 5-minute window 
allowed for collections at 30 minutes through 4 hours, and a ± 15-minute window for collections 
after 4 hours.  In the event of an AE, an unscheduled PK draw was to be performed.  
Actual sampling times were to be used to calculate plasma-derived PK parameters.  Full details 
of PK endpoints and analyses will be presented in a separate PK Analysis plan.  
 
 
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10. OTHER ANALYSES 
All additional analyses not included in this SAP, conducted after the study unblinding will be 
considered exploratory and will be presented and identified separately in the CSR. 
 
 
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11. DEVIATIONS FROM THE SAP 
Any deviations from the final version of this SAP will be described and justified in the final CSR. 
 
 
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12. CHANGES IN CONDUCT OR PLANNED ANALYSES FROM THE PROTOCOL 
None noted. 
 
 
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13. EXAMPLE SAS CODE 
Primary endpoint analysis, one-way ANOVA: 
proc mixed data=auc_data; 
  class patient treatment; 
  model auc = treatment; 
  lsmeans trt / diff=controlL ('placebo') cl alpha=0.05; 
  lsmeans trt / diff cl alpha=0.10; 
  estimate '36 and 60 mg vs. Placebo' treatment 0.5 0.5 -1 / cl; 
  estimate ’60 vs. 36 mg’ treatment -1 1 0 / cl; 
run; 
 
 
 
Primary endpoint analysis, ANCOVA: 
proc mixed data=auc_data; 
  class patient treatment; 
  model auc = treatment total_OME treatment*total_OME; 
  lsmeans trt / diff=controlL ('placebo') cl alpha=0.05; 
  lsmeans trt / diff cl alpha=0.10; 
  estimate '36 and 60 mg vs. Placebo' treatment 0.5 0.5 -1 / cl; 
  estimate ’60 vs. 36 mg’ treatment -1 1 0 / cl; 
run; 
 
 
 
Primary endpoint exploratory analysis, non-parametric ANOVA (Silverman rank test): 
proc npar1way wilcoxon correct=no data=integ_ranks;  
  class treatment;  
  var int_rank;  
run; 
 
 
 
Example SAS code for ANOVA by time point analyses: 
proc mixed data=scores; 
  class subjid trt time; 
  model score = trt time trt*time/ ddfm=kr; 
  repeated time / subject = subjid type = UN; 
  lsmeans trt*time / diff cl; 
run; 
 
Note: if the model does not converge with Unstructured covariance matrix (type=UN), then 
try TOEP, AR(1), and CS, in this order, using the first structure that converges. 
 
 
 
 
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Example SAS code for the change from baseline linear mixed-effects model: 
proc mixed data=parameter_data;  
  class patient treatment timepoint;  
  model change=baseline treatment timepoint treatment*timepoint / ddfm=kr;  
  repeated timepoint / subject = subjid type = UN; 
  lsmeans treatment*timepoint / diff cl; 
run; 
 
Note: if the model does not converge with Unstructured covariance matrix (type=UN), then 
try TOEP, AR(1), and CS, in this order, using the first structure that converges. 
 
 
 
Example SAS code for CMH analysis: 
proc freq data=parameter_data order=data;  
  tables treatment*outcome / cmh exact riskdiff;  
  weight count; 
  exact riskdiff; 
run; 
 
 
 
Example SAS code for time to event analysis: 
proc lifetest data=event_data method=KM plots=survival(failure test atrisk);  
  time hours*status(0);  
  strata treatment; 
run; 
 
 
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14. REFERENCES 
US Federal Register. (1998) International Conference on Harmonization; Guidance for Industry:  
Statistical Principles for Clinical Trials. Department of Health and Human Services:  Food and 
Drug Administration. Federal Register, Vol. 63, No. 179, September 16, 1998, page 49583. 
US Federal Register. (1996) International Conference on Harmonization; Guidance for Industry:  
Structure and Content of Clinical Study Reports. Department of Health and Human Services:  
Food and Drug Administration. Federal Register Vol. 61, July 17, 1996, page 37320.  
Nielsen, Suzanne et al., A synthesis of oral morphine equivalents (OME) for opioid utilisation 
studies, Pharmacoepidemiology and Drug Safety 2016; 25: 733–737 
Silverman, David G. et al., Integrated assessment of pain scores and rescue morphine use 
during studies of analgesic efficacy, Anesth Analg 1993;77:168-70  
 
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15. APPENDICES 
15.1 Scoring of KOOS Questionnaire 
Each item is scored as follows: None = 0, Mild = 1, Moderate = 2, Severe = 3, Extreme = 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 as follows: 
Subscale score = 100 – (Mean of subscale items)  100/4 
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. 
15.2 Scoring of PROMIS 10 Questionnaire 
This study employs PROMIS v1.1 questionnaire that is scored as follows. 
1. Recode the response to question 10 (How would you rate your pain on average) as 
follows: 
Response 
Recoded Response 
0 
5 
1, 2, 3 
4 
4, 5, 6 
3 
7, 8, 9 
2 
10 
1 
2. Reverse the response to questions 8 (How often have you been bothered by 
emotional problems such as feeling anxious, depressed or irritable?) and 9 (How 
often have you been bothered by emotional problems such as feeling anxious, 
depressed or irritable?) by subtracting them from 5. This way higher scores for 
responses always indicate better health. 
3. Calculate the Global Physical Health raw score by summing the responses for 
questions 3, 7, 10, and 9. If not all of these questions are answered, the score will be 
missing. 
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4. Calculate the Global Mental Health raw score by summing the responses for 2, 4, 5, 
and 8. If not all of these questions are answered, the score will be missing. 
5. Use the following tables to convert the global raw scores to the T-scores that will be 
used in analysis: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Global Physical Health 
Raw summed score 
T-score 
4 
16.2 
5 
19.9 
6 
23.5 
7 
26.7 
8 
29.6 
9 
32.4 
10 
34.9 
11 
37.4 
12 
39.8 
13 
42.3 
14 
44.9 
15 
47.7 
16 
50.8 
17 
54.1 
18 
57.7 
19 
61.9 
20 
67.7 
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Global Mental Health 
Raw summed score 
T-score 
4 
21.2 
5 
25.1 
6 
28.4 
7 
31.3 
8 
33.8 
9 
36.3 
10 
38.8 
11 
41.1 
12 
43.5 
13 
45.8 
14 
48.3 
15 
50.8 
16 
53.3 
17 
56.0 
18 
59.0 
19 
62.5 
20 
67.6 
 
15.3 Planned Tables, Figures, and Listings 
15.3.1 Tables 
Table 14.1.1  
All Patients 
Summary of Patient Disposition 
Table 14.1.2  
Randomized 
Patients 
Summary of Protocol Deviations 
Table 14.1.3  
Safety Population 
Summary of Demographics and Baseline Characteristics 
Table 14.1.4  
Safety Population 
Summary of Concomitant Medications, by ATC Class and 
Preferred Term 
Table 14.1.5  
Safety Population 
Summary of Medical History, by System Organ Class and 
Preferred Term 
Table 14.1.6 
Safety Population 
Summary of Study Drug Volume Administered 
Table 14.2.1.1  
mITT Population 
ANOVA Analysis of Rest NRS AUC12-96 (Primary Analysis) 
Table 14.2.1.2  
PP Population 
ANOVA Analysis of Rest NRS AUC12-96   
Table 14.2.1.3  
mITT Population 
ANOVA Analysis of Rest NRS AUC12-96 – Scheduled Rest 
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NRS and Pre-rescue NRS Scores) (Sensitivity Analysis) 
Table 14.2.1.4  
mITT Population 
ANOVA Analysis of Rest NRS AUC12-96 – Scheduled Rest 
NRS Scores (Sensitivity Analysis) 
Table 14.2.1.5  
mITT Population 
Rest NRS AUC12-96 and Total Opioid Use, Silverman Rank 
Analysis (Exploratory Analysis) 
Table 14.2.1.6 
mITT Population 
ANCOVA Analysis of Rest NRS AUC12-96 (Exploratory 
Analysis)  
Table 14.2.2.1 
mITT Population 
ANOVA Analysis of Rest NRS AUC   
Table 14.2.2.2 
PP Population 
ANOVA Analysis of Rest NRS AUC   
Table 14.2.2.3 
mITT Population 
ANOVA Analysis of Evoked NRS AUC   
Table 14.2.2.4 
PP Population 
ANOVA Analysis of Evoked NRS AUC   
Table 14.2.3.1 
mITT Population 
ANOVA Analysis of Total Opioid Consumption in OME Dose  
Table 14.2.3.2 
PP Population 
ANOVA Analysis of Total Opioid Consumption in OME Dose  
Table 14.2.4.1 
mITT Population 
ANOVA Analysis of Total Non-Opioid Analgesic Consumption 
in mg   
Table 14.2.4.2 
PP Population 
ANOVA Analysis of Total Non-Opioid Analgesic Consumption 
in mg   
Table 14.2.5.1 
mITT Population 
Time to Cessation of Opioid Use  
Table 14.2.5.2 
PP Population 
Time to Cessation of Opioid Use  
Table 14.2.5.3 
mITT Population 
Analysis of Percentage of Patients Who Are Opioid Free  
Table 14.2.5.4 
PP Population 
Analysis of Percentage of Patients Who Are Opioid Free  
Table 14.2.6.1 
mITT Population 
Repeated Measures Analysis of Rest NRS Scores, by Time 
Point  
Table 14.2.6.2 
PP Population 
Repeated Measures Analysis of Rest NRS Scores, by Time 
Point  
Table 14.2.7.1.1 
mITT Population 
Repeated Measures Analysis of Knee Range of Motion and 
Change from Baseline  
Table 14.2.7.1.2 
PP Population 
Repeated Measures Analysis of Knee Range of Motion and 
Change from Baseline  
Table 14.2.7.2.1 
mITT Population 
Repeated Measures Analysis of Knee Range of Motion and 
Change from T48  
Table 14.2.7.2.2 
PP Population 
Repeated Measures Analysis of Knee Range of Motion and 
Change from T48  
Table 14.2.7.3.1 
mITT Population 
Analysis of Percentage of Patients with Active Flexion > 90° 
and > 115°  
Table 14.2.7.3.2 
PP Population 
Analysis of Percentage of Patients with Active Flexion > 90° 
and > 115°  
Table 14.2.7.4.1 
mITT Population 
Categorical Analysis of Knee Extension  
Table 14.2.7.4.2 
PP Population 
Categorical Analysis of Knee Extension  
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Table 14.2.8.1.1 
mITT Population 
Repeated Measures Analysis of KOOS Questionnaire and 
Changes from Baseline  
Table 14.2.8.1.2 
PP Population 
Repeated Measures Analysis of KOOS Questionnaire and 
Changes from Baseline  
Table 14.2.8.2.1 
mITT Population 
Repeated Measures Analysis of KOOS Questionnaire and 
Changes from T96  
Table 14.2.8.2.2 
PP Population 
Repeated Measures Analysis of KOOS Questionnaire and 
Changes from T96  
Table 14.2.9.1 
mITT Population 
Repeated Measures Analysis of Performance Based 
Outcome Measures (PBOM)  
Table 14.2.9.2 
PP Population 
Repeated Measures Analysis of Performance Based 
Outcome Measures (PBOM)  
Table 14.2.10.1 
mITT Population 
Repeated Measures Analysis of PROMIS Questionnaire  
Table 14.2.10.2 
PP Population 
Repeated Measures Analysis of PROMIS Questionnaire  
Table 14.2.11.1 
mITT Population 
Analysis of Percentage of Patients Who Used Opioid Rescue 
Medications  
Table 14.2.11.2 
PP Population 
Analysis of Percentage of Patients Who Used Opioid Rescue 
Medications  
Table 14.2.12.1 
mITT Population 
Analysis of Percentage of Patients Who Experienced an AE 
of Lack of Efficacy During the In-patient Portion of the Study  
Table 14.2.12.2 
PP Population 
Analysis of Percentage of Patients Who Experienced an AE 
of Lack of Efficacy During the In-patient Portion of the Study  
Table 14.2.13.1.1 
mITT Population 
Analysis of Discharge Readiness [1]  
Table 14.2.13.1.2 
PP Population 
Analysis of Discharge Readiness [1]  
Table 14.2.13.2.1 
mITT Population 
Time to Discharge Readiness [1]  
Table 14.2.13.2.2 
PP Population 
Time to Discharge Readiness [1]  
Table 14.2.14.1.1 
 mITT Population 
Rest NRS Scores by Time Point (Primary Analysis - Post-
Rescue Medication Imputation and Post-dropout Imputation) 
Table 14.2.14.1.2 
 PP Population 
Rest NRS Scores by Time Point (Primary Analysis - Post-
Rescue Medication Imputation and Post-dropout Imputation) 
Table 14.2.14.2.1 
 mITT Population 
Rest NRS Scores by Time Point (Sensitivity Analysis of 
Primary Endpoint - Post-Rescue Medication Imputation Only) 
Table 14.2.14.2.2 
 PP Population 
Rest NRS Scores by Time Point (Sensitivity Analysis of 
Primary Endpoint - Post-Rescue Medication Imputation Only) 
Table 14.2.14.3.1 
 mITT Population 
Rest NRS Scores by Time Point (Sensitivity Analysis of 
Primary Endpoint - No Imputations, Observed Scores Only) 
Table 14.2.14.3.2 
 PP Population 
Rest NRS Scores by Time Point (Sensitivity Analysis of 
Primary Endpoint - No Imputations, Observed Scores Only) 
Table 14.2.14.4.1 
 mITT Population 
Evoked NRS Scores by Time Point (Post-dropout Imputation) 
Table 14.2.14.4.2 
 PP Population 
Evoked NRS Scores by Time Point (Post-dropout Imputation) 
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Table 14.2.14.5.1 
 mITT Population 
Evoked NRS Scores by Time Point (No Imputations, 
Observed Scores Only) 
Table 14.2.14.5.2 
 PP Population 
Evoked NRS Scores by Time Point (No Imputations, 
Observed Scores Only) 
Table 14.3.1.1 
Safety Population 
Overall Summary of Treatment Emergent Adverse Events 
(TEAEs)  
Table 14.3.1.2 
Safety Population 
Summary of Treatment Emergent Adverse Events, by System 
Organ Class and Preferred Term  
Table 14.3.1.3 
Safety Population 
Summary of Treatment Related Treatment Emergent Adverse 
Events (TEAEs), by System Organ Class and Preferred Term  
Table 14.3.1.4 
Safety Population 
Summary of Serious Treatment Emergent Adverse Events 
(TEAEs), by System Organ Class and Preferred Term  
Table 14.3.1.5 
Safety Population 
Summary of Treatment Emergent Adverse Events (TEAEs) 
Leading to Study Discontinuation, by System Organ Class 
and Preferred Term  
Table 14.3.1.6 
Safety Population 
Summary of Treatment Emergent Adverse Events, by System 
Organ Class, Preferred Term, and Severity  
Table 14.3.1.7 
Safety Population 
Summary of Treatment Emergent Adverse Events, by System 
Organ Class, Preferred Term, and Relationship to Study Drug  
Table 14.3.1.8 
Safety Population 
Summary of Serious Treatment Emergent Adverse Events, 
by System Organ Class, Preferred Term, and Relationship to 
Study Drug  
Table 14.3.1.9 
Safety Population 
Summary of Fatal Serious Adverse Events, by Preferred 
Term  
Table 14.3.2.1.1 
Safety Population 
Summary of Chemistry Laboratory Tests: Results and 
Change from Baseline  
Table 14.3.2.1.2 
Safety Population 
Summary of Chemistry Laboratory Tests: Shift from Baseline  
Table 14.3.2.2.1 
Safety Population 
Summary of Coagulation Laboratory Tests: Results and 
Change from Baseline  
Table 14.3.2.2.2 
Safety Population 
Summary of Coagulation Laboratory Tests: Shift from 
Baseline  
Table 14.3.2.3.1 
Safety Population 
Summary of Hematology Laboratory Tests: Results and 
Change from Baseline  
Table 14.3.2.3.2 
Safety Population 
Summary of Hematology Laboratory Tests: Shift from 
Baseline  
Table 14.3.2.4.1 
Safety Population 
Summary of Urinalysis Laboratory Tests: Results and 
Change from Baseline  
Table 14.3.2.4.2 
Safety Population 
Summary of Urinalysis Laboratory Tests: Shift from Baseline  
Table 14.3.3 
Safety Population 
Summary of Vital Signs: Results and Change from Baseline  
Table 14.3.4 
Safety Population 
Summary of ECG Overall Interpretation  
Table 14.3.5 
Safety Population 
Summary of Surgical Site Assessment  
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Table 14.3.6 
Safety Population 
Summary of Neurosensory Examination  
Table 14.3.7 
Safety Population 
Summary of Rebound Pain Assessment  
 
15.3.2 Figures 
Figure 14.2.1.1.1 
mITT Population 
Mean Rest NRS Scores Over Time (Primary Analysis - Post-
Rescue Medication Imputation and Post-Dropout Imputation), 
by Treatment Group  
Figure 14.2.1.1.2 
PP Population 
Mean Rest NRS Scores Over Time (Primary Analysis - Post-
Rescue Medication Imputation and Post-Dropout Imputation), 
by Treatment Group  
Figure 14.2.1.2.1 
mITT Population 
Mean Rest NRS Scores Over Time (Sensitivity Analysis of 
Primary Endpoint - Post-Rescue Medication Imputation Only), 
by Treatment Group  
Figure 14.2.1.2.2 
PP Population 
Mean Rest NRS Scores Over Time (Sensitivity Analysis of 
Primary Endpoint - Post-Rescue Medication Imputation Only), 
by Treatment Group 
Figure 14.2.1.3.1 
mITT Population 
Mean Rest NRS Scores Over Time (Sensitivity Analysis of 
Primary Endpoint - No Imputation, Observed Scores Only), by 
Treatment Group  
Figure 14.2.1.3.2 
PP Population 
Mean Rest NRS Scores Over Time (Sensitivity Analysis of 
Primary Endpoint - No Imputations, Observed Scores Only), by 
Treatment Group 
Figure 14.2.1.4.1 
mITT Population 
Mean Evoked NRS Scores Over Time (Post-dropout 
Imputation) , by Treatment Group  
Figure 14.2.1.4.2 
PP Population 
Mean Evoked NRS Scores Over Time ((Post-dropout 
Imputation), by Treatment Group  
Figure 14.2.1.5.1 
mITT Population 
Mean Evoked NRS Scores Over Time (No Imputations, 
Observed Scores Only), by Treatment Group 
Figure 14.2.1.5.2 
PP Population 
Mean Evoked NRS Scores Over Time (No Imputations, 
Observed Scores Only), by Treatment Group 
Figure 14.2.1.6 
mITT Population 
Silverman Rank Analysis Scores, by Treatment Group  
Figure 14.2.2.1.1 
mITT Population 
Mean Rest NRS AUC, by Treatment Group  
Figure 14.2.2.1.2 
PP Population 
Mean Rest NRS AUC, by Treatment Group  
Figure 14.2.2.2.1 
mITT Population 
Mean Evoked NRS AUC, by Treatment Group  
Figure 14.2.2.2.2 
PP Population 
Mean Evoked NRS AUC, by Treatment Group  
Figure 14.2.3.1.1 
mITT Population 
Total Opioid Consumption in OME Doses, by Treatment Group  
Figure 14.2.3.1.2 
PP Population 
Total Opioid Consumption in OME Doses, by Treatment Group  
Figure 14.2.3.2.1 
mITT Population 
Total Non-opioid Analgesic Consumption (mg), by Treatment 
Group  
Figure 14.2.3.2.2 
PP Population 
Total Non-opioid Analgesic Consumption (mg), by Treatment 
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Group  
Figure 14.2.3.3.1 
mITT Population 
Time to Cessation of Opioid Use  
Figure 14.2.3.3.2 
PP Population 
Time to Cessation of Opioid Use  
Figure 14.2.3.4.1 
mITT Population 
Cumulative Opioid Use  
Figure 14.2.3.4.2 
PP Population 
Cumulative Opioid Use  
Figure 14.2.4.1 
mITT Population 
Time to Discharge Readiness  
Figure 14.2.4.2 
PP Population 
Time to Discharge Readiness  
 
15.3.3 Listings 
Listing 16.2.1.1 
All Patients 
Randomization and Study Population  
Listing 16.2.1.2 
All Patients 
Informed Consent and Re-Consent  
Listing 16.2.1.3 
All Patients 
Eligibility  
Listing 16.2.1.4 
All Patients 
Patient Disposition/Early Termination  
Listing 16.2.2 
All Patients 
Protocol Deviations  
Listing 16.2.4.1 
All Randomized Patients 
Demographics and Baseline Characteristics  
Listing 16.2.4.2 
All Randomized Patients 
Medical / Surgical History  
Listing 16.2.4.3 
All Randomized Patients 
Prior and Concomitant Medications 
Listing 16.2.4.4 
All Randomized Patients 
Rescue Medication Administration 
Listing 16.2.4.5 
All Randomized Patients 
Non-Medication Therapies 
Listing 16.2.4.6 
All Randomized Patients  
Surgery 
Listing 16.2.5   
All Randomized Patients 
Study Drug Administration, Pain Assessment 
Training, and Discharge   
Listing 16.2.6.1   
All Randomized Patients 
Pain Intensity Assessment (Rest NRS)   
Listing 16.2.6.2   
All Randomized Patients 
Pain Intensity Assessment (Evoked NRS)   
Listing 16.2.6.3   
All Randomized Patients 
Primary Endpoint Rest NRS AUC   
Listing 16.2.6.4   
All Randomized Patients 
Secondary and Exploratory Rest NRS AUC Efficacy 
Endpoints (LOCF)  
Listing 16.2.6.5   
All Randomized Patients 
Evoked NRS AUC Efficacy Endpoints (LOCF)  
Listing 16.2.6.6   
All Randomized Patients 
Total Opioid Consumption (OME Dose) and Non-
opioid Analgesic Consumption (mg) Efficacy 
Endpoints  
Listing 16.2.6.7   
All Randomized Patients 
Opioid-free Efficacy Endpoints  
Listing 16.2.6.8 
All Randomized Patients 
Knee Range of Motion  
Listing 16.2.6.9.1 
All Randomized Patients 
KOOS Questionnaire Scales  
Listing 16.2.6.9.2 
All Randomized Patients 
KOOS Questionnaire Details  
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Listing 16.2.6.10 
All Randomized Patients 
Sit to Stand Test  
Listing 16.2.6.11 
All Randomized Patients 
Walking Speed Test  
Listing 16.2.6.12 
All Randomized Patients 
Timed Up and Go Test  
Listing 16.2.6.13.1 
All Randomized Patients 
PROMIS Questionnaire Scales  
Listing 16.2.6.13.2 
All Randomized Patients 
PROMIS Questionnaire Details  
Listing 16.2.6.14   
All Randomized Patients 
Use of Rescue Medications Efficacy Endpoints  
Listing 16.2.6.15 
All Randomized Patients 
Discharge Readiness  
Listing 16.2.7.1   
All Randomized Patients 
Adverse Events   
Listing 16.2.7.2   
All Randomized Patients 
Serious Adverse Events   
Listing 16.2.7.3   
All Randomized Patients 
Treatment Related Adverse Events  
Listing 16.2.7.4   
All Randomized Patients 
Adverse Events Leading to Study Discontinuation  
Listing 16.2.8.1 
All Randomized Patients 
Chemistry Laboratory Test Results  
Listing 16.2.8.2 
All Randomized Patients 
Coagulation Laboratory Test Results  
Listing 16.2.8.3 
All Randomized Patients 
Hematology Laboratory Test Results  
Listing 16.2.8.4 
All Randomized Patients 
Urinalysis Laboratory Test Results  
Listing 16.2.8.5 
All Randomized Patients 
Alcohol and Urine Drug Screen Tests  
Listing 16.2.8.6 
All Randomized Patients 
Pregnancy Test  
Listing 16.2.9.1   
All Randomized Patients 
Vital Signs   
Listing 16.2.9.2   
All Randomized Patients 
12-Lead Electrocardiogram   
Listing 16.2.9.3 
All Randomized Patients 
Physical Examination   
Listing 16.2.9.4   
All Randomized Patients 
Surgical Site Assessment and Rebound Pain 
Assessment   
Listing 16.2.9.5   
All Randomized Patients 
Neurosensory Examination   
Listing 16.2.9.6   
All Randomized Patients 
Knee X-Ray   
 
 
 
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16. DOCUMENT HISTORY 
Version 
# 
Summary of Changes 
Section Changed 
Date 
1.0 
Initial document released 
NA 
21Jun2020 
2.0 
• 
specify treatment group (planned or 
treatment received) will be analyzed for each 
analysis population 
• 
Add the rule of using the higher score if the 
same date/time results not covered by the 
current situation 
• 
Remove “ If additional opioids, other than 
the study rescue medications, are 
identified on the concomitant medications 
eCRF page, those additional medications 
will also be included in the opioid use 
calculation”  because CM page will NOT be 
checked (data cleaning will address the 
issue)  
• 
Add 3 sets of tables/figures to visualize the 
effect of censoring scheduled rest NRS 
scores due to the administration of rescue 
medication 
• 
For OF24-96 (one of the key secondary 
endpoints), one-sided Fisher's exact test will 
be used instead of the two-sided CMH test 
• 
Add a category of  < 0o, for  active extension 
and passive extension due to negative value 
• 
4.1 
• 
7.3.2 
• 
7.3.5 
• 
7.4.3.5 
• 
7.4.6 
• 
7.4.8 
07Oct2020 
3.0 
• 
Update the definition of Per-Protocol 
population to include subjects who 
experienced AE of LOE  
• 
4.1 
 
 
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Viewed: 11/12/2020 5:03:40 PM 
Electronic Record and Signature Disclosure: 
      Accepted: 12/16/2019 1:58:19 PM
      ID: 1e97b2f0-14cb-42ed-891b-25a007858d2e
Witness Events
Signature
Timestamp
Notary Events
Signature
Timestamp
Envelope Summary Events
Status
Timestamps


Envelope Summary Events
Status
Timestamps
Envelope Sent
Hashed/Encrypted
11/12/2020 1:51:33 PM
Certified Delivered
Security Checked
11/12/2020 1:54:03 PM
Signing Complete
Security Checked
11/12/2020 1:54:32 PM
Completed
Security Checked
11/13/2020 2:10:24 AM
Payment Events
Status
Timestamps
Electronic Record and Signature Disclosure


ELECTRONIC RECORD AND SIGNATURE DISCLOSURE
Please read the information below carefully and thoroughly. By checking the “I agree to use
Electronic Records and Signatures” box in the DocuSign system, you confirm you can access
this information electronically to your satisfaction and agree to these terms and conditions
below. 
Getting paper copies
At any time, you may request from us a paper copy of any record provided or made available
electronically to you by us. You will have the ability to download and print documents we send
to you through the DocuSign system during and immediately after signing session. If you wish
for us to send you paper copies of any such documents from our office to you, please contact
your Lotus Lead Project Manager. 
Withdrawing your consent 
If you decide to receive documents from us electronically, you may at any time change your
mind and tell us thereafter that you want to receive documents only in paper format. If you want
to withdraw your consent and receive future documents in paper format, please contact your
Lotus Lead Project Manager. 
Consequences of changing your mind
If you elect to receive documents only in paper format, it will slow the speed at which we can
complete certain steps in transactions with you and delivering services to you because we will
need first to send the documents to you in paper format, and then wait until we receive back from
you and your execution of such paper documents. To indicate to us that you are changing your
mind within the DocuSign system, you must withdraw your consent using the DocuSign “
Withdraw Consent” form on the signing page of a DocuSign envelope instead of signing it. This
will indicate to us that you have withdrawn your consent to receive documents electronically
from us and you will no longer be able to use the DocuSign system to receive documents
electronically from us or to sign electronically documents from us. 
All documents will be sent to you electronically
Unless you tell us otherwise in accordance with the procedures described herein, we will provide
electronically to you through the DocuSign system all documents that require your signature
during the course of our relationship with you. All documents will be sent to you through your
e-mail as recorded in the study-specific Study Contact Sheet. If you do not agree with this
process, please let us know as described below. Please also see the paragraph immediately above
that describes the consequences of your electing not to receive delivery of the notices and
disclosures electronically from us. 
How to contact Lotus Clinical Research, LLC:
You may contact us to let us know of your changes as to how we may contact you electronically,
to request paper copies of certain information from us, and to withdraw your prior consent to
receive notices and disclosures electronically:
 
To advise Lotus Clinical Research, LLC of your new e-mail address 
To let us know of a change in your e-mail address, you must send an email message to your
Lotus Lead Project Manager and in the body of such request you must state: your previous
e-mail address, your new e-mail address. We do not require any other information from you to
change your email address. 
In addition, you must notify DocuSign, Inc. to arrange for your new email address to be reflected
Electronic Record and Signature Disclosure created on: 8/14/2017 10:16:15 AM
Parties agreed to: HENRY FOEHL, Leonid Zeitlin, Sam Teichman, Song Liou, Nina Green


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