Clinical trial NCT03974932
Conditions: Analgesia
Keywords: total knee arthroplasty postoperative pain multimodal analgesia
Sponsor: Heron Therapeutics
Start date: 2019-06-05; Completion date: 2021-01-07
Enrollment: 116 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
Phase 3b, open-label single-arm study in which all subjects receive HTX-011 as part of a scheduled non-opioid MMA regimen.

Detailed description:

Arms: arm 1: HTX-011 + MMA arm 2: HTX-011 + MMA arm 3: HTX-011 + MMA arm 4: HTX-011 + MMA
Interventions: intervention 1: HTX-011 intervention 2: Ibuprofen intervention 3: Acetaminophen intervention 4: Celecoxib intervention 5: +/- Bupivacaine HCl intervention 6: Luer Lock Applicator intervention 7: HTX-011
Intervention descriptions: intervention 1: Dual-acting local anesthetic. Dose 1. intervention 2: NSAID. intervention 3: Analgesic. intervention 4: NSAID. intervention 5: Local anesthetic. intervention 6: Applicator for instillation. intervention 7: Dual-acting local anesthetic. Dose 2.

Protocol documents:
Prot_000.pdf: 
Document Type:  
Study Protocol 
Official Title:  
A Phase 3b, Open-Label Study of HTX-011 as Part of a 
Scheduled Non-Opioid Multimodal Analgesic Regimen in 
Subjects Undergoing Total Knee Arthroplasty 
NCT Number:  
NCT03974932 
Document Date:  
02-Jul-2020 
 


Confidentiality Statement 
This document contains confidential information of Heron Therapeutics, Inc. 
Do not copy or distribute without prior written permission of the Sponsor. 
Any unauthorized use, reproduction, publication, or dissemination is strictly prohibited. 
 
 
CLINICAL STUDY PROTOCOL: HTX-011-306 
Protocol Title: 
A Phase 3b, Open-Label Study of HTX-011 as Part of a 
Scheduled Non-Opioid Multimodal Analgesic Regimen in 
Subjects Undergoing Total Knee Arthroplasty 
Brief Title: 
TKA Study of HTX-011 in an MMA Regimen 
Investigational Product: 
HTX-011 (bupivacaine and meloxicam) extended-release solution 
Phase of Development: 
3b 
Sponsor: 
Heron Therapeutics, Inc. 
4242 Campus Point Court, Suite 200 
San Diego, CA 92121 
1-858-251-4400 
Medical Monitor: 
 
 
 
Medical Project Leader: 
  
 
 
 
Protocol Version: 
Version 6 
02 July 2020 
 
Version 5 
12 September 2019 
 
Version 4 
07 August 2019 
 
Version 3 
26 June 2019 
 
Version 2 
29 May 2019 
 
Version 1 
30 April 2019 
 
 


Protocol No: HTX-011-306, Version 6 
Heron Therapeutics, Inc. 
TKA Study of HTX-011 in an MMA Regimen 
Confidential 
2 
SPONSOR SIGNATURE 
 
Protocol Title: 
A Phase 3b, Open-Label Study of HTX-011 as Part of a Scheduled 
Non-Opioid Multimodal Analgesic Regimen in Subjects 
Undergoing Total Knee Arthroplasty 
Protocol Number: 
HTX-011-306 
 
 
This protocol Version 6 has been reviewed and approved by the Sponsor. 
 
 
The electronic signature is appended. 
 
 
Heron Therapeutics, Inc. 
 
 


Protocol No: HTX-011-306, Version 6 
Heron Therapeutics, Inc. 
TKA Study of HTX-011 in an MMA Regimen 
Confidential 
3 
INVESTIGATOR AGREEMENT 
CLINICAL STUDY PROTOCOL: HTX-011-306 
TITLE: A Phase 3b, Open-Label Study of HTX-011 as Part of a Scheduled Non-Opioid 
Multimodal Analgesic Regimen in Subjects Undergoing Total Knee Arthroplasty 
I have read the protocol and agree that it contains all necessary details for carrying out this study. 
I am qualified by education, experience, and training to conduct this clinical research study. I 
will conduct the study as outlined herein. 
I will provide copies of the protocol, the Investigator’s Brochure, and all other information on 
the investigational product that were furnished to me by the Sponsor to all physicians and other 
study personnel responsible to me who participate in this study, and will discuss this material 
with them to ensure that they are fully informed regarding the investigational product and the 
conduct of the study. 
I agree to keep records on all subject information (ie, medical records, Case Report Forms, and 
informed consent statements), study drug shipment and return forms, and all other information 
collected during the study in accordance with local and national Good Clinical Practice (GCP) 
guidelines. 
 
Principal Investigator: 
 
Address: 
 
Signature: 
 
Date: 
 
 


Protocol No: HTX-011-306, Version 6 
Heron Therapeutics, Inc. 
TKA Study of HTX-011 in an MMA Regimen 
Confidential 
4 
PROTOCOL SYNOPSIS 
NAME OF SPONSOR: 
Heron Therapeutics, Inc. 
NAME OF FINISHED PRODUCT: 
HTX-011 (bupivacaine and meloxicam) 
extended-release solution 
NAME OF ACTIVE INGREDIENTS: 
bupivacaine and meloxicam 
PROTOCOL NUMBER: 
HTX-011-306 
PHASE OF DEVELOPMENT: 
3b 
PROTOCOL TITLE: A Phase 3b, Open-Label Study of HTX-011 as Part of a Scheduled Non-Opioid 
Multimodal Analgesic Regimen in Subjects Undergoing Total Knee Arthroplasty 
STUDY SITES: Up to 6 sites in the United States (US). 
STUDY OBJECTIVES: 
Primary 
• To assess pain control following HTX-011 as part of a scheduled non-opioid multimodal analgesic 
(MMA) regimen in subjects undergoing total knee arthroplasty (TKA). 
Secondary 
• To assess total opioid use following HTX-011 as part of a scheduled non-opioid MMA regimen in 
this study population. 
• To assess the proportion of subjects who are opioid-free after receiving HTX-011 as part of a 
scheduled non-opioid MMA regimen in this study population. 
• To assess the safety and tolerability of HTX-011 in a multimodal setting in this study population. 
• To characterize the pharmacokinetic (PK) parameters of bupivacaine and meloxicam in this study 
population. 
BACKGROUND AND RATIONALE FOR THE STUDY: Up to 70% of patients have moderate to 
severe pain after surgery, and as a result, many receive opioids. Poorly managed pain and opioid-related 
adverse reactions resulting in worse patient outcomes and increased hospital costs. Opioid use also 
increases the risk of long-term use and abuse. Therefore, there is a significant unmet need for a more 
effective non-opioid analgesic that provides sustained pain relief and reduces or eliminates the need for 
opioids, especially in the first 72 hours following surgery. 
Heron Therapeutics, Inc. (Heron) has developed HTX-011 for application into the surgical site to reduce 
postoperative pain for 72 hours and the need for opioid analgesics. HTX-011 is a novel, non-opioid, 
fixed-dose, extended-release anesthetic containing bupivacaine and low-dose meloxicam formulated in a 
proprietary polymer that enables extended release of the products simultaneously for approximately 
3 days. Bupivacaine is an amide-type local anesthetic and meloxicam is a nonsteroidal anti-inflammatory 
drug (NSAID). HTX-011 is administered as a single dose. In a prior Phase 2b study in TKA (Study 209), 
HTX-011 400 mg/12 mg with or without ropivacaine injected into the posterior capsule significantly 
reduced pain over 48 hours and 72 hours compared with saline placebo despite the absence of a 
background scheduled MMA regimen. Although almost all subjects required opioid rescue during the 
72-hour postoperative period, HTX-011 reduced total opioid consumption. 
This Phase 3b study will evaluate if HTX-011 administered as the foundation of a scheduled non-opioid 
MMA regimen can further improve pain control and lead to greater reduction or eliminate the need for 
opioids following primary unilateral TKA. Multimodal analgesia for the treatment of postoperative pain is 


Protocol No: HTX-011-306, Version 6 
Heron Therapeutics, Inc. 
TKA Study of HTX-011 in an MMA Regimen 
Confidential 
5 
recommended in the American Pain Society guidelines. The analgesic regimen in Cohorts 1 to 3 in this 
study, acetaminophen and celecoxib, was selected based on published literature. Acetaminophen and 
celecoxib have different mechanisms of action and may therefore increase effectiveness without 
increasing risk. The study will also evaluate the contribution of bupivacaine HCl injection into the 
posterior capsule on the reduction of postoperative pain in Cohort 3. 
An additional fourth cohort has been added to test the hypothesis that the postoperative nonspecific 
cyclooxygenase (COX) inhibition of ibuprofen will contribute more to postoperative analgesia and 
therefore work better with HTX-011, as opposed to the COX-2 specific inhibition gained from celecoxib, 
which contributes more to an anti-inflammatory effect and therefore may be duplicative to the impact of 
the local meloxicam applied as part of HTX-011. 
METHODOLOGY: This is a Phase 3b, open-label, multicohort study in which all subjects will receive 
HTX-011 as part of a scheduled non-opioid MMA regimen.  
Study Overview 
Subjects will be screened within 28 days prior to the planned surgery date and eligibility will be 
confirmed on the day of surgery. Subjects who meet the eligibility criteria will be enrolled in the study 
and will undergo primary unilateral TKA under bupivacaine spinal anesthesia (≤20 mg).  
All subjects will receive HTX-011 as part of a non-opioid MMA regimen consisting of acetaminophen, an 
NSAID, and a gabapentanoid prior to surgery, a single dose of HTX-011 during surgery, and scheduled 
acetaminophen and an NSAID for 7 days following surgery. Up to 115 subjects will be dosed in 
4 sequential cohorts:  
• Cohort 1: Approximately 50 subjects will be administered  a single dose of HTX-011 400 mg/12 mg 
via periarticular application into the surgical site during surgery. 
• Cohort 2: Approximately 15 subjects will be administered a single dose of HTX-011 400 mg/12 mg 
via periarticular application into the surgical site during surgery. Drains will be prohibited. 
• Cohort 3: Approximately 30 subjects will be randomized into 2 groups. In Group A, subjects will be 
administered a single dose of HTX-011 300 mg/9 mg via periarticular application into the surgical 
site during surgery. In Group B, subjects will be administered a single dose of HTX-011 
300 mg/9 mg via periarticular application into the surgical site and 100 mg bupivacaine HCl injected 
into the posterior capsule during surgery. Drains will be prohibited. 
• Cohort 4: Up to approximately 20 subjects will be administered a single dose of HTX-011 
400 mg/12 mg via periarticular application into the surgical site during surgery. 
On the day of surgery (Day 1), subjects will be administered oral (PO) acetaminophen 1 g, PO celecoxib 
200 mg, and PO pregabalin 300 mg just before being taken to the operating room. During surgery, a 
single dose of HTX-011 will be administered via periarticular application into the surgical site in all study 
cohorts. Bupivacaine HCl will be administered into the posterior capsule in Group B of Cohort 3. The use 
of intravenous (IV) fentanyl up to 4 μg/kg will be permitted during surgery for intraoperative pain 
control. Subjects will remain in the hospital/research facility for 72 hours from the start of study drug 
administration to undergo postoperative efficacy, safety, and PK assessments.  
Subjects will receive a scheduled non-opioid MMA regimen over the 72-hour postoperative period 
consisting of PO acetaminophen 1 g every 8 hours and PO celecoxib 200 mg every 12 hours (Cohorts 1, 
2, and 3) or PO acetaminophen 1 g every 8 hours and PO ibuprofen 600 mg every 6 hours (Cohort 4).  
After the 72-hour assessments have been completed, subjects may be discharged. Subjects in all cohorts 
will continue a scheduled MMA regimen for 4 days after discharge consisting of PO ibuprofen alternating 
with PO acetaminophen. Thereafter, subjects may continue acetaminophen and/or ibuprofen as needed. 
Subjects will return to the study site on Days 11 and 29 for follow-up assessments. 
 


Protocol No: HTX-011-306, Version 6 
Heron Therapeutics, Inc. 
TKA Study of HTX-011 in an MMA Regimen 
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Inpatient Postoperative Rescue Medication 
During the 72-hour postoperative period, subjects should only receive rescue medication upon request for 
pain control. Rescue medication should not be given for pain prophylaxis, but only for treating 
postoperative pain. Prior to the administration of the first dose of rescue medication, if the subject has not 
already had at least 1 postoperative pain score assessed, then pain intensity scores using the visual 
analogue scale (VAS) and numeric rating scale (NRS) must be obtained. 
Postoperative rescue medication will consist only of any 1 or more of the following opioid medications, 
as needed: PO immediate-release oxycodone (≤10 mg within a 4-hour period), IV morphine (2.5 mg to 
5 mg within a 4-hour period), and/or IV hydromorphone (0.5 mg to 1.0 mg within a 4-hour period). 
Combination products containing an opioid and non-opioid are not allowed. With the exception of the 
protocol-specified MMA medications, no other analgesic agents, including other NSAIDs, are permitted 
during the 72-hour postoperative period. Note: Acetaminophen is not to be given as a rescue medication 
as it is part of the postoperative scheduled MMA regimen. 
Opioid Prescriptions at and After Discharge 
If a subject did not receive any opioids or received <10 mg of oxycodone within 12 hours prior to 
discharge, the subject should not receive an opioid prescription at discharge. If a subject received ≥10 mg 
of oxycodone within 12 hours prior to discharge, the Investigator may provide the subject with a 
prescription for immediate-release PO oxycodone tablets: no more than thirty 5 mg immediate-release 
oxycodone, take 1 to 2 pills (5 mg to 10 mg) every 4 hours as needed. The prescription must indicate that 
substitutions with any other opioid-containing product are not permitted, including combination 
opioid/non-opioid products. 
Sites will record if subjects are discharged with an opioid prescription and information about the opioid 
prescription. All subjects (whether or not they were discharged with an opioid prescription) will be 
provided a daily diary to record any opioid medication use from discharge through the Day 11 Visit. Sites 
will record all site- or subject-initiated contact between discharge and the Day 11 Visit and if any contact 
resulted in issuing an opioid prescription. 
Postoperative Analgesia After Discharge 
Upon discharge, subjects will be instructed to manage their pain while awake over the next 4 days with 
the following scheduled MMA regimen: PO ibuprofen 600 mg every 6 hours, alternating with PO 
acetaminophen 1 g every 6 hours, so that an analgesic is taken approximately every 3 hours. Thereafter, 
subjects may continue one or both of the MMA medications as needed, but should not exceed ibuprofen 
600 mg every 6 hours or acetaminophen 1 g every 6 hours (maximum ibuprofen dose of 2.4 g/day and 
maximum acetaminophen dose of 4 g/day). 
Other Scheduled Study Medications 
All subjects will also receive IV tranexamic acid (TXA) and PO acetylsalicylic acid for antifibrinolysis 
and deep vein thrombosis (DVT) prophylaxis, respectively. TXA 1g IV will be administered within 
approximately 4 hours prior to the start of surgery and a second dose will be administered up to 
approximately 8 hours later. Subjects will receive acetylsalicylic acid 325 mg PO twice a day (BID) 
following surgery until discharge. 
Prohibited Medications 
Other than the protocol-required study medications, any drug formulation containing bupivacaine or 
meloxicam is prohibited before surgery (within 5 days for bupivacaine and within 10 days for 
meloxicam), during surgery, and following surgery through Day 11 Visit. Refer to exclusion criteria 4 
through 13 for medications that are prohibited during the study. 
NUMBER OF PLANNED SUBJECTS: Approximately 115 subjects will be enrolled and dosed. 


Protocol No: HTX-011-306, Version 6 
Heron Therapeutics, Inc. 
TKA Study of HTX-011 in an MMA Regimen 
Confidential 
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STUDY POPULATION: 
Inclusion Criteria 
Each subject must meet all of the following criteria to be enrolled in this study: 
1. Is able to provide written informed consent. 
2. Is able to adhere to the study visit schedule and complete all study assessments. 
3. Is male or female, and ≥18 years of age at screening. 
4. Is scheduled to undergo primary unilateral TKA under spinal anesthesia (all cohorts) and without 
drains in Cohorts 2 and 3. 
5. Has not previously undergone TKA in either knee. 
6. Has an American Society of Anesthesiologists Physical Status of I, II, or III. 
7. Is able to walk at least 20 feet with optional use of a 4-legged walker for balance. 
8. Female subjects are eligible only if all of the following apply: 
a. Not pregnant (female subject of child-bearing potential must have a negative urine pregnancy 
test at Screening and on Day 1 before surgery). 
b. Not lactating. 
c. Not planning to become pregnant during the study. 
d. Is surgically sterile; or is at least 2 years post-menopausal; or is in a monogamous 
relationship with a partner who is surgically sterile; or is practicing double-barrier 
contraception; or practicing abstinence (must agree to use double-barrier contraception in the 
event of sexual activity); or is using an insertable, injectable, transdermal, or combination PO 
contraceptive approved by the US Food and Drug Administration (FDA) and commits to the 
use of an acceptable form of birth control from the Screening Visit until 30 days after study 
drug administration. Note: women in only a same-sex relationship do not need to meet this 
criterion. 
Exclusion Criteria 
A subject who meets any of the following criteria will be excluded from the study: 
1. Has a planned concurrent surgical procedure (eg, bilateral TKA) during the study. 
2. Has a pre-existing, concurrent, acute or chronic, painful physical/restrictive condition expected to 
require analgesic treatment in the postoperative period for pain that is not strictly related to the 
knee surgery and which may confound the postoperative assessments. 
3. Has a contraindication or a known or suspected history of hypersensitivity or clinically significant 
idiosyncratic reaction (including methemoglobinemia) to bupivacaine (or other local anesthetics), 
NSAIDs (eg, meloxicam, ibuprofen, celecoxib), oxycodone, morphine, hydromorphone, TXA, 
fentanyl, pregabalin, acetaminophen, or acetylsalicylic acid. 
4. Using or expected to use Factor IX Complex or anti-inhibitor coagulant concentrates during the 
study. 
5. Has known or suspected daily use of opioids for 7 or more consecutive days within the previous 
6 months. 
6. Has taken NSAIDs (including meloxicam) within 10 days prior to the scheduled surgery with the 
exception of subjects on low-dose (≤100 mg) daily acetylsalicylic acid for cardioprotection. 
7. Has taken long-acting opioids within 3 days prior to the scheduled surgery. 
8. Has taken any opioids within 24 hours prior to the scheduled surgery. 
9. Has been administered bupivacaine within 5 days prior to the scheduled surgery. 
10. Has been administered any local anesthetic within 72 hours prior to the scheduled surgery, other 
than for pretreatment prior to a needle placement, to treat an adverse event (AE) that occurs after 


Protocol No: HTX-011-306, Version 6 
Heron Therapeutics, Inc. 
TKA Study of HTX-011 in an MMA Regimen 
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signing the informed consent form (ICF), or to decrease venous irritation caused by propofol, if 
needed (in which case, no more than a single administration of lidocaine 1% 20 mg IV may be 
administered). 
11. Has initiated treatment with any of the following medications within 1 month prior to study drug 
administration or is taking any of these medications to control pain: selective serotonin reuptake 
inhibitors (SSRIs), selective norepinephrine reuptake inhibitors (SNRIs), gabapentin, pregabalin, 
duloxetine, or COX-2 inhibitors. (Note: If a subject is taking one of these medications for a 
reason other than pain control, the subject must be on a stable scheduled dose [ie, not “as 
needed”] for at least 1 month prior to study drug administration). Anxiolytics prior to surgery are 
permitted, if necessary. 
12. Has been administered systemic steroids within 5 half-lives or 10 days prior to administration of 
study drug (whichever is longer). Note that for purposes of this exclusion criterion, inhaled, 
ophthalmic, and over-the-counter steroids are not considered systemic. 
13. Previously participated in a clinical study or received an investigational product or device in a 
clinical trial within 30 days or within 5 elimination half-lives (whichever is longer) prior to the 
scheduled surgery, or is planning to take part in another clinical trial while participating in this 
study. 
14. Has a known or suspected history of drug abuse, a positive drug screen on the day of surgery, or a 
history of alcohol abuse (within 10 years). Note: Subjects with a positive drug screen who are 
taking an allowed, prescribed medication that is known to result in a positive drug test 
(eg, amphetamine and dextroamphetamine for attention-deficit/hyperactivity disorder, 
benzodiazepine for anxiety disorder) may be eligible for participation in the study. Subjects with 
a positive drug screen for cannabinoids on the day of surgery will not be allowed to participate in 
the study. 
15. Has a medical condition such that, in the opinion of the Investigator, participating in the study 
would pose a health risk to the subject or confound the postoperative assessments. Conditions 
may include, but are not limited to, any of the following: 
a. History of clinically significant cardiac abnormality such as myocardial infarction within 
6 months prior to signing the ICF, New York Heart Association class III or IV, or clinically 
significant abnormalities of electrocardiogram (ECG) or cardiac function. 
b. History of coronary artery bypass graft surgery within 12 months prior to signing the ICF. 
c. Severe liver function impairment as defined by Child-Pugh Class C, having an aspartate 
aminotransferase >3 × the upper limit of normal (ULN), or having an alanine 
aminotransferase >3 × ULN. 
d. Severe kidney function impairment as defined by creatinine clearance (Cockcroft-Gault) 
<30 mL/min or on dialysis. 
e. History of known or suspected coagulopathy or uncontrolled anticoagulation (platelet count 
<100,000/μL; hemoglobin <12 g/dL; or hematocrit <35%). 
f. Loss of sensation in extremities or significant peripheral neuropathy. 
g. Known history of glucose-6-phosphate dehydrogenase deficiency. 
16. Is currently undergoing treatment for hepatitis B, hepatitis C, or HIV. 
17. Has uncontrolled anxiety, psychiatric, or neurological disorder that, in the opinion of the 
Investigator, might interfere with study assessments. 
18. Has acquired defective color vision or acute gastrointestinal ulcers, either of which could interfere 
with scheduled study medications. 
19. Has any chronic neuromuscular deficit of either femoral nerve function or thigh musculature. 
20. Has any chronic condition or disease that would compromise neurological or vascular 


Protocol No: HTX-011-306, Version 6 
Heron Therapeutics, Inc. 
TKA Study of HTX-011 in an MMA Regimen 
Confidential 
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assessments. 
21. Had a malignancy in the last year, with the exception of nonmetastatic basal cell or squamous cell 
carcinoma of the skin or localized carcinoma in situ of the cervix. 
22. Has undergone 3 or more surgeries within 12 months prior to signing the ICF, other than for 
diagnostic procedures (eg, colonoscopy). 
23. Has a body mass index (BMI) >40 kg/m2. 
INVESTIGATIONAL PRODUCT, DOSE, AND MODE OF ADMINISTRATION: 
HTX-011 is a fixed-dose, extended-release anesthetic that contains bupivacaine and low-dose meloxicam. 
Bupivacaine is an amide-type local anesthetic and meloxicam is an NSAID. 
 
. 
HTX-011 will be supplied by the Sponsor as a clear, pale yellow to yellow, viscous liquid in single-dose 
20 mL glass vials. 
All subjects will receive a single dose of HTX-011. Subjects in Cohorts 1, 2, and 4 will receive 
400 mg/12 mg (bupivacaine/meloxicam doses). Subjects in Cohort 3 will receive 300 mg/9 mg.  
HTX-011 will be administered intraoperatively by periarticular application into the surgical site with a 
Luer lock applicator (without a needle) distributed to 3 areas: (1) the posterior capsule (except Group B of 
Cohort 3), (2) the anteromedial tissues and periosteum, and (3) the anterolateral tissues and periosteum. 
REFERENCE THERAPY, DOSE, AND MODE OF ADMINISTRATION: None. 
ADDITIONAL STUDY MEDICATION, DOSE, AND MODE OF ADMINISTRATION: 
Additional study medication includes bupivacaine HCl, scheduled non-opioid MMA, and antifibrinolysis 
and DVT prophylaxis. Study sites will supply the additional study medication. 
Bupivacaine HCl 
All subjects will be administered bupivacaine HCl 0.5% or 0.75%, per institutional practice, as part of the 
spinal anesthesia during surgery. The dose of bupivacaine should not exceed a maximum of 20 mg 
(ie, maximum of 4 mL of bupivacaine 0.5% or maximum of 2.6 mL of bupivacaine 0.75%). 
Subjects in Group B of Cohort 3 will be administered 100 mg of bupivacaine HCl 0.25% or 0.5% as a 
40 mL injection into the posterior capsule during surgery just prior to placement of the prosthesis 
(ie, 40 mL of 0.25% or 20 mL of 0.5% diluted with 20 mL of 0.9% Normal Saline for a total of 40 mL). 
Scheduled Non-Opioid Multimodal Analgesic Regimen 
All subjects will follow a scheduled MMA regimen.  
Preoperatively, all subjects will receive PO acetaminophen 1 g, PO celecoxib 200 mg, and PO pregabalin 
300 mg just before being taken to the operating room.  
After surgery, subjects will receive a scheduled non-opioid MMA regimen for 7 days. The first dose of 
the postoperative MMA regimen will be administered once the subject is able to tolerate PO intake. For 
the first 3 days after surgery, the MMA regimen will consist of PO acetaminophen 1 g every 8 hours and 
PO celecoxib 200 mg every 12 hours (Cohorts 1, 2, and 3) or PO acetaminophen 1 g every 8 hours and 
PO ibuprofen 600 mg every 6 hours (Cohort 4). For the next 4 days, the MMA regimen for all cohorts 
will consist of PO ibuprofen 600 mg every 6 hours alternating with PO acetaminophen 1 g every 6 hours 
(maximum ibuprofen dose of 2.4 g/day and maximum acetaminophen dose of 4 g/day) while the subject 
is awake, so that an analgesic is taken approximately every 3 hours. 
Antifibrinolysis and DVT Prophylaxis 
All subjects will be administered TXA and acetylsalicylic acid for antifibrinolysis and DVT prophylaxis, 
respectively, consistent with clinical practice for TKA. TXA 1g IV will be administered within 
approximately 4 hours prior to the start of surgery and a second dose will be administered up to 
approximately 8 hours later. Subjects will receive acetylsalicylic acid 325 mg PO BID following surgery 


Protocol No: HTX-011-306, Version 6 
Heron Therapeutics, Inc. 
TKA Study of HTX-011 in an MMA Regimen 
Confidential 
10 
until discharge. 
DURATION OF TREATMENT: Subjects will receive a single dose of study drug (HTX-011) during 
surgery and 7 days of a scheduled non-opioid MMA regimen. Subjects in Group B of Cohort 3 will also 
receive bupivacaine HCl via injection into the posterior capsule during surgery. The total duration of 
study participation for each subject (from Screening through the Day 29 Visit) will be up to 61 days. The 
overall duration of the study is anticipated to be approximately 16 months. 
STUDY ASSESSMENTS: 
Efficacy, safety, and PK assessments will be performed. The start of study drug administration will be 
considered Time 0 for all assessments. 
Efficacy Assessments 
• VAS and NRS of pain intensity at rest (NRS-R) assessments. Assessments should be performed when 
the subject is in the resting position (either seated comfortably or lying down) for at least 5 minutes 
prior to obtaining the pain scores. 
• Opioid rescue medications: Date, time of administration, amount, and type of all opioid rescue 
medication taken from study drug administration through 72 hours. 
• Discharge readiness assessment per the Modified Postanaesthetic Discharge Scoring System 
(MPADSS) criteria. (Note: This study instrument assesses a subject’s potential readiness to be 
discharged and should be repeated at all scheduled timepoints. It is not meant to be used to decide 
whether or not to discharge a subject from the study, as subjects are required to remain in the 
hospital/research facility for at least 72 hours.) 
• Patient Global Assessment (PGA) of pain control. 
• Overall benefit of analgesia score (OBAS). 
• Treatment Satisfaction Questionnaire for Medication (TSQM-9). 
• Time to ambulation (defined as the ability to walk at least 20 feet with optional use of a 4-legged 
walker for balance. All subjects will be encouraged to ambulate as early as possible during the 
72-hour postoperative period. 
• Ability to participate in scheduled rehabilitation sessions. 
• Whether the subject is discharged home or to a skilled nursing facility. 
• Opioid prescription at discharge. 
• Site- or subject-initiated postdischarge contact through the Day 11 Visit. 
• Opioid prescription after discharge through the Day 11 Visit. 
• Subject daily diary to record whether opioids were taken from discharge through the Day 11 Visit. 
Safety Assessments 
• AEs from the time the subject signs the ICF through the Day 29 Visit. 
• Physical examination. 
• Vital signs, including blood pressure, resting heart rate, respiratory rate, and temperature. 
• Wound healing assessment using the Southampton Wound Scoring Scale. 
• Clinical laboratory tests (hematology and serum chemistry). 
Pharmacokinetic Assessments 
Blood samples will be collected to measure the plasma concentrations of bupivacaine and meloxicam (all 
cohorts) and alpha-1-acid glycoprotein (Cohort 4 only). Blood samples may also be used to evaluate other 
study drug components. 


Protocol No: HTX-011-306, Version 6 
Heron Therapeutics, Inc. 
TKA Study of HTX-011 in an MMA Regimen 
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STUDY ENDPOINTS: 
Primary Efficacy Endpoint 
• Mean area under the curve (AUC) of VAS scores from 12 through 48 hours (AUC12-48). 
Secondary Efficacy Endpoints 
• Mean AUC of VAS scores through 72 hours. 
• Mean AUC of the NRS-R scores through 72 hours. 
• Proportion of subjects with severe pain at each timepoint and through 72 hours. 
• Mean total postoperative opioid consumption (in IV morphine milligram equivalents [MME]) 
through 72 hours. 
• Proportion of subjects who are opioid-free through 72 hours and through Day 11. 
• Proportion of subjects who are opioid-free through 72 hours who remain opioid-free through 
Day 11. 
• Median time to first opioid rescue medication through 72 hours. 
• Proportion of subjects who do not receive an opioid prescription at discharge. 
• Proportion of subjects who do not receive an opioid prescription between discharge and the Day 11 
Visit. 
• Proportion of subjects achieving a score of “good” or better (>1) pain control based on PGA at each 
timepoint. 
• Median time to first ambulation through 72 hours. 
• Proportion of subjects unable to participate in each rehabilitation session because of pain. 
• Proportion of subjects who first achieve an MPADSS score ≥9 at each timepoint. 
• Proportion of subjects who are discharged home vs to a skilled nursing facility. 
• Mean OBAS at each timepoint. 
• Mean TSQM-9 score. 
Safety Endpoints 
• Incidence of treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), and 
opioid-related adverse events (ORAEs). 
• Change from baseline in clinical laboratory results. 
• Change from baseline in vital signs. 
• Wound healing assessment results at each assessed timepoint. 
PK Endpoints (Cohorts 1, 2, and 4) 
• Maximum concentration (Cmax). 
• Time of occurrence of maximum concentration (Tmax). 
PK Endpoints (Cohort 3) 
• Cmax. 
• Tmax. 
• Area under the concentration-time curve from Time 0 to the time of the last quantitative 
concentration (AUClast). 
• Area under the concentration-time curve from Time 0 extrapolated to infinity (AUCinf). 
• Apparent terminal elimination rate constant (λz). 


Protocol No: HTX-011-306, Version 6 
Heron Therapeutics, Inc. 
TKA Study of HTX-011 in an MMA Regimen 
Confidential 
12 
• Apparent terminal half-life (t1/2). 
STATISTICAL METHODS:  
Determination of Sample Size 
The sample size of 115 subjects was selected empirically without formal statistical assumptions. 
Efficacy Analyses 
All efficacy analyses will be carried out on the Safety Population. All efficacy data will be listed and 
summarized by cohort and by treatment group. 
Handling of Missing Data 
For any missing pain scores observed in subjects who complete the 72-hour observation period, VAS and 
NRS-R scores will be imputed via last observation carried forward (LOCF), in which the most recent 
postdose value is used for a subsequent missing value. For subjects who do not have a postdose value 
prior to their first missing value, the median of the postdose values at the relevant timepoint from subjects 
with observed data will be used. In subjects who withdraw from the study prior to the end of 72-hour 
observation period, missing VAS and NRS scores through 72 hours that were to be collected following 
withdrawal will be imputed via worst observation carried forward (WOCF), in which the worst (highest) 
VAS and NRS-R scores observed prior to withdrawal will be used for post-withdrawal values through 
72 hours. Analyses that adjust for the effect of opioid rescue medication will perform windowed worst 
observation carried forward (wWOCF) following LOCF/WOCF (ie, perform LOCF/WOCF first, then 
apply wWOCF). The number and percentage of missing pain intensity scores will be summarized. 
Safety Analyses 
All safety data will be listed and summarized by cohort and by treatment group. TEAEs will be coded and 
tabulated by System Organ Class and Preferred Term. Incidence of TEAEs, SAEs, and ORAEs will be 
summarized. Associated laboratory parameters, such as hepatic profile, renal function, and hematology 
values, will be grouped and presented together in summary tables. Individual subject values will be listed 
and values outside of the standard reference range will be flagged. Changes in vital sign parameters will 
be summarized. 
PK Analyses 
Plasma bupivacaine and meloxicam concentrations will be determined using validated liquid 
chromatography tandem-mass spectrometry assays. Concentrations will be calculated by interpolation 
from a calibration curve. PK parameters for bupivacaine and meloxicam will be calculated using 
noncompartmental analysis, as appropriate. Additional exploratory analyses may be performed, as 
appropriate, to facilitate cross-study comparisons and to fully characterize the concentration-time profiles 
of each analyte or other study drug components. 
In Cohort 4, concentrations of alpha-1-acid glycoprotein will be summarized using descriptive statistics. 
As an exploratory analysis, ex-vivo protein binding of bupivacaine will be determined using equilibrium 
dialysis. PK parameters for free bupivacaine will be calculated using noncompartmental analysis, as 
appropriate. 
Interim Analysis 
No formal interim analyses are planned. 


Protocol No: HTX-011-306, Version 6 
Heron Therapeutics, Inc. 
TKA Study of HTX-011 in an MMA Regimen 
Confidential 
13 
SCHEDULE OF EVENTS 
 
 
Screening 
3-Day Inpatient Period 
Out 
patient 
Site Visits 
 
 
D1 
D2 
D3 
D4 
D5-D8 D11 D29 
ETa 
 
 
Preop OR 
30 min 1h 
2h 
4h 
6h 
8h 12h 20h 24h 36h 48h 60h 72h 
Assessments 
Time Window 
≤28 
days 
±5 
min 
±10 
min 
±15 
min 
±30 
min 
±30 
min 
±30 
min 
±30 
min 
±1h ±1h ±2h 
±2h 
±2h 
±2h 
 
±2d 
±4d 
Obtain informed consent  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine drug screenb 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test (WOCBP 
only)b  
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assess/confirm eligibility 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
Xc 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Xd 
Vital signse 
X 
X 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
 
 
Xd 
12-lead ECG (triplicate)e 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subject training for pain 
assessments 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology and serum chemistry 
tests 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
Xf 
Administer TXA IVg 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Administer preoperative MMA: 
PO acetaminophen, celecoxib, 
and pregabalinh 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Surgery 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Administer HTX-011 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Administer bupivacaine HCl as 
injection into posterior capsule  
(Cohort 3 Group B only) 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Administer acetylsalicylic acidi 
 
 
X 
X 
X 
X 
 
 
 
 
Administer scheduled 
postoperative MMA regimenj 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Pain intensity assessment (VAS) 
 
X 
 
 
Xk 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
X 


Protocol No: HTX-011-306, Version 6 
Heron Therapeutics, Inc. 
TKA Study of HTX-011 in an MMA Regimen 
Confidential 
14 
 
 
Screening 
3-Day Inpatient Period 
Out 
patient 
Site Visits 
 
 
D1 
D2 
D3 
D4 
D5-D8 D11 D29 
ETa 
 
 
Preop OR 
30 min 1h 
2h 
4h 
6h 
8h 12h 20h 24h 36h 48h 60h 72h 
Assessments 
Time Window 
≤28 
days 
±5 
min 
±10 
min 
±15 
min 
±30 
min 
±30 
min 
±30 
min 
±30 
min 
±1h ±1h ±2h 
±2h 
±2h 
±2h 
 
±2d 
±4d 
Pain intensity assessment 
(NRS-R)  
 
X 
 
 
Xk 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
Ambulation assessmentl 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Rehabilitation assessmentm 
 
 
 
X 
X 
X 
 
 
 
 
 
Discharge readiness per 
MPADSSn 
 
 
 
 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
 
 
 
PGA of pain control 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
 
OBAS assessment 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
 
TSQM-9 questionnaire 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
 
Wound healing assessment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
X 
PK blood samplee (Cohorts 1+2) 
 
Xo 
 
 
 
 
X 
 
 
 
X 
X 
 
X 
 
 
 
 
 
 
PK blood samplee (Cohort 3) 
 
Xo 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
PK blood samplee (Cohort 4) 
 
Xo 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
 
 
 
Blood sample for alpha-1-acid 
glycoprotein e (Cohort 4) 
 
Xo 
 
 
 
 
X 
 
 
X 
X 
X 
 
X 
 
X 
 
 
 
 
Discharge subject 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Record if opioid prescription at 
discharge 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Provide opioid daily diary to all 
subjectsp 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Record site or subject contact 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subjects record opioid use in 
daily diaryq 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review subject diary at siter 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Xf 
Concomitant medicationss 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse eventse, t 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: AE, adverse event; D or d, day; ECG, electrocardiogram; eCRF, electronic Case Report Form; ET, Early Termination; h, hour; min, minutes; ICF, informed consent 
form; IV, intravenous; LAST, local anesthetic systemic toxicity; MMA, multimodal analgesic; MPADSS, Modified Postanaesthetic Discharge Scoring System; 
NRS-R, Numeric Rating Scale of pain intensity score at rest; OBAS, overall benefit of analgesia score; OR, operating room; PGA, Patient Global Assessment of pain control; 
PK, pharmacokinetic; PO, oral; Preop, preoperative; TSQM-9, Treatment Satisfaction Questionnaire for Medication; TXA, tranexamic acid; VAS, Visual Analogue Scale; 
WOCBP, women of childbearing potential. 


Protocol No: HTX-011-306, Version 6 
Heron Therapeutics, Inc. 
TKA Study of HTX-011 in an MMA Regimen 
Confidential 
15 
Notes: The start of HTX-011 administration will be considered Time 0 for all efficacy, safety, and PK assessments. For assessments at timepoints when the subject is asleep, an 
attempt should be made to wake the subject. If there is no response, the assessments at these timepoints may be recorded as “Not Done.” Assessments that can be done without 
waking the subject (eg, blood collection for PK) should be completed. When PK and pain intensity assessments coincide, the pain intensity assessments should be conducted 
before the blood draw. See Section 6 for more information on study assessments and procedures. 
a Subjects who withdraw from the study early will be asked to complete ET procedures based on the timing of their withdrawal. 
b The urine drug screen and urine pregnancy test should be performed first. Results should be confirmed negative prior to performing any additional assessments and prior to 
initiation of surgery. Subjects with a positive drug screen who are taking an allowed, prescribed medication that is known to result in a positive drug test may be eligible for 
participation in the study. Subjects who fail the drug test may be rescreened at the discretion of the Investigator. 
c Includes height, weight, and body mass index calculation. 
d Only if subject withdraws prior to 72 hours. 
e If signs and symptoms of suspected LAST are observed, unscheduled vital sign measurements, 12-lead ECGs, and blood sample collection for PK (all cohorts) and alpha-1-acid 
glycoprotein analysis (Cohort 4 only) must be promptly performed. 
f Only if subject withdraws prior to the Day 11 Visit. 
g TXA 1 g IV will be administered within approximately 4 hours prior to the start of surgery. A second dose will be administered up to approximately 8 hours after the initial 
dose.  
h Administer PO acetaminophen 1 g, PO celecoxib 200 mg, and PO pregabalin 300 mg just before the subject is taken to the operating room. 
I From study drug administration until hospital discharge, subjects should receive acetylsalicylic acid 325 mg PO twice a day. 
j The first dose of the MMA regimen will be administered once the subject is able to tolerate PO intake. For the first 3 days, the scheduled MMA regimen will consist of PO 
acetaminophen 1 g every 8 hours and PO celecoxib 200 mg every 12 hours (Cohorts 1, 2, and 3) or PO acetaminophen 1 g every 8 hours and PO ibuprofen 600 mg every 6 hours 
(Cohort 4). For the next 4 days, the scheduled MMA regimen for all cohorts will consist of PO ibuprofen 600 mg every 6 hours, alternating with PO acetaminophen 1 g every 
6 hours (maximum ibuprofen dose of 2.4 g/day and maximum acetaminophen dose of 4 g/day), so that an analgesic is taken approximately every 3 hours while the subject is 
awake. 
k Prior to the administration of the first dose of opioid rescue medication, if the subject has not already had at least 1 postoperative pain score assessed, then VAS and NRS-R 
scores must be obtained. 
l Defined as the ability to walk at least 20 feet with optional use of a 4-legged walker for balance. All subjects will be encouraged to ambulate as early as possible during the 
72-hour postoperative period. The date and time of first ambulation must be recorded. 
m Subjects will participate in rehabilitation on the evening of Day 1, and in the morning and evening of Days 2 and 3. 
n This study instrument assesses a subject’s potential readiness to be discharged and should be repeated at all scheduled timepoints. It is not meant to be used to decide whether or 
not to discharge a subject from the study.  
o Preoperative blood samples must be collected before administering the spinal anesthesia. 
p All subjects (whether or not they were discharged with an opioid prescription) must be provided a daily diary at discharge to record opioid use through the Day 11 Visit. 
q Subjects will complete a daily diary to record if they take any opioid medication from discharge through Day 11 Visit.  
r Subject diary results will be reviewed at the Day 11 Visit. If a subject recorded “yes” for taking an opioid, sites must record the medication on concomitant medication eCRF. 
s Record all medications taken from the time the subject signs the ICF through the Day 29 Visit. 
t Record all AEs from the time the subject signs the ICF through the Day 29 Visit. 


Protocol No: HTX-011-306, Version 6 
Heron Therapeutics, Inc. 
TKA Study of HTX-011 in an MMA Regimen 
Confidential 
16 
TABLE OF CONTENTS 
SPONSOR SIGNATURE ................................................................................................................2 
INVESTIGATOR AGREEMENT...................................................................................................3 
PROTOCOL SYNOPSIS ................................................................................................................4 
SCHEDULE OF EVENTS ............................................................................................................13 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ..................................................22 
1. 
INTRODUCTION ......................................................................................................24 
1.1. 
Background Information and Study Rationale ...........................................................24 
1.2. 
Rationale for Study Design, Doses, and Control Groups ...........................................25 
1.3. 
Potential Risks and Benefits .......................................................................................26 
1.3.1. 
HTX-011 .....................................................................................................................26 
1.3.1.1. 
Safety ..........................................................................................................................26 
1.3.1.2. 
Efficacy .......................................................................................................................27 
1.3.1.3. 
Potential Risks Associated With HTX-011 ................................................................27 
1.3.2. 
Other Scheduled Study Medications ..........................................................................28 
1.3.2.1. 
Bupivacaine ................................................................................................................28 
2. 
STUDY OBJECTIVES ..............................................................................................30 
2.1. 
Primary Objective .......................................................................................................30 
2.2. 
Secondary Objectives .................................................................................................30 
3. 
INVESTIGATIONAL PLAN AND ENDPOINTS ....................................................31 
3.1. 
Description of the Study Design .................................................................................31 
3.1.1. 
Overall Study Design ..................................................................................................31 
3.1.2. 
Postoperative Analgesia Medications .........................................................................32 
3.1.2.1. 
Inpatient Postoperative Rescue Medication................................................................32 
3.1.2.2. 
Opioid Prescriptions at and After Discharge ..............................................................32 
3.1.2.3. 
Postoperative Analgesia After Discharge ...................................................................32 
3.1.3. 
Antifibrinolysis and Deep Vein Thrombosis Prophylaxis ..........................................33 
3.1.4. 
Postoperative Assessments .........................................................................................33 
3.2. 
Study Endpoints ..........................................................................................................33 
3.2.1. 
Primary Efficacy Endpoint .........................................................................................33 
3.2.2. 
Secondary Efficacy Endpoints ....................................................................................33 
3.2.3. 
Safety Endpoints .........................................................................................................34 


Protocol No: HTX-011-306, Version 6 
Heron Therapeutics, Inc. 
TKA Study of HTX-011 in an MMA Regimen 
Confidential 
17 
3.2.4. 
PK Endpoints (Cohorts 1, 2, and 4) ............................................................................34 
3.2.5. 
PK Endpoints (Cohort 3) ............................................................................................34 
3.3. 
Study Duration ............................................................................................................35 
4. 
STUDY ENROLLMENT AND WITHDRAWAL ....................................................36 
4.1. 
Study Population .........................................................................................................36 
4.1.1. 
Inclusion Criteria ........................................................................................................36 
4.1.2. 
Exclusion Criteria .......................................................................................................36 
4.2. 
Method of Assigning Subjects to Treatment Groups .................................................38 
4.2.1. 
Procedures for Handling Subjects Who Do Not Meet the Study Eligibility 
Criteria ........................................................................................................................39 
4.3. 
Blinding ......................................................................................................................39 
4.4. 
Subject Withdrawal and Replacement ........................................................................39 
4.4.1. 
Subject Withdrawal ....................................................................................................39 
4.4.2. 
Subject Replacement ..................................................................................................39 
5. 
STUDY TREATMENT ..............................................................................................40 
5.1. 
Study Drug (HTX-011) ...............................................................................................40 
5.1.1. 
Description of Investigational Product .......................................................................40 
5.1.2. 
Manufacturing, Packaging, and Labeling ...................................................................40 
5.1.3. 
Study Drug Storage .....................................................................................................40 
5.1.4. 
Study Drug Preparation ..............................................................................................40 
5.1.5. 
Study Drug Administration.........................................................................................40 
5.1.6. 
Study Drug Compliance .............................................................................................41 
5.1.7. 
Study Drug Accountability .........................................................................................41 
5.2. 
Injection of Bupivacaine HCl into the Posterior Capsule (Group B of Cohort 
3 Only) ........................................................................................................................41 
5.3. 
Additional Scheduled Concomitant Medications .......................................................41 
6. 
STUDY PROCEDURES AND ASSESSMENTS......................................................43 
6.1. 
Medical History and Demographics ...........................................................................43 
6.1.1. 
Medical History ..........................................................................................................43 
6.1.2. 
Demographics .............................................................................................................43 
6.2. 
Prior and Concomitant Therapy ..................................................................................43 
6.2.1. 
Allowed Concomitant Medications ............................................................................43 
6.2.2. 
Prohibited Therapy .....................................................................................................44 


Protocol No: HTX-011-306, Version 6 
Heron Therapeutics, Inc. 
TKA Study of HTX-011 in an MMA Regimen 
Confidential 
18 
6.2.2.1. 
Medications Prohibited Prior to Surgery ....................................................................44 
6.2.2.2. 
Medications Prohibited During Surgery .....................................................................44 
6.2.2.3. 
Medications Prohibited During the Postoperative Period ..........................................44 
6.3. 
Efficacy Assessments .................................................................................................44 
6.3.1. 
Pain Intensity Assessments .........................................................................................44 
6.3.2. 
Use of Opioid Medications .........................................................................................45 
6.3.2.1. 
Opioid Rescue Medication Prior to Discharge ...........................................................45 
6.3.3. 
Opioid Medication After Discharge ...........................................................................45 
6.3.4. 
Discharge Readiness ...................................................................................................45 
6.3.5. 
Patient Global Assessment of Pain Control ................................................................45 
6.3.6. 
Overall Benefit of Analgesia Assessment ..................................................................45 
6.3.7. 
Treatment Satisfaction ................................................................................................45 
6.3.8. 
Ambulation and Rehabilitation ...................................................................................45 
6.3.9. 
Discharge Information ................................................................................................46 
6.4. 
Safety Assessments .....................................................................................................46 
6.4.1. 
Adverse Events ...........................................................................................................46 
6.4.2. 
Physical Examinations ................................................................................................46 
6.4.3. 
Vital Signs ..................................................................................................................46 
6.4.4. 
12-Lead Electrocardiograms .......................................................................................46 
6.4.5. 
Wound Healing Evaluation .........................................................................................47 
6.4.6. 
Clinical Laboratory Tests ...........................................................................................47 
6.4.7. 
Local Anesthetic Systemic Toxicity (LAST) Assessment .........................................48 
6.5. 
Pharmacokinetic Assessments ....................................................................................48 
7. 
TIMING OF PROCEDURES AND ASSESSMENTS ..............................................49 
7.1. 
Screening Period (Within 28 Days Before Surgery) ..................................................49 
7.2. 
Treatment and Postoperative Observation Period ......................................................50 
7.2.1. 
Day of Surgery (Day 1) ..............................................................................................50 
7.2.1.1. 
Prior to Surgery ...........................................................................................................50 
7.2.1.2. 
Surgery and Study Treatment Administration ............................................................51 
7.2.2. 
Postoperative Assessment Period (Up to 72 Hours) ...................................................51 
7.2.2.1. 
Study Medication During Inpatient Period .................................................................51 
7.2.2.2. 
Study Procedures and Assessments During Inpatient Period .....................................51 
7.2.3. 
Discharge ....................................................................................................................53 


Protocol No: HTX-011-306, Version 6 
Heron Therapeutics, Inc. 
TKA Study of HTX-011 in an MMA Regimen 
Confidential 
19 
7.3. 
Follow-Up Period .......................................................................................................53 
7.3.1. 
Day 5 Until Day 11 Visit ............................................................................................53 
7.3.2. 
Day 11 Visit (±2 Days) ...............................................................................................53 
7.3.3. 
Day 29 Visit (±4 Days) ...............................................................................................54 
7.4. 
Early Termination Visit ..............................................................................................54 
7.5. 
Unscheduled Visits and Assessments .........................................................................54 
8. 
SAFETY MONITORING AND REPORTING .........................................................56 
8.1. 
Definition of Safety Parameters..................................................................................56 
8.1.1. 
Definition of an Adverse Event ..................................................................................56 
8.1.2. 
Definition of a Serious Adverse Event .......................................................................57 
8.1.3. 
Definition of Unanticipated Problems ........................................................................58 
8.2. 
Classification of Adverse Events ................................................................................58 
8.2.1. 
Severity of Adverse Events ........................................................................................58 
8.2.2. 
Relationship to Study Drug ........................................................................................58 
8.3. 
Time Period and Frequency for Event Assessment and Follow Up ...........................59 
8.3.1. 
Adverse Event and Serious Adverse Event Monitoring .............................................59 
8.3.2. 
Follow-Up of Events ...................................................................................................59 
8.4. 
Reporting Procedures ..................................................................................................60 
8.4.1. 
Reporting Serious Adverse Events to the Sponsor .....................................................60 
8.4.2. 
Reporting Unanticipated Problems to the Sponsor .....................................................61 
8.4.3. 
Regulatory Reporting Requirements ..........................................................................61 
8.4.4. 
Pregnancy Reporting ..................................................................................................62 
8.5. 
Safety Oversight .........................................................................................................62 
9. 
OTHER STUDY RESTRICTIONS ...........................................................................63 
9.1. 
Contraception ..............................................................................................................63 
9.2. 
Continuous Passive Motion Machines........................................................................63 
10. 
STATISTICAL CONSIDERATIONS .......................................................................64 
10.1. 
General Considerations ...............................................................................................64 
10.2. 
Determination of Sample Size ....................................................................................64 
10.3. 
Analysis Populations ..................................................................................................64 
10.4. 
Statistical Analysis Methods.......................................................................................64 
10.4.1. 
Disposition and Demographics ...................................................................................64 
10.4.2. 
Efficacy Analysis ........................................................................................................64 


Protocol No: HTX-011-306, Version 6 
Heron Therapeutics, Inc. 
TKA Study of HTX-011 in an MMA Regimen 
Confidential 
20 
10.4.2.1. 
Handling of Missing Data ...........................................................................................64 
10.4.3. 
Safety Analysis ...........................................................................................................65 
10.4.4. 
Pharmacokinetic Analysis ..........................................................................................65 
10.5. 
Interim Analysis ..........................................................................................................66 
11. 
QUALITY ASSURANCE AND QUALITY CONTROL .........................................67 
12. 
REGULATORY AND ETHICAL CONSIDERATIONS ..........................................68 
12.1. 
Regulatory Authority Approval ..................................................................................68 
12.2. 
Ethical Conduct of the Study ......................................................................................68 
12.3. 
Ethics Committee Approval .......................................................................................68 
12.4. 
Informed Consent Process ..........................................................................................68 
12.5. 
Confidentiality ............................................................................................................69 
13. 
STUDY ADMINISTRATION ...................................................................................71 
13.1. 
Clinical Monitoring ....................................................................................................71 
13.2. 
Source Documents and Record Retention ..................................................................71 
13.3. 
Management of Protocol Amendments and Deviations .............................................71 
13.3.1. 
Protocol Modification .................................................................................................71 
13.3.2. 
Protocol Deviations ....................................................................................................71 
13.4. 
Financial Disclosure ...................................................................................................72 
13.5. 
Criteria For Suspending the Study ..............................................................................72 
13.6. 
Publication and Information Disclosure Policy ..........................................................72 
14. 
REFERENCE LIST ....................................................................................................74 
APPENDIX A. AMERICAN SOCIETY OF ANESTHESIOLOGISTS PHYSICAL 
STATUS CLASSIFICATION SYSTEM ...................................................................77 
APPENDIX B. BODY MASS INDEX (BMI) CALCULATION ..............................................78 
APPENDIX C. PAIN INTENSITY ASSESSMENTS USING THE VISUAL 
ANALOGUE SCALE (VAS) .....................................................................................79 
APPENDIX D. PAIN INTENSITY ASSESSMENTS USING THE NUMERIC 
RATING SCALE (NRS) ............................................................................................80 
APPENDIX E. DISCHARGE READINESS ASSESSMENT - MODIFIED 
POSTANAESTHETIC DISCHARGE SCORING SYSTEM CRITERIA ................81 
APPENDIX F. PATIENT GLOBAL ASSESSMENT (PGA) OF PAIN CONTROL ...............82 
APPENDIX G. OVERALL BENEFIT OF ANALGESIA SCORE (OBAS) .............................83 
APPENDIX H. TREATMENT SATISFACTION QUESTIONNAIRE FOR 
MEDICATION (TSQM-9) .........................................................................................84 


Protocol No: HTX-011-306, Version 6 
Heron Therapeutics, Inc. 
TKA Study of HTX-011 in an MMA Regimen 
Confidential 
21 
APPENDIX I. WOUND HEALING ASSESSMENT - SOUTHAMPTON WOUND 
SCORING SYSTEM ..................................................................................................86 
 
LIST OF TABLES 
Table 1: 
Clinical Laboratory Tests ...........................................................................................47 
 


Protocol No: HTX-011-306, Version 6 
Heron Therapeutics, Inc. 
TKA Study of HTX-011 in an MMA Regimen 
Confidential 
22 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Definition 
AE 
Adverse event 
ASA 
American Society of Anesthesiologists 
AUC 
Area under the curve  
BID 
Twice a day 
BMI 
Body mass index 
CFR 
Code of Federal Regulations 
Cmax 
Maximum concentration 
COX 
Cyclooxygenase  
CV 
Cardiovascular  
DVT 
Deep vein thrombosis 
EC 
Ethics Committee  
ECG 
Electrocardiogram  
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
h 
Hour(s) 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
IV 
Intravenous(ly)  
LAST 
Local anesthetic systemic toxicity 
LOCF 
Last observation carried forward 
min 
Minute(s) 
MMA 
Multimodal analgesic 
MME 
Morphine milligram equivalents 
MPADSS 
Modified Postanaesthetic Discharge Scoring System 
NRS 
Numeric rating scale  
NRS-R 
NRS scores of pain intensity at rest  
NSAID 
Nonsteroidal anti-inflammatory drug 
OBAS 
Overall benefit of analgesia score 


Protocol No: HTX-011-306, Version 6 
Heron Therapeutics, Inc. 
TKA Study of HTX-011 in an MMA Regimen 
Confidential 
23 
Abbreviation 
Definition 
ORAE 
Opioid-related adverse event 
PGA 
Patient Global Assessment 
PK 
Pharmacokinetic(s) 
PO 
By mouth, orally 
SAE 
Serious adverse event 
SAR 
Serious adverse reaction 
TEAE 
Treatment-emergent adverse event 
Tmax 
Time of occurrence of maximum concentration 
TKA 
Total knee arthroplasty 
TSQM 
Treatment Satisfaction Questionnaire for Medication 
TXA 
Tranexamic acid 
ULN 
Upper limit of normal 
US 
United States 
VAS 
Visual Analogue Scale 
WOCF 
Worst observation carried forward 
wWOCF 
Windowed worst observation carried forward 
Note: Abbreviations defined in the text but not used again in the text are not included in this List of Abbreviations. 
Abbreviations used only in a table or figure are also excluded from this List of Abbreviations; they are defined in 
the table or figure footnotes. 
 


Protocol No: HTX-011-306, Version 6 
Heron Therapeutics, Inc. 
TKA Study of HTX-011 in an MMA Regimen 
Confidential 
24 
1. 
INTRODUCTION 
1.1. 
Background Information and Study Rationale 
Up to 70% of patients have moderate to severe pain after surgery, and the most severe pain 
occurs within the first 72 hours (Apfelbaum 2003; Gan 2014; Lynch 1997; Meissner 2015; 
Misiolek 2014; Singla 2014; Svensson 2000). Administering a local anesthetic (eg, bupivacaine, 
ropivacaine, or levobupivacaine) perioperatively is a relatively simple and safe means of 
providing postoperative pain relief. A major limitation of most currently available local 
anesthetics is that their duration of effect is only 6 to 12 hours (Kehlet 2011). Consequently, 
many patients are given opioids to manage pain. The requirement for opioids postoperatively is a 
serious manifestation of ineffective pain control. Exposure to opioids can lead to opioid-related 
adverse reactions resulting in worse patient outcomes and increased hospital costs (Cashman 
2004; Chan 2013; Coley 2002; Jarzyna 2011; Kessler 2013; Lee 2015; Lee 2016; Oderda 2013; 
Ramachandran 2011; Shirakami 2005; Stephens 2003; Wheeler 2002). Patients can quickly 
transition from acute opioid use to chronic use. Orthopedic surgery can be a point of first 
exposure to opioids for patients as it has one of the highest rates of opioid prescribing (Morris 
2015). Reduced exposure to opioids and better pain management is associated with improved 
patient outcomes as well as reduced risk for the development of persistent pain and chronic 
opioid use and abuse (Barnett 2017). Therefore, there is a significant unmet need for a more 
effective non-opioid analgesic that provides sustained pain relief and reduces or eliminates the 
need for opioids, especially in the first 72 hours following surgery. 
Heron Therapeutics, Inc. (Heron) has developed HTX-011 for application into the surgical site to 
reduce postoperative pain for up to 72 hours and the need for opioid analgesics. 
 
 
 
 Bupivacaine and meloxicam are approved in the United States (US), Europe, 
and other regions and have a long history of clinical use. Unlike other local anesthetics, 
HTX-011 is not injected; it is applied without a needle to coat the pain-generating tissues in the 
surgical site. After single-dose administration, the polymer enables extended release of 
bupivacaine and meloxicam simultaneously for approximately 3 days. Low-dose meloxicam in 
HTX-011 does not provide analgesic activity on its own (Viscusi 2017). Rather, meloxicam 
reduces the local inflammation caused by surgery and normalizes the local pH, which enhances 
penetration of bupivacaine into the nerves, thereby potentiating bupivacaine’s analgesic effect 
(Dasta 2018). 
In a prior adequate and well-controlled Phase 2b study in total knee arthroplasty (TKA; 
Study 209), HTX-011 400 mg/12 mg (bupivacaine/meloxicam doses) with or without 
ropivacaine injected into the posterior capsule significantly reduced pain over 48 hours and 
72 hours compared with saline placebo despite the absence of a background scheduled 
multimodal analgesic (MMA) regimen and with only opioid rescue medication options. 
Although almost all subjects required opioid rescue during the 72-hour postoperative period, 
subjects who received HTX-011 demonstrated lower opioid consumption through 72 hours than 
subjects who received saline placebo or bupivacaine HCl. This Phase 3b study will evaluate if 
HTX-011 administered as the foundation of a scheduled non-opioid MMA regimen can further 


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improve pain control and lead to a greater reduction or eliminate the need for opioids following 
primary unilateral TKA. The study will also evaluate the contribution of bupivacaine HCl 
injection into the posterior capsule on the reduction of postoperative pain. 
1.2. 
Rationale for Study Design, Doses, and Control Groups 
This is an open-label multicohort study. Cohorts 1, 2, and 4 will evaluate HTX-011 400 mg/12 
mg via periarticular application into the surgical site. This dose and administration technique 
were evaluated in the prior Phase 2b TKA study (Study 209). Drains are no longer commonly 
used; therefore, Cohort 2 will prohibit the use of drains to evaluate the impact, if any, on 
postoperative analgesia. 
Cohort 3 will evaluate HTX-011 300 mg/9 mg with or without bupivacaine HCl 100 mg, a local 
anesthetic commonly used in TKA. The use of drains will also be prohibited in Cohort 3. 
HTX-011 will be administered via periarticular application into the surgical site. Bupivacaine 
HCl will be injected into the posterior capsule to see if anesthetizing that area contributes to the 
reduction of initial postoperative pain. The 100 mg dose of bupivacaine HCl injection was 
selected as this dose has been used in combination with liposomal bupivacaine in TKA (Dysart 
2016). As such, HTX-011 300 mg/9 mg was selected to use with 100 mg bupivacaine HCl to 
compare the efficacy of this cohort with Cohort 1 where HTX-011 400 mg/12 mg will be 
administered into the surgical site.  
All subjects will follow a scheduled non-opioid MMA regimen. Multimodal analgesia for the 
treatment of postoperative pain is recommended in the American Pain Society guidelines (Chou 
2016) and is supported by literature suggesting that using both acetaminophen and nonsteroidal 
anti-inflammatory drugs (NSAIDs), which have different mechanisms of action, can increase 
effectiveness without increasing risk (Ong 2010). The scheduled MMA regimen selected for 
Cohorts 1, 2, and 3 (acetaminophen, celecoxib, and pregabalin before surgery and 
acetaminophen and celecoxib for the first 72 hours after surgery) is the same as the PILLAR 
study, a randomized, controlled study that evaluated liposomal bupivacaine administered with a 
standardized MMA regimen in TKA (Dysart 2016; Mont 2018). The scheduled MMA regimen 
for Cohort 4 will be similar to Cohorts 1, 2, and 3, but includes ibuprofen instead of celecoxib 
during the first 72 hours after surgery. The hypothesis is that the postoperative non-specific 
cyclooxygenase (COX) inhibition of ibuprofen will contribute more to postoperative analgesia 
and therefore work better with HTX-011, as opposed to the COX-2-specific inhibition gained 
from celecoxib, which contributes more to an anti-inflammatory effect and therefore may be 
duplicative to the impact of the local meloxicam applied as part of HTX-011. 
Pain will be assessed using 2 different validated pain rating scales, the visual analogue scale 
(VAS) and the numeric rating scale (NRS) (Breivik 2008; Haefeli 2006). The primary efficacy 
endpoint for this study, area under the curve (AUC) of the VAS pain intensity scores from 
12 through 48 hours (AUC12-48), is consistent with the study goal to assess pain control and is the 
same as the primary endpoint reported for the PILLAR study (Mont 2018). The primary endpoint 
is also consistent with Draft Food and Drug Administration (FDA) Guidance for Industry on 
Analgesic Indications: Developing Drug and Biological Products (February 2014), which states 
that “pain intensity is the fundamental measure that defines the efficacy of an analgesic drug.” 
Safety assessments in this study are considered standard for clinical studies and this surgical 
model. Evaluations will include adverse event (AE) and serious adverse event (SAE) recording, 


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hematology and serum chemistry, vital signs, physical examinations, and wound healing 
assessments. 
The pharmacokinetic (PK) timepoints for this study were selected to characterize systemic 
exposure of bupivacaine and meloxicam to confirm that exposures are consistent with historical 
values obtained in Study 209. In addition, in Cohort 4 scheduled blood draws will also be 
performed to evaluate the impact of surgery on alpha-1-acid glycoprotein concentrations, which 
impacts the free fraction of bupivacaine. If potential signs and symptoms of local anesthetic 
systemic toxicity (LAST) are observed, a blood sample for PK and alpha-1-acid glycoprotein 
analysis will also be collected. 
1.3. 
Potential Risks and Benefits 
1.3.1. 
HTX-011 
As of 27 September 2019, a total of 1,362 adult subjects (1,352 undergoing surgery and 
10 healthy volunteers) have received HTX-011 as a single dose ranging from 30 mg/0.9 mg to 
600 mg/18 mg across 12 clinical studies. 
1.3.1.1. 
Safety 
Safety data from 504 subjects who received HTX-011 via instillation into the surgical site in two 
Phase 3 studies (Study 301 in bunionectomy and Study 302 in herniorrhaphy) and two Phase 2b 
studies (Study 209 in TKA and Study 211 in augmentation mammoplasty) were pooled for 
analysis. Results from these studies revealed that the safety profile of a single dose of HTX-011 
was similar to the well-established safety profile of bupivacaine HCl. The types of 
treatment-emergent adverse events (TEAEs) reported for HTX-011 were generally similar across 
studies; the most common TEAEs were nausea, constipation, dizziness, vomiting, and headache. 
These TEAEs were also the most common TEAEs in the saline placebo and bupivacaine HCl 
groups. Of these 5 most common TEAEs, those with an incidence higher in the HTX-011 group 
than in the saline placebo group were constipation (17.3% vs 14.6%), vomiting (16.9% vs 
15.0%), and headache (11.7% vs 8.9%). The majority of TEAEs were mild or moderate in 
severity. The incidence of severe TEAEs was low and similar across all treatment groups. 
There were no clinically meaningful differences in laboratory results, vital sign measurements, or 
electrocardiogram (ECG) findings. There was no evidence of LAST based on a comprehensive 
review of potential LAST-related TEAEs, LAST assessment questionnaire responses, 
bupivacaine plasma concentrations, 12-lead ECG/Holter monitoring findings, and vital sign 
results. Finally, bone healing and wound healing were not affected by HTX-011. 


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Serious Adverse Events 
As of 23 October 2019, no deaths were reported for subjects who received HTX-011. The 
incidence of SAEs in subjects who received HTX-011 was low (1.5%) and was similar to saline 
placebo (1.2%) and bupivacaine HCl (2.2%). 
 
 
 
 
 
 
 
 
 
 
1.3.1.2. 
Efficacy 
In Phase 3 studies in bunionectomy and herniorrhaphy, a single dose of HTX-011 (60 mg/1.8 mg 
and 300 mg/9 mg, respectively) significantly reduced pain and opioid consumption through 
72 hours compared with both bupivacaine HCl and saline placebo. The efficacy of HTX-011 has 
also been demonstrated in Phase 2 studies in subjects undergoing TKA, augmentation 
mammoplasty, and abdominoplasty at HTX-011 doses up to 400 mg/12 mg. The efficacy of 
HTX-011 was also evaluated when administered as the foundation of a non-opioid MMA 
regimen. In completed studies in bunionectomy and herniorrhaphy, the regimens resulted in 
further reduction of pain and opioid consumption. 
1.3.1.3. 
Potential Risks Associated With HTX-011 
An identified risk for HTX-011 is incision site erythema, which was observed primarily in 
bunionectomy. Most events were self-limiting, mild or moderate in severity, and resolved 
without intervention or sequelae. Use of HTX-011 in subjects with allergies to or 
hypersensitivity to bupivacaine, meloxicam, or any of the components of HTX-011 is 
contraindicated. For more information on HTX-011, refer to the HTX-011 Investigator’s 
Brochure. For more information on the active ingredients, bupivacaine and meloxicam, refer to 
the local product labels. 
1.3.1.3.1. Potential Risks Associated With Bupivacaine 
Potential risks for bupivacaine include dose-related central nervous system and cardiovascular 
(CV) system toxicity, including, but not limited to, perioral tingling, metallic taste, visual and 
auditory disturbances, muscle twitching, seizure, acidosis, shortness of breath, bradycardia, 
hypotension, hypoxia, and cardiac arrest. Cases of methemoglobinemia have been reported in 
association with local anesthetic use (MARCAINE USPI 2018). Although all patients receiving a 
local anesthetic are at risk for methemoglobinemia, patients with glucose-6-phosphate 
dehydrogenase deficiency, congenital or idiopathic methemoglobinemia, cardiac or pulmonary 
compromise, and concurrent exposure to oxidizing agents or their metabolites are more 
susceptible to developing clinical manifestations of the condition. Patients with a known history 
of glucose-6-phosphate dehydrogenase deficiency or with congenital or idiopathic 


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methemoglobinemia are excluded from this study. Close monitoring for symptoms and signs of 
methemoglobinemia is recommended. 
1.3.1.3.2. Potential Risks Associated With Meloxicam 
Potential risks for meloxicam include the common AEs (≥5% and greater than placebo) of 
diarrhea, upper respiratory tract infections, dyspepsia, and influenza-like symptoms (MOBIC 
USPI 2018). Other potential risks include CV adverse reactions, gastrointestinal bleeding, and 
abnormal liver tests . NSAIDs may cause an increased risk of serious CV thrombotic events, 
myocardial infarction, and stroke, which can be fatal. Patients with known CV disease or risk 
factors for CV disease may be at greater risk. NSAIDs may also cause an increased risk of 
serious gastrointestinal AEs including inflammation, bleeding, ulceration, and perforation of the 
esophagus, stomach, or intestines, which can be fatal. Patients with a prior history of peptic ulcer 
disease and/or gastrointestinal bleeding who use NSAIDs have a greater than 10-fold increased 
risk for developing a gastrointestinal bleed compared to patients without these risk factors. 
Elderly patients are at greater risk for serious gastrointestinal events. Elevations of one or more 
liver tests may occur in patients taking NSAIDs, including meloxicam. Exacerbation of asthma 
related to aspirin sensitivity, reduction in renal blood flow, and renal toxicity are reported risks 
after exposure to NSAIDs. Serious skin AEs such as exfoliative dermatitis, Stevens-Johnson 
Syndrome, and toxic epidermal necrolysis, which can be fatal, can occur without warning. It is 
unclear how applicable these potential risks are for meloxicam when given as single dose via 
instillation into the surgical site (a novel administration method for meloxicam) for postoperative 
pain as part of a fixed-dose combination (eg, HTX-011).  
1.3.2. 
Other Scheduled Study Medications 
Common, as well as uncommon but severe, adverse drug reactions that are associated with the 
other study medications are listed below. The Investigator should refer to the respective package 
inserts for detailed information on risks associated with the scheduled study medications 
(bupivacaine, pregabalin, celecoxib, acetaminophen, ibuprofen, fentanyl, tranexamic acid 
[TXA], acetylsalicylic acid) and any other approved medications that may be administered while 
a subject participates in this study (eg, anesthetics, antibiotics). 
1.3.2.1. 
Bupivacaine 
Potential risks associated with bupivacaine are addressed in Section 1.3.1.3.1. 
1.3.2.1.1. Pregabalin 
Common adverse drug reactions with pregabalin include dizziness, sleepiness, dry mouth, 
swelling of hands and feet, blurred vision, weight gain, and trouble concentrating. An uncommon 
but severe adverse drug reactions, reported in a small number of people, was suicidal thoughts. 
1.3.2.1.2. Celecoxib 
Common adverse drug reactions with celecoxib include headache, upper respiratory tract 
infections, dyspepsia, and diarrhea. Uncommon but severe adverse drug reactions include 
gastrointestinal ulceration, bleeding, and perforation. Other uncommon but serious adverse 
reactions which occur in <0.1% of subjects include syncope, congestive heart failure, ventricular 


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fibrillation, cerebrovascular accident, peripheral gangrene, thrombophlebitis, pancreatitis, 
cholelithiasis, thrombocytopenia, aseptic meningitis, suicide, acute renal failure, sepsis, and 
sudden death. 
1.3.2.1.3. Acetaminophen 
Common adverse drug reactions with acetaminophen include nausea, vomiting, headache, and 
insomnia. An uncommon but severe adverse drug reaction may include severe skin rash and liver 
failure. 
1.3.2.1.4. Ibuprofen 
Common adverse drug reactions with ibuprofen are gastrointestinal (nausea, epigastric pain, 
heartburn, diarrhea, abdominal distress cramps or pain, nausea and vomiting, indigestion, 
constipation, bloating and flatulence, decreased appetite), dizziness, headache, nervousness, 
tinnitus, rash, pruritus, fluid retention, and elevated liver function tests. Less common but severe 
adverse drug reactions which can be fatal include myocardial infarction and stroke, serious 
gastrointestinal bleeding, ulceration, and perforation of the stomach or intestines, serious allergic 
reactions, new or worsening of high blood pressure, congestive heart failure and edema, renal 
toxicity including papillary necrosis, and serious skin reactions (such as exfoliative dermatitis, 
Stevens-Johnson syndrome, and toxic epidermal necrolysis). 
1.3.2.1.5. Tranexamic Acid 
Common adverse drug reactions with TXA include visual abnormalities, nausea, vomiting, 
diarrhea, allergic dermatitis, and thromboembolic events. An uncommon but severe adverse drug 
reaction, hypotension, has been reported when the intravenous (IV) injection rate is too rapid. 
1.3.2.1.6. Acetylsalicylic Acid 
Common adverse drug reactions of aspirin include vomiting, stomach pain, heartburn, 
drowsiness, and nausea. Uncommon but severe risks include stomach ulcers, stomach bleeding, 
and worsening asthma. 
1.3.2.1.7. Opioid Medications 
Common adverse drug reactions associated with opioids include nausea, constipation, vomiting, 
headache, itchiness, dizziness, drowsiness, excessive sweating, and impaired concentration and 
reaction abilities. Drinking alcohol may further decrease mental functions and increase the risk 
of liver damage. Uncommon but severe adverse drug reactions include hypoxia, respiratory 
arrest, cardiac arrest, hypotension, and/or shock. Opioids have the risk of addiction, abuse, and 
misuse, which can lead to overdose and death. 


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2. 
STUDY OBJECTIVES 
2.1. 
Primary Objective 
The primary objective is to assess pain control following HTX-011 as part of a scheduled 
non-opioid MMA regimen in subjects undergoing TKA. 
2.2. 
Secondary Objectives 
The secondary objectives are as follows: 
• To assess total opioid use following HTX-011 as part of a scheduled non-opioid 
MMA regimen in this study population. 
• To assess the proportion of subjects who are opioid-free after receiving HTX-011 as 
part of a scheduled non-opioid MMA regimen in this study population. 
• To assess the safety and tolerability of HTX-011 in a multimodal setting in this study 
population. 
• To characterize the PK parameters of bupivacaine and meloxicam in this study 
population. 


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3. 
INVESTIGATIONAL PLAN AND ENDPOINTS 
3.1. 
Description of the Study Design 
3.1.1. 
Overall Study Design 
This is a Phase 3b, open-label, multicohort study in which subjects undergoing a primary 
unilateral TKA will receive HTX-011 as part of a scheduled non-opioid MMA regimen. Subjects 
will be screened within 28 days prior to the planned surgery date and eligibility will be 
confirmed on the day of surgery. Subjects who meet the eligibility criteria will be enrolled and 
will undergo primary unilateral TKA under bupivacaine spinal anesthesia (≤20 mg). All subjects 
will receive HTX-011 as part of a non-opioid MMA regimen consisting of acetaminophen, an 
NSAID, and a gabapentanoid prior to surgery, a single dose of HTX-011 during surgery, and 
scheduled acetaminophen and an NSAID for 7 days following surgery. Up to 115 subjects will 
be dosed in 4 sequential cohorts: 
• Cohort 1: Approximately 50 subjects will be administered a single dose of HTX-011 
400 mg/12 mg via periarticular application into the surgical site during surgery. 
• Cohort 2: Approximately 15 subjects will be administered a single dose of HTX-011 
400 mg/12 mg via periarticular application into the surgical site during surgery. 
Drains will be prohibited. 
• Cohort 3: Approximately 30 subjects will be randomized into 2 groups. In Group A, 
subjects will be administered a single dose of HTX-011 300 mg/9 mg via periarticular 
application into the surgical site during surgery. In Group B, subjects will be 
administered a single dose of HTX-011 300 mg/9 mg via periarticular application into 
the surgical site and 100 mg bupivacaine HCl injected into the posterior capsule 
during surgery. Drains will be prohibited. 
• Cohort 4: Up to approximately 20 subjects will be administered a single dose of 
HTX-011 400 mg/12 mg via periarticular application into the surgical site during 
surgery. 
On the day of surgery (Day 1), subjects will be administered oral (PO) acetaminophen 1 g, 
PO celecoxib 200 mg, and PO pregabalin 300 mg just before being taken to the operating room. 
During surgery, a single dose of HTX-011 will be administered via periarticular application into 
the surgical site in all study cohorts, as described in Section 5.1.5. Bupivacaine HCl will be 
administered into the posterior capsule in Group B of Cohort 3. The use of IV fentanyl up to 
4 μg/kg will be permitted during surgery for intraoperative pain control. Subjects will receive 
antifibrinolysis and deep vein thrombosis (DVT) prophylaxis medications as described in 
Section 3.1.3. 
Subjects will remain in the hospital/research facility for 72 hours from the start of study drug 
administration to undergo postoperative efficacy, safety, and PK assessments. The study staff 
will follow standard safety precautions to prevent postoperative falls. Subjects will receive a 
scheduled non-opioid MMA regimen over the 72-hour postoperative period consisting of PO 
acetaminophen 1 g every 8 hours and PO celecoxib 200 mg every 12 hours (Cohorts 1, 2, and 3) 


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or PO acetaminophen 1 g every 8 hours and PO ibuprofen 600 mg every 6 hours (Cohort 4). The 
first dose of the MMA regimen will be administered once the subject is able to tolerate PO 
intake. 
After the 72-hour assessments have been completed, subjects may be discharged. Subjects will 
be discharged with instructions to follow a scheduled MMA regimen for 4 days after discharge 
consisting of PO ibuprofen alternating with PO acetaminophen (all cohorts), as described in 
Section 3.1.2.3. Thereafter, subjects may continue acetaminophen and/or ibuprofen as needed. 
Subjects will return to the study site on Days 11 and 29 for follow-up assessments. 
3.1.2. 
Postoperative Analgesia Medications 
3.1.2.1. 
Inpatient Postoperative Rescue Medication 
During the 72-hour postoperative period, subjects should only receive rescue medication upon 
request for pain control. Rescue medication should not be given for pain prophylaxis, but only 
for treating postoperative pain. Prior to the administration of the first dose of rescue medication, 
if the subject has not already had at least 1 postoperative pain score assessed, then pain intensity 
scores using the VAS and NRS must be obtained. 
Postoperative rescue medication will consist only of any 1 or more of the following opioid 
medications, as needed: PO immediate-release oxycodone (≤10 mg within a 4-hour period), 
IV morphine (2.5 mg to 5 mg within a 4-hour period), and/or IV hydromorphone (0.5 mg to 
1.0 mg within a 4-hour period). Combination products containing an opioid and non-opioid are 
not allowed. With the exception of the protocol-specified MMA medications, no other analgesic 
agents, including other NSAIDs, are permitted during the 72-hour postoperative period. Note: 
Acetaminophen is not to be given as a rescue medication as it is part of the postoperative 
scheduled MMA regimen. 
3.1.2.2. 
Opioid Prescriptions at and After Discharge 
If a subject did not receive any opioids or received <10 mg of oxycodone within 12 hours prior 
to discharge, the subject should not receive an opioid prescription at discharge. If a subject 
received ≥10 mg of oxycodone within 12 hours prior to discharge, the Investigator may provide 
the subject with a prescription for immediate-release PO oxycodone tablets: no more than thirty 
5 mg immediate-release oxycodone, take 1 to 2 pills PO (5 mg to 10 mg) every 4 hours as 
needed. The prescription must indicate that substitutions with any other opioid-containing 
product are not permitted, including combination opioid/non-opioid products. 
Sites will record if subjects are discharged with an opioid prescription and information about the 
opioid prescription. All subjects (whether or not they were discharged with an opioid 
prescription) will be provided a daily diary to record any opioid medication use from discharge 
through the Day 11 Visit. Sites will record all site- or subject-initiated contact between discharge 
and the Day 11 Visit and if any contact resulted in issuing an opioid prescription. 
3.1.2.3. 
Postoperative Analgesia After Discharge 
Upon discharge, subjects will be instructed to manage their pain while awake over the next 
4 days with the following scheduled MMA regimen: PO ibuprofen 600 mg every 6 hours, 
alternating with PO acetaminophen 1 g every 6 hours, so that an analgesic is taken approximately 


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every 3 hours. Thereafter, subjects may continue one or both of the MMA medications as 
needed, but should not exceed ibuprofen 600 mg every 6 hours or acetaminophen 1 g every 
6 hours (maximum ibuprofen dose of 2.4 g/day and maximum acetaminophen dose of 4 g/day). 
3.1.3. 
Antifibrinolysis and Deep Vein Thrombosis Prophylaxis 
All subjects will receive IV TXA and PO acetylsalicylic acid for antifibrinolysis and DVT 
prophylaxis, respectively, consistent with clinical practice for TKA. TXA 1g IV will be 
administered within approximately 4 hours prior to the start of surgery and a second dose will be 
administered up to approximately 8 hours later (Themistoklis 2017). Subjects will receive 
acetylsalicylic acid 325 mg PO twice a day (BID) following surgery until discharge. Surgeons 
may also use additional DVT prophylaxis as per their standard of care. 
3.1.4. 
Postoperative Assessments 
Efficacy assessments will include pain intensity assessments using the VAS and the NRS; the 
use of opioid rescue medication; discharge readiness and discharge information; Patient Global 
Assessment (PGA) of pain control; the subject’s assessment of overall benefit of analgesia score 
(OBAS); the subject’s satisfaction with their scheduled non-opioid MMA regimen; and 
ambulation and rehabilitation assessments. 
Safety assessments will include AE recording, physical examinations, vital signs, clinical safety 
laboratory tests (hematology and serum chemistry), and wound healing assessments. 
Blood samples will be collected for bupivacaine and meloxicam PK analysis (all cohorts) and for  
alpha-1-acid glycoprotein (Cohort 4 only). Blood samples may be used to evaluate other study 
drug components. 
More information on study procedures and assessments is provided in Section 6. The timing of 
procedures and assessments is provided in Section 7 and the SCHEDULE OF EVENTS table. 
3.2. 
Study Endpoints 
3.2.1. 
Primary Efficacy Endpoint 
The primary endpoint of this study is the mean AUC12-48 of VAS scores. 
3.2.2. 
Secondary Efficacy Endpoints 
The secondary endpoints of this study are as follows: 
• Mean AUC of VAS scores through 72 hours. 
• Mean AUC of NRS-R scores through 72 hours. 
• Proportion of subjects with severe pain at each timepoint and through 72 hours. 
• Mean total postoperative opioid consumption (in IV morphine milligram equivalents 
[MME]) through 72 hours. 
• Proportion of subjects who are opioid-free through 72 hours and through Day 11. 
• Proportion of subjects who are opioid-free through 72 hours who remain opioid-free 
through Day 11. 


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• Median time to first opioid rescue medication through 72 hours. 
• Proportion of subjects who do not receive an opioid prescription at discharge. 
• Proportion of subjects who do not receive an opioid prescription between discharge 
and the Day 11 Visit. 
• Proportion of subjects achieving a score of “good” or better (>1) pain control based 
on PGA at each timepoint. 
• Median time to first ambulation through 72 hours. 
• Proportion of subjects unable to participate in each rehabilitation session because of 
pain. 
• Proportion of subjects who first achieve a Modified Postanaesthetic Discharge 
Scoring System (MPADSS) score ≥9 at each timepoint. 
• Proportion of subjects who are discharged home vs to a skilled nursing facility. 
• Mean OBAS at each timepoint. 
• Mean Treatment Satisfaction Questionnaire for Medication (TSQM-9) score. 
3.2.3. 
Safety Endpoints 
The safety endpoints of this study are as follows: 
• Incidence of TEAEs, SAEs, and opioid-related adverse events (ORAEs). 
• Change from baseline in clinical laboratory results. 
• Change from baseline in vital signs. 
• Wound healing assessment results at each assessed timepoint. 
3.2.4. 
PK Endpoints (Cohorts 1, 2, and 4) 
The PK endpoints for Cohorts 1 and 2 of this study are as follows: 
• Maximum concentration (Cmax). 
• Time of occurrence of maximum concentration (Tmax). 
3.2.5. 
PK Endpoints (Cohort 3) 
The PK endpoints for Cohort 3 of this study are as follows: 
• Cmax. 
• Tmax. 
• Area under the concentration-time curve from Time 0 to the time of the last 
quantitative concentration (AUClast). 
• Area under the concentration-time curve from Time 0 extrapolated to infinity 
(AUCinf). 


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• Apparent terminal elimination rate constant (λz). 
• Apparent terminal half-life (t1/2). 
3.3. 
Study Duration 
The overall duration of the study is anticipated to be approximately 16 months. The total 
duration of study participation for each subject (from Screening through the Day 29 Visit) will 
be up to 61 days. 
For regulatory reporting purposes, the end of the study is defined as the date of the last subject’s 
last assessment (scheduled or unscheduled). 


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4. 
STUDY ENROLLMENT AND WITHDRAWAL 
4.1. 
Study Population 
Approximately 115 subjects will be enrolled and dosed in the study at up to approximately 
6 study sites in the US. 
4.1.1. 
Inclusion Criteria 
Each subject must meet all of the following criteria to be enrolled in this study: 
1. Is able to provide written informed consent. 
2. Is able to adhere to the study visit schedule and complete all study assessments. 
3. Is male or female, and ≥18 years of age at screening. 
4. Is scheduled to undergo primary unilateral TKA under spinal anesthesia (all cohorts) and 
without drains in Cohorts 2 and 3. 
5. Has not previously undergone TKA in either knee. 
6. Has an American Society of Anesthesiologists (ASA) Physical Status of I, II, or III. 
7. Is able to walk at least 20 feet with optional use of a 4-legged walker for balance. 
8. Female subjects are eligible only if all of the following apply: 
a. Not pregnant (female subject of child-bearing potential must have a negative urine 
pregnancy test at Screening and on Day 1 before surgery). 
b. Not lactating. 
c. Not planning to become pregnant during the study. 
d. Is surgically sterile; or is at least 2 years post-menopausal; or is in a monogamous 
relationship with a partner who is surgically sterile; or is practicing double-barrier 
contraception; or practicing abstinence (must agree to use double-barrier 
contraception in the event of sexual activity); or is using an insertable, injectable, 
transdermal, or combination PO contraceptive approved by the US FDA and commits 
to the use of an acceptable form of birth control from the Screening Visit until 
30 days after study drug administration. Note: women in only a same-sex relationship 
do not need to meet this criterion. 
4.1.2. 
Exclusion Criteria 
A subject who meets any of the following criteria will be excluded from the study: 
1. Has a planned concurrent surgical procedure (eg, bilateral TKA) during the study. 
2. Has a pre-existing, concurrent, acute or chronic, painful physical/restrictive condition 
expected to require analgesic treatment in the postoperative period for pain that is not 
strictly related to the knee surgery and which may confound the postoperative 
assessments. 


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3. Has a contraindication or a known or suspected history of hypersensitivity or clinically 
significant idiosyncratic reaction (including methemoglobinemia) to bupivacaine (or 
other local anesthetics), NSAIDs (eg, meloxicam, ibuprofen, celecoxib), oxycodone, 
morphine, hydromorphone, TXA, fentanyl, pregabalin, acetaminophen, or acetylsalicylic 
acid. 
4. Using or expected to use Factor IX Complex or anti-inhibitor coagulant concentrates 
during the study. 
5. Has known or suspected daily use of opioids for 7 or more consecutive days within the 
previous 6 months. 
6. Has taken NSAIDs (including meloxicam) within 10 days prior to the scheduled surgery 
with the exception of subjects on low-dose (≤100 mg) daily acetylsalicylic acid for 
cardioprotection. 
7. Has taken long-acting opioids within 3 days prior to the scheduled surgery. 
8. Has taken any opioids within 24 hours prior to the scheduled surgery. 
9. Has been administered bupivacaine within 5 days prior to the scheduled surgery. 
10. Has been administered any local anesthetic within 72 hours prior to the scheduled 
surgery, other than for pretreatment prior to a needle placement, to treat an AE that 
occurs after signing the informed consent form (ICF), or to decrease venous irritation 
caused by propofol, if needed (in which case, no more than a single administration of 
lidocaine 1% 20 mg IV may be administered). 
11. Has initiated treatment with any of the following medications within 1 month prior to 
study drug administration or is taking any of these medications to control pain: selective 
serotonin reuptake inhibitors (SSRIs), selective norepinephrine reuptake inhibitors 
(SNRIs), gabapentin, pregabalin, duloxetine, or COX-2 inhibitors. (Note: If a subject is 
taking one of these medications for a reason other than pain control, the subject must be 
on a stable scheduled dose [ie, not “as needed”] for at least 1 month prior to study drug 
administration). Anxiolytics prior to surgery are permitted, if necessary. 
12. Has been administered systemic steroids within 5 half-lives or 10 days prior to 
administration of study drug (whichever is longer). Note that for purposes of this 
exclusion criterion, inhaled, ophthalmic, and over-the-counter steroids are not considered 
systemic. 
13. Previously participated in a clinical study or received an investigational product or device 
in a clinical trial within 30 days or within 5 elimination half-lives (whichever is longer) 
prior to the scheduled surgery, or is planning to take part in another clinical trial while 
participating in this study. 
14. Has a known or suspected history of drug abuse, a positive drug screen on the day of 
surgery, or a history of alcohol abuse (within 10 years). Note: Subjects with a positive 
drug screen who are taking an allowed, prescribed medication that is known to result in a 
positive drug test (eg, amphetamine and dextroamphetamine for 
attention-deficit/hyperactivity disorder, benzodiazepine for anxiety disorder) may be 


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eligible for participation in the study. Subjects with a positive drug screen for 
cannabinoids on the day of surgery will not be allowed to participate in the study. 
15. Has a medical condition such that, in the opinion of the Investigator, participating in the 
study would pose a health risk to the subject or confound the postoperative assessments. 
Conditions may include, but are not limited to, any of the following: 
a. History of clinically significant cardiac abnormality such as myocardial infarction 
within 6 months prior to signing the ICF, New York Heart Association class III or IV, 
or clinically significant abnormalities of ECG or cardiac function. 
b. History of coronary artery bypass graft surgery within 12 months prior to signing the 
ICF. 
c. Severe liver function impairment as defined by Child-Pugh Class C, having an 
aspartate aminotransferase >3 × the upper limit of normal (ULN), or having an 
alanine aminotransferase >3 × ULN. 
d. Severe kidney function impairment as defined by creatinine clearance 
(Cockcroft-Gault) <30 mL/min or on dialysis. 
e. History of known or suspected coagulopathy or uncontrolled anticoagulation (platelet 
count <100,000/μL; hemoglobin <12 g/dL; or hematocrit <35%). 
f. Loss of sensation in extremities or significant peripheral neuropathy. 
g. Known history of glucose-6-phosphate dehydrogenase deficiency. 
16. Is currently undergoing treatment for hepatitis B, hepatitis C, or HIV. 
17. Has uncontrolled anxiety, psychiatric, or neurological disorder that, in the opinion of the 
Investigator, might interfere with study assessments. 
18. Has acquired defective color vision or acute gastrointestinal ulcers, either of which could 
interfere with scheduled study medications. 
19. Has any chronic neuromuscular deficit of either femoral nerve function or thigh 
musculature. 
20. Has any chronic condition or disease that would compromise neurological or vascular 
assessments. 
21. Had a malignancy in the last year, with the exception of nonmetastatic basal cell or 
squamous cell carcinoma of the skin or localized carcinoma in situ of the cervix. 
22. Has undergone 3 or more surgeries within 12 months prior to signing the ICF, other than 
for diagnostic procedures (eg, colonoscopy). 
23. Has a body mass index (BMI) >40 kg/m2. 
4.2. 
Method of Assigning Subjects to Treatment Groups 
The study is an open-label, multicohort study. 
In Cohorts 1, 2, and 4, subjects who meet the eligibility criteria will be enrolled. 
In Cohort 3, subjects who meet the eligibility criteria will be randomized in a 1:1 ratio to 
2 treatment groups. Randomization should be done within 1 business day prior to the day of 


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surgery. Subjects will be randomized using a computer-generated randomization scheme. No 
subject may receive study drug prior to randomization. 
4.2.1. 
Procedures for Handling Subjects Who Do Not Meet the Study Eligibility 
Criteria 
Subjects who fail to meet the eligibility criteria should not, under any circumstances, receive 
study drug. In the event a subject does not meet the eligibility criteria, but receives study drug, 
the Investigator should inform the Sponsor immediately. The Sponsor’s Medical Monitor and the 
Investigator will discuss whether to allow the subject to continue on study. 
4.3. 
Blinding 
Not applicable because this is an open-label study. 
4.4. 
Subject Withdrawal and Replacement 
4.4.1. 
Subject Withdrawal 
Subjects are free to withdraw from the study at any time without prejudice to further treatment. 
A subject may also be withdrawn from the study by the Investigator or the Sponsor at any time if 
either determines that it is not in the subject’s best interest to continue participation. 
Possible reasons for early withdrawal include the following: 
• AE. 
• Withdrawal by subject. 
• Death. 
• Lost to follow up. 
• Pregnancy. 
• Investigator’s decision. 
• Sponsor’s decision. 
• Failure to meet enrollment criteria at Day 1. 
The date and the primary reason for early withdrawal will be recorded on the electronic case 
report form (eCRF). At the time of withdrawal from the study, every attempt should be made to 
complete the Early Termination Visit assessments (Section 7.4). 
4.4.2. 
Subject Replacement 
Subjects enrolled in Cohorts 1, 2, or 4 who withdraw early from the study for any reason will not 
be replaced. 
Any subject who is randomized in Cohort 3 but withdraws from the study prior to study drug 
administration will be replaced by the next eligible study subject. The replacement subject will 
be assigned to the same treatment group as the subject who withdrew. 


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5. 
STUDY TREATMENT 
All subjects will receive a single dose of study drug intraoperatively while undergoing TKA. 
Study drug is defined as HTX-011 (investigational product). HTX-011 will be supplied by the 
Sponsor. 
Subjects in Group B of Cohort 3 will also be administered bupivacaine HCl via injection into the 
posterior capsule during surgery. Bupivacaine HCl will be supplied by study sites. 
5.1. 
Study Drug (HTX-011) 
5.1.1. 
Description of Investigational Product 
HTX-011 is a clear, pale yellow to yellow, viscous liquid supplied in single-dose, 20 mL glass 
vials. The vials serve only as a closed container for the drug product. For administration of study 
drug, the formulation in the vials will be aseptically transferred to sterile syringes as described in 
the Pharmacy Manual. 
5.1.2. 
Manufacturing, Packaging, and Labeling 
HTX-011 will be manufactured according to Good Manufacturing Practices. 
HTX-011 will be packaged and labeled by the Sponsor or designee and will be packed and 
dispatched to comply with shipping and storage conditions. HTX-011 labeling will comply with 
all applicable national and local laws and regulations. 
5.1.3. 
Study Drug Storage 
At the study site, HTX-011 should be stored at a controlled room temperature of 20°C to 25°C 
(with excursions permitted from 15°C to 30°C). To protect from light, HTX-011 should be 
stored in the original packaging until time of use. The study drug storage area should be locked 
with restricted access. A temperature log must be maintained to monitor the storage area’s 
temperature. 
5.1.4. 
Study Drug Preparation 
HTX-011 will be prepared at the study site. HTX-011 cannot be mixed with water, saline, or 
other local anesthetics because the product will become very viscous and difficult to administer. 
Refer to the Pharmacy Manual for details on the study drug preparation. 
5.1.5. 
Study Drug Administration 
HTX-011 will be administered by periarticular application into the surgical site with a Luer lock 
applicator (without a needle) to the following 3 areas: 
1. Posterior capsule (except Group B of Cohort 3). 
2. Anteromedial tissues and periosteum. 
3. Anterolateral tissues and periosteum. 


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The goal of this method of application is even distribution of the drug throughout the entire joint 
lining containing sensory nerve fibers including capsule, synovium, and periosteum. 
Refer to the Pharmacy Manual for details on the study drug administration. 
5.1.6. 
Study Drug Compliance 
Because HTX-011 is being administered as a component of the surgical procedure, a lack of 
treatment compliance is not expected. 
5.1.7. 
Study Drug Accountability 
HTX-011 provided for this study will be used only as directed in the study protocol. In 
accordance with Good Clinical Practice (GCP), Investigators are required to maintain accurate 
and up-to-date records of all HTX-011 to permit reconciliation. The Investigator or designee 
must maintain adequate records of distribution, including the date received, number and units 
received, lot numbers, dispensing, and return or destruction of all HTX-011 (ie, accountability or 
dispensing logs). 
All HTX-011 records must be readily available for inspection by the site’s Clinical Monitor 
and/or auditor. The Clinical Monitor is responsible for verifying the accuracy of the HTX-011 
records at the study site. All returns, disposal, or destruction must be approved by the Sponsor in 
writing. 
5.2. 
Injection of Bupivacaine HCl into the Posterior Capsule (Group B of 
Cohort 3 Only) 
Bupivacaine HCl 100 mg 0.25% or 0.5% will be administered as a 40 mL injection into the 
posterior capsule just prior to placement of the prosthesis (ie, 40 mL of 0.25% or 20 mL of 0.5% 
diluted with 20 mL of 0.9% Normal Saline for a total of 40 mL). Bupivacaine HCl should be 
injected evenly with at least 10 to 15 injection points. Refer to the Pharmacy Manual for details 
on administration. 
5.3. 
Additional Scheduled Concomitant Medications 
Anesthesia: Bupivacaine 0.5% or 0.75%, per institutional practice, will be administered as part 
of the spinal anesthesia during surgery. The dose of bupivacaine should not exceed a maximum 
of 20 mg (ie, maximum of 4 mL of bupivacaine 0.5% or maximum of 2.6 mL of bupivacaine 
0.75%). 
Scheduled MMA Regimen: Just before being taken to the operating room, all subjects will 
receive PO acetaminophen 1 g, PO celecoxib 200 mg, and PO pregabalin 300 mg. For the first 
3 days after surgery, all subjects will receive PO acetaminophen 1 g every 8 hours and PO 
celecoxib 200 mg every 12 hours (Cohorts 1, 2, and 3) or PO acetaminophen 1 g every 8 hours 
and PO ibuprofen 600 mg every 6 hours (Cohort 4). For the next 4 days, the MMA regimen for 
all cohorts will consist of PO ibuprofen 600 mg every 6 hours alternating with PO 
acetaminophen 1 g every 6 hours (maximum ibuprofen dose of 2.4 g/day and maximum 
acetaminophen dose of 4 g/day) while the subject is awake, so that an analgesic is taken 
approximately every 3 hours. 


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Antifibrinolysis and DVT prophylaxis: All subjects will also be administered TXA IV and 
acetylsalicylic acid PO for antifibrinolysis and DVT prophylaxis, respectively. TXA 1g IV will 
be administered within approximately 4 hours prior to the start of surgery and a second dose will 
be administered up to approximately 8 hours later. Subjects will receive acetylsalicylic acid 
325 mg PO BID following surgery until discharge. 


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6. 
STUDY PROCEDURES AND ASSESSMENTS 
The following sections describe the study procedures and assessments that will be performed 
during the study. The timing of procedures and assessments is provided in Section 7 and the 
SCHEDULE OF EVENTS table. 
6.1. 
Medical History and Demographics 
6.1.1. 
Medical History 
A complete medical history will be obtained to ensure subjects qualify for the study. Medical 
history will be obtained through subject interview. A review of the subject’s medical records 
from their primary care physician is recommended. Data collected will include medical and 
surgical history. 
6.1.2. 
Demographics 
Demographic information collected will include age, sex, race, and ethnicity. 
6.2. 
Prior and Concomitant Therapy 
All medications taken by subjects between signing the ICF and the Day 29 Visit will be 
recorded. The dosing regimen of “prn” should not be recorded on the eCRF. 
During the 72-hour postoperative period, the name, dose, and route, as well as the start date and 
time, of concomitant medications must be recorded. Medications include prescription or 
over-the-counter medications (including herbal products and vitamins). For subjects entering on 
a stable dose of permitted medication, any change in dose should also be recorded. Note: All 
medications received during this period must have a start time recorded, except for IV fluids and 
oxygen during surgery, which do not need to be recorded unless being used to treat an AE. 
After the 72-hour period until the Day 29 Visit, at least the start date of each concomitant 
medication should be recorded. 
6.2.1. 
Allowed Concomitant Medications 
All treatments that the Investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the Investigator in keeping with the standard of medical care. 
Antiemetic medications may be given to treat nausea and/or vomiting, but should not be 
administered prophylactically (ie, as a routine preventative in the absence of signs or symptoms 
of nausea or vomiting). 
During surgery, the use of fentanyl up to 4 μg/kg IV is permitted for intraoperative pain control; 
postoperative fentanyl use is not permitted. 
Opioid rescue medications permitted to treat pain during the 72-hour postoperative period 
include of any 1 or more of the following opioid medications, as needed: PO immediate-release 
oxycodone (≤10 mg within a 4-hour period), IV morphine (2.5 mg to 5 mg within a 4-hour 
period), and/or IV hydromorphone (0.5 mg to 1.0 mg within a 4-hour period). Combination 
products containing an opioid and non-opioid are not allowed. 


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After 7 days of the schedule non-opioid MMA regimen, subjects may continue one or both of the 
MMA medications as needed, but should not exceed ibuprofen 600 mg every 6 hours or 
acetaminophen 1 g every 6 hours (maximum ibuprofen dose of 2.4 g/day and maximum 
acetaminophen dose of 4 g/day). 
6.2.2. 
Prohibited Therapy 
6.2.2.1. 
Medications Prohibited Prior to Surgery 
Any drug formulation containing bupivacaine or meloxicam is prohibited before surgery (within 
5 days for bupivacaine and within 10 days for meloxicam). Refer to exclusion criteria 4 through 
13 for medications that are prohibited prior to the scheduled surgery (Section 4.1.2). 
6.2.2.2. 
Medications Prohibited During Surgery 
Intraoperative administration of opioids or any other analgesics (including ketamine), local 
anesthetics, or anti-inflammatory agents except as specified by the protocol (ie, HTX-011, 
bupivacaine, fentanyl) is prohibited, unless needed to treat an AE that occurs after signing the 
ICF, for pretreatment prior to a needle placement, or to decrease venous irritation (eg, caused by 
propofol, in which case no more than a single administration of lidocaine 1% 20 mg IV may be 
administered). 
6.2.2.3. 
Medications Prohibited During the Postoperative Period 
With the exception of the scheduled non-opioid MMA regimen (Section 5.2) and permitted 
opioid rescue medications (Section 6.2.1), no other analgesic agents, including pregabalin and 
other NSAIDs, are permitted through Day 11. 
6.3. 
Efficacy Assessments 
6.3.1. 
Pain Intensity Assessments 
Subjects will be asked to evaluate their current pain level at scheduled timepoints after surgery. 
The subject should be in the resting position (either seated comfortably or lying down) for at 
least 5 minutes prior to obtaining the pain scores. Pain intensity scores will be assessed using 
2 different pain scales: VAS and NRS (Breivik 2008; Haefeli 2006). Subjects will receive 
training by the site on how to provide pain intensity assessments. 
The VAS consists of a straight 10-cm line that represents pain ranging from “no pain” to “pain as 
bad as it could be” (see Appendix C). Subjects will be asked to mark their current pain level on 
the line. The distance between “no pain at all” and the subject’s mark defines the subject’s pain. 
The NRS is an 11-point scale (0 to 10) where 0 represents “no pain” and 10 represents “worst 
pain imaginable” (see Appendix D). Subjects will be asked to rate their current pain level on this 
scale. 


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6.3.2. 
Use of Opioid Medications 
6.3.2.1. 
Opioid Rescue Medication Prior to Discharge 
The name, dose, and route as well as the date and time of administration of any opioid rescue 
medication must be recorded in the subject’s eCRF during the 72-hour postoperative period. 
More information on opioid rescue medications permitted is provided in Section 3.1.2. 
6.3.3. 
Opioid Medication After Discharge 
All subjects (whether or not they were discharged with an opioid prescription) will be provided a 
daily diary to record any opioid medication use from discharge through the Day 11 Visit. 
Sites will also record all site or subject-initiated contact between discharge and the Day 11 Visit 
and if any resulted in issuing an opioid prescription. 
6.3.4. 
Discharge Readiness 
Discharge readiness will be assessed using the MPADSS criteria, which considers a number of 
clinical variables: vital signs, ambulation, nausea/vomiting, pain, and surgical bleeding (Chung 
1995). This study instrument assesses a subject’s potential readiness to be discharged and should 
be repeated at all scheduled timepoints. It is not meant to be used to decide whether or not to 
discharge a subject from the study. Subjects are required to remain in the hospital/research 
facility for 72 hours. See Appendix E for the MPADSS criteria. 
6.3.5. 
Patient Global Assessment of Pain Control 
Subjects will be asked to evaluate their pain control over the preceding 24 hours using a 4-point 
PGA scale where 0 represents “poor” and 3 represents “excellent” (Rothman 2009). See 
Appendix F for the PGA scale. 
6.3.6. 
Overall Benefit of Analgesia Assessment 
Subjects will be questioned about their overall benefit of analgesia using a 7-item, 
multidimensional, quality assessment questionnaire (Lehmann 2010). The 7 items address pain, 
vomiting, itching, sweating, freezing, dizziness, and overall satisfaction with postoperative pain 
and make up the OBAS. See Appendix G for the OBAS scale. 
6.3.7. 
Treatment Satisfaction 
Subjects will be asked to evaluate their satisfaction with their scheduled non-opioid MMA 
regimen for the treatment of their TKA-related pain using the TSQM-9 (Bharmal 2009). Subjects 
will answer 9 questions related to effectiveness, convenience, and global satisfaction (see 
Appendix H). 
6.3.8. 
Ambulation and Rehabilitation 
Sites will assess the subject’s time to ambulate. Ambulation is defined as the ability walk at least 
20 feet with optional use of a 4-legged walker for balance. All subjects will be encouraged to 
ambulate as early as possible during the 72-hour postoperative period. The date and time of first 
ambulation must be recorded. 


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Sites will also assess the subject’s ability to participate in scheduled rehabilitation sessions on the 
evening of Day 1 and in the morning and evening of Days 2 and 3 according to institution’s 
guidelines. 
6.3.9. 
Discharge Information 
Sites will record when subjects are discharged and if subjects are discharged home or to a skilled 
nursing facility. 
Sites will also record if subjects are discharged with an opioid prescription and information about 
the opioid prescription. See Section 3.1.2.2 for guidance on providing an opioid prescription at 
discharge. 
6.4. 
Safety Assessments 
6.4.1. 
Adverse Events 
All AEs, regardless of causality or seriousness, will be recorded from the time the subject signs 
the ICF through the Day 29 Visit. Additional safety information is provided in Section 8. 
6.4.2. 
Physical Examinations 
Scheduled physical examinations will include an evaluation of the following: head, eyes, ears, 
nose, and throat as well as CV, respiratory, gastrointestinal, neurological, dermatological, and 
musculoskeletal systems. 
Baseline height and weight measurements will be conducted and BMI calculated (Appendix B). 
Unscheduled physical examinations may also be performed (the extent of which is to be 
determined by the Investigator) at any time during the study if indicated by a change in the 
subject’s medical history or condition. 
Any abnormal physical examination finding deemed clinically significant by the Investigator 
must be recorded as an AE. 
6.4.3. 
Vital Signs 
Vital sign measurements will include blood pressure, resting heart rate, respiration rate, and body 
temperature. Subjects should be in a supine position (includes sitting in a recliner chair) for at 
least 5 minutes before measuring vital signs. 
Any abnormal vital sign result deemed clinically significant by the Investigator must be recorded 
as an AE. 
6.4.4. 
12-Lead Electrocardiograms 
Standard digital 12-lead ECGs will be performed in triplicate during Screening. Subjects should 
be in a supine position (includes sitting in a recliner chair) for at least 5 minutes before the initial 
ECG recording. The mean of the 3 ECG recordings will be used as the baseline result. 
Any abnormal ECG result deemed clinically significant by the Investigator must be recorded as 
an AE. 


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6.4.5. 
Wound Healing Evaluation 
Surgical wound healing will be assessed using the Southampton Wound Scoring System 
(Appendix I). Surgical wound healing will be evaluated by the Investigator or other medically 
qualified clinical site personnel; every attempt should be made by the site to use the same 
assessor for individual subject assessments. 
Only an abnormal wound healing finding deemed clinically significant by the Investigator must 
be recorded as an AE and should be followed to resolution. 
6.4.6. 
Clinical Laboratory Tests 
Blood and urine samples will be collected for diagnostic screening tests and for safety laboratory 
tests (hematology and serum chemistry). A list of clinical laboratory tests and parameters is 
provided in Table 1. 
Scheduled hematology and serum chemistry tests will be performed by a central laboratory. 
Urine samples collected during the Screening period for pregnancy and drug screening will be 
tested at the study site using kits provided by the central laboratory. 
Laboratory results will be reviewed by the Investigator. Laboratory values outside of the normal 
reference range will be evaluated for clinical significance. Only an abnormal laboratory value 
deemed clinically significant by the Investigator must be recorded as an AE. Results for any 
unscheduled local laboratory tests deemed abnormal and clinically significant must be recorded 
on an eCRF. 
Refer to the Laboratory Manual for detailed instructions on sample collection, processing, and 
shipping procedures. 
Table 1: 
Clinical Laboratory Tests 
Diagnostic Screening Tests (Study Sites): 
Urine 
Pregnancy test: Human chorionic gonadotropin test (female subjects of child-bearing potential only) 
Drug screen: Amphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine, opiates/opioids, and 
phencyclidine 
Safety Laboratory Tests (Central Laboratory): 
Hematology 
Serum Chemistry 
Red blood cell count  
Hematocrit  
Hemoglobin  
Mean corpuscular volume 
Platelet count 
White blood cell count (with automated 
differential) 
Alanine aminotransferase 
Albumin  
Alkaline phosphatase  
Aspartate aminotransferase 
Bicarbonate  
Blood urea nitrogen 
Calcium  
Chloride  
Creatinine  
Direct bilirubin 
Gamma-glutamyltransferase 
Glucose  
Lactate dehydrogenase 
Magnesium  
Phosphorus  
Potassium  
Sodium  
Total bilirubin 
Total protein 
Uric acid 


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6.4.7. 
Local Anesthetic Systemic Toxicity (LAST) Assessment 
If signs and symptoms of suspected LAST are observed, the following assessments must be 
promptly performed: vital sign measurements, 12-lead ECGs, and blood sample collection to 
measure bupivacaine plasma concentrations (all cohorts) and alpha-1-acid glycoprotein 
concentrations (Cohort 4 only). 
6.5. 
Pharmacokinetic Assessments 
Blood samples for bupivacaine and meloxicam PK analysis will be collected from all subjects. 
Blood samples for alpha-1-acid glycoprotein analysis will be collected from subjects in Cohort 4. 
Blood samples may also be used to evaluate other study drug components. 
Blood samples may be drawn using a properly maintained indwelling cannula. Samples for 
bupivacaine and meloxicam PK analysis will be sent to a bioanalytical laboratory for analysis. In 
Cohort 4, ex vivo protein binding of bupivacaine will be determined to support PK analysis of 
free bupivacaine. Samples for alpha-1-acid glycoprotein, which impacts the free fraction of 
bupivacaine, will be sent to a central laboratory for analysis. Detailed instructions on sample 
collection, processing, storage, and shipping procedures are provided in the Laboratory Manual. 


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7. 
TIMING OF PROCEDURES AND ASSESSMENTS 
This section lists the study procedures and assessments that will be performed at scheduled 
timepoints during the study. Information on study procedures and assessments is provided in 
Section 6. 
Unless there is a safety concern, every effort should be made to avoid protocol deviations. For 
assessments at timepoints when the subject is asleep, an attempt should be made to wake the 
subject. If there is no response, the assessments at these timepoints may be recorded as “Not 
Done.” Assessments that can be done without waking the subject (eg, blood collection for PK) 
should be completed. Additional visits and/or assessments are permitted if clinically indicated in 
the opinion of the Investigator. 
When the following assessments are scheduled at the same timepoint, it is recommended that 
they be performed in this order: 
• Pain intensity assessment (VAS and NRS-R). 
• PGA of pain control assessment. 
• Vital sign measurements. 
• 12-lead ECG recording (in triplicate). 
• Blood sample collection. 
• Physical examination. 
• Wound healing assessment. 
7.1. 
Screening Period (Within 28 Days Before Surgery) 
After providing written informed consent, potential study subjects will undergo Screening 
procedures to confirm eligibility to participate in the study. Screening procedures must be 
performed within 28 days prior to surgery. The Investigator must evaluate the subject’s medical 
history and the results of all Screening assessments to determine study eligibility. 
Results of the following tests should be confirmed as negative prior to performing any additional 
assessments: 
• Urine drug screen test (all subjects): A subject who fails the drug test may be 
rescreened at the discretion of the Investigator after discussion with the Study 
Medical Monitor. Subjects with a positive drug screen who are taking an allowed, 
prescribed medication that is known to result in a positive drug test (eg, amphetamine 
and dextroamphetamine for attention-deficit/hyperactivity disorder, benzodiazepine 
for anxiety disorder) may be eligible for participation in the study. 
• Urine pregnancy test (female subjects of child-bearing potential only). 


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Additional screening procedures and assessments will include the following: 
• Medical history. 
• Demographic recording. 
• Physical examination (including weight, height, and BMI calculation). 
• Vital sign measurements. 
• 12-lead ECG recording (in triplicate). 
• Blood sample collection for the hematology and serum chemistry. 
• Subject training for pain intensity assessments. 
• Ambulation assessment. 
• AE recording (from the time the subject signs the ICF). 
• Prior and concomitant medication recording (from the time the subject signs the ICF). 
7.2. 
Treatment and Postoperative Observation Period 
7.2.1. 
Day of Surgery (Day 1) 
7.2.1.1. 
Prior to Surgery 
On Day 1, subjects will be reassessed for study eligibility. Results of the following should be 
confirmed as negative prior to performing any additional assessments: 
• Urine drug screen test (all subjects). 
• Urine pregnancy test (female subjects of child bearing potential only). 
Subjects who continue to meet the eligibility criteria will be admitted to the surgical unit. The 
following additional study procedures and assessments will be performed before surgery: 
• Vital sign measurements. 
• Blood sample collection for PK (before administering the spinal anesthesia). 
• Blood sample collection for alpha-1-acid glycoprotein (before administering the 
spinal anesthesia) (Cohort 4 only). 
• Subject training for pain intensity assessments (refresher training). 
• VAS pain intensity assessment. 
• NRS-R assessment. 
• AE recording. 
• Prior and concomitant medication recording. 
Within approximately 4 hours prior to the start of surgery, TXA 1 g IV will be administered. 
Just before the subject is taken to the operating room, acetaminophen 1 g PO, celecoxib 200 mg 
PO, and pregabalin 300 mg PO will be administered. 


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7.2.1.2. 
Surgery and Study Treatment Administration 
Subjects will undergo a primary unilateral TKA under bupivacaine spinal anesthesia. Sites 
should follow intraoperative safety monitoring in accordance with ASA Standards for Basic 
Anesthetic Monitoring (American Society of Anesthesiologists 2015). The use of drains is 
prohibited in Cohorts 2 and 3. The start and stop time of surgery and additional surgical details 
should be recorded in the eCRF. The start time of the skin incision will be considered the start of 
surgery. Placement of the last suture will be considered the end of surgery. 
Subjects will be administered study drug (HTX-011; all cohorts) and bupivacaine HCl (Group B 
of Cohort 3 only) unless they experience a clinically significant event during surgery 
(eg, excessive bleeding, hemodynamic instability) that would render the subject medically 
unstable or complicate their postoperative course. Study drug and bupivacaine HCl will be 
applied into the surgical site prior to wound closure. More information on the administration 
techniques are provided in Section 5.1.5 and Section 5.2, respectively. 
The start and stop times of study drug dosing will be recorded in the eCRF. Details of 
administration will be recorded on a worksheet, which will be used in the dictation of the 
surgical notes and will become part of the source document. Note: The start of study drug 
administration will be considered Time 0 for all efficacy, safety, and PK assessments. 
Concomitant medications used during surgery will be recorded (note that IV fluids and oxygen 
are not required to be recorded unless being used to treat an AE). AEs will also be recorded. 
After immediate postoperative recovery, subjects will be transferred to the postanesthesia care 
unit. 
7.2.2. 
Postoperative Assessment Period (Up to 72 Hours) 
Subjects will remain in the hospital/research facility for 72 hours after study drug administration. 
During the inpatient period, subjects will be administered a scheduled non-opioid MMA regimen 
and medication for DVT prophylaxis (Section 7.2.2.1) and will undergo safety, efficacy, and PK 
assessments (Section 7.2.2.2). 
7.2.2.1. 
Study Medication During Inpatient Period 
As soon as subjects are able to tolerate oral intake, they will be started on a MMA regimen 
consisting of PO acetaminophen 1 g every 8 hours and PO celecoxib 200 mg every 12 hours 
(Cohorts 1, 2, and 3) or PO acetaminophen 1 g every 8 hours and PO ibuprofen 600 mg every 
6 hours (Cohort 4). 
Subjects will also receive TXA 1 g IV up to approximately 8 hours after the presurgery dose of 
TXA and acetylsalicylic acid 325 mg PO BID until hospital discharge. Surgeons may also use 
additional DVT prophylaxis as per their standard of care. 
Subjects may be administered opioid rescue medication if needed to treat pain, as detailed in 
Section 3.1.2.1. 
7.2.2.2. 
Study Procedures and Assessments During Inpatient Period 
Study procedures and assessments that will be performed during the 72-hour postoperative 
period are listed below. All timepoints are referenced to the start of study drug administration. 


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Actual times will be recorded for all events, and any deviation outside the specified ranges must 
be clearly documented in the subject’s study records. 
• VAS and NRS-R assessments: 1 hour (±10 min), 2 hour (±15 min), 4 hours 
(±30 min), 6 hours (±30 min), 8 hours (±30 min), 12 hours (±30 min), 24 hours 
(±1 h), 36 hours (±2 h), 48 hours (±2 h), 60 hours (±2 h), and 72 hours (±2 h). 
− Note: If a subject requires rescue medication before the 1-hour pain intensity 
assessments, then an unscheduled VAS and NRS-R score must be obtained before 
administering the first dose of rescue medication. These do not replace the 1-hour 
VAS and NRS-R assessments. 
• PGA of pain control assessment: 24 hours (±1 h), 48 hours (±2 h), and 72 hours 
(±2 h). 
• Vital sign measurements: 24 hours (±1 h), 48 hours (±2 h), and 72 hours (±2 h). 
• Blood sample for hematology and serum chemistry: 72 hours (±2 h). 
• Blood sample collection for PK (Cohorts 1 and 2): 4 hours (±30 min), 20 hours 
(±1 h), 24 hours (±1 h), and 48 hours (±2 h). 
• Blood sample collection for PK (Cohort 3): 30 minutes (±5 min), 1 hour (±10 min), 
2 hours (±15 min), 4 hours (±30 min), 6 hours (±30 min), 8 hours (±30 min), 12 hours 
(±30 min), 20 hours (±1 h), 24 hours (±1 h), 36 hours (±2 h), 48 hours (±2 h), 
60 hours (±2 h), and 72 hours (±2 h). 
• Blood sample collection for PK (Cohort 4): 30 minutes (±5 min), 1 hour (±10 min), 
2 hours (±15 min), 4 hours (±30 min), 6 hours (±30 min), 8 hours (±30 min), 12 hours 
(±30 min), 20 hours (±1 h), 24 hours (±1 h), 48 hours (±2 h), and 72 hours (±2 h). 
• Blood sample collection for alpha-1-acid glycoprotein (Cohort 4): 4 hours 
(±30 min), 12 hours (±30 min), 20 hours (±1 h), 24 hours (±1 h), 48 hours (±2 h), and 
72 hours (±2 h).  
• Physical examination: 72 hours (±2 h; height and weight not required). 
• Discharge readiness assessment per the MPADSS criteria: 2 hours (±15 min); 
4 hours (±30 min), 6 hours (±30 min), 8 hours (±30 min), 12 hours (±30 min), 
24 hours (±1 h), 36 hours (±2 h), 48 hours (±2 h), 60 hours (±2 h), and 72 hours 
(±2 h). 
• OBAS assessment: 24 hours (±1 h), 48 hours (±2 h), and 72 hours (±2 h). 
• TSQM-9 questionnaire: 72 hours (±2 h). 
• Wound healing assessment: 72 hours (±2 h). 
• AE recording: (Note: the start date and time of all AEs during this timeframe must 
be recorded). 
• Concomitant medication recording: (Note: the start date and time of all 
concomitant medications during this timeframe must be recorded.) 


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All subjects will be encouraged to ambulate as early as possible during the 72-hour postoperative 
period and will be evaluated for the time to first ambulation postsurgery. Subjects will also 
participate in rehabilitation on the evening of Day 1, and in the morning and evening of Days 2 
and 3. 
7.2.3. 
Discharge 
After the 72-hour assessments have been completed, subjects may be discharged if medically 
ready. If a subject is not ready to be discharged due to an AE, it should be recorded as an SAE. If 
a subject is ready for discharge but is not discharged for any reason other than AE, the reason 
should be recorded on the eCRF. 
When a subject is discharged, the site will record the following: 
• The time of discharge. 
• If the subject is discharged home or to a skilled nursing facility. 
• If the subject is discharged with an opioid prescription and information about the 
opioid prescription. See Section 3.1.2.2 for guidance on providing an opioid 
prescription at discharge. 
Sites will also provide subjects with the following at the time of discharge: 
• Instructions on managing pain after discharge (see Section 3.1.2.3). 
• A diary that subjects will complete daily to record if they take any opioid medication 
from 72 hours through the Day 11 Visit. Note: All subjects, whether or not they were 
discharged with an opioid prescription, will receive an opioid diary. 
7.3. 
Follow-Up Period 
7.3.1. 
Day 5 Until Day 11 Visit 
Subjects will continue their scheduled MMA regimen (PO ibuprofen alternating with PO 
acetaminophen) for 4 days after discharge (Days 5 through 8) and then as needed thereafter (see 
Section 3.1.2.3). Subjects will complete their opioid diary each day through the Day 11 Visit. 
Sites will record all site- or subject-initiated contact between discharge and the Day 11 Visit and 
if any resulted in issuing an opioid prescription. 
7.3.2. 
Day 11 Visit (±2 Days) 
All subjects will return to the study site and will have the following procedures and assessments: 
• VAS pain intensity assessment. 
• NRS-R assessment. 
• PGA of pain control assessment. 
• Blood sample collection for the hematology and serum chemistry. 
• OBAS assessment. 


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• TSQM-9 questionnaire. 
• Wound healing assessment. 
• Review subject opioid daily diary results. 
• AE recording. 
• Concomitant medication recording. 
7.3.3. 
Day 29 Visit (±4 Days) 
All subjects will return to the study site and will have the following procedures and assessments: 
• VAS pain intensity assessment. 
• NRS-R assessment. 
• Wound healing assessment. 
• AE recording. 
• Concomitant medication recording. 
7.4. 
Early Termination Visit 
Subjects who withdraw early from the study will be asked to complete the following Early 
Termination procedures and assessments: 
• Vital sign measurements (only if subject withdrew prior to 72 hours). 
• Physical examination (only if subject withdrew prior to 72 hours [height and weight 
not required]). 
• Blood sample collection for hematology and serum chemistry (only if subject 
withdrew prior to the Day 11 Visit). 
• Review subject diary results (only if subject withdrew prior to the Day 11 Visit). 
• VAS pain intensity assessment. 
• NRS-R assessment. 
• Wound healing assessment. 
• AE recording. 
• Concomitant medication recording. 
7.5. 
Unscheduled Visits and Assessments 
If signs and symptoms of suspected LAST are observed, unscheduled vital sign measurements, 
12-lead ECGs, and blood sample collection for PK (all cohorts) and alpha-1-acid glycoprotein 
(Cohort 4 only) must be promptly performed. 
Unscheduled visits and assessments should also be performed if clinically indicated in the 
opinion of the Investigator. Except when urgent clinical evaluation is necessary, it is expected 


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that the Investigator will have the subject return for an unscheduled visit rather than directing the 
subject to a hospital emergency room. 
The results of any unscheduled assessments should be recorded. 


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8. 
SAFETY MONITORING AND REPORTING 
Investigators are responsible for the detection and documentation of AEs, SAEs, unanticipated 
problems, and pregnancies, as detailed in this protocol. 
Investigators must review the HTX-011 Investigator’s Brochure so as to be aware of the 
safety-related events that may be anticipated with its use. Investigators will also be versed in the 
latest standard of care guidelines. 
8.1. 
Definition of Safety Parameters 
8.1.1. 
Definition of an Adverse Event 
An AE is defined as any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related. 
An AE may be any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a study drug, whether or not 
considered causally associated with the use of the study drug. Any abnormal physical 
examination finding, laboratory value, vital sign result, ECG finding, or wound healing 
assessment finding deemed clinically significant by the Investigator must be reported as an AE. 
A clinical diagnosis, rather than a change in a laboratory analyte or other assessment, should be 
recorded (eg, anemia rather than low hemoglobin value). 
Examples of AEs include the following: 
• Significant or unexpected worsening or exacerbation of the condition or indication 
under study. 
• Exacerbation of a chronic or intermittent pre-existing condition, including either an 
increase in frequency or intensity of the condition (eg, abnormal physical examination 
finding). 
• Signs, symptoms, or clinical sequelae of a suspected interaction. 
• Signs, symptoms, or clinical sequelae of a suspected overdose of the study drug or a 
concurrent medication (overdose per se should not be reported as an AE or SAE, 
unless nonserious or serious sequelae occur). 
• The following abnormal laboratory results: 
− Any laboratory abnormality suggestive of a new disease/organ toxicity or a 
worsening of a pre-existing condition. 
− Any laboratory abnormality that required the subject to have investigational 
product interrupted or discontinued. 
− Any laboratory abnormality that required the subject to receive specific treatment 
for the laboratory abnormality. 
− Any laboratory abnormality that required additional diagnostic intervention, 
and/or follow-up visits (excluding repeat testing to confirm the abnormality). 


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The following examples are not considered AEs: 
• Medical or surgical procedure (eg, endoscopy, appendectomy), although the condition 
that leads to the procedure is an AE. 
• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) 
(including laboratory values) present or detected at the start of the study that do not 
worsen. 
• The disease or disorder being studied; or expected progression, signs, or symptoms of 
the disease or disorder being studied, unless they become more severe or occur with a 
greater frequency than expected for the subject’s condition. 
• Transient paresthesia that is considered to be clinically normal (would be expected to 
occur as a long-acting local anesthetic wears off). 
8.1.2. 
Definition of a Serious Adverse Event 
An AE or suspected adverse reaction is considered “serious” if, in the view of either the 
Investigator or Sponsor, it results in any of the following outcomes: 
• Death. 
• A life-threatening AE (ie, an AE that presented an immediate risk of death from the 
event as it occurred. This criterion is not intended to include an AE that, had it 
occurred in a more severe form, might have caused death.) 
• Inpatient hospitalization or prolongation of existing hospitalization. 
• A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions. 
• A congenital anomaly/birth defect. 
• Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the patient or subject and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition. 
Examples of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or convulsions that do 
not result in inpatient hospitalization, or the development of drug dependency or drug 
abuse. 
The following events do not meet the definition of an SAE: hospitalization for elective treatment 
of a pre-existing condition that does not worsen from baseline, hospitalization for a standard 
procedure for study drug administration and routine monitoring of the studied indication not 
associated with any deterioration in condition, social or convenience admission to a hospital, 
prolongation of a hospitalization for social or convenience reasons not associated with the 
occurrence of an AE, or hospitalization or an emergency room visit that lasts less than 24 hours 
and does not meet the criteria of an important medical or a life-threatening event. 
According to 21 Code of Federal Regulations (CFR) 812.3(s), an unanticipated adverse device 
effect means any serious adverse effect on health or safety or any life-threatening problem or 


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death caused by, or associated with, a device, if that effect, problem, or death was not previously 
identified in nature, severity, or degree of incidence in the investigational plan or application 
(including a supplementary plan or application), or any other unanticipated serious problem 
associated with a device that relates to the rights, safety, or welfare of subjects. 
8.1.3. 
Definition of Unanticipated Problems 
Unanticipated problems are incidents, experiences, or outcomes that meet all of the following 
criteria: 
• Unexpected in terms of nature, severity, or frequency given (a) the research 
procedures that are described in the protocol-related documents, such as the research 
protocol and informed consent document approved by the Ethics Committee (EC; 
includes Institutional Review Boards [IRBs], Independent Ethics Committees [IECs], 
and Research Ethics Boards [REBs]) and (b) the characteristics of the participant 
population being studied. 
• Related or possibly related to participation in the research (“possibly related” means 
there is a reasonable possibility that the incident, experience, or outcome may have 
been caused by the procedures involved in the research). 
• Suggest that the research places subjects or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized. 
An unanticipated adverse device effect is defined in Section 8.1.2. 
8.2. 
Classification of Adverse Events 
8.2.1. 
Severity of Adverse Events 
The Investigator will assess the severity of each AE based on his/her clinical judgment using one 
of the following categories: 
• Mild: Event is easily tolerated by the subject, causes minimal discomfort, and does 
not interfere with everyday activities. 
• Moderate: Event results in a low level of inconvenience or concern with the 
therapeutic measures. Moderate events may cause some interference with 
functioning. 
• Severe: Event interrupts a participant’s usual daily activity and may require systemic 
drug therapy or other treatment. Severe events are usually potentially life-threatening 
or incapacitating. 
8.2.2. 
Relationship to Study Drug 
The Investigator will assess the relationship of each AE to study drug (HTX-011) based on 
his/her clinical judgment. The Investigator’s assessment of an AE’s relationship to study drug is 
part of the documentation process, but it is not a factor in determining what is or is not reported 
in the study. If there is any doubt as to whether a clinical observation is an AE, the event should 


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be reported. The Sponsor’s assessment of relationship may differ from the Investigator’s 
assessment. 
Relationship to study drug will be assessed according to the following guidelines: 
• Possibly related: The AE is known to occur with the study drug, there is a reasonable 
possibility that the study drug caused the AE, or there is a temporal relationship 
between the study drug and event. Reasonable possibility means that there is evidence 
to suggest a causal relationship between the study drug and the AE. 
• Unlikely related: There is not a reasonable possibility that the administration of the 
study drug caused the event, there is no temporal relationship between the study drug 
and event onset, or an alternate etiology has been established. 
Even in situations in which minimal information is available for initially reporting an SAE, it is 
important that the Investigator always make an assessment of causality for every event before 
entering the information into the eCRF or completing the SAE reporting form, in the event 
electronic data capture (EDC) is not available. The causality assessment is one of the criteria 
used when determining regulatory reporting requirements. The Investigator may change his or 
her opinion of causality in light of follow-up information and amend the SAE information 
accordingly in the eCRF or the SAE reporting form, as applicable. 
8.3. 
Time Period and Frequency for Event Assessment and Follow Up 
8.3.1. 
Adverse Event and Serious Adverse Event Monitoring 
All AEs regardless of causality or seriousness will be recorded from the time the subject signs 
the ICF through the Day 29 Visit. Note: the start time of all AEs during the 72-hour 
postoperative period must also be recorded. 
For subjects who received study drug, if an Investigator becomes aware of an SAE that occurs 
after the subject’s last study visit and the Investigator considers the event to be possibly related 
to the study drug, the Investigator needs to report the SAE to the Sponsor as described in 
Section 8.4.1. 
8.3.2. 
Follow-Up of Events 
After the occurrence of an AE or SAE, the Investigator is required to follow each subject 
proactively and provide further information on the subject’s condition. All AEs and SAEs 
documented at a previous visit or contact and designated as ongoing will be reviewed at 
subsequent visits or contacts. 
Nonserious AEs will be followed after the last scheduled study visit until the event resolves, the 
condition stabilizes, or until the event is otherwise explained or judged by the Investigator to be 
no longer clinically significant (unless the subject is lost to follow-up or withdraws consent). 


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The Investigator will assess the outcome of each AE using the following categories: 
• Recovered/Resolved: The event resolved or the subject recovered without sequelae. 
An event (either serious or nonserious) occurred and had an endpoint, and the subject 
experienced no restrictions. Examples include stent placement for coronary artery 
disease (a device implanted is not a sequela), an appendectomy (a scar is not a 
sequela), a postoperative wound infection, or an upper respiratory tract infection. 
• Recovered/Resolved with sequelae: The event has at least one secondary outcome 
that may result in permanent disability, functional limitation, or both. Such sequelae 
are usually limited to SAEs. Examples include hip replacement resulting in foot drop 
(foot drop is not the intended outcome but is a risk of surgery), stroke resulting in 
paralysis, or emboli formation after a bacterial infection resulting in a renal infarct 
and loss of renal function. 
• Recovering/Resolving: The event is improving. 
• Not recovered/Not resolved: At the end of the study, a nonserious event either has 
not changed in intensity or may not have recovered to baseline values, and the 
outcome is unknown. Examples include headache, low-grade fever, or nausea. 
• Unknown: The subject has withdrawn from the study prematurely or is lost to 
follow-up, and the status of the event is unknown. 
• Fatal 
SAEs will be followed until the event resolves (ie, when the event no longer meets any of the 
seriousness criteria), the condition stabilizes, or the event is otherwise explained or judged by the 
Investigator to be no longer clinically significant (unless the subject is lost to follow-up or 
withdraws consent). The Investigator will ensure that follow-up information provided to the 
Sponsor includes results of any additional laboratory tests or investigations, histopathologic 
examinations, or consultations with other healthcare professionals that serve to clarify the nature 
of the event, the cause of the event, or both. New or updated information will be recorded as 
outlined in Section 8.4.1. 
8.4. 
Reporting Procedures 
8.4.1. 
Reporting Serious Adverse Events to the Sponsor 
If the Investigator determines that an event that occurs during the course of this study meets the 
protocol definition of an SAE due to any cause, regardless of relationship to study drug, he/she 
must notify the Sponsor by entering the SAE information into the eCRF within 24 hours of the 
Investigator becoming aware of the SAE. 
If EDC is not available, the Investigator must complete an SAE reporting form and email it to the 
Sponsor within 24 hours of the Investigator becoming aware of the SAE. The Investigator 
must also enter the SAE information into the eCRF as soon as possible thereafter. 
Email Address: 
Heron_PV@ubc.com 


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In the initial email, the Investigator must provide to the Sponsor the following eCRF pages, 
completed to the greatest extent possible: 
• AE record. 
• Medical history. 
• Prior and concomitant medications. 
Also, the following documents are to be forwarded: any laboratory results, diagnostic test results, 
or medical reports relevant to the SAE. 
EDC is the primary method for notification of SAE information. In rare circumstances and in the 
absence of email capacity, notification by fax or telephone is acceptable, with a copy of the SAE 
reporting form sent by overnight mail. Initial notification via telephone does not replace the need 
for the Investigator to complete the SAE information in the eCRF within the time frames 
outlined. 
If the Investigator does not have all information regarding an SAE, he/she must not wait to 
receive additional information before notifying the Sponsor of the event. The SAE must be 
updated when additional information is received. Follow-up information received on all SAEs 
must be forwarded to the Sponsor using the same timelines as for an initial report. 
The Investigator must notify the Sponsor by reporting any unanticipated adverse device effect 
within 24 hours of the Investigator becoming aware of the effect. 
8.4.2. 
Reporting Unanticipated Problems to the Sponsor 
If the Investigator determines that an event meets the protocol definition of an unanticipated 
problem, he/she must notify the Sponsor by completing an Unanticipated Problem Form and 
emailing it to the Sponsor within 24 hours of the Investigator becoming aware of the 
problem. 
Email Address: 
Heron_PV@ubc.com 
The following information will be included with unanticipated problem reporting: 
• Protocol identifying information: protocol title, protocol number, and Investigator’s 
name. 
• A detailed description of the event, incident, experience, or outcome. 
• An explanation of the basis for determining that the event, incident, experience, or 
outcome represents an unanticipated problem. 
It is the Investigator’s responsibility to report any unanticipated problems to the Sponsor and 
their EC, as required by local regulations. 
8.4.3. 
Regulatory Reporting Requirements 
The Investigator must promptly report all SAEs and unanticipated adverse device effects to the 
Sponsor in accordance with the procedures detailed in Section 8.4.1. The Sponsor has a legal 
responsibility to notify, as appropriate, both the local regulatory authority and other regulatory 
agencies about the safety of a product under clinical investigation. Prompt notification of SAEs 


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by the Investigator to the appropriate project contact for SAE receipt is essential so that serious 
suspected adverse reactions that are either unexpected or observed with increasing occurrence be 
reported and legal obligations and ethical responsibilities regarding the safety of other subjects 
are met. 
Investigator letters are prepared according to Sponsor policy and are forwarded to the 
Investigators as necessary. An Investigator letter is prepared for any suspected adverse reaction 
that is attributable to study drug, serious, and unexpected. The purpose of the Investigator letter 
is to fulfill specific regulatory and GCP requirements regarding the product under investigation. 
The Investigator, or responsible person according to local requirements, must comply with 
requirements related to the reporting of SAEs to the EC. 
The Sponsor is responsible for informing ECs, Investigators, and regulatory authorities of any 
finding that could adversely affect the safety of subjects or affect the conduct of the study. 
Events will be reported to regulatory authorities in accordance with expedited and period 
reporting requirements. 
8.4.4. 
Pregnancy Reporting 
Pregnancy is not considered to be an AE; however, any subject who becomes pregnant during 
the study must be withdrawn from the study immediately. Female subjects who become pregnant 
within 28 days after receiving study drug should also notify the Investigator. The Investigator 
must attempt to follow the pregnancy to term or termination in order to report on outcome and 
health status of mother and child. 
The Investigator must notify the Sponsor of any pregnancy by completing a Pregnancy Form and 
emailing it to the Sponsor within 24 hours after the Investigator becomes aware of the 
pregnancy. 
Email Address: 
Heron_PV@ubc.com 
8.5. 
Safety Oversight 
An internal Product Safety and Risk Management Committee will monitor safety data on a 
periodic basis throughout the study, including regular review of AEs (including SAEs), 
laboratory results, and other safety assessments. 
The criteria for suspending the study are provided in in Section 13.5. 


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9. 
OTHER STUDY RESTRICTIONS 
9.1. 
Contraception 
Female subjects of childbearing potential must use an acceptable form of contraception in the 
event of sexual activity from the Screening Visit until 30 days after study drug administration. 
Acceptable forms of contraception include double-barrier contraception or an insertable, 
injectable, transdermal, or combination PO contraceptive approved by the US FDA. Subjects 
practicing abstinence must agree to use double-barrier contraception in the event of sexual 
activity. 
Note: This does not apply to women in only a same-sex relationship or women in a monogamous 
relationship with a surgically sterile partner. 
9.2. 
Continuous Passive Motion Machines 
Continuous passive motion machines are not required in this study; however, if they are to be 
used, they are not allowed within the first 12 hours after study drug administration. 


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10. 
STATISTICAL CONSIDERATIONS 
10.1. 
General Considerations 
All efficacy and safety data will be listed by subject. Unless otherwise specified, baseline is 
defined as the last observed measurement, whether scheduled or unscheduled, prior to study drug 
administration. Continuous variables will be summarized using the number of subjects with data 
(n), mean, SD, median, minimum, and maximum. Selected continuous variable summaries will 
also include the SE. Categorical variables will be summarized using frequency counts and 
percentages. 
10.2. 
Determination of Sample Size 
The sample size of 115 subjects was selected empirically without formal statistical assumptions. 
10.3. 
Analysis Populations 
Safety Population: All subjects who receive study drug will be included in the Safety Population. 
This population will be used for all summaries of efficacy and safety data. 
PK  Population: All subjects who receive at least 1 dose of study drug and have sufficient data to 
calculate PK parameters will be included in the PK Population. Any subject with a study drug 
predose concentration exceeding 5% of the Cmax for that individual will be excluded from the PK 
Population for that analyte. 
10.4. 
Statistical Analysis Methods 
10.4.1. 
Disposition and Demographics 
The number and percentage of subjects in each analysis population will be summarized. Subject 
disposition, including the number of subjects screened, dosed, completing the 72-hour 
postoperative observation period, completing the study, and not completing the study by reason 
for withdrawal will be summarized for the Safety Population. Subject demographics and baseline 
characteristics will be summarized for the Safety Population and will include age, age category, 
sex, race, ethnicity, height, weight, and BMI. 
10.4.2. 
Efficacy Analysis 
All efficacy data will be listed and summarized by cohort and treatment group. All opiate 
dosages and formulations will have the MME calculated (Opioid Morphine Equivalent 
Conversion Factors, Centers for Disease Control and Prevention, Atlanta, GA, May 2014). 
During the 72-hour postoperative period, subjects who do not use a specific opioid rescue 
medication during a period of interest will have the specific opioid dose set to 0 for that period 
and will be characterized as “opioid-free” for that time interval. 
10.4.2.1. Handling of Missing Data 
Due to the required 72-hour inpatient postoperative observation period, the amount of missing 
data is expected to be very low. For any missing data observed through 72 hours in subjects who 


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complete the 72-hour postoperative observation period, VAS and NRS-R scores will be imputed 
via last observation carried forward (LOCF), in which the most recent postdose value is used for 
a subsequent missing value. For subjects who do not have a postdose value prior to their first 
missing value, the median of the postdose values at the relevant timepoint from subjects with 
observed data will be used. Predose values will not be carried forward to postdose timepoints. In 
subjects who withdraw from the study prior to the end of 72-hour observation period, missing 
pain intensity scores through 72 hours that were to be collected following withdrawal will be 
imputed via worst observation carried forward (WOCF), in which the worst (highest) pain 
intensity score observed prior to withdrawal will be used for postwithdrawal values through 
72 hours. Analyses that adjust for the effect of opioid rescue medication will perform windowed 
worst observation carried forward (wWOCF) following LOCF/WOCF (ie, perform 
LOCF/WOCF first, then apply wWOCF). The number and percentage of missing pain intensity 
scores will be summarized. 
10.4.3. 
Safety Analysis 
All safety data will be listed and summarized by cohort and treatment group. AEs that occur 
between the time the subject signs the ICF and the start of study drug administration will be 
considered pretreatment AEs. AEs that start during or after study drug administration, or AEs 
with an onset prior to study drug administration that worsen after study drug administration will 
be considered TEAEs. All TEAEs will be coded and tabulated by System Organ Class and 
Preferred Term. The incidence of TEAEs, SAEs, and ORAEs will be summarized. TEAEs 
leading to study withdrawal, if any, will be listed separately. 
Associated laboratory parameters, such as hepatic profile, renal function, and hematology values, 
will be grouped and presented together in summary tables. For each laboratory test, individual 
subject values will be listed and values outside of the standard reference range will be flagged. 
Shift tables will be produced showing the frequency of shifts from baseline to the lowest and to 
the highest on-study value in and out of the normal range as well as by visit. Laboratory 
parameters will also be summarized by visit. 
The change from baseline to each visit for vital sign variables will be summarized. Abnormal 
vital sign values will be flagged and listed. 
Wound healing assessment results will be summarized at each timepoint. 
10.4.4. 
Pharmacokinetic Analysis 
Plasma bupivacaine and meloxicam concentrations will be determined using validated liquid 
chromatography tandem-mass spectrometry assays. Concentrations will be calculated by 
interpolation from a calibration curve. PK parameters for bupivacaine and meloxicam will be 
calculated using noncompartmental analysis, as appropriate. Additional exploratory analyses 
may be performed, as appropriate, to facilitate cross-study comparisons and to fully characterize 
the concentration-time profiles of each analyte or other study drug components.  
In Cohort 4, concentrations of alpha-1-acid glycoprotein will be summarized using descriptive 
statistics. As an exploratory analysis, ex vivo protein binding of bupivacaine will be determined 
using equilibrium dialysis. PK parameters for free bupivacaine will be calculated using 
noncompartmental analysis, as appropriate. 


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10.5. 
Interim Analysis 
No formal interim analyses are planned. 


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11. 
QUALITY ASSURANCE AND QUALITY CONTROL 
Quality assurance and quality control systems will be implemented and maintained by the 
Sponsor and its designee(s), as appropriate, following Standard Operating Procedures (SOPs) to 
ensure that the clinical study is conducted and the data are generated, documented (recorded), 
and reported in compliance with the protocol, International Council for Harmonisation (ICH) E6 
GCP guidelines, and applicable regulatory requirements. The accuracy, completeness, and 
reliability of the study data presented to the Sponsor, however, are the responsibility of the 
Investigator. The Investigator or designee must record all required data using the prespecified 
data collection method defined by the Sponsor or its designee. 
The study will be monitored regularly by the Sponsor (Section 13.1) and may be audited or 
inspected by the Sponsor (or designee), EC, and/or regulatory authorities at any time during the 
study or after study completion. In the event of an audit, the Investigator agrees to allow the 
Sponsor, representatives of the Sponsor, the competent authority, or other regulatory agencies 
direct access to all study records. The Investigator will immediately notify the Sponsor of all 
audits or inspections scheduled by any regulatory authority and promptly forward to the Sponsor 
copies of any audit or inspection reports received. 


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12. 
REGULATORY AND ETHICAL CONSIDERATIONS 
12.1. 
Regulatory Authority Approval 
The Sponsor will obtain approval to conduct the study from the appropriate regulatory agency in 
accordance with any applicable country-specific regulatory requirements before any site may 
initiate the study in that country. 
12.2. 
Ethical Conduct of the Study 
This study will be conducted in compliance with the protocol and all applicable regulatory 
requirements in accordance with ICH/GCP and in general conformity with the most recent 
version of the Declaration of Helsinki. 
12.3. 
Ethics Committee Approval 
The Investigator or the Sponsor is responsible for submitting the following documents to the ECs 
for review and, if applicable, approval: study protocol, ICF(s), Investigator’s Brochure, 
recruitment materials, information about study compensation to subjects, and any information for 
presentation to potential subjects by ECs. 
The Investigator is responsible for providing the Sponsor with the written EC approval prior to 
commencing the study (ie, before shipment of study drug to the site). All amendments to the 
protocol require review and approval by the EC before the changes to the study are implemented. 
All changes to the ICF will be approved by the EC; a determination will be made regarding 
whether previously consented participants need to be reconsented. If any other information 
previously approved by the EC for presentation to potential subjects is amended during the 
study, the Investigator is also responsible for ensuring EC review and reapproval. 
Study sites must adhere to all requirements stipulated by their respective ECs. This may include, 
but not be limited to, notifying the EC of serious and unexpected AEs or other local safety 
reporting requirements, submitting a final status report, or providing a synopsis of the study 
report upon study completion. 
12.4. 
Informed Consent Process 
Note: All references to “subject” in this section refer to the study subject or his/her legally 
authorized representative. 
The Sponsor (or its designee) will provide Investigators with an ICF for this study. Investigators 
may adapt the information to suit the needs of their institution, if necessary (although it must 
reflect the required elements of informed consent specified in 21 CFR Part 50.25). The final ICF 
must be accepted by the Sponsor and approved by the EC. Investigators must provide the 
Sponsor with an unsigned copy of the final ICF before and after it is approved by the EC. If any 
new information becomes available that might affect subjects’ willingness to participate in the 
study, or if any amendments to the protocol require changes to the ICF, the Sponsor will provide 
Investigators with a revised ICF. 


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Prior to participating in any study-related procedure, each subject must sign and date an 
EC-approved ICF written in a language the subject can understand. The ICF should be as 
nontechnical as practical and understandable to the subject. The ICF must provide the subject 
with all the information necessary to make an informed decision about their participation in the 
study, including the nature and intended purpose of the study, possible benefits, possible risks, 
disclosures of the subject’s personal and personal health information for purposes of conducting 
the study. The ICF details the requirements of the participant and the fact that he/she is free to 
withdraw at any time without giving a reason and without prejudice to his/her further medical 
care. Before informed consent is obtained, the subject should be given ample time and 
opportunity to inquire about the details of the study. All questions must be answered to the 
satisfaction of the subject. 
Once signed, the original ICF will be stored in the Investigator’s site file and made available for 
review by the Sponsor. Documentation of the informed consent discussion must be noted in the 
subject’s case history. All subjects will receive a copy of their signed and dated ICF. 
If the ICF is revised during the study and requires the subject to be reconsented, informed 
consent will be obtained in the same manner as for the original ICF. 
12.5. 
Confidentiality 
All information provided by Heron Therapeutics, Inc. and all data and information generated by 
the site as part of the study (other than a subject’s medical records) will be kept confidential by 
the Investigator and site staff. This information and data will not be used by the Investigator or 
other site personnel for any purpose other than conducting the study and will not be released to 
any unauthorized third party without prior written approval of the Sponsor. These restrictions do 
not apply to the following: 1) information that becomes publicly available through no fault of the 
Investigator or site staff, 2) information that must be disclosed in confidence to an EC solely for 
the evaluation of the study results, 3) information that must be disclosed in order to provide 
appropriate medical care to a study subject, or 4) study results that may be published as 
described in Section 13.6. If a written contract for the conduct of the study is executed and that 
contract includes confidentiality provisions inconsistent with this statement, that contract’s 
confidentiality provisions shall apply rather than this statement; provided, however, that the 
confidentiality provisions in any written contract shall not be less restrictive than this statement. 
The Investigator agrees to comply with all applicable national, state, and local laws and 
regulations relating to the privacy of subjects’ health information. The Investigator shall ensure 
that study subjects authorize the use and disclosure of protected health information in accordance 
with the privacy regulations of the Health Insurance Portability and Accountability Act (HIPAA) 
and in a form satisfactory to the Sponsor. 
The subject’s contact information will be securely stored at each clinical site for internal use 
during the study. Throughout the study, a subject’s source data will only be linked to the 
Sponsor’s clinical study database or documentation via a unique identification number. Copies of 
any subject source documents that are provided to the Sponsor must have certain personally 
identifiable information removed (ie, subject name, address, and other identifier fields not 
collected in the subject’s eCRF). At the end of the study, all records will continue to be kept in a 
secure location for as long a period as dictated by the EC and institutional regulations. 


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To comply with ICH guidelines for GCP and to verify compliance with this protocol, the 
Sponsor requires that the Investigator permit its monitor or designee’s monitor, representatives 
from any regulatory authority, the Sponsor’s designated auditors, and the appropriate ECs to 
review the subject’s original medical records (source data or documents), including, but not 
limited to, clinical laboratory test result reports, ECG reports, admission and discharge 
summaries for hospital admissions occurring during a subject’s study participation, and autopsy 
reports. Access to a subject’s original medical records requires the specific authorization by the 
subject as part of the informed consent process (Section 12.4). 


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13. 
STUDY ADMINISTRATION 
13.1. 
Clinical Monitoring 
The Sponsor (or its designee) is responsible for ensuring the proper conduct of the study. This 
includes ensuring the subjects’ rights and well-being are protected, the conduct of the study is 
within compliance of an approved protocol and GCPs, and the integrity of the data are accurate, 
complete, and verifiable from source documentation. At regular intervals during the study, the 
Sponsor’s study monitors will contact the study site via site visits, telephone calls, emails, and 
letters in order to review study progress and the eCRF completion and to address any concerns or 
questions regarding the study conduct. During monitoring visits, the following aspects of study 
conduct will be carefully reviewed: subjects’ informed consent documents, subject recruitment 
procedures, subjects’ compliance with the study procedures, source-data verification, drug 
accountability, use of concomitant therapy by subjects, AE and SAE documentation and 
reporting, and the quality of data. 
13.2. 
Source Documents and Record Retention 
Each study site will maintain study documents and records as specified in ICH E6, Section 8 
(Essential Documents for the Conduct of a Clinical Trial) and as required by regulatory and 
institutional requirements. These include, but are not limited to the following: the study protocol, 
eCRF, delegation of authority log, pharmacy dispensing records, drug accountability logs, AE 
reports, subject source data (original or certified copies), correspondence with health authorities 
and ECs, ICFs, monitoring visit logs, laboratory certification or quality control procedures, and 
laboratory reference ranges. Access to study documents and records will be strictly controlled 
(Section 12.5). 
Study records must be retained for at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or until at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product. However, these 
documents should be retained for a longer period if required by applicable regulatory 
requirements or if agreed to in the Clinical Trial Agreement. It is the responsibility of the 
Sponsor to inform the site as to when these documents no longer need to be retained. 
13.3. 
Management of Protocol Amendments and Deviations 
13.3.1. 
Protocol Modification 
The protocol cannot be modified except in a formal protocol amendment by the Sponsor. 
13.3.2. 
Protocol Deviations 
A protocol deviation is a change, divergence, or departure from the study design or procedures 
defined in this protocol. The Investigator will notify the EC of any protocol deviations as 
required by EC guidelines and site requirements. Protocol deviations will be documented at the 
site and in the Sponsor files. The Sponsor is responsible for notifying the regulatory authorities 
of any protocol deviations, if required. 


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13.4. 
Financial Disclosure 
Investigators are required to inform the Sponsor of all disclosable financial interests or 
arrangements (including those of their spouse and dependent children), prior to study initiation at 
the site, at study completion, and 1 year after study completion in accordance with 21 CFR 
Part 54. In addition, the Investigator or subinvestigators must promptly notify the Sponsor if 
there are any reportable changes that occur during the above described period. 
Disclosable financial interests or arrangements, or the absence thereof will be recorded on the 
Financial Disclosure for Clinical Investigators Form. 
Any Investigator(s) added as investigational staff to the FDA 1572 form must complete the 
Financial Disclosure for Clinical Investigators Form at the start of his/her participation in the 
study. The Financial Disclosure for Clinical Investigators Form for any Investigator(s) leaving 
the study prior to completion will also be obtained. 
13.5. 
Criteria For Suspending the Study 
If the Sponsor, Investigator, or officials from regulatory agencies discover conditions arising 
during the study that indicate that the study should be halted or that a study site should be closed, 
this action may be taken after appropriate consultation between the Sponsor and Investigator(s). 
Reasons for suspending the study to assess whether terminating the study early, modifying the 
study, or closing a site is warranted include, but are not limited to, the following: 
• A single death or 3 non-fatal SAEs that are determined by the Sponsor to be possibly 
related to study drug or any scheduled study medication for which a clear alternative 
cause is not readily apparent. 
• Discovery of an unexpected, significant, or unacceptable risk to the subjects. 
• Failure of the Investigator to comply with the protocol, GCP regulations and 
guidelines, or local requirements. 
• Insufficient adherence to protocol requirements or an unacceptably high rate of 
missing, erroneous, or improperly collected data. 
• Insufficiently complete and/or evaluable data. 
• Inadequate recruitment of subjects by the Investigator. 
• Sponsor decision. 
If the study is terminated early by the Sponsor, written notification documenting the reason for 
study termination will be provided to the Investigator and regulatory authorities. The Investigator 
will promptly inform the EC and provide the reason(s) for study termination. 
13.6. 
Publication and Information Disclosure Policy 
All information provided by the Sponsor and all data and information generated by the site as 
part of the study (other than a subject’s medical records) are the sole property of Heron 
Therapeutics, Inc. 


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For clinical interventional studies in patients, Heron will post study results on websites such as 
https://clinicaltrials.gov/ and https://eudract.ema.europa.eu/ in accordance with FDA and 
European Union reporting rules. Regardless of study outcome, Heron commits to submit for 
publication results of its interventional clinical studies according to the prespecified plans for 
data analysis. Wherever possible, Heron also plans to submit for publication the results of any 
nonclinical or technology studies while protecting any proprietary information. 
Any publication or presentation of the results of this study may only be made in compliance with 
the provisions outlined in the executed Clinical Trial Agreement. Heron has developed a policy 
for the publication of scientific and clinical data that follows the recommendations of the 
International Committee of Medical Journal Editors (ICMJE), the Consolidated Standards of 
Reporting Trials (CONSORT) group, and Good Publication Practice (GPP). A copy of this 
policy will be made available to the Investigator upon request. 
When the study is completed or prematurely terminated, the Sponsor or designee will ensure a 
Clinical Study Report is written in compliance with ICH E3 (Structure and Content of Clinical 
Study Reports) and submitted to the regulatory authorities, as required by the applicable 
regulatory requirement(s). Where required by applicable regulatory requirements, an Investigator 
signatory will be identified for the approval of the Clinical Study Report. The Investigator will 
be provided reasonable access to statistical tables, listings, and figures, as well as relevant 
reports, and will have the opportunity to review the complete study results. 


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14. 
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APPENDIX A. AMERICAN SOCIETY OF ANESTHESIOLOGISTS 
PHYSICAL STATUS CLASSIFICATION SYSTEM 
 
ASA PS 
Classification 
Definition 
Examples, including, but not limited to: 
ASA I 
A normal healthy patient 
Healthy, non-smoking, no or minimal alcohol 
use  
ASA II  
A patient with mild systemic 
disease 
Mild diseases only without substantial 
functional limitations. Examples include, but 
not limited to: current smoker, social alcohol 
drinker, pregnancy, obesity (30 < BMI <40), 
well-controlled DM/HTN, mild lung disease 
ASA III  
A patient with severe systemic 
disease 
Substantial functional limitations; one or more 
of moderate to severe diseases. Examples 
include, but not limited to: poorly controlled 
DM or HTN; COPD; morbid obesity (BMI 
≥40); active hepatitis; alcohol dependence or 
abuse; implanted pacemaker; moderate 
reduction of ejection fraction; ESRD undergoing 
regularly scheduled dialysis; premature infant 
PCA <60 weeks; history (>3 months) of MI, 
CVA, TIA, or CAD/stents 
ASA IV 
A patient with severe systemic 
disease that is a constant threat 
to life 
Examples include, but not limited to: recent 
(<3 months) of MI, CVA, TIA, or CAD/stents; 
ongoing cardiac ischemia or severe valve 
dysfunction; severe reduction of ejection 
fraction; sepsis; DIC; ARD or ESRD not 
undergoing regularly scheduled dialysis 
ASA V 
A moribund patient who is not 
expected to survive without the 
operation 
Examples include, but not limited to: ruptured 
abdominal/thoracic aneurysm, massive trauma, 
intracranial bleed with mass effect, ischemic 
bowel in the face of significant cardiac 
pathology or multiple organ/system dysfunction 
ASA VI 
A declared brain-dead patient 
whose organs are being 
removed for donor purposes 
 
Abbreviations: ARD, acute renal disease; ASA, American Society of Anesthesiologists; BMI, body mass index; CAD, 
coronary artery disease; COPD, chronic obstructive pulmonary disease; CVA, cerebrovascular accident; DIC, 
disseminated intravascular coagulation; DM, diabetes mellitus; ESRD, end stage renal disease; HTN, hypertension; MI, 
myocardial infarction; PCA, postconceptional age; PS, physical status; TIA, transient ischemic attack. 
Note: 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.) 
Source: ASA Physical Status Classification System approved by the ASA House of Delegates on October 15, 2014. 


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APPENDIX B. BODY MASS INDEX (BMI) CALCULATION 
 
BMI = Weight in kilograms/(height in meters)2 
Meters = inches × 0.0254 
Kilograms = pounds × 0.453592 
 
Example: 
For a man who weighs 165 pounds and is 71 inches tall: 
165 lbs. × 0.453592 = 74.8 kg 
71 in. × 0.0254 = 1.803 m 
74.8/(1.803 × 1.803) = 23.01 kg/m2 


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APPENDIX C. PAIN INTENSITY ASSESSMENTS USING THE VISUAL 
ANALOGUE SCALE (VAS) 
 
For all VAS pain intensity assessments, subjects will be asked to mark their current pain level on 
a 10-cm line that represents pain ranging from “no pain” to “pain as bad as it could be.” The site 
will measure to the nearest millimeter the distance between “no pain at all” and the subject’s 
mark, which defines the subject’s pain that will be recorded in the case report form. 
The example VAS provided in this appendix is not to scale and must not be used for the 
assessment. Use the Visual Analogue Scale provided by the Sponsor. 
 
 
 
Reference: Adapted from Haefeli M, Elfering A. Pain assessment. Eur Spine J. 2006;15(1):S17-S24. 


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APPENDIX D. PAIN INTENSITY ASSESSMENTS USING THE 
NUMERIC RATING SCALE (NRS) 
 
 
“On a scale of 0 to 10, please rate your pain by marking an ‘X’ in the appropriate box that 
best describes your pain NOW.” 
 
The response must be one of the following: 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No Pain 
 
 
 
 
 
 
 
 
 
Worst Pain 
Imaginable 
 
Reference: Adapted from Breivik H, Borchgrevink PC, Allen SM, et al. Assessment of pain. Br J Anaesth. 2008;101(1):17-24. 


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APPENDIX E. DISCHARGE READINESS ASSESSMENT - MODIFIED 
POSTANAESTHETIC DISCHARGE SCORING SYSTEM 
CRITERIA 
 
The Modified Postanaesthetic Discharge Scoring System (MPADSS) will be used to assess the 
subject’s discharge readiness. This assessment will be used for data collection only and is not 
intended to interfere with the hospital’s policy for determining when the subject should be 
discharged. Only subjects who achieve a score of 9 or higher will be considered ready for 
discharge. 
Parameter 
Score 
Vital Signs  
 
Within 20% of preoperative value 
2 
20% to 40% of preoperative value 
1 
>40% of preoperative value 
0 
Ambulation 
 
Steady gait/no dizziness 
2 
With assistance 
1 
None/dizziness 
0 
Nausea/Vomiting 
 
Minimal 
2 
Moderate 
1 
Severe 
0 
Pain 
 
Minimal 
2 
Moderate 
1 
Severe 
0 
Surgical Bleeding 
 
Minimal 
2 
Moderate 
1 
Severe 
0 
Reference: Chung, F. Discharge criteria--a new trend. Can J Anaesth. 1995;42(11):1056-1058. 
 


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APPENDIX F. PATIENT GLOBAL ASSESSMENT (PGA) OF PAIN 
CONTROL 
 
“Overall, please rate how well your pain has been controlled during the last 24 hours?” 
 
The response must be one of the following: 
• Poor (0) 
• Fair (1) 
• Good (2) 
• Excellent (3) 
 
Reference: Adapted from Rothman M, Vallow S, Damaraju CV, and Hewitt DJ. Using the patient global assessment of the 
method of pain control to assess new analgesic modalities in clinical trials. Current Medical Research and Opinion. 
2009;25,1433-1443. 


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APPENDIX G. OVERALL BENEFIT OF ANALGESIA SCORE (OBAS) 
 
 
 
Rating 
1 Please rate your current pain at rest on a scale between 0=minimal pain 
and 4=maximum imaginable pain 
|__| 
2 Please grade any distress and bother from vomiting in the past 24 h  
(0=not at all to 4=very much) 
|__| 
3 Please grade any distress and bother from itching in the past 24 h  
(0=not at all to 4=very much) 
|__| 
4 Please grade any distress and bother from sweating in the past 24 h  
(0=not at all to 4=very much) 
|__| 
5 Please grade any distress and bother from freezing in the past 24 h  
(0=not at all to 4=very much) 
|__| 
6 Please grade any distress and bother from dizziness in the past 24 h  
(0=not at all to 4=very much) 
|__| 
7 How satisfied are you with your pain treatment during the past 24 h  
(0=not at all to 4= very much)? 
4 - |__| = |__| 
 
Overall Benefit of Analgesia Score: 
|__|__| 
To calculate the OBAS score, compute the sum of the scores in items 1 through 6 and add 
‘4-score in item 7’ 
Example OBAS calculation: A subject patient with minimal pain (NRS=0), severe 
vomiting (NRS=4), and no itching, sweating, and freezing who is slightly dizzy (NRS=1), 
and is not very satisfied with his postoperative pain treatment (NRS=1) has an OBAS of 8. 
Note that a low score indicates high benefit. 
Reference: Adapted from Lehmann N, Joshi GP, Dirkmann D, Weiss M, Gulur P, Peters J, et al. Development and longitudinal 
validation of the overall benefit of analgesia score: a simple multi-dimensional quality assessment instrument. Br J Anaesth. 
2010;105(4):511-518. 
 


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APPENDIX H. TREATMENT SATISFACTION QUESTIONNAIRE FOR 
MEDICATION (TSQM-9) 
 
The TSQM-9 will be used to assess the subject’s satisfaction with their scheduled non-opioid 
multimodal analgesic (MMA) regimen for the treatment of their TKA-related pain. Subjects will 
answer 9 questions related to effectiveness, convenience, and global satisfaction. 
TSQM-9 Questions 
Response Options 
Effectiveness 
 
How satisfied or dissatisfied are you with the 
ability of the medication to prevent or treat your 
condition? 
Extremely dissatisfied 
Very dissatisfied 
Dissatisfied  
Somewhat satisfied 
Satisfied  
Very satisfied 
Extremely satisfied 
How satisfied or dissatisfied are you with the way 
the medication relieves your symptoms? 
Extremely dissatisfied 
Very dissatisfied 
Dissatisfied  
Somewhat satisfied 
Satisfied  
Very satisfied 
Extremely satisfied 
How satisfied or dissatisfied are you with the 
amount of time it takes the medication to start 
working? 
Extremely dissatisfied 
Very dissatisfied 
Dissatisfied 
Somewhat satisfied 
Satisfied 
Very satisfied 
Extremely satisfied 
Convenience 
 
How easy or difficult is it to use the medication in 
its current form? 
Extremely difficult 
Very difficult 
Difficult 
Somewhat easy 
Easy 
Very easy 
Extremely easy 


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TSQM-9 Questions 
Response Options 
How easy or difficult is it to plan when you will 
use the medication each time? 
Extremely difficult 
Very difficult 
Difficult 
Somewhat easy 
Easy 
Very easy 
Extremely easy 
How convenient or inconvenient is it to take the 
medication as instructed? 
Extremely inconvenient 
Very inconvenient 
Inconvenient 
Somewhat convenient 
Convenient  
Very convenient 
Extremely convenient 
Global Satisfaction 
 
Overall, how confident are you that taking this 
medication is a good thing for you? 
Not at all confidant 
A little confidant 
Somewhat confidant 
Very confidant 
Extremely confidant 
How certain are you that the good things about 
your medication outweigh the bad things? 
Not at all certain 
A little certain 
Somewhat certain 
Very certain 
Extremely certain 
Taking all things into account, how satisfied or 
dissatisfied are you with this medication? 
Extremely dissatisfied 
Very dissatisfied 
Dissatisfied 
Somewhat satisfied 
Satisfied 
Very satisfied 
Extremely satisfied 
Reference: Bharmal M, Payne K, Atkinson M, Desrosiers M-P, Morisky DE, Gemmen E. Validation of an abbreviated Treatment 
Satisfaction Questionnaire for Medication (TSQM-9) among patients on antihypertensive medications. Health Qual Life 
Outcomes. 2009;7:36. 
 


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APPENDIX I. WOUND HEALING ASSESSMENT - SOUTHAMPTON 
WOUND SCORING SYSTEM 
 
Grade 
Appearance 
0 
Normal healing 
I. 
Normal healing with mild bruising or erythema: 
 
a 
Some bruising 
b 
Considerable bruising 
c 
Mild erythema 
II. 
Erythema plus other signs of inflammation: 
 
a 
At 1 point 
b 
Around sutures 
c 
Along wound 
d 
Around wound 
III. 
Clear or haemoserous discharge: 
 
a 
At 1 point only (≤2cm) 
b 
Along wound (>2 cm) 
c 
Large volume 
d 
Prolonged (>3 days) 
Major complication 
IV. 
Pus: 
 
a 
At 1 point only (≤2cm) 
b 
Along wound (>2 cm) 
V. 
Deep or severe wound infection with or without tissue breakdown; haematoma 
requiring aspiration 
References: 
Alam SI, Khan MY, Gul A, Jan QA. Surgical site infection. Professional Med J. 2014;21(2):377-381. 
Bailey I. Community surveillance of complications after hernia surgery. BMJ. 1992;304:469-471. 
 


Signature Page for VV-CLIN-004483 v1.0
Signature Page for VV-CLIN-004483 v1.0
Approval
2020 22:57:30 GMT+0000

SAP_001.pdf: 
Document Type:  
Statistical Analysis Plan 
Official Title:  
A Phase 3b, Open-Label Study of HTX-011 as Part of a 
Scheduled Non-Opioid Multimodal Analgesic Regimen in 
Subjects Undergoing Total Knee Arthroplasty 
NCT Number:  
NCT03974932 
Document Date:  
01-Jul-2021 
 


Confidentiality Statement 
This document contains confidential information of Heron Therapeutics, Inc. 
Do not copy or distribute without written permission of the Sponsor. 
Any authorized use, reproduction, publication, or dissemination is strictly prohibited. 
STUDY HTX-011-306 
 
A PHASE 3B, OPEN-LABEL STUDY OF HTX-011 AS PART OF A SCHEDULED 
NON-OPIOID MULTIMODAL ANALGESIC REGIMEN IN SUBJECTS 
UNDERGOING TOTAL KNEE ARTHROPLASTY 
 
01 July 2021 
 
Statistical Analysis Plan 
 
Version 3.0   
 
Prepared by: 
 
 
Heron Therapeutics, Inc. 
4242 Campus Point Court, Suite 200 
San Diego, CA 92121  
USA 
 
 
Upon review of this document, the undersigned approves the statistical analysis plan. The 
analysis methods are acceptable, and the table, listing, and figure shell production can begin. 
 
 
 
 
Approved by: 
 
 
 
Date:   
 
 
 
 
 
Heron Therapeutics, Inc. 
 
 
  
Approved by: 
 
 
 
Date:   
 
 
 
 
Heron Therapeutics, Inc. 
 
 
  
 
 
 


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TABLE OF CONTENTS 
1. 
ADMINISTRATIVE STRUCTURE ........................................................ 6 
1.1. 
Sponsor and Oversight .............................................................................. 6 
1.2. 
Data Quality Assurance ............................................................................ 6 
2. 
INTRODUCTION .................................................................................... 6 
3. 
OBJECTIVES ........................................................................................... 7 
4. 
INVESTIGATIONAL PLAN ................................................................... 7 
4.1. 
Overall Study Design and Plan ................................................................. 7 
4.2. 
Assessments .............................................................................................. 8 
4.3. 
Endpoints .................................................................................................. 9 
4.3.1. 
Efficacy Endpoints .................................................................................... 9 
4.3.2. 
Safety Endpoints ..................................................................................... 10 
5. 
GENERAL STATISTICAL CONSIDERATIONS ................................ 10 
5.1. 
Sample Size ............................................................................................ 11 
5.2. 
Randomization, Stratification, and Blinding .......................................... 11 
5.3. 
Analysis Populations .............................................................................. 11 
5.3.1. 
Safety Population .................................................................................... 11 
5.3.2. 
Layout of Efficacy and Safety Analyses ................................................ 12 
5.4. 
Other Important Considerations ............................................................. 12 
5.4.1. 
Definition of Baseline ............................................................................. 12 
5.4.2. 
Calculation of Change and Percent Change from Baseline .................... 12 
5.4.3. 
Study Day Calculation for Reporting Purposes ...................................... 12 
5.4.4. 
72 Hour Postoperative Observation Period ............................................ 13 
5.4.5. 
Day 11 Visit Period ................................................................................ 14 
5.4.6. 
Visit Windows ........................................................................................ 14 
5.4.7. 
Handling of Missing and Partial Data .................................................... 14 
6. 
SUBJECT DISPOSITION ...................................................................... 15 
7. 
DEMOGRAPHICS, CHARACTERISTICS, AND MEDICAL 
HISTORY ............................................................................................... 16 
7.1. 
Demographics and Baseline Characteristics ........................................... 16 
7.2. 
Medical History ...................................................................................... 16 
7.3. 
Protocol Deviations ................................................................................ 16 
8. 
TREATMENTS AND MEDICATIONS ................................................ 17 


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8.1. 
Prior and Concomitant Medications ....................................................... 17 
8.2. 
Rescue Medication .................................................................................. 17 
8.3. 
Surgery Procedure .................................................................................. 17 
8.4. 
Study Treatment ...................................................................................... 17 
9. 
EFFICACY ANALYSIS ........................................................................ 18 
9.1. 
Primary Efficacy Endpoint ..................................................................... 18 
9.1.1. 
Primary Analysis .................................................................................... 18 
9.1.2. 
Sensitivity Analyses ................................................................................ 19 
9.2. 
Secondary Efficacy Endpoints ................................................................ 19 
10. 
SAFETY ANALYSIS ............................................................................ 25 
10.1. 
Adverse Events ....................................................................................... 25 
10.1.1. 
Incidence of Treatment Emergent Adverse Events ................................ 26 
10.1.2. 
Relationship of Adverse Events to Study Drug ...................................... 26 
10.1.3. 
Severity of Adverse Event ...................................................................... 26 
10.1.4. 
Serious Adverse Events .......................................................................... 26 
10.1.5. 
Adverse Events Leading to Study Withdrawal ....................................... 27 
10.1.6. 
Potential Opioid-related Adverse Events ................................................ 27 
10.1.7. 
Death ....................................................................................................... 27 
10.2. 
Clinical Laboratory Evaluations ............................................................. 27 
10.2.1. 
Hematology ............................................................................................. 28 
10.2.2. 
Blood Chemistry ..................................................................................... 28 
10.2.3. 
Urine Pregnancy Test and Urine Drug Screen ....................................... 29 
10.3. 
Vital Sign Measurements ........................................................................ 29 
10.4. 
Electrocardiogram ................................................................................... 30 
10.5. 
Physical Examination ............................................................................. 30 
10.6. 
Wound Healing Assessment ................................................................... 30 
11. 
INTERIM ANALYSIS ........................................................................... 30 
11.1. 
Interim Analysis ...................................................................................... 30 
11.2. 
Data Safety Monitoring Board ................................................................ 30 
12. 
REFERENCES ....................................................................................... 32 
APPENDIX 1. IMPUTATION OF PARTIAL AND MISSING DATES .............. 33 
APPENDIX 2. DOCUMENT REVISION HISTORY ........................................... 34 


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List of Abbreviations 
Abbreviation 
Term 
AE 
Adverse event  
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANOVA 
Analysis of variance 
AST 
Aspartate aminotransferase 
ATC 
Anatomic Therapeutic Classification 
AUC 
Area under the curve 
bpm 
Beats per minute 
BMI 
Body mass index 
BUN 
Blood urea nitrogen 
CI 
Confidence interval 
CRO 
Contract Research Organization 
CSR 
Clinical study report 
CTM 
Clinical trial materials 
DBP 
Diastolic blood pressure 
DM 
Data management 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
eDISH 
Evaluation of drug-induced serious hepatotoxicity 
GGT 
Gamma glutamyltransferase 
HCl 
Hydrochloride 
HR 
Heart rate 
IM 
Intramuscular 
IV 
Intravenous(ly) 
K-M 
Kaplan-Meier 
LAST 
Local anesthetic systemic toxicity 
LDH 
Lactic dehydrogenase 
LLN 
Lower limit of normal 
LOCF 
Last observation carried forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
MME 
Morphine milligram equivalent 
MPADSS 
Modified Postanaesthetic Discharge Scoring System 
NRI 
Nonresponder imputation 
NRS 
Numeric rating scale 
NRS-R 
Numeric rating scale of pain intensity at rest 
NSAID 
Nonsteroidal anti-inflammatory drug 
OBAS 
Overall benefit of analgesia score 
ORAE 
Opioid-related adverse event 
PACU 
Postanesthesia care unit 
PGA 
Patient’s Global Assessment 
PK 
Pharmacokinetic(s) 
PO 
Oral(ly) 
PR 
Per rectum 
PRN 
As needed 
PT 
Preferred Term 
RBC 
Red blood cell 


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SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SBP 
Systolic blood pressure 
SD 
Standard deviation 
SDA 
Study drug administration 
SDTM 
Study Data Tabulation Model 
SDTMIG 
Study Data Tabulation Model Implementation Guide 
SE 
Standard error 
SI 
Standard international 
SOC 
System Organ Class 
TEAE 
Treatment-emergent adverse event 
TSQM 
Treatment Satisfaction Questionnaire for Medication 
ULN 
Upper limit of normal 
US 
United States 
WBC 
White blood cell 
WHODrug 
World Health Organization Drug Dictionary 
WOCF 
Worst observation carried forward 
wWOCF 
Windowed worst observation carried forward 


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1. 
ADMINISTRATIVE STRUCTURE 
1.1. 
Sponsor and Oversight 
This study is being conducted under the sponsorship of Heron Therapeutics, Inc. (Heron).  
The data management (DM) is being performed under contract with 
 
 and the statistical analyses are being performed under 
contract with 
, with oversight from Heron.  
 is a contract research 
organization (CRO). 
1.2. 
Data Quality Assurance 
The Clinical Operations, DM, and Biostatistics departments at the CROs will collaborate 
internally and with the Sponsor to ensure that the data collected and analyzed for this study 
are of the highest quality possible and meet the data standards set for the study.  This will be 
accomplished in part through programmed edit checks which will be reviewed by the data 
managers, statisticians, programmers, and other team members on an ongoing basis to 
evaluate whether any checks need to be added or any existing checks need to be modified.  In 
addition, periodic reviews of listings of accumulating data, assessment of data query trends, 
and resulting retraining of study site personnel will be performed to further ensure data 
quality.  
2. 
INTRODUCTION  
This statistical analysis plan (SAP) presents a detailed plan of the statistical methods to be 
used during the reporting and analysis of efficacy and safety data collected in this study. This 
SAP does not include the planned analysis and reporting of pharmacokinetics (PK) 
assessments in the study. Planned PK analysis will be presented in a separate PK analysis 
plan. 
This SAP was prepared prior to data analysis to provide full details of analyses to be 
presented in the clinical study report (CSR), including a technical and detailed elaboration of 
the statistical analysis methods presented in the protocol.  Revisions can be made to this SAP 
while the study is ongoing; however, it must be finalized prior to database lock.  Any 
deviations from the analysis plan provided in the SAP will be fully documented in the final 
CSR. 
This SAP should be read in conjunction with the study protocol and the electronic case report 
forms (eCRFs). 
   


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3. 
OBJECTIVES 
Primary Objective: 
 
The primary objective is to assess pain control following HTX-011 as part of a scheduled 
non-opioid multimodal analgesic (MMA) regimen in subjects undergoing total knee 
arthroplasty (TKA). 
Secondary Objectives: 
• To assess total opioid use following HTX-011 as part of a scheduled non-opioid 
MMA regimen in this study population. 
 
• To assess the proportion of subjects who are opioid-free after receiving HTX-011 as 
part of a scheduled non-opioid MMA regimen in this study population. 
 
• To assess the safety and tolerability of HTX-011 in a multimodal setting in this study 
population. 
 
• To characterize the pharmacokinetic (PK) parameters of bupivacaine and meloxicam 
in this study population 
4. 
INVESTIGATIONAL PLAN 
4.1. 
Overall Study Design and Plan 
This is a Phase 3b, open-label study to evaluate if HTX-011 administered as the foundation 
of a scheduled non-opioid MMA regimen can further improve pain control and lead to a 
greater reduction or eliminate the need for opioids following a primary unilateral TKA. 
Subjects who meet the eligibility criteria will be enrolled in the study in 1 of 4 cohorts and 
will undergo primary unilateral TKA under bupivacaine spinal anesthesia (≤ 20 mg). All 
subjects will be administered a single dose of HTX-011 as follows:  
• Cohort 1: Approximately 50 subjects will be administered a single dose of HTX-011 
400 mg/12 mg via periarticular application into the surgical site during surgery. 
• Cohort 2: Approximately 15 subjects will be administered a single dose of HTX-011 
400 mg/12 mg via periarticular application into the surgical site during surgery. 
Drains will be prohibited. 
• Cohort 3: Approximately 30 subjects will be randomized at 1:1 ratio into 2 groups. In 
Group A, subjects will be administered a single dose of HTX-011 300 mg/9 mg via 
periarticular application into the surgical site during surgery. In Group B, subjects 
will be administered a single dose of HTX-011 300 mg/9 mg via periarticular 


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application into the surgical site and 100 mg bupivacaine HCl injected into the 
posterior capsule during surgery. Drains will be prohibited. 
• Cohort 4: Up to approximately 20 subjects will be administered a single dose of 
HTX-011 400 mg/12 mg via periarticular application into the surgical site during 
surgery. 
Just before being taken to the operating room, all subjects will receive PO acetaminophen 1 
g, PO celecoxib 200 mg, and PO pregabalin 300 mg. After surgery, subjects will receive a 
scheduled non-opioid MMA regimen for 7 days. The first dose of postoperative MMA 
regimen will be administered once the subject is able to tolerate PO intake. For the first 3 
days after surgery, all subjects will receive PO acetaminophen 1 g every 8 hours and PO 
celecoxib 200 mg every 12 hours (Cohorts 1, 2 and 3) or PO acetaminophen 1 g every 8 
hours and PO ibuprofen 600 mg every 6 hours (Cohort 4). For the next 4 days, the MMA 
regimen for all cohorts will consist of PO ibuprofen 600 mg every 6 hours alternating with 
PO acetaminophen 1 g every 6 hours (maximum ibuprofen dose of 2.4 g/day and maximum 
acetaminophen dose of 4 g/day) while the subject is awake, so that an analgesic is taken 
approximately every 3 hours.  
4.2. 
Assessments 
The start of HTX-011 (ie, study drug) administration will be considered Time 0 for all 
assessments. 
Efficacy assessments will include the following: 
• VAS and NRS of pain intensity at rest (NRS-R) assessments. Assessments should be 
performed when the subject is in the resting position (either seated comfortably or 
lying down) for at least 5 minutes prior to obtaining the pain scores. 
• Opioid rescue medications: Date, time of administration, amount, and type of all 
opioid rescue medication taken from study drug administration through 72 hours. 
• Discharge readiness assessment per the Modified Postanaesthesic Discharge Scoring 
System (MPADSS) criteria.  
• Patient Global Assessment (PGA) of pain control. 
• Overall benefit of analgesia score (OBAS). 
• Treatment Satisfaction Questionnaire for Medication (TSQM-9). 
• Time to ambulation. 
• Ability to participate in scheduled rehabilitation sessions. 


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• Whether the subject is discharged home or to a skilled nursing facility. 
• Opioid prescription at discharge. 
• Site- or subject-initiated postdischarge contact through the Day 11 Visit. 
• Opioid prescription after discharge through the Day 11 Visit. 
• Subject daily diary to record whether opioids were taken from discharge through the 
Day 11 Visit 
Safety assessments will include the following: 
• AEs from the time the subject signs the ICF through the Day 29 Visit. 
• Physical examination. 
• Vital signs, including blood pressure, resting heart rate, respiratory rate, and 
temperature. 
• Wound healing assessment using the Southampton Wound Scoring Scale. 
• Clinical laboratory tests (hematology and serum chemistry). 
4.3. 
Endpoints 
4.3.1. 
Efficacy Endpoints 
The primary efficacy endpoint is the mean area under the curve (AUC) of VAS scores from 
12 to 48 hours (AUC12-48)  
The secondary efficacy endpoints are: 
• Mean AUC of VAS scores through 72 hours. 
• Mean AUC of NRS-R scores through 72 hours. 
• Proportion of subjects severe pain at each timepoint and through 72 hours. 
• Mean total postoperative opioid consumption (in IV morphine milligram equivalents 
[MME]) through 72 hours. 
• Proportion of subjects who are opioid-free through 72 hours and through Day 11. 
• Proportion of subjects who are opioid-free through 72 hours who remain opioid-free 
through Day 11. 
• Median time to first opioid rescue medication through 72 hours. 


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• Proportion of subjects who do not receive an opioid prescription at discharge. 
• Proportion of subjects who do not receive an opioid prescription between discharge 
and the Day 11 Visit. 
• Proportion of subjects achieving a score of “good” or better (>1) pain control based 
on PGA at each timepoint. 
• Median time to first ambulation through 72 hours. 
• Proportion of subjects unable to participate in each rehabilitation session because of 
pain. 
• Proportion of subjects who first achieve a MPADSS score ≥9 at each timepoint. 
• Proportion of subjects who are discharged home vs to a skilled nursing facility. 
• Mean OBAS at each timepoint. 
• Mean TSQM-9 score. 
4.3.2. 
Safety Endpoints 
The safety endpoints are: 
 
• Incidence of treatment-emergent adverse events (TEAEs), serious adverse events 
(SAEs), and opioid-related adverse events (ORAEs). 
• Change from baseline in clinical laboratory results. 
• Change from baseline in vital signs. 
• Wound healing assessment results at each assessed timepoint. 
5. 
GENERAL STATISTICAL CONSIDERATIONS 
Continuous data will be presented using descriptive statistics: number of subjects (n), mean, 
standard deviation (SD), median, minimum and maximum.  Descriptive statistics on efficacy 
measures will also include the standard error (SE).  Categorical data will be summarized by 
the number and percent of subjects.  Data will be displayed in all listings sorted subject 
number and visit/study day.  When count data are presented, the percent will be suppressed 
when the count is zero in order to draw attention to the non-zero counts.  A row denoted 
“Missing” will be included in count tabulations where necessary to account for dropouts and 
missing values.  The denominator for all percentages will be the number of subjects in that 
treatment group within the population of interest, unless otherwise stated.  Non-zero 


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percentages will be rounded to one decimal place, except 100% will be displayed without 
any decimal places.  Additional rounding rules are as follows: 
• If the original value has 0 decimal places: mean, median will have one decimal place 
and SD and SE will have 2 decimal places 
• If the original value has 1 decimal place: mean, median will have 2 decimal places 
and SD and SE will have 3 decimal places 
• If the original value has 2 or more decimal places: mean, median, SD, and SE will all 
have 3 decimal places 
Minimum and maximum will always have the same decimal places as the original measure, 
up to a maximum of 3 decimal places.  The above rounding rules will not be applied to 
original measures displayed in listings. 
Values that are collected with “<” or “>” signs will be analyzed as the numerical value 
without the sign in tables and figures.  In listings, these data will be reported as collected 
with the sign. 
All efficacy and safety data will be collected electronically.  Datasets will be created using 
the Study Data Tabulation Model (SDTM) v. 1.4 or higher, conforming to the SDTM 
Implementation Guide (SDTMIG) v. 3.2 or higher.  Datasets, tables, listings, and figures will 
be programmed using SAS® v. 9.4 or higher.  All efficacy and safety data will be listed via 
the SDTM datasets and selected efficacy and safety data will be listed via programmed 
listings. 
5.1. 
Sample Size 
The sample size of  115 subjects was selected empirically without formal statistical 
assumptions. 
5.2. 
Randomization, Stratification, and Blinding 
This is a Phase 3b, open-label, multi-cohort study. In Cohorts 1 and 2, subjects who meet the 
eligibility criteria are enrolled. In Cohort 3, subjects who meet the eligibility criteria are 
randomized in a 1:1 ratio to 2 treatment groups (Section 4.1) using a computer-generated 
randomization scheme.  
5.3. 
Analysis Populations 
5.3.1. 
Safety Population 
The Safety Population will consist of all subjects who receive study drug.  This population 
will be used for all summaries of efficacy and safety data.   


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5.3.2. 
Layout of Efficacy and Safety Analyses 
All efficacy and safety analyses will be performed using descriptive statistics on the Safety 
Population, treatment group and cohort (Table 1). In addition, a Total column that pools 
cohorts 1, 2, 3 and 4 will be added to all tables except for efficacy tables. 
Table 1: 
Layout of Summary 
Cohort 1 
HTX-011 
400 mg/12 
mg + MMA 
Cohort 2 
HTX-011 
400 mg/12 
mg +MMA 
Pooled Cohorts 
1 and 2 
HTX-011 400 
mg/ 12 mg + 
MMA 
Cohort 3 
Cohort 4 
HTX-011 
400 mg/12 
mg +MMA 
Pooled 
Cohorts 1, 2 
and 4 
 HTX-011 
400 mg/ 12 
mg + MMA 
Group A 
HTX-011 
300 mg/9 
mg + MMA 
Group B 
HTX-011 300 
mg/9 mg + Bupi 
100 mg + MMA 
5.4. 
Other Important Considerations 
5.4.1. 
Definition of Baseline 
Baseline data are defined as the last observed measurement collected, whether scheduled or 
unscheduled, prior to the start of study drug administration.   
5.4.2. 
Calculation of Change and Percent Change from Baseline 
Change from Baseline to any timepoint t (Ct) is calculated as follows: 
 
Ct = Mt – MB, where: 
• Mt is the measurement of interest at timepoint t 
• MB is the measurement of interest at Baseline 
Percent change from Baseline to any timepoint (Pt) is calculated as follows: 
 
Pt = 100*(Ct/MB) 
5.4.3. 
Study Day Calculation for Reporting Purposes 
The following convention will be used to calculate study day for reporting purposes: 
• The study day of study drug administration is Study Day 1 
• For measurements that are on or after the date of study drug administration:  
o Study Day = date of measurement – date of study drug administration + 1 
• For measurements that are prior to the date of study drug administration: 
o Study Day = date of measurement – date of study drug administration 
For all subjects, the day of study drug administration should be the same day as the day of 
the surgical procedure. 


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5.4.4. 
72 Hour Postoperative Observation Period 
The 72 hour postoperative observation period will be defined as the period of time from the 
start date/time of study drug administration to the later of the date/time of the NRS or VAS 
assessments at the nominal 72-hour postoperative timepoint. 
However, if the date/time of the NRS and VAS assessments at nominal 72-hour 
postoperative timepoint are both missing, the following will be applied depending on study 
endpoints. 
• For AUC, ORAE through 72 hours, and time to first ambulation through 72 hours,  
the 72 hour postoperative observation period will be defined as the start date/time of 
study drug administration + 72 hours. 
• For analyses of opioid use (including opioid MME, opioid-free, time to first opioid) 
through 72 hours, the following will be applied. 
o If  subject early terminated prior to 72 hours, the opioid use through 72 hours 
will be based on concomitant medication and the 72 hour postoperative 
observation period will be defined as from the start date/time of study drug 
administration through the time of early termination.  
o If subject did not early terminate prior to 72 hours and was discharged on or 
after (≥) 72 hours from dosing start time, the opioid use through 72 hours will 
be based on concomitant medication and the 72 hour postoperative 
observation period will be defined as from the start date/time of study drug 
administration + 72 hours.  
o If subject did not early terminate prior to 72 hours and was discharged prior to 
(<) 72 hours, the opioid use through 72 hours  will be based on concomitant 
medication (through discharge) and opioid diary (from the date of discharge to 
Day 4).  In this case the 72 hour postoperative observation period will be 
defined as from the start date/time of study drug administration + 72 hours (or 
Day 4). For analysis of time to first opioid through 72 hours, if opioid 
collected during this period of time contains missing time (for example, as 
recorded in opioid diary), the time of opioid use will be imputed as “00:00” 
for analysis.  
▪ In this case only, opioid use from 72 hours through Day 11 will be 
defined as from Day 5 through Day 11 based on opioid diary only. 
Subjects who have a reported VAS or NRS score at the nominal 72-hour postoperative 
timepoint will be considered as completing the 72 hour postoperative observation period. 


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5.4.5. 
Day 11 Visit Period 
Subjects will be provided a daily diary to record any opioid medication use from discharge 
through the Day 11 Visit. Sites will record all site- or subject-initiated contact between 
discharge and the Day 11 Visit and whether any contact resulted in issuing an opioid 
prescription. 
The Day 11 Visit has a 2-day window (ie, Day 11 ±2 days [Study Day 9 through Study 
Day 13]). The Day 11 Visit period is defined as below and will be applied for opioid diary 
and subject/site call back analyses. 
• If Day 11 Visit date (or study exit date) ≥ Study Day 11 or the Day 11 Visit is 
missing but subject continued on study beyond Study Day 11: the Day 11 Visit period 
is through the Day 11 Visit date (or study exit date) or Study Day 13, whichever 
happens first. 
• If Study Day 9 ≤ Day 11 Visit date (or study exit date) < study day 11: the Day 11 
visit period is through Day 11 Visit date (or study exit date).  
• If Day 11 Visit date (or study exit date) < Study Day 9: the Day 11 Visit period is 
through Study Day 9. 
5.4.6. 
Visit Windows 
Due to the short duration of the study, no programmatically defined visit windows are 
applied to map unscheduled or early termination visits to nominal scheduled visits for this 
study. 
5.4.7. 
Handling of Missing and Partial Data 
The amount of missing data during the primary efficacy analysis period is expected to be 
very low due to the protocol-required 72-hour hospitalization of all subjects following 
surgery.   
For any data that is missing through 72 hours in subjects who complete the 72-hour 
postoperative observation period, the pain intensity scores (VAS or NRS) will be imputed via 
last observation carried forward (LOCF), in which the most recent postdose nonmissing 
value is used for a subsequent missing value.  If there is no postdose value available prior to 
the first missing value, then the median of values from subjects with observed values within 
the same treatment group at the relevant timepoint will be used.    
In subjects who withdraw from the study prior to 72 hours, missing pain intensity scores 
through 72 hours that were to be collected following withdrawal will be imputed via worst 
observation carried forward (WOCF), in which the worst (highest) pain intensity score 


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observed prior to withdrawal will be used for post-withdrawal values through 72 hours. Any 
missing pain intensity scores prior to the point of withdrawal will be imputed via LOCF. 
For binary endpoints (those involving proportions of subjects) not involving the pain 
intensity scores, any subject with missing data at a timepoint will be considered as not 
meeting the criterion for the endpoint at that timepoint.  This is known as nonresponder 
imputation (NRI).  Binary endpoints involving the pain intensity scores (such as proportion 
of subjects with severe pain) through 72 hours will be constructed following windowed worst 
observation carried forward (wWOCF) (see Section 9.1.1 for details).  
A table displaying the number and percentage of subjects with missing VAS and NRS pain 
intensity scores at each nominal timepoint and overall will be produced. 
For median time in hours to first opioid rescue administration, subjects who complete the 
72-hour observation period without receiving an opioid or discontinue from the study prior to 
72 hours without receiving an opioid will be censored at the time of completion or 
discontinuation, whichever is earlier. 
For the median time in hours to first ambulation postsurgery, subjects who complete the 
72-hour observation period without ambulation or discontinue from the study prior to 72 
hours without ambulation will be censored at the time of completion or discontinuation, 
whichever is earlier. For subjects who reported an ambulation date but no corresponding 
ambulation time, mean imputation will be performed based on the average ambulation time 
among subjects within the same cohort who were able to ambulate and who reported a 
complete ambulation date and time. 
All safety results will be summarized using observed cases with no imputation. 
For partial dates involving AE start dates and concomitant medication start dates, the 
algorithms for imputation will vary depending upon the parameter; the details can be found 
in Appendix 1.  No other partial dates will be imputed.  
6. 
SUBJECT DISPOSITION 
A summary of disposition of subjects will include the number and percentage of subjects for 
the following categories: subjects enrolled (signed the informed consent form), subjects 
randomized (Cohort 3 only), subjects who failed screening with reasons for screen failure, 
subjects in the Safety Population, subjects completing the 72-hour postoperative observation 
period, subjects completing the study through Day 29, and subjects not completing the study 
by reason for withdrawal.  Only 1 reason for study withdrawal will be recorded for each 
subject.   


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7. 
DEMOGRAPHICS, CHARACTERISTICS, AND MEDICAL 
HISTORY 
7.1. 
Demographics and Baseline Characteristics 
Demographics and baseline characteristics will be presented in tables using descriptive 
statistics.  Demographics consist of age, age category, sex, race, and ethnicity.  Baseline 
characteristics consist of weight, height, and body mass index (BMI).  A subject’s age in 
years is calculated using the integer part of the difference in number of days between the date 
that informed consent is signed and date of birth divided by 365.25, or is recorded directly on 
the eCRF.  The number and percentage of subjects in the following age categories will be 
presented: 18-44, 45-54, 55-64, 65-74, 75-84, and ≥ 85. 
Demographics and baseline characteristics will be presented for the Safety Population. 
7.2. 
Medical History 
Medical history will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA®) version 22.0.  Medical history will be summarized for the Safety Population and 
will display the number and percentage of subjects with a past and/or concomitant disease or 
past surgeries by System Organ Class (SOC) and Preferred Term (PT).   
7.3. 
Protocol Deviations 
Deviations and violations from the protocol will be recorded.  Protocol deviations will be 
classified into 1 of the following categories: 
• Informed consent procedures 
• Eligibility criteria 
• Prohibited concomitant medication/therapy 
• Study procedures not done 
• Safety reporting 
• Study drug dosing/administration 
• Out of window procedure and/or visit 
• Other 
 
Classification of deviations as major protocol violations will be decided on a case-by-case 
basis.  All protocol deviations and major protocol deviations will be presented in a summary 
table by protocol deviation category for the Safety Population.   


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8. 
TREATMENTS AND MEDICATIONS 
8.1. 
Prior and Concomitant Medications 
Prior medications are defined as medications with a stop date occurring before Day 1.  
Concomitant medications are defined as medications that are ongoing on Day 1 or with a 
start date occurring on or after Day 1.  Medications with start and stop dates which bracket 
Day 1, or for which missing start and/or stop dates make it impossible to determine the prior 
or concomitant status, will be summarized as concomitant medications. 
All medications will be coded with the World Health Organization Drug Dictionary Global 
B3 Format (WHODrug Global B3), March 2019. 
Prior and concomitant medications will be summarized separately by drug class and generic 
drug name.  At each level of summarization, a subject is counted once if that subject reports 
1 or more medications at that level.  Drug class will correspond to the Anatomical 
Therapeutic Classification (ATC) Level 2 term. 
All prior and concomitant medications will be summarized for the Safety Population.   
8.2. 
Rescue Medication 
All concomitant opioid pain medications with a start date/time within the 72-hour 
postoperative period (see Section 5.4.4 for details) will be included in rescue medication 
analyses. An exception will be fentanyl administered perioperatively on the date of surgery 
for intraoperative pain management; this is not counted as rescue medication.  
Opioid rescue medication in IV morphine milligram equivalency (MME) dose (see Section 
9.2 for details) will be summarized for 0-24 hours, 0-48 hours, and 0-72 hours.  In addition, 
proportion of subjects who received any rescue medication as well as each rescue within the 
72-hour postoperative period will also be provided. 
8.3. 
Surgery Procedure 
Surgery details including the knee subject to the surgical procedure (left or right), incision 
length in centimeters, drain usage, posterior ligament (CR or PS), surgical approach, 
tourniquet time, estimated blood loss, and the duration of surgery will be summarized.  
Duration of surgery will be calculated as completion time minus start time, reported in 
minutes.  
8.4. 
Study Treatment 
All subjects will receive a single dose of study drug (HTX-011) intraoperatively while 
undergoing TKA.  As such, extent of exposure to study drug will be reported in the CSR as 
the number of subjects who received study drug in the Safety Population.  A summary of 


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treatment compliance will not be produced, as by definition it will be 100% for the Safety 
Population. Duration of study drug administration will be calculated as completion time 
minus start time, reported in minutes. 
The proportion of subjects who received preoperative MMA regimen will be summarized by 
each preoperative MMA medication (ie, acetaminophen, celecoxib, and pregabalin) using 
descriptive statistics. 
The average daily use and total use of each postoperative MMA medication (ie, 
acetaminophen and celecoxib for Cohorts 1-3 and acetaminophen and ibuprofen for 
Cohort 4) will be tabulated using descriptive statistics through 72 hours. 
9. 
EFFICACY ANALYSIS 
9.1. 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the mean AUC of the VAS scores from 12 through 48 hours 
(AUC12-48). 
9.1.1. 
Primary Analysis 
During the first 72 hours following surgery, the VAS  is measured at hours 1, 2, 4, 6, 8, 12, 
24, 36, 48, 60, and 72.  Using the trapezoidal rule and letting Pt = the VAS  pain intensity 
score at time t, then:  
(𝑡−𝑡−1) 𝑃𝑡−1 + 𝑃𝑡
2
 
 
is the trapezoidal area between timepoints t and t-1.  The AUC12-48 is thus calculated as 
follows: 
 
𝐴𝑈𝐶12−48 = ∫𝑓(𝑡)𝑑𝑡≈∑(𝑡𝑖−𝑡𝑖−1) 𝑃𝑖−1 + 𝑃𝑖
2
48
𝑖=24
48
12
 
 
The primary endpoint of mean AUC12-48 of the VAS will be analyzed using descriptive 
statistics.   
To adjust for the duration effect of opioid rescue medication, wWOCF method will be 
implemented as the primary analysis method for endpoints involving VAS pain intensity 
scores. In this method, pain intensity scores observed during the analgesic window (duration 
of effect) of any opioid rescue medication will be replaced with the worst (highest) postdose 
nonmissing VAS pain intensity score observed prior to the rescue medication window, with 
the following exception: if the VAS pain intensity score for a windowed observation is 


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higher than the worst pre-window score, then it will not be replaced.  wWOCF will be 
performed following LOCF/WOCF (ie, perform LOCF/WOCF first, then apply wWOCF).  
See Table  in Section 9.2 for predefined analgesic windows for each opioid medication.  
9.1.2. 
Sensitivity Analyses 
A sensitivity analyses will be performed on the primary endpoint by reproducing the primary 
analysis but without adjusting the VAS pain intensity scores for the use of opioid rescue 
medications (ie, without applying wWOCF). 
9.2. 
Secondary Efficacy Endpoints 
Mean AUC of VAS scores through 72 hours 
The AUC0-12, AUC0-24, AUC0-48, AUC0-72, AUC24-48, AUC48-72, AUC24-72, AUC12-72 of the 
VAS pain intensity scores will be analyzed similarly as the AUC12-48 of VAS pain intensity 
scores, with appropriate adjustment to the calculation to reflect the time period of interest.  In 
addition, to explore the effect of drain usage, the AUC0-12, AUC12-48, AUC0-24, AUC0-48, 
AUC0-72  of the VAS pain intensity scores will be summarized by drain usage in Cohorts 1 
and 2 by the surgeon(s) who participated in Cohort 2. 
In addition, the mean VAS pain intensity scores will be summarized at each assessed 
timepoint through Day 29. Mean VAS pain intensity scores will also be plotted in a line 
graph over time through 72 hours, with associated SEs at each timepoint. 
Mean AUC of NRS-R scores through 72 hours 
The AUC0-12, AUC12-48, AUC0-24, AUC0-48, AUC0-72, AUC24-48, AUC48-72, AUC24-72, AUC12-72 
of the NRS-R pain intensity scores will be analyzed similarly as the AUC12-48 of VAS pain 
intensity scores, with appropriate adjustment to the calculation to reflect the time period of 
interest using NRS-R pain intensity scores.  
In addition, the mean NRS-R pain intensity scores will be summarized at each assessed 
timepoint through Day 29. Mean NRS-R pain intensity scores will also be plotted in a line 
graph over time through 72 hours, with associated SEs at each timepoint. 
Proportion of subjects with severe pain at each timepoint and through 72 hours  
Proportions of subjects with severe pain (an NRS score ≥ 7 or a VAS score ≥ 75 mm)  at 
each timepoint will be summarized using descriptive statistics. 
Proportions of subjects with severe pain  at any timepoint through 72 hours as well as 
through 24 and 48 hours will be analyzed similarly. 
Mean total postoperative opioid consumption (in IV morphine milligram equivalents 
[MME]) through 72 hours 


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Analyses of opioid consumption will be based on observed data only. 
The endpoints involving postoperative opioid consumption will be analyzed as follows: 
Determination of morphine equivalents 
Use of opioid rescue medication will be summarized by preferred term.  All opiate dosages 
and formulations will have the MME calculated (Opioid Morphine Equivalent Conversion 
Factors, Centers for Disease Control and Prevention, Atlanta, GA, May 2014).  
Protocol-allowed postoperative rescue medications consist of oral (PO) immediate-release 
oxycodone (≤ 10 mg within a 4-hour period as needed), intravenous (IV) morphine (2.5 to 5 
mg within a 4-hour period as needed), and/or IV hydromorphone (0.5 to 1.0 mg in a 4-hour 
window). Combination products containing an opioid and non-opioid are not allowed. With 
the exception of PO acetaminophen and PO celecoxib, which are administered as part of the 
scheduled MMA regimen, no other analgesic agents, including other nonsteroidal anti-
inflammatory drugs (NSAIDs), are permitted during the 72-hour postoperative observation 
period.  
Table  displays the MME along with the analgesic windows of selected opioid rescue 
medications for wWOCF purposes.  Protocol-allowed postoperative opioid rescue 
medications are checked.  Opioid medications that are not protocol-allowed will be logged as 
protocol violations, but will still be subject to MME conversion for analysis. 
Table 2: 
Analgesic Windows and Morphine Milligram Equivalents for Opioid 
Rescue Medications 
Medication 
Route 
Window 
(h) 
MME Factor 
Protocol Allowed 
CODEINE 
PO 
6 
0.05 
 
 
HYDROMORPHONE 
HYDROCHLORIDE 
PO 
4 
1.33 
 
 
HYDROMORPHONE 
HYDROCHLORIDE 
IV 
4 
6.67 
 
✓ 
FENTANYL 
IV 
1 
50.00 
 
 
HYDROCODONE 
PO 
6 
0.40 
 
 
MORPHINE 
IV 
4 
1.00 
 
✓ 
MORPHINE 
PO 
4 
0.33 
 
 
MORPHINE 
IM 
4 
1.00 
 
 
MORPHINE 
PR 
4 
1.00 
 
 
OXYCODONE 
IV 
4 
1.00 
 
 
OXYCODONE 
IM 
4 
1.00 
 
 
OXYCODONE 
PO 
6 
0.50 
 
✓ 
SUFENTANIL 
PO 
2 
500.00 
 
 
TRAMADOL 
IV 
6 
0.06 
 
 
TRAMADOL 
PO 
6 
0.04 
 
 
Abbreviations: h, hour; IM, intramuscular; IV, intravenous; MME, morphine milligram equivalent; PO, oral; 
PR, per rectum. 
Note: MME = opioid dose × MME factor. 
 


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Analysis method 
Rescue medication use is collected from 0-72 hours.  Average daily use and total use will be 
tabulated using descriptive statistics for overall opioids as well as oxycodone, morphine and 
hydromorphone during the following periods: 0-12, 12-48, 0-24, 24-48, 0-48, 48-72, 24-72, 
12-72, and 0-72 hours.  Subjects who did not use a specific rescue medication during a period 
of interest will have their dose set to 0 for that period. In addition, the total use, individual 
daily use at each study day between study day 4 and study day 11, as well as average daily 
use (ie, total use averaged over the number of days with non-missing diary reported) of 
overall opioids as well as oxycodone will be summarized after discharge through Day 11 
visit (based on opioid daily diary only).  For opioid consumption based on diary, MME will 
be calculated using observed data only. 
Proportion of subjects who are opioid-free through 72 hours and through Day 11 
Opioid-free status will be determined based on observed data only. 
Subjects who have a total MME postoperative opioid dose = 0 through 72 hours will be 
characterized as “opioid-free” through 72 hours. The proportion of subjects who are opioid-
free through 72 hours will be analyzed using descriptive statistics. The proportion of subjects 
who are opioid free through 24 hours (ie, MME=0 through 24 hours) and proportion of 
subjects who are opioid free through 48 hours (ie, MME=0 through 48 hours) will be 
analyzed similarly. In addition, the proportion of subjects who are opioid-free from 12 to 48 
hours (ie, MME=0 from 12 to 48 hours) will also be summarized in a similar manner. 
If subject was discharged on or after (≥) 72 hours from start of study drug administration, 
opioid-free from 72 hours through Day 11 is defined as MME=0 from 72 hours to discharge 
and answering “No” to the question “Did you take any opioid medication” from discharge 
through Day 11.  If subject was discharged prior to (<) 72 hours from start of study drug 
administration, the opioid-free from 72 hours through Day 11 is defined as answering “No” 
to the question “Did you take any opioid medication”  from Day 5 through Day 11 (see 
Section 5.4.4 for details). Subjects who report “Yes” during the period of interest will not be 
considered opioid-free during this period. The proportion of subjects who are opioid-free 
through Day 11 will be analyzed using descriptive statistics.  The number of pills by overall 
and by opioid type (ie, oxycodone or other) taken after discharge through Day 11 as collected 
in daily diary will also be summarized. 
In addition, opioid-free from 48 hours through day 11 (based on concomitant medication and 
opioid diary), from 72 hours through Day 11 (based on concomitant medication [if 
discharged after 72 hours] and opioid diary) and from discharge through Day 11 (based on 
opioid diary only) will be analyzed using descriptive statistics.   


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Proportion of subjects who are opioid-free through 72 hours who remain opioid-free 
through Day 11 
Among subjects who are opioid-free through 72 hours (ie, MME=0 through 72 hours), the 
proportion of subjects who remain opioid-free from 72 hours through Day 11  will be 
summarized using descriptive statistics. 
Median time to first opioid rescue medication through 72 hours 
Median time in hours to first opioid rescue medication through 72 hours will be summarized 
using K-M estimates of the median time along with associated 95% CI.  Subjects who 
withdraw from the study prior to 72 hours or who complete the 72-hour timepoint without 
having taken opioid rescue medication will be censored at the time of study withdrawal or at 
72 hours, whichever is earlier. 
Proportion of subjects who do not receive an opioid prescription at discharge 
If a subject received ≥ 10 mg of oxycodone within 12 hours prior to discharge, the 
Investigator may provide the subject with a prescription of immediate-release PO oxycodone 
tables: no more than thirty 5 mg immediate-release oxycodone. The proportion of subjects 
who do not receive an opioid prescription at discharge will be summarized using descriptive 
statistics. In addition, the proportion of subjects who receive an opioid prescription at 
discharge and the number of pills prescribed among these subjects will also be summarized. 
Proportion of subjects who do not receive an opioid prescription between discharge and 
the Day 11 Visit 
Sites will record all site-initiated or subject-initiated contact between discharge and Day 11 
visit and if any result in issuing an opioid prescription.  The proportion of subjects who do 
not receive an opioid prescription between discharge and Day 11 Visit will be summarized 
using descriptive statistics. 
In addition, the proportion of subjects who initiate contact with site or receive site-initiated 
contact to discuss pain related to surgery will be summarized. 
Among subjects who had contact data, the proportion of subjects who report to have taken 
their multimodal regimen as instructed at all contacts will also be summarized.  
In addition, the proportion of subjects who did not follow their MMA regimen as instructed 
among those who received a postdischarge opioid prescription will also be summarized. 
Proportion of subjects achieving a score of “good” or better (>1) pain control based on 
PGA at each timepoint 


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PGA of pain control is a 4-point scale in which subjects rate how well their pain has been 
controlled (Rothman, Vallow et al. 2009). The possible responses to the question are: 
• 0: Poor 
• 1: Fair 
• 2: Good 
• 3: Excellent 
 
The proportion of subjects answering in each category will be reported at each timepoint.  
The proportion of subjects achieving a score of “good” or better (>1) pain control based on 
PGA will be analyzed at each timepoint using descriptive statistics. 
Median time to first ambulation through 72 hours 
Median time in hours to first ambulation postsurgery will be summarized using K-M 
estimates of the median time along with associated 95% CI.  Subjects who withdraw from the 
study prior to 72 hours or who complete the 72-hour timepoint without ambulation will be 
censored at the time of study withdrawal or at 72 hours, whichever is earlier. 
Proportion of subjects unable to participate in each rehabilitation session because of 
pain 
The proportion of subjects unable to participate in each rehabilitation session because of pain 
at each timepoint and at any time through 72 hours will be summarized using descriptive 
statistics. 
Proportion of subjects who first achieve an MPADSS score ≥9 at each timepoint 
Discharge readiness is assessed using the MPADSS criteria, which considers a number of 
clinical variables: vital signs, ambulation, nausea/vomiting, pain, and surgical bleeding 
(Chung 1995). The proportion of subjects who first achieve an MPADSS score ≥ 9 by each 
timepoint will be analyzed cumulatively (ie, by 2 hours, by 4 hours, by 6 hours, ≤ 8 hours, 
etc.) using descriptive statistics. 
Proportion of subjects who are discharged home vs to a skilled nursing facility 
Site will record if subjects are discharged home or to a skilled nursing facility. The 
proportion of subjects who are discharged home vs to a skilled nursing facility will be 
summarized using descriptive statistics. 
Mean OBAS at each timepoint 
Overall benefit of analgesia is collected using a 7-item, multidimensional, quality assessment 
questionnaire (Lehmann, Joshi et al. 2010) addressing pain, vomiting, itching, sweating, 


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freezing, dizziness, and overall satisfaction with postoperative pain.  Each of the 7 items is 
rated on a scale of 0-4 as follows: 
• Item 1 (pain): 0 = “minimal pain”, 4 = “maximum imaginable pain” 
• Items 2-7: 0 = “not at all”, 4 = “very much” 
 
The OBAS for a subject is calculated by summing the scores in items 1-6 plus the difference 
between 4 and the score in item 7 for that subject: 
 
𝑂𝐵𝐴𝑆= (4 −𝑖𝑡𝑒𝑚7) + ∑𝑖𝑡𝑒𝑚𝑖
6
𝑖=1
 
Therefore the range of possible scores goes from 0 (answering 0 to the first 6 questions and 4 
to question 7) to 28 (answering 4 to the first 6 questions and 0 to question 7).  Question 7 is 
scored inversely because it is the only question where higher scores represent better 
outcomes. 
Mean OBAS at each timepoint will be summarized with descriptive statistics. 
 
Mean TSQM-9 score 
Subjects will be asked to evaluate their satisfaction with their scheduled non-opioid  MMA 
regimen for the treatment of their TKA-related pain using the TSQM-9 questionnaire 
(Bharmal, Payne et al. 2009).  
The TSQM-9 contains 9 items which make up the Effectiveness, Convenience, and Global 
Satisfaction domains. Scores for each domain are computed by adding the TSQM items in 
each domain and then transforming the composite score into a value ranging from 0 to 100. 
A score can be computed for a domain only if no more than one item is missing from that 
domain (IQVIA 2018).  
Effectiveness Domain: 
([(Item 1 + Item 2 + Item 3) – 3] divided by 18) * 100  
If one item is missing  
([(Sum(the two completed items – 2] divided by 12) * 100 
Convenience Domain: 
([Sum(Item 4 to Item 6) – 3] divided by 18) * 100  
If one item is missing  
([(Sum(the two completed items)) – 2] divided by 12) * 100 


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Global Satisfaction Domain: 
([Sum(Item 7 to Item 9) – 3] divided by 14) * 100  
If either Item 7 or 8 is missing  
([(Sum(the two completed items)) – 2] divided by 10) * 100  
If Item 9 is missing  
([(Sum(Item7 and Item8)) – 2] divided by 8) * 100 
The scores from individual question as well as for each domain will be summarized using 
descriptive statistics at each timepoint.   
10. 
SAFETY ANALYSIS 
All analyses of safety data will be conducted using the Safety Population.  Statistical 
hypothesis testing will not be performed on any safety results.  No imputation of missing 
safety data will be performed except in the case of partial AE and concomitant medication 
onset dates (Appendix 1). 
10.1. 
Adverse Events 
An AE is defined as any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related.  A TEAE is any AE which occurs any time 
during or after study drug administration, or any AE with an onset prior to study drug 
administration that worsens during or after study drug administration.  An AE may be any 
unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a study drug, whether or not considered 
causally associated with the use of the study drug. Any abnormal laboratory value, vital sign 
result, or ECG finding deemed clinically significant by the Investigator, regardless of causal 
relationship, must be reported as an AE.  
For an event to be a TEAE, it must meet one of the following conditions: 
• Begins on Study Day 1, during or after administration of study drug 
• Begins after Study Day 1 
• Begins before Study Day 1 and worsens in severity during or after the Study Day 1 
administration of study drug 
AEs with unknown onset dates or unknown end dates will be counted as TEAEs unless the 
event resolves before Study Day 1.   
AEs will be coded using MedDRA version 22.0.  Only TEAEs will be presented in AE 
tables, according to the SOC and PT.  Any AEs that occur and resolve prior to Study Day 1 


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or are ongoing but do not worsen on or after Study Day 1 will be considered pretreatment 
AEs and will appear in the AE listing but not in TEAE tables. 
10.1.1. 
Incidence of Treatment Emergent Adverse Events 
The incidence of TEAEs table will include only 1 occurrence of a PT per subject.  If a 
subject reports the same PT multiple times, then that PT will only be incremented by 1 since 
subject counts will be presented.  As with the PT, if a subject reports multiple TEAEs within 
the same SOC, then that SOC will only be incremented by 1 since subject counts will be 
presented.  For tables showing incidence by SOC and PT, SOCs will be sorted by the 
internationally agreed order and PTs will be sorted within SOC in descending order of 
incidence.  For tables showing incidence by PT only, the PTs will be sorted in descending 
order of incidence.   
An overall summary of TEAEs will be presented, and will include the following: 
• Number of TEAEs 
• Number of subjects with at least 1 TEAE 
• Number of subjects with at least 1 TEAE possibly related to study drug  
• Number of subjects with at least 1 severe TEAE 
• Number of subjects with at least 1 TEAE leading to study withdrawal 
• Number of subjects with at least 1 ORAE 
• Number of treatment-emergent SAEs (TESAEs) 
• Number of subjects with at least 1 TESAE 
• Number of subjects with at least 1 TESAE possibly related  to study drug 
• Number of subjects with fatal TEAEs 
The incidence of all TEAEs will be presented by SOC and PT and separately by PT only.   
10.1.2. 
Relationship of Adverse Events to Study Drug 
The incidence of TEAEs possibly related to study drug will be presented in a table by SOC 
and PT.   
10.1.3. 
Severity of Adverse Event 
The incidence of severe TEAEs will be presented in a table by SOC and PT.     
10.1.4. 
Serious Adverse Events 
Incidence of TESAEs will be presented in a table by SOC and PT.  The incidence of TESAE 
tables will include only 1 occurrence of a PT per subject.  If a subject reports the same 
TESAE multiple times, then that PT will only be incremented by 1 since subject counts will 
be presented.  As with the PT, if a subject reports multiple TESAEs within the same SOC, 
then that SOC will only be incremented by 1 since subject counts will be presented.  All 
SAEs will also be listed separately. 


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Incidence of TESAEs related to study drug will also be summarized by SOC and PT. 
10.1.5. 
Adverse Events Leading to Study Withdrawal 
All TEAEs reported with “Withdrawal from Study” checked on the eCRF will be presented 
in a listing. 
10.1.6. 
Potential Opioid-related Adverse Events 
Incidence of TEAEs that are potential opioid-related AEs, regardless of whether a subject 
actually received an opioid medication, will be presented by PT.  Prespecified PTs that 
constitute potential opioid-related AEs  include the following: 
• Nausea 
• Vomiting 
• Constipation 
• Pruritus 
• Pruritus generalised 
• Somnolence 
• Respiratory depression 
• Urinary retention 
 
Incidence of potential ORAEs will be presented separately as follows: 
• Incidence of potential ORAEs  
• Incidence of potential ORAEs through the 72-hour postoperative observation period 
• Incidence of potential ORAEs in the subset of subjects who received at least 1 opioid 
rescue medication during the 72-hour postoperative observation period 
• Incidence of potential ORAEs through the 72-hour postoperative observation period 
in the subset of subjects who received at least 1 opioid rescue medication during the 
72-hour postoperative observation period 
10.1.7. 
Death 
Any subject deaths during this study will be collected and presented in a listing.  The 
information that is presented will include date of death, days on study, cause of death, and 
relationship of death to study drug. 
10.2. 
Clinical Laboratory Evaluations 
Laboratory assessments will be performed by a central laboratory (hematology and serum 
chemistry) or locally (pregnancy test and drug screen).  All summaries of central laboratory 
data will be based on the standard international (SI) units provided by the central lab.  
Associated laboratory parameters such as hepatic profile, renal function, and hematology 
values will be grouped and presented together. 


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Summary tables for hematology and chemistry including actual values and change from 
Baseline values will be presented for clinical laboratory tests with numeric values.  These 
tables will include each visit (Baseline, 72 hours, and Day 11), highest postdose value, lowest 
postdose value, and last postdose value. 
Laboratory data will also be summarized using shift tables where appropriate.  Each subject’s 
hematology and serum chemistry values will be flagged as “low”, “normal”, or “high” 
relative to the normal ranges of the central laboratory.  
Laboratory data collected at unscheduled visits will be included in listings and will contribute 
to tables of shifts from Baseline and in tables showing changes from Baseline to highest 
value, lowest value, and last value.  Unscheduled laboratory results will not be windowed for 
the purposes of assigning a nominal visit. 
Listings of laboratory values will include flags for values outside the central laboratory 
normal ranges that indicate how far out of the normal range a value is.  For example, a value 
that is ≥ 3 times the upper limit of normal (ULN) but below 4 times the upper limit of normal 
will have a “3H” flag.  Flag multipliers will show values that are 1, 2, 3, 4, 5, and 10 times 
relative to the ULN if high.  Values that are below the lower limit of normal (LLN) will be 
flagged simply with “L”.   
Listings of out-of-range values for hematology and chemistry will be presented separately in 
addition to listings of all laboratory values.  
10.2.1. 
Hematology 
The following laboratory tests will be included in hematology summary tables: hematocrit, 
hemoglobin, platelet count, red blood cell (RBC) count, and total and differential white blood 
cell (WBC) count (basophils, eosinophils, lymphocytes, monocytes, and neutrophils). 
10.2.2. 
Blood Chemistry 
The following laboratory tests will be included in the blood chemistry summary tables: 
alanine aminotransferase (ALT), albumin, alkaline phosphatase (ALP), aspartate 
aminotransferase (AST), bicarbonate, blood urea nitrogen (BUN), calcium, chloride, 
creatinine, direct bilirubin, gamma-glutamyltransferase (GGT), glucose, lactate 
dehydrogenase (LDH), magnesium, phosphorus, potassium, sodium, total bilirubin, total 
protein, and uric acid. 
Associated laboratory parameters such as hepatic profile (ALT, albumin, ALP, AST, direct 
bilirubin, GGT, total bilirubin), electrolytes (bicarbonate, calcium, chloride, magnesium, 
phosphorus, potassium, sodium), renal profile (BUN, creatinine), and other (glucose, LDH, 
total protein, uric acid) will be sorted/grouped together in table and listing presentations.   


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Evaluation of drug-induced serious hepatotoxicity (eDISH) scatterplots of the highest 
postdose ALT vs. total bilirubin observed at the same draw as the high ALT value, and of the 
highest postdose AST vs. total bilirubin observed at the same draw as the high AST value, 
will be produced. 
The incidence of subjects with out-of-range liver function values will be summarized at each 
visit for the following categories. Subjects with out-of-range liver function values will be 
presented in data listing as well. 
• ALT or AST: 
o > 1 x ULN  
o ≥ 2 x ULN 
o ≥ 3 x ULN 
o ≥ 4 x ULN 
o ≥ 5 x ULN  
 
• Total bilirubin ≥ 2 x ULN 
 
• ALP: 
o ≥ 1.5 x ULN 
o ≥ 2 x ULN 
 
• ALT ≥ 3 x ULN and AST ≥ 3 x ULN 
 
• ALT ≥ 3 x ULN and total bilirubin ≥ 2 x ULN 
 
• AST ≥ 3 x ULN and total bilirubin ≥ 2 x ULN 
 
• Potential Hy’s Law: (ALT or AST ≥ 3 x ULN) and ALP < 2 x ULN and total 
bilirubin ≥ 2 x ULN 
10.2.3. 
Urine Pregnancy Test and Urine Drug Screen 
Urine pregnancy test results (women of child-bearing potential) and urine drug screen results 
will be listed. 
10.3. 
Vital Sign Measurements 
Vital signs including systolic blood pressure (SBP), diastolic blood pressure (DBP), heart 
rate/pulse (HR), body temperature, and respiration rate will be collected at screening, on Day 
1 before surgery, and post-treatment at 24, 48, 72 hours, and early termination (if applicable).   
Summary tables including actual values and changes from Baseline will be presented for 
vital signs.   


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The number and percentage of subjects with out-of-range vital sign values will be presented 
using data from any postdose visit (including unscheduled visits). Subjects with out-of-range 
vital sign values will be presented in a data listing as well. The criteria for out-of-range vital 
sign values are shown in Table  :  
Table 3: 
Out-of-Range Vital Signs Values 
Vital Sign 
Low 
High 
HR 
≤50 bpm, or 
≤50 bpm and ≥15 bpm decrease from 
Baseline 
≥120 bpm, or 
≥120 bpm and ≥15 bpm increase from 
Baseline 
SBP 
≤90 mmHg, or 
≤90 mmHg and ≥20 mmHg decrease from 
Baseline 
≥160 mmHg, or 
≥160 mmHg and ≥20 mmHg increase from 
Baseline 
DBP 
≤50 mmHg, or 
≤50 mmHg and ≥15 mmHg decrease from 
Baseline 
≥100 mmHg, or  
≥100 mmHg and ≥15 mmHg increase from 
Baseline 
Abbreviations: bpm, beats per minute; DBP, diastolic blood pressure; HR, heart rate; SBP, systolic blood pressure. 
10.4. 
Electrocardiogram 
A 12-lead ECG (triplicate) will be performed at screening. The results will be listed. 
10.5. 
Physical Examination 
Physical examination will be performed at Screening, 72 hours, and early termination (if 
applicable).  Physical examination data will be listed only. 
10.6. 
Wound Healing Assessment 
Surgical wound healing will be assessed using the Southampton Wound Scoring System at 
72 hours and on Day 11, Day 29, and early termination (if applicable).  A summary of wound 
healing assessment results will be produced, showing the number and percentage of subjects 
at each visit and at worst value post-baseline by grade with subgrade breakdown and by 
Grade 0/I and Grade II/III.  Wound healing assessment results will also be listed. 
11. 
INTERIM ANALYSIS 
11.1. 
Interim Analysis 
No formal interim analyses are planned. 
11.2. 
Data Safety Monitoring Board 
An independent Data Safety Monitoring Board (DSMB) will not be involved with the 
conduct of this study.  The internal Product Safety and Risk Management Committee will 


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monitor safety data on a periodic basis throughout the study, including regular review of AEs 
(including SAEs), laboratory results and other safety assessments.   
 
 
 


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12. 
REFERENCES 
Bharmal, M., K. Payne, M. J. Atkinson, M. P. Desrosiers, D. E. Morisky and E. Gemmen 
(2009). "Validation of an abbreviated Treatment Satisfaction Questionnaire for Medication 
(TSQM-9) among patients on antihypertensive medications." Health Qual Life Outcomes 7: 
36. 
Chung, F. (1995). "Discharge criteria--a new trend." Can J Anaesth 42(11): 1056-1058. 
Hawker, G. A., S. Mian, T. Kendzerska and M. French (2011). "Measures of adult pain: 
Visual Analog Scale for Pain (VAS Pain), Numeric Rating Scale for Pain (NRS Pain), 
McGill Pain Questionnaire (MPQ), Short-Form McGill Pain Questionnaire (SF-MPQ), 
Chronic Pain Grade Scale (CPGS), Short Form-36 Bodily Pain Scale (SF-36 BPS), and 
Measure of Intermittent and Constant Osteoarthritis Pain (ICOAP)." Arthritis Care Res 
(Hoboken) 63 Suppl 11: S240-252. 
IQVIA (2018). User Manual for the Treatment Satisfaction Questionnaire for Medication 
(TSQM): 1-40. 
Lehmann, N., G. P. Joshi, D. Dirkmann, M. Weiss, P. Gulur, J. Peters and M. Eikermann 
(2010). "Development and longitudinal validation of the overall benefit of analgesia score: a 
simple multi-dimensional quality assessment instrument." Br J Anaesth 105(4): 511-518. 
Rothman, M., S. Vallow, C. V. Damaraju and D. J. Hewitt (2009). "Using the patient global 
assessment of the method of pain control to assess new analgesic modalities in clinical 
trials." Current Medical Research and Opinion 25(6): 1433-1443. 
 


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APPENDIX 1. IMPUTATION OF PARTIAL AND MISSING DATES 
Incomplete Dates of Adverse Event start 
All AE onset dates must be entered on the eCRF as complete dates.  In the rare case that all 
or part of an AE onset date is missing but an AE resolution date is present and after study 
drug administration then the AE onset date will be imputed as follows: 
 
Year of onset 
Month of onset 
Day of onset 
Onset date to be imputed as 
Missing 
Missing 
Missing 
Date of SDA 
year = year of SDA 
Missing 
Nonmissing 
Date of SDA 
year = year of SDA 
Missing 
Missing 
Set month and day to those of SDA 
year < year of SDA 
Missing 
Nonmissing 
set month to December 
year < year of SDA 
Missing 
Missing 
set month and day to December 31 
year > year of SDA 
Missing 
Nonmissing 
set month to January 
year > year of SDA 
Missing 
Missing 
set month and day to January 1 
year = year of SDA 
Month = month of SDA 
Missing 
Set day as day of SDA 
year = year of SDA 
Month < month of SDA 
Missing 
Set day as last day of onset month 
year = year of SDA 
Month > month of SDA 
Missing 
Set day as first day of onset month 
year < year of SDA 
Nonmissing 
Missing 
Set day as last day of onset month 
year > year of SDA 
Nonmissing 
Missing 
Set day as first day of onset month 
SDA = study drug administration. 
 
If AE resolution date is present and prior to study drug administration, no need to impute 
incomplete AE start date, as the AE is not treatment emergent and the event should be in the 
medical history. 
 
Concomitant Medications 
• If year and month are present and day is missing then set day to first day of month for 
start date, and set day to last day of month for end date 
• If year and day are present and month is missing then set month to January for start 
date, and set month to December for end date 
• If year is present and month and day are missing then set month and day to January 1 
for start date, and set month and day to December 31 for end date 
• Completely missing dates will not be imputed 
If start date is completely missing and end date is not prior to study drug administration, then 
the medication will be classified as concomitant; if the end date is missing, then the 
medication will be classified as ongoing.  Medications for which the start and end dates are 
completely missing will be classified as concomitant. 
 


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APPENDIX 2. DOCUMENT REVISION HISTORY 
Version 
Date 
Notes/Revisions 
1 
28JUN2019 
Initial version, based on protocol version 3 (26JUN2019) 
2 
05APR2021 
Updated version, based on protocol version 6 (02JUL2020) 
• 
Updated study design, treatment cohorts, endpoints, and sample 
size per protocol version 6 
• 
Added layout of efficacy and Safety analyses 
• 
Added analyses of AUC of pain intensity by drain usage at site 
34 
• 
Modified the Day 11 Visit Period 
• 
Added imputation for missing ambulation time while ambulation 
date was reported 
• 
Added analysis for proportion of subjects who are opioid free 
from 12 to 48 hours 
• 
Specified that opioid MME and opioid-free analyses based on 
observed data only 
 
3 
01JUL2021 
Updated version, based on protocol version 6 (02JUL2020).  Updated 
Section 5.3.2 Layout of Efficacy and Safety Analyses by adding a Pooled 
Cohorts 1, 2, and 4 treatment column for all safety and efficacy tables and 
a Total column for all tables except efficacy tables.