Conditions: Postoperative Pain
Keywords: knee knee replacement arthroplasty joint replacement knee pain
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 285
Healthy volunteers: no

Brief summary:
This is a Phase 2b, randomized, double-blind, saline placebo- and active-controlled, multicenter study in subjects undergoing primary unilateral total knee arthroplasty (TKA) to evaluate the analgesic efficacy, safety, and pharmacokinetics (PK) of HTX-011 administered via infiltration to the surgical site.

Detailed description:

Arms:
arm 1: HTX-011 (bupivacaine/meloxicam), 200 mg/6 mg via instillation arm 2: HTX-011 (bupivacaine/meloxicam), 200 mg/6 mg via injection and instillation (combination) arm 3: Saline placebo via injection arm 4: Bupivacaine HCl without epinephrine, 125 mg via injection arm 5: HTX-011 (bupivacaine/meloxicam), 400 mg/12 mg via instillation arm 6: HTX-011 (bupivacaine/meloxicam), 400 mg/12 mg via instillation; Ropivacaine, 50 mg via injection arm 7: Saline placebo via injection arm 8: Bupivacaine HCl without epinephrine, 125 mg via injection

Interventions: intervention 1: HTX-011 intervention 2: Saline Placebo intervention 3: Bupivicaine HCl intervention 4: Ropivacaine
Intervention descriptions: intervention 1: HTX-011 (bupivacaine/meloxicam), via instillation intervention 2: Saline placebo via injection intervention 3: Bupivacaine HCl without epinephrine intervention 4: Ropivacaine, via injection

Protocol document:
Prot_000.pdf: 
Document Type:  
Study Protocol 
Official Title:  
A Phase 2b, Randomized, Double-Blind, Saline Placebo- and Active-
Controlled, Multicenter Study of HTX-011 via Infiltration for 
Postoperative Analgesia in Subjects Undergoing Total Knee 
Arthroplasty 
NCT Number:  
NCT03015532 
Document Date:  
21-Dec-2017 
 


Confidentiality Statement 
This document contains confidential information of Heron Therapeutics, Inc. 
Do not copy or distribute without written permission of the Sponsor. 
Any unauthorized use, reproduction, publication, or dissemination is strictly prohibited. 
 
 
 
CLINICAL STUDY PROTOCOL: HTX-011-209 
Protocol Title: 
A Phase 2b, Randomized, Double-Blind, Saline Placebo- and 
Active-Controlled, Multicenter Study of HTX-011 via 
Infiltration for Postoperative Analgesia in Subjects 
Undergoing Total Knee Arthroplasty 
Brief Title: 
Total knee arthroplasty infiltration study for postoperative 
analgesia 
Investigational Product: 
HTX-011 (extended-release 2.5% bupivacaine and 
0.075% meloxicam) 
Phase of Development: 
2b 
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 
Version 5 
Version 4 
Version 3 
Version 2 
Version 1 
21 December 2017 
28 August 2017 
16 May 2017 
28 March 2017 
19 January 2017 
30 November 2016 


Protocol No: HTX-011-209 
Page 2 of 87 
Version 6 
 
Heron Therapeutics, Inc. 
Confidential 
INVESTIGATOR AGREEMENT 
CLINICAL STUDY PROTOCOL: HTX-011-209 
TITLE: A Phase 2b, Randomized, Double-Blind, Saline Placebo- and Active-Controlled, 
Multicenter Study of HTX-011 via Infiltration for Postoperative Analgesia 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, 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-011-209 
Page 3 of 87 
Version 6 
 
Heron Therapeutics, Inc. 
Confidential 
PROTOCOL SYNOPSIS 
Sponsor: Heron Therapeutics, Inc. 
Protocol Number: HTX-011-209 
Name of Investigational Product: 
HTX-011 (extended-release 2.5% bupivacaine 
and 0.075% meloxicam) 
Protocol Title: 
A Phase 2b, Randomized, Double-Blind, Saline Placebo- and 
Active-Controlled, Multicenter Study of HTX-011 via Infiltration 
for Postoperative Analgesia in Subjects Undergoing Total Knee 
Arthroplasty 
Name of Active Ingredients: 
Bupivacaine and meloxicam 
Phase of Development: 2b 
Study Objectives: 
Primary Objectives: 
 To compare the efficacy and duration of analgesia achieved following periarticular infiltration of HTX-011 with 
that of saline placebo in subjects undergoing unilateral total knee arthroplasty (TKA). 
Secondary Objectives: 
 To compare the efficacy and duration of analgesia for HTX-011 with that of bupivacaine HCl without 
epinephrine in this study population. 
 To evaluate additional efficacy parameters, including opioid load, in this study population. 
 To evaluate the efficacy and duration of analgesia for HTX-011 administered using different techniques in this 
study population.  
 To characterize the bupivacaine and meloxicam pharmacokinetic (PK) profiles following administration of 
HTX-011 in this study population. 
 To assess the safety and tolerability of HTX-011 in this study population. 
Methodology: This is a Phase 2b, randomized, double-blind, saline placebo- and active-controlled, multicenter 
study in subjects undergoing primary unilateral TKA. Cohort 1 will evaluate HTX-011 administered into the 
surgical site via different techniques compared with saline placebo and bupivacaine HCl to determine whether to 
proceed to Cohort 2. If a decision is made to proceed to Cohort 2, HTX-011 will be evaluated compared with saline 
placebo and bupivacaine HCl at the dose and administration technique recommended by an internal Interim Review 
Committee (IRC). 
All subjects will be screened within 21 days prior to surgery. Subjects who meet the Screening eligibility criteria 
will be randomized. Randomization may be done up to 1 business day prior to the day of surgery. On the day of 
surgery (Day 0), subjects who continue to meet the eligibility criteria will undergo primary unilateral TKA under 
general anesthesia.  
Just before being taken to the operating room prior to the start of surgery, each subject in Cohort 2 will be 
administered pregabalin orally (PO; 150 mg) and acetaminophen intravenously (IV; no more than 1 g [1000 mg] in a 
6-hour window, as per the approved prescribing information) to reduce initial postoperative pain. 
In the study, a single dose of study drug (HTX-011 with or without ropivacaine, bupivacaine HCl without 
epinephrine, or saline placebo) will be administered intraoperatively by infiltration to the surgical site (eg, 
periarticular instillation, periarticular injection, or a combination of periarticular injection and instillation). 
Specifically in Cohort 2, HTX-011 will be administered via periarticular instillation with or without ropivacaine via 
periarticular injection. 
During surgery, the use of fentanyl up to 4 μg/kg will be permitted for intraoperative pain control. Just prior to the 
end of the surgery, all subjects will receive an additional 75 µg of fentanyl IV to minimize the variability of the 
impact of fentanyl on postoperative care (for example, the maximum total amount of fentanyl used during surgery 
for a 70 kg subject should not exceed 355 µg [4 μg/kg × 70 kg = 280 μg for intraoperative pain control + 75 μg at 
the end of the case = 355 μg total]).  
Following surgery and immediate postoperative recovery, subjects will be transferred to the postanesthesia care unit 
(PACU). Subjects will remain in the hospital/research facility for a minimum of 72 hours after study drug 


Protocol No: HTX-011-209 
Page 4 of 87 
Version 6 
 
Heron Therapeutics, Inc. 
Confidential 
Sponsor: Heron Therapeutics, Inc. 
Protocol Number: HTX-011-209 
Name of Investigational Product: 
HTX-011 (extended-release 2.5% bupivacaine 
and 0.075% meloxicam) 
Protocol Title: 
A Phase 2b, Randomized, Double-Blind, Saline Placebo- and 
Active-Controlled, Multicenter Study of HTX-011 via Infiltration 
for Postoperative Analgesia in Subjects Undergoing Total Knee 
Arthroplasty 
Name of Active Ingredients: 
Bupivacaine and meloxicam 
Phase of Development: 2b 
administration to undergo postoperative assessments. After the 72-hour assessments have been completed, subjects 
may be discharged. Subjects will return to the study site on Days 10 and 28 to complete follow-up assessments. 
Postoperative Opioid Rescue Medications 
Subjects should only receive rescue medication upon request for pain control, as needed, during the 72-hour 
postoperative observation period. Rescue medication should not be given for pain prophylaxis, but only for pain 
treatment. 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 a Numeric Rating Scale (NRS) score at rest (NRS-R) followed by a 
Numeric Rating Scale score with activity (NRS-A) pain score must be obtained. 
Postoperative rescue medication will consist of IV morphine and/or PO immediate-release oxycodone. For the first 
2 hours in the PACU, the subject may receive up to 15 mg IV morphine, as needed. Thereafter, the subject may 
receive up to 10 mg in a 2-hour period, as needed. In addition, the subject may also receive up to 10 mg of PO 
immediate-release oxycodone within any 4-hour period, as needed, from after study drug administration through 
72 hours. No other analgesic agents are permitted during the 72-hour postoperative observation period (except as 
specified by the protocol; see below).  
After 72 hours, the analgesic regimen may be adjusted for each subject individually as deemed appropriate by the 
physician responsible for the postoperative care and in accordance with the verbal discharge instructions. See the 
Study Reference Manual for more information on postoperative pain management after discharge. Subjects will 
complete a daily diary to record if they take an opioid medication between 72 hours and Day 28. 
Required Antifibrinolysis and Deep Vein Thrombosis (DVT) Prophylaxis 
All subjects are required to receive tranexamic acid (TXA) and acetylsalicylic acid (ASA) during the study. TXA 1g 
IV will be administered prior to the start of surgery and a second dose will be administered up to approximately 
8 hours later. For the time period after study drug administration until hospital discharge, subjects should receive 
ASA 325 mg PO twice a day; surgeons may also use additional DVT prophylaxis as per their standard of care. 
Use of Other Analgesics 
With the exception of preoperative administration of PO pregabalin and IV acetaminophen (in Cohort 2 only), 
intraoperative administration of study drug (including ropivacaine in 1 arm in Cohort 2) and fentanyl, 
protocol-specified postoperative opioid rescue medications, and ASA for DVT prophylaxis, no other analgesic 
agents, including ketamine and nonsteroidal anti-inflammatory drugs (NSAIDs), are permitted from the time the 
subject signs the informed consent form (ICF) through 72 hours after study drug administration, except under the 
following circumstances: to treat an adverse event (AE), for pretreatment prior to needle placement, or to decrease 
venous irritation caused by propofol (in which case, no more than a single administration of lidocaine 1% 20 mg IV 
may be administered). Nerve block may also not be used as a form of analgesia on Day 0 and for at least 72 hours 
after study drug administration. 
Interim Analyses 
An internal IRC will review unblinded, summary-level efficacy, safety, and PK data from Cohort 1 to determine if 
enrollment should be initiated in Cohort 2. The interim analysis will be performed after at least 80% of the planned 
number of subjects in Cohort 1 have all of their pain intensity and opioid use data through the 72-hour postoperative 
assessments entered into electronic clinical database. The IRC will operate under a written, detailed IRC Charter. 
There will be no interim analyses on data collected during Cohort 2. 
Treatment Cohorts 
The study will include 2 cohorts. 
Cohort 1 


Protocol No: HTX-011-209 
Page 5 of 87 
Version 6 
 
Heron Therapeutics, Inc. 
Confidential 
Sponsor: Heron Therapeutics, Inc. 
Protocol Number: HTX-011-209 
Name of Investigational Product: 
HTX-011 (extended-release 2.5% bupivacaine 
and 0.075% meloxicam) 
Protocol Title: 
A Phase 2b, Randomized, Double-Blind, Saline Placebo- and 
Active-Controlled, Multicenter Study of HTX-011 via Infiltration 
for Postoperative Analgesia in Subjects Undergoing Total Knee 
Arthroplasty 
Name of Active Ingredients: 
Bupivacaine and meloxicam 
Phase of Development: 2b 
Approximately 60 subjects will be randomized to 1 of the following 4 treatment groups in a 2:2:1:1 ratio: 
 HTX-011 200 mg/6 mg (6.8 mL) via periarticular instillation into the surgical site (20 subjects) 
 HTX-011 200 mg/6 mg (6.8 mL) via a combination of periarticular injection and instillation into the surgical site 
(20 subjects) 
 Saline placebo (6.8 mL) via periarticular injection into the surgical site (10 subjects) 
 Bupivacaine HCl without epinephrine 0.25% (125 mg, 50 mL) via periarticular injection into the surgical site 
(10 subjects) 
Cohort 2 
Cohort 2 was planned as an optional cohort. Following a review of the results from Cohort 1, the IRC recommended 
initiating enrollment in Cohort 2 with a single dose level of HTX-011 400 mg/12 mg (bupivacaine/meloxicam 
doses; 13.7 mL) in each HTX-011 treatment group.  
Approximately 200 subjects will be randomized to 1 of the following 4 treatment groups in a 1:1:1:1 ratio: 
 HTX-011 400 mg/12 mg (13.7 mL) via periarticular instillation into the surgical site (50 subjects) 
 HTX-011 400 mg/12 mg (13.7 mL) via periarticular instillation into the surgical site and ropivacaine 0.5% 
(50 mg, 10 mL) via periarticular injection into the surgical site (posterior capsule) (50 subjects) 
 Saline placebo (13.7 mL) via periarticular injection into the surgical site (50 subjects) 
 Bupivacaine HCl without epinephrine 0.25% (125 mg, 50 mL) via periarticular injection into the surgical site 
(50 subjects) 
Number of Planned Subjects: Up to approximately 260 subjects will be randomized.  
Study Sites: Up to approximately 30 sites in the United States (US) 
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, adhere to the study visit schedule, and complete all study 
assessments. 
2. Is male or female, and ≥18 years of age at screening. 
3. Is scheduled to undergo primary unilateral TKA under general anesthesia. 
4. Has not previously undergone TKA in either knee. 
5. Has an American Society of Anesthesiologists Physical Status of I, II, or III. 
6. Is able to demonstrate motor function by performing a timed 20-meter walk unassisted, but with the optional 
use of a 4-legged walker for balance. 
7. Female subjects are eligible only if all of the following apply: 
a. 
Not pregnant (female subject of child-bearing potential must have a negative urine pregnancy test at 
screening and on Day 0 before surgery). 
b. Not lactating. 
c. 
Not planning to become pregnant during the study. 
d. Surgically sterile; or at least 2 years post-menopausal; or have a monogamous partner who is surgically 
sterile; or is practicing double-barrier contraception; or practicing abstinence (must agree to use 
double-barrier contraception in the event of sexual activity); or using an insertable, injectable, transdermal, 


Protocol No: HTX-011-209 
Page 6 of 87 
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Heron Therapeutics, Inc. 
Confidential 
Sponsor: Heron Therapeutics, Inc. 
Protocol Number: HTX-011-209 
Name of Investigational Product: 
HTX-011 (extended-release 2.5% bupivacaine 
and 0.075% meloxicam) 
Protocol Title: 
A Phase 2b, Randomized, Double-Blind, Saline Placebo- and 
Active-Controlled, Multicenter Study of HTX-011 via Infiltration 
for Postoperative Analgesia in Subjects Undergoing Total Knee 
Arthroplasty 
Name of Active Ingredients: 
Bupivacaine and meloxicam 
Phase of Development: 2b 
or combination oral contraceptive approved by the US Food and Drug Administration (FDA) for greater 
than 2 months prior to screening and commits to the use of an acceptable form of birth control for the 
duration of the study and for 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 with any of the following criteria will be excluded from the study: 
1. Has a planned concurrent surgical procedure (eg, bilateral TKA). 
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 to bupivacaine and ropivacaine (or other local anesthetics), meloxicam (or other NSAIDs), oxycodone, 
morphine, TXA, fentanyl, pregabalin, acetaminophen, or ASA. 
4. Has known or suspected daily use of opioids for 7 or more consecutive days within the previous 6 months. 
5. Has taken NSAIDs (including meloxicam) within at least 10 days prior to surgery with the exception of subjects 
on low-dose (<100 mg) daily acetylsalicylic acid for cardioprotection. 
6. Has taken long-acting opioids within 3 days prior to surgery. 
7. Has taken any opioids within 24 hours prior to the scheduled surgery. 
8. Has been administered bupivacaine within 5 days prior to the scheduled surgery. 
9. 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 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). 
10. 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 cyclooxygenase-2 (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. 
11. 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 steroids are not considered 
systemic. 
12. 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 informed consent, 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 of signing the ICF. 
c. 
History of 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. History of severe kidney function impairment as defined by creatinine clearance (Cockcroft Gault) 
<30 mL/min, being on dialysis, and/or having a serum creatinine >2 × ULN. 
e. 
History of known or suspected coagulopathy or uncontrolled anticoagulation. 


Protocol No: HTX-011-209 
Page 7 of 87 
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Heron Therapeutics, Inc. 
Confidential 
Sponsor: Heron Therapeutics, Inc. 
Protocol Number: HTX-011-209 
Name of Investigational Product: 
HTX-011 (extended-release 2.5% bupivacaine 
and 0.075% meloxicam) 
Protocol Title: 
A Phase 2b, Randomized, Double-Blind, Saline Placebo- and 
Active-Controlled, Multicenter Study of HTX-011 via Infiltration 
for Postoperative Analgesia in Subjects Undergoing Total Knee 
Arthroplasty 
Name of Active Ingredients: 
Bupivacaine and meloxicam 
Phase of Development: 2b 
f. 
Loss of sensation in extremities or significant peripheral neuropathy. 
13. As per subject history and/or medical records, has active infection or is currently undergoing treatment for 
Hepatitis B, Hepatitis C, or human immunodeficiency virus (HIV). 
14. Has uncontrolled anxiety, psychiatric, or neurological disorder that, in the opinion of the Investigator, might 
interfere with study assessments. 
15. Has any chronic neuromuscular deficit of either femoral nerve function or thigh musculature. 
16. Has any chronic condition or disease that would compromise neurological or vascular assessments. 
17. 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. 
18. Has a known or suspected history of drug abuse, a positive drug screen on the day of surgery, or a recent history 
of alcohol abuse. 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 taking medical marijuana are not allowed to participate in the study. 
19. Previously participated in an HTX-011 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 surgery, or is planning to take 
part in another clinical trial while participating in this study. 
20. Has undergone 3 or more surgeries in 12 months prior to signing the ICF, other than for diagnostic procedures 
(eg, colonoscopy). 
21. Has a body mass index (BMI) >39 kg/m2. 
Investigational Product, Dose, and Mode of Administration: 
HTX-011 is an extended-release, fixed-ratio combination product that contains bupivacaine (a local anesthetic as the 
free base) and low-dose meloxicam (an NSAID) incorporated in a bioerodible polymer (termed Biochronomer®). 
HTX-011 will be supplied by the Sponsor as a sterile, viscous liquid.  
A single dose of HTX-011 will be administered by infiltration to the surgical site (eg, periarticular instillation, 
periarticular injection, or a combination of periarticular injection and instillation). 
Reference Therapy, Dose, and Mode of Administration: 
Bupivacaine HCl without epinephrine 0.25% (125 mg) and saline placebo (0.9% sodium chloride solution) will be 
administered by periarticular injection into the surgical site. 
Bupivacaine HCl and saline placebo will be supplied by sites. 
Duration of Treatment: Subjects will receive a single dose of study drug. The overall duration of the study is 
anticipated to be approximately 18 months. The total duration of study participation for each subject (from 
Screening through the Day 28 Visit) will be up to 54 days. 
Criteria for Evaluation: 
Efficacy, safety, and PK assessments will be performed. The start of study drug administration will be 
considered as Time 0 for all efficacy, safety, and PK assessments. The start of HTX-011 administration will be 
considered as Time 0 whether or not administered with ropivacaine. 
Efficacy Assessments: 
 Pain intensity scores using the NRS-R (either seated comfortably or lying down) on Day 0 before surgery, at 1, 
2, 4, 6, 8, 12, 24, 36, 48, 60, and 72 hours, and at Day 10 and Day 28.  
 Pain intensity scores using the NRS-A (the prescribed activity is a straight leg raise of the surgical leg while the 


Protocol No: HTX-011-209 
Page 8 of 87 
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Heron Therapeutics, Inc. 
Confidential 
Sponsor: Heron Therapeutics, Inc. 
Protocol Number: HTX-011-209 
Name of Investigational Product: 
HTX-011 (extended-release 2.5% bupivacaine 
and 0.075% meloxicam) 
Protocol Title: 
A Phase 2b, Randomized, Double-Blind, Saline Placebo- and 
Active-Controlled, Multicenter Study of HTX-011 via Infiltration 
for Postoperative Analgesia in Subjects Undergoing Total Knee 
Arthroplasty 
Name of Active Ingredients: 
Bupivacaine and meloxicam 
Phase of Development: 2b 
subject is lying down or seated in a recliner [recumbent]), on Day 0 before surgery, at 1, 2, 4, 6, 8, 12, 24, 36, 48, 
60, and 72 hours, and at Day 10 and Day 28. Continuous passive motion (CPM) 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. 
 Date, time of administration, and amount of all opioid rescue medication taken through 72 hours. 
 Subject daily diary to record if any opioids were taken from 72 hours through Day 28. 
 Patient Global Assessment (PGA) of pain control at 24, 48, and 72 hours, and on Day 28. 
 Ability to participate in rehabilitation session at 6, 12, 24, 36, 48, 60, and 72 hours. 
 Ability to ambulate (defined as the ability to walk more than 3 steps with an assisted device) on Day 0 before 
surgery and at 6, 12, 24, 48, and 72 hours. 
 Discharge readiness assessment per the Modified Postanaesthetic Discharge Scoring System (MPADSS) criteria 
at 2, 4, 6, 8, 12, 24, 36, 48, 60, and 72 hours. Discharge readiness assessment will be repeated for subjects who 
remain hospitalized at 96 and 120 hours. (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 on whether 
or not to discharge a subject from the study, as subjects are required to remain in the hospital/research facility for 
72 hours.)  
 Subject’s satisfaction with postoperative pain control at 24, 48, and 72 hours, and on Day 10 using a 5-point 
Likert scale.  
 Overall benefit of analgesia score (OBAS) at 24, 48 and 72 hours, and at Day 28. 
Safety Assessments: 
 AEs from the time the subject signs the ICF through Day 28. 
 Clinical safety laboratory tests (hematology and serum chemistry) at Screening Visit, at 24 hours (hematology 
only) and at 72 hours, and Day 10 (hematology and serum chemistry). 
 Physical examination at Screening Visit and 72 hours; Screening Visit will include height, weight, and BMI 
calculation. 
 Wound healing assessment at 72 hours, and on Day 10 and Day 28. Wound healing assessment will be repeated 
for subjects who remain hospitalized at 96 and 120 hours. 
 Vital signs (resting heart rate, blood pressure, and respiration rate) at Screening Visit, Day 0 before surgery, and 
post-treatment at 24, 48, and 72 hours. 
 ECG at Screening Visit. 
 Continuous Holter monitoring beginning at least 24 hours prior to surgery through 72 hours. 
 Motor function assessment (ie, ability to perform a timed 20-meter walk) at Screening Visit; at 6, 12, 24, 48, and 
72 hours; and on Day 10. 
Pharmacokinetic Assessments: 
Blood samples for bupivacaine and meloxicam PK analysis will be collected at the following timepoints: on Day 0 
before surgery; at 30 minutes; and at 1, 2, 4, 6, 8, 12, 20, 22, 24, 26, 28, 36, 48, 60, and 72 hours after the start of 
study drug administration; and on Day 6 and Day 10. (Note: when PK and NRS pain intensity assessments coincide, 
the NRS pain intensity assessments should be conducted before the blood draw. The Day 6 PK sample may be 
collected by a visiting nurse or at the study site.) 


Protocol No: HTX-011-209 
Page 9 of 87 
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Heron Therapeutics, Inc. 
Confidential 
Sponsor: Heron Therapeutics, Inc. 
Protocol Number: HTX-011-209 
Name of Investigational Product: 
HTX-011 (extended-release 2.5% bupivacaine 
and 0.075% meloxicam) 
Protocol Title: 
A Phase 2b, Randomized, Double-Blind, Saline Placebo- and 
Active-Controlled, Multicenter Study of HTX-011 via Infiltration 
for Postoperative Analgesia in Subjects Undergoing Total Knee 
Arthroplasty 
Name of Active Ingredients: 
Bupivacaine and meloxicam 
Phase of Development: 2b 
Study Endpoints: 
Primary Efficacy Endpoint 
 
Mean area under the curve (AUC) of the NRS-R pain intensity scores through 48 hours (AUC0-48).  
Key Secondary Efficacy Endpoint 
 Mean AUC of the NRS-R pain intensity scores through 72 hours (AUC0-72). 
Other Secondary Efficacy Endpoints 
 Mean total postoperative opioid consumption (in morphine equivalents) through 24, 48, and 72 hours. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety Endpoints 
 Incidence of treatment-emergent AEs (TEAEs), serious TEAEs (SAEs), and opioid-related TEAEs (ORAEs) 
through Day 28. 
 Change from baseline in clinical laboratory results. 
 Change from baseline in Holter data. 
 Change from baseline in vital signs at each assessed timepoint. 


Protocol No: HTX-011-209 
Page 10 of 87 
Version 6 
 
Heron Therapeutics, Inc. 
Confidential 
Sponsor: Heron Therapeutics, Inc. 
Protocol Number: HTX-011-209 
Name of Investigational Product: 
HTX-011 (extended-release 2.5% bupivacaine 
and 0.075% meloxicam) 
Protocol Title: 
A Phase 2b, Randomized, Double-Blind, Saline Placebo- and 
Active-Controlled, Multicenter Study of HTX-011 via Infiltration 
for Postoperative Analgesia in Subjects Undergoing Total Knee 
Arthroplasty 
Name of Active Ingredients: 
Bupivacaine and meloxicam 
Phase of Development: 2b 
 Wound healing assessment at 72 hours and on Day 10 and Day 28.  
 Proportion of subjects able to complete a timed 20-meter walk test unassisted at 6, 12, 24, 48, and 72 hours and 
on Day 10. 
Pharmacokinetic Endpoints 
 Maximum observed plasma concentration (Cmax). 
 AUC from Time 0 to the last collection time after study drug administration (AUC0-last). 
 AUC from Time 0 extrapolated to infinity (AUC0-∞). 
 Time to maximum plasma concentration (Tmax). 
 Apparent terminal elimination rate constant (λz). 
 Apparent terminal elimination half-life (t1/2el). 
Statistical Methods: 
Efficacy Analyses:  
Cohorts 1 and 2 will be analyzed separately with no data pooling across cohorts. In Cohort 1, each arm of HTX-011 
will be tested against each control arm. In Cohort 2, the following treatment comparisons will be performed in a 
hierarchical order for the primary and key secondary endpoints: 
1. Mean AUC0-48 of the NRS-R pain intensity scores for HTX-011 400 mg/12 mg (13.7 mL) via periarticular 
instillation and ropivacaine 50 mg via periarticular injection vs. saline placebo. 
2. Mean AUC0-48 of the NRS-R pain intensity scores for HTX-011 400 mg/12 mg (13.7 mL) via periarticular 
instillation vs. saline placebo. 
3. Mean AUC0-72 of the NRS-R pain intensity scores for HTX-011 400 mg/12 mg (13.7 mL) via periarticular 
instillation and ropivacaine 50 mg via periarticular injection vs. saline placebo. 
4. Mean AUC0-72 of the NRS-R pain intensity scores for HTX-011 400 mg/12 mg (13.7 mL) via periarticular 
instillation vs. saline placebo. 
In order to account for multiple treatment comparisons on the primary and key secondary endpoints in Cohort 2, a 
strict testing hierarchy will be applied to control study-wise alpha level at 0.05. If the first treatment comparison is 
statistically significant (p≤0.05), then the second treatment comparison will be tested. If the second treatment 
comparison is statistically significant, then the third treatment comparison will be tested. Sequential testing will 
continue in this manner down the hierarchical order until a treatment comparison fails to meet statistical 
significance, after which all subsequent treatment comparisons will be considered exploratory.  
The primary endpoint of mean AUC0-48 of the NRS-R pain intensity scores will be analyzed using an analysis of 
variance (ANOVA) model with treatment as the main effect. Results will be expressed as mean AUCs and standard 
deviations (SDs), least-squares mean differences and standard errors (SEs) with associated 95% confidence intervals 
(CIs), and p-values. Other continuous efficacy endpoints will be analyzed similarly to the primary endpoint. 
Categorical endpoints will be analyzed using Fisher’s exact test. Results will be expressed as the number and 
percentage of subjects meeting the relevant endpoint, differences in proportions with 95% CIs, and p-values. 
Median time in hours to first opioid rescue administration will be analyzed using Kaplan-Meier methods. 
Safety Analyses: 
All safety data will be listed and summarized by treatment group; no statistical hypothesis testing will be performed. 
All TEAEs will be coded and tabulated by System Organ Class and Preferred Term. Incidence of TEAEs and SAEs 


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Sponsor: Heron Therapeutics, Inc. 
Protocol Number: HTX-011-209 
Name of Investigational Product: 
HTX-011 (extended-release 2.5% bupivacaine 
and 0.075% meloxicam) 
Protocol Title: 
A Phase 2b, Randomized, Double-Blind, Saline Placebo- and 
Active-Controlled, Multicenter Study of HTX-011 via Infiltration 
for Postoperative Analgesia in Subjects Undergoing Total Knee 
Arthroplasty 
Name of Active Ingredients: 
Bupivacaine and meloxicam 
Phase of Development: 2b 
will be summarized and presented in descending order of frequency according to the highest dose of HTX-011 
studied. 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. 
Interim Analysis: 
One interim analysis is planned for Cohort 1. An internal IRC will review unblinded, summary-level data from 
Cohort 1 to make study design decisions. The interim analysis will be performed after at least 80% of the planned 
number of subjects in Cohort 1 have all of their pain intensity and opioid use data through the 72-hour postoperative 
assessments entered into electronic clinical database. The internal IRC will be composed of 1 Sponsor representative 
from the Clinical Research, Biometrics, Pharmacovigilance, Regulatory, and Pharmaceutical and Translational 
Sciences functions. The IRC will operate under a written, detailed IRC Charter. 
There will be no interim analyses on data collected during Cohort 2. 
Determination of Sample Size: 
Cohort 1: The sample size of up to approximately 60 subjects was selected empirically without formal statistical 
assumptions. 
Cohort 2: The mean (SD) AUC0-48 in the saline placebo and HTX-011 400 mg/12 mg groups after adjusting for 
opioid rescue medication use is expected to be approximately 425 (90) and 365 (90), respectively. Using a 2-sample 
t-test, 50 subjects per treatment group results in approximately 90% power to detect a statistically significant 
treatment effect with α = 0.05, 2-sided. 




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Abbreviations: BMI, body mass index; d, day; ECG, electrocardiogram; ET, Early Termination Visit; hr, hour; IV, intravenous(ly); min, minutes; MPADSS, Modified 
Postanaesthetic Discharge Scoring System; NRS-A, Numeric Rating Scale with activity; NRS-R, Numeric Rating Scale at rest; OBAS, overall benefit of analgesia score; 
OR, operating room; PGA, Patient Global Assessment; PK, pharmacokinetic; Preop, preoperative; WOCBP, women of child-bearing potential; D10, Day 10; D28, 
Day 28. 
* The start of study drug administration will be considered as Time 0 for all efficacy, safety, and PK assessments. The start of HTX-011 administration will be considered 
as Time 0 whether or not administered with ropivacaine. 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 awakening the subject (eg, blood collection for 
PK sample) should be completed. See Section 6 for more information on study procedures and assessments. 
a Subjects who withdraw from the study before their Day 28 Visit will be asked to complete Early Termination procedures. 
b Result must be negative and confirmed prior to initiation of surgery. A subject who fails the drug test may be rescreened at the discretion of the Investigator. 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 taking medical marijuana are not 
allowed to participate in the study. 
c Includes height, weight, and BMI calculation. 
d Only if subject withdraws prior to 72 hours. 
e Only if subject withdraws prior to Day 10. 
f Only if subject withdraws prior to Day 28. 
g Subjects will be required to have continuous reading of the Holter monitor at least 24 hours before surgery. If a Holter monitor safety alert is received after study drug 
administration, obtain vital sign measurements and collect a blood sample for PK analysis to evaluate for local anesthetic systemic toxicity (LAST).  
h Subjects who meet the Screening eligibility criteria will be randomized. Randomization may be done up to 1 business day prior to study drug administration. Subject 
does not need to be present for randomization to occur. 
i Hematology at 24 hours; hematology and serum chemistry at all other timepoints. 
j Each subject in Cohort 2 will be given a single, oral dose of pregabalin 150 mg prior to the start of surgery. 
k TXA 1 g IV will be administered prior to the start of surgery. A second dose will be administered up to approximately 8 hours after the initial dose. 
l Each subject in Cohort 2 will be administered a single dose of acetaminophen IV (no more than 1 g [1000 mg] in a 6-hour window, as per the approved prescribing 
information) prior to the start of surgery. 
m NRS-R should be assessed while the subject is either seated comfortably or lying down. 
n NRS-A assessments should be performed after NRS-R. The prescribed activity for NRS-A is a straight leg raise of the surgical leg while the subject is lying down or 
seated in a recliner (recumbent). If the subject cannot perform the activity, the NRS should still be completed. 
o Defined as the ability to walk more than 3 steps with an assisted device. 
p 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 on 
whether or not to discharge a subject from the study. Discharge readiness assessments will be repeated for any subject who remains hospitalized at 96 and 120 hours. 
q Wound healing assessments will be repeated for any subject who remains hospitalized at 96 and 120 hours. 
r If a cardiac or neurological treatment-emergent adverse event occurs during the study, a blood sample should be collected at the time that the event is noted to determine 
the plasma bupivacaine concentration. 
s A PK sample should be collected 30 minutes (±5 min) after the start of study drug administration even if the subject is still in the operating room. 
t PK samples may be collected by a visiting nurse or at the study site.  
u Subjects will complete a daily diary to record use of opioids for pain from 72 hours through Day 28. 
v At the Screening Visit, ensure subject is not taking any prohibited medications. Record all medications taken between the day of signing the Informed Consent Form 
and Day 28. 
w Adverse events will be collected from the time the subject signs the Informed Consent Form through Day 28. 


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TABLE OF CONTENTS 
INVESTIGATOR AGREEMENT.............................................................................................2 
PROTOCOL SYNOPSIS ..........................................................................................................3 
SCHEDULE OF EVENTS ......................................................................................................12 
TABLE OF CONTENTS .........................................................................................................14 
LIST OF APPENDICES ..........................................................................................................19 
LIST OF TABLES ...................................................................................................................19 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ............................................20 
1. 
INTRODUCTION ..........................................................................................................22 
1.1. 
Background Information and Study Rationale ............................................................22 
1.2. 
Rationale for Study Design, Doses, and Control Groups ............................................22 
1.3. 
Potential Risks and Benefits ........................................................................................24 
2. 
STUDY OBJECTIVES ..................................................................................................27 
2.1. 
Primary Objective ........................................................................................................27 
2.2. 
Secondary Objectives...................................................................................................27 
3. 
INVESTIGATIONAL PLAN AND ENDPOINTS .......................................................28 
3.1. 
Description of the Study Design ..................................................................................28 
3.1.1. 
Overall Study Design .............................................................................................28 
3.1.2. 
Treatment Groups ..................................................................................................29 
3.1.3. 
Postoperative Opioid Rescue Medications ............................................................29 
3.1.4. 
Required Antifibrinolysis and Deep Vein Thrombosis (DVT) Prophylaxis .........30 
3.1.5. 
Use of Other Analgesics ........................................................................................30 
3.1.6. 
Postoperative Assessments ....................................................................................30 
3.2. 
Study Endpoints ...........................................................................................................31 
3.2.1. 
Efficacy Endpoints .................................................................................................31 
3.2.1.1. 
Primary Efficacy Endpoint ..............................................................................31 
3.2.1.2. 
Secondary Efficacy Endpoints .........................................................................31 
3.2.2. 
Safety Endpoints ....................................................................................................32 
3.2.3. 
Pharmacokinetic Endpoints ...................................................................................32 
3.3. 
Study Duration .............................................................................................................32 
4. 
STUDY ENROLLMENT AND WITHDRAWAL ........................................................33 
4.1. 
Study Population ..........................................................................................................33 
4.1.1. 
Inclusion Criteria ...................................................................................................33 


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4.1.2. 
Exclusion Criteria ..................................................................................................33 
4.2. 
Method of Assigning Subjects to Treatment Groups ...................................................35 
4.2.1. 
Procedures for Handling Randomized Subjects Who Do Not Meet the Study 
Eligibility Criteria ..................................................................................................35 
4.3. 
Blinding........................................................................................................................35 
4.3.1. 
Breaking the Blind .................................................................................................36 
4.4. 
Subject Withdrawal and Replacement .........................................................................36 
4.4.1. 
Subject Withdrawal ................................................................................................36 
4.4.2. 
Subject Replacement ..............................................................................................37 
5. 
STUDY TREATMENT .................................................................................................38 
5.1. 
Description of Investigational Product ........................................................................38 
5.2. 
Manufacturing, Packaging, and Labeling ....................................................................38 
5.3. 
Storage .........................................................................................................................38 
5.4. 
Preparation ...................................................................................................................38 
5.5. 
Study Drug Administration ..........................................................................................38 
5.5.1. 
Study Drug Administration in Cohort 1 ................................................................38 
5.5.1.1. 
HTX-011 ..........................................................................................................39 
5.5.1.2. 
Bupivacaine HCl and Saline Placebo ..............................................................43 
5.5.2. 
Study Drug Administration in Cohort 2 ................................................................45 
5.5.2.1. 
HTX-011 Without Ropivacaine .......................................................................45 
5.5.2.2. 
HTX-011 With Ropivacaine ............................................................................47 
5.5.2.3. 
Bupivacaine HCl and Saline Placebo ..............................................................47 
5.6. 
Study Drug Compliance ...............................................................................................49 
5.7. 
Study Drug Accountability ..........................................................................................49 
6. 
STUDY PROCEDURES AND ASSESSMENTS .........................................................50 
6.1. 
Medical History and Demographics ............................................................................50 
6.1.1. 
Medical History .....................................................................................................50 
6.1.2. 
Demographics ........................................................................................................50 
6.2. 
Prior and Concomitant Therapy ...................................................................................50 
6.3. 
Efficacy Assessments...................................................................................................50 
6.3.1. 
Pain Intensity Assessment......................................................................................50 


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6.3.2. 
Use of Opioid Rescue Medications ........................................................................51 
6.3.2.1. 
Subject Daily Diary..........................................................................................51 
6.3.3. 
Patient Global Assessment of Pain Control ...........................................................51 
6.3.4. 
Rehabilitation and Ambulation ..............................................................................51 
6.3.5. 
Discharge Readiness ..............................................................................................51 
6.3.6. 
Satisfaction With Postoperative Pain Control ........................................................51 
6.3.7. 
Overall Benefit of Analgesia Assessment..............................................................52 
6.4. 
Safety Assessments ......................................................................................................52 
6.4.1. 
Adverse Events ......................................................................................................52 
6.4.2. 
Local Anesthetic Systemic Toxicity Assessment ..................................................52 
6.4.3. 
Physical Examinations ...........................................................................................52 
6.4.4. 
Vital Signs ..............................................................................................................52 
6.4.5. 
12-Lead Electrocardiograms and Holter Monitoring .............................................53 
6.4.6. 
Wound Healing Assessment ..................................................................................53 
6.4.7. 
Motor Function Assessment ..................................................................................53 
6.4.8. 
Clinical Laboratory Tests .......................................................................................53 
6.5. 
Pharmacokinetic Assessments .....................................................................................54 
7. 
TIMING OF PROCEDURES AND ASSESSMENTS ..................................................55 
7.1. 
Screening Period ..........................................................................................................55 
7.2. 
Treatment and Postoperative Observation Period........................................................56 
7.2.1. 
Day of Surgery (Day 0)..........................................................................................56 
7.2.1.1. 
Prior to Surgery ................................................................................................56 
7.2.1.2. 
Surgery and Study Drug Administration .........................................................56 
7.2.2. 
Postoperative Assessment Period (Up to 72 Hours) ..............................................57 
7.2.3. 
End of the Postoperative Assessment Period .........................................................58 
7.3. 
Follow-Up Period.........................................................................................................59 
7.3.1. 
Day 10 Visit (±2 Days) ..........................................................................................59 
7.3.2. 
Day 28 Visit (±4 Days) ..........................................................................................59 
7.4. 
Early Termination Visit ...............................................................................................59 
7.5. 
Unscheduled Visits and Assessments ..........................................................................60 
8. 
SAFETY MONITORING AND REPORTING .............................................................61 
8.1. 
Definition of Safety Parameters ...................................................................................61 
8.1.1. 
Definition of an Adverse Event .............................................................................61 


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8.1.2. 
Definition of a Serious Adverse Event ..................................................................62 
8.1.3. 
Definition of a Suspected Adverse Reaction .........................................................63 
8.1.4. 
Definition of a Serious Suspected Adverse Reaction ............................................63 
8.1.5. 
Definition of Unanticipated Problems ...................................................................63 
8.2. 
Classification of Adverse Events .................................................................................63 
8.2.1. 
Severity of Adverse Events ....................................................................................63 
8.2.2. 
Relationship to Study Drug ....................................................................................63 
8.3. 
Time Period and Frequency for Event Assessment and Follow Up ............................64 
8.3.1. 
Adverse Event and Serious Adverse Event Monitoring ........................................64 
8.3.2. 
Follow-Up of Events ..............................................................................................64 
8.4. 
Reporting Procedures ...................................................................................................65 
8.4.1. 
Reporting Serious Adverse Events to the Sponsor ................................................65 
8.4.2. 
Reporting Unanticipated Problems to the Sponsor ................................................66 
8.4.3. 
Regulatory Reporting Requirements ......................................................................66 
8.4.4. 
Pregnancy Reporting ..............................................................................................67 
8.5. 
Safety Oversight...........................................................................................................67 
9. 
STUDY RESTRICTIONS .............................................................................................68 
9.1. 
Prohibited Medications ................................................................................................68 
9.2. 
Contraception ...............................................................................................................68 
9.3. 
Prohibited Treatment ...................................................................................................68 
10. 
STATISTICAL CONSIDERATIONS ...........................................................................69 
10.1. General Considerations ................................................................................................69 
10.2. Determination of Sample Size .....................................................................................69 
10.3. Analysis Populations ....................................................................................................69 
10.4. Statistical Analysis Methods ........................................................................................69 
10.4.1. 
Disposition and Demographics ..............................................................................69 
10.4.2. 
Efficacy Analysis ...................................................................................................70 
10.4.2.1. 
Primary Efficacy Analysis ...............................................................................70 
10.4.2.2. 
Secondary Efficacy Analyses ..........................................................................70 
10.4.2.3. 
Handling of Missing Data ................................................................................71 
10.4.3. 
Safety Analysis ......................................................................................................71 
10.4.4. 
Pharmacokinetic Analysis ......................................................................................72 
10.5. Interim Analysis ...........................................................................................................72 


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11. 
QUALITY ASSURANCE AND QUALITY CONTROL .............................................73 
12. 
REGULATORY AND ETHICAL CONSIDERATIONS .............................................74 
12.1. Regulatory Authority Approval ...................................................................................74 
12.2. Ethical Conduct of the Study .......................................................................................74 
12.3. Ethics Committee Approval .........................................................................................74 
12.4. Informed Consent Process ...........................................................................................74 
12.5. Confidentiality .............................................................................................................75 
13. 
STUDY ADMINISTRATION .......................................................................................77 
13.1. Clinical Monitoring ......................................................................................................77 
13.2. Source Documents and Record Retention ...................................................................77 
13.3. Management of Protocol Amendments and Deviations ..............................................77 
13.3.1. 
Protocol Modification ............................................................................................77 
13.3.2. 
Protocol Violations and Deviations .......................................................................77 
13.4. Financial Disclosure.....................................................................................................78 
13.5. Stopping Criteria: Suspension or Termination of Study or Investigational Site .........78 
13.5.1. 
Suspension of Study ...............................................................................................78 
13.5.2. 
Termination of Study or Investigational Site .........................................................78 
13.6. Publication and Information Disclosure Policy ...........................................................79 
14. 
REFERENCE LIST ........................................................................................................80 


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LIST OF APPENDICES 
Appendix A: 
American Society of Anesthesiologists Physical Status 
Classification System ...........................................................................82 
Appendix B: 
Discharge Readiness Assessment – Modified Postanaesthetic 
Discharge Scoring System Criteria ......................................................83 
Appendix C: 
Wound Healing Assessment – Southampton Wound Scoring 
System ..................................................................................................84 
Appendix D: 
Pain Intensity Assessments Using the Numeric Rating Scale (NRS) ..85 
Appendix E: 
Patient Global Assessment (PGA) of Pain Control .............................86 
Appendix F: 
Overall Benefit of Analgesia Assessment............................................87 
 
LIST OF TABLES 
Table 1: 
Clinical Laboratory Tests .....................................................................54 
 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
AE 
Adverse event 
ANOVA 
Analysis of variance 
ASA 
Acetylsalicylic acid 
AUC 
Area under the curve  
BMI 
Body mass index 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
Cmax 
Maximum observed plasma concentration 
CONSORT 
Consolidated Standards of Reporting Trials 
COX-2 
Cyclooxygenase-2 
CPM 
Continuous passive motion 
CTM 
Clinical trial material 
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 
GPP 
Good Publication Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human immunodeficiency virus 
hr(s) 
Hour(s) 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
ICMJE 
International Committee of Medical Journal Editors 
IEC 
Independent Ethics Committee 
IP 
Investigational product  
IRB 
Institutional Review Board 
IRC 
Interim Review Committee 
ITT 
Intent-to-Treat  
IV 
Intravenous(ly)  


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LAST 
Local anesthetic systemic toxicity 
LOCF 
Last observation carried forward 
Min 
Minute  
mITT 
Modified Intent-to-Treat 
MPADSS 
Modified Postanaesthetic Discharge Scoring System 
NRS 
Numeric Rating Scale 
NRS-A 
NRS scores with activity  
NRS-R 
NRS scores at rest (in a dependent position) 
NSAID 
Nonsteroidal anti-inflammatory drug 
OBAS 
Overall benefit of analgesia score 
ORAE 
Opioid-related treatment-emergent adverse event 
PACU 
Postanesthesia care unit 
PGA 
Patient Global Assessment 
PK 
Pharmacokinetic(s) 
PMMA 
Polymethyl methacrylate 
PO 
By mouth, orally 
REB 
Research Ethics Board 
SAE 
Serious adverse event 
SAR 
Serious adverse reaction 
SC 
Subcutaneous  
SNRI 
Selective norepinephrine reuptake inhibitors 
SOP 
Standard Operating Procedures 
SSRI 
Selective serotonin reuptake inhibitors 
t1/2el 
Apparent terminal elimination half-life 
TEAE 
Treatment-emergent adverse event 
TKA 
Total knee arthroplasty 
Tmax 
Time to maximum plasma concentration 
TXA 
Tranexamic acid 
ULN 
Upper limit of normal 
US 
United States 
wWOCF 
Windowed worst observation carried forward 
λz 
Apparent terminal elimination rate constant 


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1. 
INTRODUCTION 
1.1. 
Background Information and Study Rationale 
It is estimated that up to 80% of patients suffer from moderate to severe pain during the first 
24 to 48 hours after surgery (Gan, 2014). Consequently, many are given narcotic analgesics for 
pain management. Administering a local anesthetic is a relatively simple and safe means of 
providing postoperative pain relief and promoting a quicker recovery; however, a major 
limitation of local anesthetics is their short duration of effect (6 to 12 hours following surgery) 
(Kehlet, 2011). The development of an extended-release local anesthetic that would provide pain 
relief during this critical postoperative timeframe and reduce the need for narcotics would be of 
clinical significance.  
Nonsteroidal anti-inflammatory drugs (NSAIDs) have long been used in the treatment of 
postoperative pain (Moote, 1992), and there is evidence that there may be a synergistic 
interaction between local anesthetics and NSAIDs when locally administered together (Ortiz, 
2011). 
Heron is developing HTX-011 for the management of postoperative pain. HTX-011 is an 
extended-release, fixed-ratio combination product that contains bupivacaine (a local anesthetic as 
the free base) and low-dose meloxicam (an NSAID) incorporated in a bioerodible polymer 
(termed Biochronomer). When HTX-011 is administered, the polymer undergoes controlled 
hydrolysis in the tissue resulting in the extended release of bupivacaine and meloxicam. The 
extended release is achieved using a proprietary vehicle formulation consisting of the novel 
tri[ethylene glycol]-based poly[orthoester] polymer (AP135) in combination with different 
excipients approved for human use (dimethyl sulfoxide, glycerol triacetate [triacetin], and maleic 
acid). 
This is a Phase 2b, randomized, double-blind, saline placebo- and active-controlled, multicenter 
study in subjects undergoing primary unilateral total knee arthroplasty (TKA) to evaluate the 
analgesic efficacy, safety, and pharmacokinetics (PK) of HTX-011 administered via infiltration 
to the surgical site. Cohort 1 will evaluate HTX-011 administered into the surgical site via 
different techniques compared with saline placebo and bupivacaine HCl to determine whether to 
proceed to Cohort 2. If a decision is made to proceed to Cohort 2, HTX-011 will be evaluated 
compared with saline placebo and bupivacaine HCl at the dose and administration technique 
recommended by an internal Interim Review Committee (IRC). 
1.2. 
Rationale for Study Design, Doses, and Control Groups 
TKA is an accepted model of postoperative pain. TKA produces generally reliable and persistent 
pain symptoms for a period typically lasting longer than 72 hours from the surgery, which allows 
for analysis of acute analgesia over an extended period of time. Nonclinical studies with 
HTX-011 demonstrated a lack of adverse effects on bone healing, supporting the appropriateness 
of TKA as a model for clinical evaluation. The compatibility of HTX-011 with polymethyl 
methacrylate (PMMA) bone cement was also studied (Simplex® HV with Gentamicin from 
Stryker and Palacos® R from Zimmer). A range of tests were performed on cylinders of both 
types of cement exposed to HTX-011 in vitro to determine the effect that HTX-011 had on cured 


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cement. Tests included compression testing, surface hardness, molecular weight determination 
by gel permeation chromatography, and identification and quantification of leachable 
components. Based on the results of this study, the mechanical properties of PMMA bone 
cement are not affected by HTX-011. The compressive strength, surface hardness, and molecular 
weight of PMMA bone cement were not changed by the presence of HTX-011. The only 
leachables observed were components from the bone cement known to leach into interstitial fluid 
in vivo. Consistent with published studies, these compounds were observed at 
microgram/milliliter concentrations; concentrations that are well below levels that would present 
a toxicity concern. Therefore, HTX-011 should not affect the mechanical properties of bone 
cement provided it is administered as described in Section 5.5, avoiding placement of the drug 
between the bone, the implant, and the cement where it could potentially interfere with the 
space-filling properties of the cement. 
Wound infiltration is an effective method of pain management in TKA, and the technique for 
administration is described and reviewed in multiple articles (Busch, 2006; Essving, 2010; Affas, 
2011; Surdam, 2015). In this study, HTX-011 will be administered via infiltration to the surgical 
site (eg, periarticular instillation, periarticular injection, or a combination of periarticular 
injection and instillation) to compare different administration techniques. In Cohort 2, HTX-011 
will be administered with or without ropivacaine. Bupivacaine HCl without epinephrine and 
saline placebo will be used as active control and placebo control, respectively, for efficacy and 
safety evaluations.  
Single doses of HTX-011 up to 400 mg/12 mg, inclusive (based on bupivacaine dose), will be 
evaluated in the study. Doses up to 600 mg/18 mg have been evaluated in previous HTX-011 
clinical studies. A Phase 1, saline placebo-controlled study evaluated single doses of 
100 mg/3 mg, 200 mg/6 mg, and 400 mg/12 mg of HTX-011 administered to healthy volunteers 
via subcutaneous (SC) injection. All doses were well tolerated, and therapeutically relevant 
plasma bupivacaine levels were sustained for 2 to 3 days in the absence of the large initial peak 
observed with commercially available formulations of the drug (bupivacaine HCl). The analgesic 
effects of HTX-011 persisted through 96 hours, which closely correlated with plasma 
bupivacaine concentrations. HTX-011 doses up to 600 mg/18 mg have also been administered in 
concluded and ongoing Phase 2 studies; current data show that they have been generally well 
tolerated. 
The 28-day duration of postoperative assessments is considered appropriate for determining the 
acute analgesic effect-time curve, safety, and PK profiles for HTX-011. 
One interim analysis is planned for Cohort 1. An internal IRC will review unblinded, 
summary-level efficacy, safety, and PK data from Cohort 1 to make study design decisions. The 
IRC will determine if enrollment should continue in Cohort 2. The IRC will also make decisions 
on the number of treatment groups, HTX-011 dose, study drug administration technique for 
HTX-011, and the number of subjects treated, as outlined in Section 3.1.2. The interim analysis 
will be performed after at least 80% of the planned number of subjects in Cohort 1 have all of 
their pain intensity and opioid use data through the 72-hour postoperative assessments entered 
into electronic clinical database. The choice of 72 hours was based on results from all HTX-011 
clinical studies to date, which showed that the time to maximum plasma concentration (Tmax) for 
bupivacaine is less than 24 hours. An interim analysis after the 72-hour assessments will 


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therefore include maximal exposure to study drug. There will be no interim analyses on data 
collected during Cohort 2. 
The study will employ a randomized and double-blind design to minimize potential bias in 
subject selection as well as efficacy and safety assessments. The site’s pharmacy staff and 
surgical staff will not be blinded to the treatment assignments because HTX-011 is a colored and 
viscous liquid whereas bupivacaine HCl and saline placebo are not, and the volume of study drug 
to be administered varies by treatment group. However, subjects will not be aware of the study 
drug they are receiving, and once surgery is complete and the subject is transferred to the 
postanesthesia care unit (PACU), the Investigator and all staff involved in efficacy and safety 
assessments will be blinded to treatment assignments until after database lock. 
As a postoperative pain study, the primary efficacy endpoint is the area under the curve (AUC) 
of Numeric Rating Scale (NRS) pain intensity scores with activity (NRS-A) from the start of 
study drug administration through 72 hours. Secondary efficacy endpoints will be assessed 
through 72 hours and beyond and include assessments of opioid use, including the time to first 
use of opioid rescue medication, as recommended by draft Food and Drug Administration (FDA) 
guidelines (FDA Draft Guidance for Industry, Analgesic Indications: Developing Drug and 
Biological Products [February 2014]). 
1.3. 
Potential Risks and Benefits 
As of the 23 October 2017, a total of 1,649 subjects have been treated in 9 completed, concluded, 
or ongoing studies in the HTX-011 clinical development program. This includes two Phase 1 
studies in healthy volunteers and six Phase 2 and one Phase 3 studies in subjects undergoing 
elective surgery (bunionectomy, herniorrhaphy, abdominoplasty, TKA, and augmentation 
mammoplasty). Three studies are ongoing and remain blinded (Studies 209, 211, and 302). An 
estimated 612 subjects have received a single dose of HTX-011 at doses ranging from 
30 mg/0.9 mg to 600 mg/18 mg. HTX-011 was administered via SC injection (10 subjects), local 
administration into the surgical site (an estimated 541 subjects), or nerve block (an estimated 
61 subjects). An additional 265 subjects received an earlier formulation: HTX-011-19 
(158 subjects) or HTX-011-49 (107 subjects). 
Study 102 was a Phase 1 study that evaluated a single dose of HTX-011 400 mg/12 mg 
administered via SC injection in 10 healthy volunteers. The most common treatment-emergent 
adverse events (TEAEs) were administration site reactions including bruising, pain, warmth, 
erythema, nodule, and swelling. Study 02 was a Phase 1 study that evaluated 2 earlier 
formulations, HTX-011-19 and HTX-011-49, in healthy volunteers. Subjects received a single 
SC dose of 1 of these formulations at doses ranging from 100 mg/3 mg to 400 mg/12 mg or 
saline placebo. The 2 most common TEAEs were contusion and erythema at the site of 
administration. All TEAEs in both Phase 1 studies were mild in severity and all resolved. No 
serious adverse events (SAEs) were reported in either study. 
HTX-011 has been evaluated in Phase 2a clinical studies in nonvisceral and visceral surgical 
models. In Phase 2a bunionectomy, herniorrhaphy, and abdominoplasty studies, subjects 
undergoing surgery received a single dose of HTX-011 ranging from 30 mg/0.9 mg to 
600 mg/18 mg. HTX-011 was administered via local administration into the surgical site 
(injection [with or without a Mayo block], instillation [with or without a Luer-lock applicator], or 


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a combination of injection and instillation). HTX-011 was generally well tolerated. The majority 
of TEAEs were mild or moderate in severity and resolved without sequelae. In these studies, the 
3 most common TEAEs in the HTX-011-treatment groups were nausea, vomiting, and headache 
for bunionectomy; constipation, nausea, and headache for herniorrhaphy; and nausea, 
constipation, and headache for abdominoplasty. Two serious adverse reactions (SARs; SAEs 
considered related to study drug by the Investigator and/or the Sponsor) were reported in subjects 
who received HTX-011. In the bunionectomy study, 1 SAR of non-healing postoperative wound 
was reported in a subject who received HTX-011 200 mg/6 mg. In the abdominoplasty study, 
1 SAR of wound dehiscence was reported in a subject who received HTX-011 300 mg/9 mg. 
 
 
 
 
 
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. 
Potential risks for bupivacaine include dose-related cardiovascular (CV) and central nervous 
system toxicity (MARCAINE USPI, 2011; MARCAIN SmPC, 2016). Close attention should be 
given to conditions that may represent reported toxicities associated with bupivacaine including, 
but not limited to, perioral tingling, metallic taste, visual and auditory disturbances, muscle 
twitching, seizure, acidosis, shortness of breath, bradycardia (heart rate <50 beats per minute 
with symptoms), hypotension (systolic blood pressure <90 mmHg or symptomatic decrease from 
baseline), low oxygen saturation (≤90% for ≥1 minute), and cardiac arrest. 
Potential risks for meloxicam include CV adverse reactions, gastrointestinal bleeding, and liver 
tests elevations (MOBIC SmPC, 2015; MOBIC Tablets USPI, 2016). NSAIDs may cause an 
increased risk of serious CV thrombotic events, myocardial infarction, and stroke, which can be 
fatal, and this risk may increase with duration of use. Patients with 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 bleeding, ulceration, and perforation of the stomach or intestines, 
which can be fatal. Elderly patients are at greater risk for serious gastrointestinal events. 
Borderline elevations of 1 or more liver tests may occur in patients taking NSAIDs, including 
meloxicam, which may worsen. A patient with symptoms and/or signs suggesting liver 
dysfunction, or in whom an abnormal liver function test has occurred, should be evaluated for 
evidence of the development of a more severe hepatic reaction. It is unclear how applicable these 
potential risks are for meloxicam when given as a single dose via local administration (a novel 
administration method for meloxicam) for postoperative pain as part of a fixed-ratio combination 
(eg, HTX-011). 
Potential risks for ropivacaine include dose related CV and central nervous system toxicity 
(Naropin USPI, 2012; Naropin SmPC, 2017). Close attention should be given to conditions that 
may represent reported toxicities associated with ropivacaine including, but not limited to, 
perioral tingling, metallic taste, visual and auditory disturbances, muscle twitching, seizure, 
acidosis, shortness of breath, bradycardia (heart rate <50 beats per minute with symptoms), 
hypotension (systolic blood pressure <90 mmHg or symptomatic decrease from baseline), low 


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oxygen saturation (≤90% for ≥1 minute), and cardiac arrest. Unintended intravascular 
administration may result in cardiac arrhythmia and cardiac arrest.  
Use of HTX-011 in subjects with hypersensitivity to bupivacaine, meloxicam, ropivacaine or any 
of the components of HTX-011 is contraindicated. 
As seen in the Phase 2a clinical studies, a single dose of HTX-011 given via local administration 
into the surgical site resulted in superior postoperative analgesia compared with bupivacaine HCl 
in all 3 studies, as indicated by significantly lower mean AUC of pain intensity scores. 
Furthermore, the analgesic effect with HTX-011 extended longer than 24 hours: over 72 hours in 
bunionectomy, over 48 hours in herniorrhaphy, and over 96 hours in complete abdominoplasty.  
The reduction in pain translated into an increase in the number of subjects who did not require 
opioids. In bunionectomy, 3 times the number of HTX-011 60 mg/1.8 mg-treated subjects were 
opioid free 24 hours following surgery compared with bupivacaine HCl (26.9% vs. 8.0%) and by 
72 hours, 17.3% of HTX-011 60 mg/1.8 mg -treated subjects remained opioid free. In 
herniorrhaphy, half (50%) of HTX-011 300 mg/9 mg-treated subjects were opioid free 72 hours 
following surgery compared with 11.8% for bupivacaine HCl. In both studies, all subjects who 
were opioid free in the first 48 hours remained opioid free through 96 hours. In addition to 
increasing the proportion of opioid-free subjects, HTX-011 reduced total opioid consumption. In 
bunionectomy, HTX-011 60 mg/1.8 mg significantly reduced total opioid consumption over 
72 hours compared with bupivacaine HCl (approximately 30% lower). Similar findings were 
noted in abdominoplasty. In herniorrhaphy, the median values for total opioid use were also 
notably lower over 72 hours for HTX-011 compared with bupivacaine HCl (2.5 mg vs. 15.0 mg). 
For more information on HTX-011, refer to the HTX-011 Investigator’s Brochure (IB). For more 
information on the active pharmaceutical ingredients, bupivacaine and meloxicam, refer to the 
local product labels. 


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2. 
STUDY OBJECTIVES 
2.1. 
Primary Objective 
The primary objective is to compare the efficacy and duration of analgesia achieved following 
periarticular infiltration of HTX-011 with that of saline placebo in subjects undergoing unilateral 
TKA. 
2.2. 
Secondary Objectives 
The secondary objectives are as follows: 
 
To compare the efficacy and duration of analgesia for HTX-011 with that of bupivacaine HCl 
without epinephrine in this study population. 
 
To evaluate additional efficacy parameters, including opioid load, in this study population. 
 
To evaluate the efficacy and duration of analgesia for HTX-011 administered using different 
techniques in this study population. 
 
To characterize the bupivacaine and meloxicam PK profiles following administration of 
HTX-011 in this study population. 
 
To assess the safety and tolerability of HTX-011 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 2b, randomized, double-blind, saline placebo- and active-controlled, multicenter 
study to evaluate the analgesic efficacy, safety, and PK of HTX-011 administered via infiltration 
to the surgical site in subjects undergoing primary unilateral TKA. 
All subjects will be screened within 21 days prior to surgery. Subjects who meet the Screening 
eligibility criteria will be randomized. Randomization may be done up to 1 business day prior to 
the day of surgery. On the day of surgery (Day 0), subjects who continue to meet the eligibility 
criteria will continue on study and will undergo primary unilateral TKA under general 
anesthesia.  
Just before being taken to the operating room prior to the start of the surgery, subjects in Cohort 
2 will be administered pregabalin orally (PO; 150 mg) and acetaminophen intravenously (IV; no 
more than 1 g [1000 mg] in a 6-hour window, as per the approved prescribing information) to 
reduce initial postoperative pain. Although not indicated for postoperative pain (Lyrica USPI, 
2009), pregabalin is used in clinical studies as multimodal perioperative analgesia (Buvanendran, 
2010; Li, 2017). Pregabalin was included in a Phase 4 study PILAR of EXPAREL in patients 
undergoing TKA (Mont, 2017). For this use, pregabalin is administered PO before surgery at 
dose levels up to 300 mg. 
A single dose of study drug (HTX-011 with or without ropivacaine, bupivacaine HCl without 
epinephrine, or saline placebo) will be administered intraoperatively by infiltration to the 
surgical site (eg, periarticular instillation, periarticular injection, or a combination of periarticular 
injection and instillation) as described in Section 5.5. Specifically in Cohort 2, HTX-011 will be 
administered via periarticular instillation with or without ropivacaine via periarticular injection. 
During surgery, the use of fentanyl up to 4 μg/kg will be permitted for intraoperative pain 
control. Just prior to the end of the surgery, all subjects will receive an additional 75 µg of 
fentanyl IV to minimize the variability of the impact of fentanyl on postoperative care (for 
example, the maximum amount of fentanyl used during surgery for a 70 kg subject should not 
exceed 355 µg [4 μg/kg × 70 kg = 280 μg for intraoperative pain control + 75 μg at the end of the 
case = 355 μg total]). Following surgery and immediate postoperative recovery, subjects will be 
transferred to the PACU. Subjects will remain in the hospital/research facility for a minimum of 
72 hours after study drug administration to undergo postoperative assessments. The study staff 
will ensure adequate safety precautions are in place to prevent postoperative falls. After the 
72-hour assessments have been completed, subjects may be discharged. Subjects will return to 
the study site on Day 10 and Day 28 to complete follow-up assessments. 
An internal IRC will review unblinded, summary-level efficacy, safety, and PK data from 
Cohort 1 to determine if enrollment should be initiated in Cohort 2. The interim analysis will be 
performed after at least 80% of the planned number of subjects in Cohort 1 have all of their pain 
intensity and opioid use data through the 72-hour postoperative assessments entered into 


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electronic clinical database. The IRC will operate under a written, detailed IRC Charter. There 
will be no interim analyses on data collected during Cohort 2. 
3.1.2. 
Treatment Groups 
The study will include 2 cohorts. 
Cohort 1 
Approximately 60 subjects will be randomized to 1 of the following 4 treatment groups in a 
2:2:1:1 ratio: 
 
HTX-011 200 mg/6 mg (6.8 mL) via periarticular instillation into the surgical site 
(20 subjects) 
 
HTX-011 200 mg/6 mg (6.8 mL) via a combination of periarticular injection and instillation 
into the surgical site (20 subjects) 
 
Saline placebo (6.8 mL) via periarticular injection into the surgical site (10 subjects) 
 
Bupivacaine HCl without epinephrine 0.25% (125 mg, 50 mL) via periarticular injection into 
the surgical site (10 subjects) 
Cohort 2 
Cohort 2 was planned as an optional cohort. Following a review of the results from Cohort 1, the 
IRC recommended initiating enrollment in Cohort 2 with a single dose level of HTX-011 
400 mg/12 mg (bupivacaine/meloxicam doses; 13.7 mL) in each HTX-011 treatment group.  
Approximately 200 subjects will be randomized to 1 of the following 4 treatment groups in a 
1:1:1:1 ratio:  
 
HTX-011 400 mg/12 mg (13.7 mL) via periarticular instillation into the surgical site 
(50 subjects) 
 
HTX-011 400 mg/12 mg (13.7 mL) via periarticular instillation into the surgical site and 
ropivacaine 0.5% (50 mg, 10 mL) via periarticular injection into the surgical site (posterior 
capsule) (50 subjects) 
 
Saline placebo (13.7 mL) via periarticular injection into the surgical site (50 subjects) 
 
Bupivacaine HCl without epinephrine 0.25% (125 mg, 50 mL) via periarticular injection into 
the surgical site (50 subjects) 
3.1.3. 
Postoperative Opioid Rescue Medications 
Subjects should only receive rescue medication upon request for pain control, as needed, during 
the 72-hour postoperative observation period. Rescue medication should not be given for pain 
prophylaxis, but only for pain treatment. 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 a 
Numeric Rating Scale score at rest (NRS-R) followed by a Numeric Rating Scale score with 
activity (NRS-A) pain score must be obtained. 


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Postoperative rescue medication will consist of IV morphine and/or PO immediate-release 
oxycodone. For the first 2 hours in the PACU, the subject may receive up to 15 mg IV morphine, 
as needed. Thereafter, the subject may receive up to 10 mg in a 2-hour period, as needed. In 
addition, the subject may also receive up to 10 mg of PO immediate-release oxycodone within 
any 4-hour period as needed, from after study drug administration through 72 hours. No other 
analgesic agents are permitted during the 72-hour postoperative observation period (except as 
specified by the protocol; see Section 3.1.5).  
After 72 hours, the analgesic regimen may be adjusted for each subject individually as deemed 
appropriate by the physician responsible for the postoperative care and in accordance with the 
verbal discharge instructions. See the Study Reference Manual for more information on 
postoperative pain management after discharge. Subjects will complete a daily diary to record if 
they take an opioid medication between 72 hours and Day 28. 
3.1.4. 
Required Antifibrinolysis and Deep Vein Thrombosis (DVT) Prophylaxis 
All subjects are required to tranexamic acid (TXA) and acetylsalicylic acid (ASA) during the 
study. TXA 1 g IV will be administered prior to the start of surgery and a second dose will be 
administered up to approximately 8 hours later. For the time period after study drug 
administration until hospital discharge, subjects should receive ASA 325 mg PO twice a day; 
surgeons may also use additional DVT prophylaxis as per their standard of care. 
3.1.5. 
Use of Other Analgesics 
With the exception of preoperative administration of pregabalin and acetaminophen (in Cohort 2 
only), intraoperative administration of study drug (including ropivacaine in 1 arm in Cohort 2) 
and fentanyl, protocol-specified opioid rescue medications, and ASA for DVT prophylaxis, no 
other analgesic agents, including ketamine and NSAIDs, are permitted from the time the subject 
signs the informed consent form (ICF) through 72 hours after study drug administration, except 
under the following circumstances: to treat an adverse event (AE), for pretreatment prior to 
needle placement, or to decrease venous irritation caused by propofol (in which case, no more 
than a single administration of lidocaine 1% 20 mg IV may be administered). Nerve block may 
also not be used as a form of analgesia on Day 0 and for at least 72 hours after study drug 
administration. 
3.1.6. 
Postoperative Assessments 
Efficacy assessments will include pain intensity scores using the NRS-R (either seated 
comfortably or lying down) and the NRS-A (straight leg raise of the surgical leg while the 
subject is lying down or seated in a recliner [recumbent]); use of opioid recue medication; 
Patient Global Assessment (PGA) of pain control; assessments of rehabilitation, ambulation, and 
discharge readiness; the subject’s satisfaction with postoperative pain control; and the subject’s 
assessment of overall benefit of analgesia. 
Safety assessments will include AE recording, physical examinations, vital signs, 
electrocardiograms (ECGs), motor function assessments (timed 20-meter walk test), hematology 
and serum chemistry, and wound healing assessments. Holter monitoring will also be assessed. 


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PK assessments will include the collection of blood samples to evaluate the bupivacaine PK 
profile for HTX-011 and bupivacaine HCl, and the meloxicam PK profile for HTX-011. 
See Section 6 for more information on the study procedures and assessments. For the timing of 
procedures and assessments, see Section 7 and the SCHEDULE OF EVENTS table. 
3.2. 
Study Endpoints 
3.2.1. 
Efficacy Endpoints 
3.2.1.1. 
Primary Efficacy Endpoint 
 
Mean AUC of the NRS-R pain intensity scores through 48 hours (AUC0-48).  
3.2.1.2. 
Key Secondary Endpoint 
 
Mean AUC of the NRS-R pain intensity scores through 72 hours (AUC0-72) 
 
 
The secondary efficacy endpoints are as follows: 
 
Mean total postoperative opioid consumption (in morphine equivalents) through 24, 48, and 
72 hours. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  


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3.2.2. 
Safety Endpoints 
 
Incidence of TEAEs, SAEs, and opioid-related TEAEs (ORAEs) through Day 28. 
 
Change from baseline in clinical laboratory results. 
 
Change from baseline in Holter data. 
 
Change from baseline in vital signs at each assessed timepoint. 
 
Wound healing assessment at 72 hours and on Day 10 and Day 28. 
 
Proportion of subjects able to complete a timed 20-meter walk test unassisted at 6, 12, 24, 
48, and 72 hours and on Day 10. 
3.2.3. 
Pharmacokinetic Endpoints 
 
Maximum observed plasma concentration (Cmax). 
 
AUC from Time 0 to the last collection time after study drug administration (AUC0-last). 
 
AUC from Time 0 extrapolated to infinity (AUC0-∞). 
 
Time to maximum plasma concentration (Tmax). 
 
Apparent terminal elimination rate constant (λz). 
 
Apparent terminal elimination half-life (t1/2el). 
3.3. 
Study Duration 
The overall duration of the study is anticipated to be approximately 18 months. The total 
duration of study participation for each subject (from Screening through the Day 28 Visit) will 
be up to 54 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 
Up to approximately 260 subjects may be randomized in this study in up to approximately 
30 study sites in the United States (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, adhere to the study visit schedule, and 
complete all study assessments. 
2. Is male or female, and ≥18 years of age at screening. 
3. Is scheduled to undergo primary unilateral TKA under general anesthesia. 
4. Has not previously undergone TKA in either knee. 
5. Has an American Society of Anesthesiologists Physical Status of I, II, or III. 
6. Is able to demonstrate motor function by performing a timed 20-meter walk unassisted, 
but with the optional use of a 4-legged walker for balance. 
7. Female subjects are eligible only if all of the following apply: 
a. Not pregnant (female subject of child-bearing potential must have a negative urine 
pregnancy test at screening and on Day 0 before surgery). 
b. Not lactating. 
c. Not planning to become pregnant during the study. 
d. Surgically sterile; or at least 2 years post-menopausal; or have a monogamous partner 
who is surgically sterile; or is practicing double-barrier contraception; or practicing 
abstinence (must agree to use double-barrier contraception in the event of sexual 
activity); or using an insertable, injectable, transdermal, or combination oral 
contraceptive approved by the US FDA for greater than 2 months prior to screening 
and commits to the use of an acceptable form of birth control for the duration of the 
study and for 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 with any of the following criteria will be excluded from the study: 
1. Has a planned concurrent surgical procedure (eg, bilateral TKA). 
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 to bupivacaine and ropivacaine (or other local 
anesthetics), meloxicam (or other NSAIDs), oxycodone, morphine, TXA, fentanyl, 
pregabalin, acetaminophen, or ASA. 


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4. Has known or suspected daily use of opioids for 7 or more consecutive days within the 
previous 6 months. 
5. Has taken NSAIDs (including meloxicam) within at least 10 days prior to surgery with 
the exception of subjects on low-dose (<100 mg) daily acetylsalicylic acid for 
cardioprotection. 
6. Has taken long-acting opioids within 3 days prior to surgery. 
7. Has taken any opioids within 24 hours prior to the scheduled surgery. 
8. Has been administered bupivacaine within 5 days prior to the scheduled surgery. 
9. 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 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). 
10. 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 cyclooxygenase-2 (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. 
11. 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 steroids are not considered systemic. 
12. 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 informed consent, 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 of signing the ICF. 
c. History of 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. History of severe kidney function impairment as defined by creatinine clearance 
(Cockcroft-Gault) <30 mL/min, being on dialysis, and/or having a serum creatinine 
>2 × ULN. 
e. History of known or suspected coagulopathy or uncontrolled anticoagulation. 
f. Loss of sensation in extremities or significant peripheral neuropathy. 
13. As per subject history and/or medical records, has active infection or is currently 
undergoing treatment for Hepatitis B, Hepatitis C, or human immunodeficiency virus 
(HIV). 
14. Has uncontrolled anxiety, psychiatric, or neurological disorder that, in the opinion of the 
Investigator, might interfere with study assessments. 


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15. Has any chronic neuromuscular deficit of either femoral nerve function or thigh 
musculature. 
16. Has any chronic condition or disease that would compromise neurological or vascular 
assessments. 
17. 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. 
18. Has a known or suspected history of drug abuse, a positive drug screen on the day of 
surgery, or a recent history of alcohol abuse. 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 taking medical marijuana are not allowed to participate in the study. 
19. Previously participated in an HTX-011 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 surgery, or is planning to take part in another clinical trial while 
participating in this study. 
20. Has undergone 3 or more surgeries in 12 months prior to signing the ICF, other than for 
diagnostic procedures (eg, colonoscopy). 
21. Has a body mass index (BMI) >39 kg/m2. 
4.2. 
Method of Assigning Subjects to Treatment Groups 
Subjects who meet the Screening eligibility criteria will be randomized. Randomization may be 
done up to 1 business day prior to the day of surgery. Subjects will be randomized using a 
computer-generated randomization scheme. All randomization information will be kept in a 
secure location accessible only by the randomization personnel, the assigned Pharmacist(s) and 
his/her verifier, and the unblinded clinical monitor. No subject may receive study drug prior to 
randomization. 
4.2.1. 
Procedures for Handling Randomized 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. 
Subjects who meet the Screening eligibility criteria and are randomized but who do not meet the 
eligibility criteria on Day 0 will be withdrawn from the study without receiving study drug. In 
the event a subject does not meet the eligibility criteria, but is randomized and 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 
The study will use a double-blind design. The site’s pharmacy and surgical staff will not be 
blinded to the treatment assignments because HTX-011 is a colored and viscous liquid whereas 
bupivacaine HCl and saline placebo are not, and the volume of study drug to be administered 
varies by treatment group. However, subjects will not be aware of the study drug they are 


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receiving, and once surgery is completed and the subject is transferred to the PACU, the 
Investigator and all site staff involved in safety and efficacy assessments will be blinded to the 
treatment assignment until after database lock. The Sponsor’s study team will also be blinded to 
the treatment assignments with the exception of the clinical trial material (CTM) staff, Clinical 
Research Specialists (observers in surgery), the bioanalytical staff, Population PK modeling 
staff, and the unblinded statistician who will perform the randomization and interim analysis data 
review, but will otherwise be uninvolved in the conduct of the study. 
An internal IRC will be unblinded during the interim review of the summary-level efficacy, 
safety, and PK data from Cohort 1. 
4.3.1. 
Breaking the Blind 
The study blind should not be broken except in medical emergencies when the appropriate 
management of the subject requires knowledge of the study drug he/she received. An attempt 
should be made to contact the Sponsor before breaking the blind. If the Sponsor cannot be 
reached and the blind is broken by the Investigator, the reason for unblinding must be 
documented and the Sponsor must be contacted within 24 hours.  
The Sponsor retains the right to break the treatment code for SAEs that are unexpected and are 
suspected to be causally related to an investigational product (IP) and that potentially require 
expedited reporting to regulatory authorities. 
All circumstances leading to the premature unblinding must be clearly documented. 
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: 
 
Adverse event  
 
Consent withdrawal 
 
Death 
 
Lost to follow up 
 
Investigator’s decision 
 
Sponsor’s decision 
 
Screen fail on Day 0 
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 (see Section 7.4). 


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4.4.2. 
Subject Replacement 
Any subject who is randomized 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 primary 
unilateral TKA. Study drug is defined as HTX-011 (IP) with or without ropivacaine, bupivacaine 
HCl without epinephrine (active control), or saline placebo (control).  
HTX-011 will be supplied by the Sponsor. Bupivacaine HCl, ropivacaine 0.5%, and saline 
placebo will be supplied by study sites.  
5.1. 
Description of Investigational Product 
HTX-011 is a slightly yellow, viscous, semi-solid gel liquid. HTX-011 is supplied in prefilled 
sterile syringes and/or vials. The prefilled syringes and vials serve only as a closed container for 
the drug product. For administration of study drug, the formulation in the prefilled syringes 
and/or vials will be aseptically transferred to sterile syringes. 
5.2. 
Manufacturing, Packaging, and Labeling 
HTX-011 will be manufactured according to Good Manufacturing Practices, and packaged and 
labeled by the Sponsor or designee. HTX-011 will be packed and dispatched to comply with 
shipping and storage conditions. HTX-011 labeling will comply with all applicable federal and 
local laws and regulations. 
5.3. 
Storage 
HTX-011 should be stored at the study site in a refrigerator at 2ºC to 8ºC. The refrigerator should 
be in a locked area with restricted access. A temperature log should be maintained to monitor the 
refrigerator’s temperature. 
Saline placebo, ropivacaine, and bupivacaine HCl will be stored as per the prescribing 
information. 
5.4. 
Preparation 
Study drug will be prepared at the study site by an unblinded study pharmacist or staff. Refer to 
the Pharmacy Manual for details on study drug preparation. 
5.5. 
Study Drug Administration 
5.5.1. 
Study Drug Administration in Cohort 1 
This section describes the administration technique of study drug in Cohort 1: HTX-011, 
bupivacaine HCl, and saline placebo. 
HTX-011 will be administered via one of the following techniques to the surgical wound: 
 
Periarticular instillation 
 
Periarticular injection 


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 
Combination (both periarticular injection and instillation) 
Bupivacaine HCl and saline placebo will be administered by periarticular injection only. 
However, note the following difference in volume: 
 
The volume of bupivacaine HCl (0.25% without epinephrine) is 50 mL 
 
The volume of saline placebo will vary depending on the cohort 
5.5.1.1. 
HTX-011 
5.5.1.1.1. 
Periarticular Instillation 
The total volume of HTX-011 is to be administered intraoperatively. It is important to be 
cautious because the total volume of HTX-011 is lower than the usual volume of bupivacaine 
HCl. For example, in Cohort 1, the total volume of HTX-011 is only 6.8 mL. 
Instillation is the direct topical coating of the periosteum and joint capsule with HTX-011. This 
will be done using syringes with a Luer-lock applicator (without a needle). To avoid study drug 
interference with the properties of polymethylmethacrylate bone cement, care should be taken to 
avoid contact between study drug and the cement. 
HTX-011 will be instilled as follows: half (½) the volume onto the posterior capsule, a quarter 
(¼) to the anteromedial tissues and periosteum, and a quarter (¼) to the anterolateral tissues and 
periosteum. Study drug should be prepared in 4 syringes, each containing equal volumes of study 
drug. 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. 
1. Posterior Capsular Administration 
a. Drug instillation to the posterior capsule is performed after cementation of the 
components and placement of the tibial tray/spacer. It is expected that irrigation and 
suction will be complete before study drug administration. The surgeon may utilize 
pulsatile lavage and irrigate as desired after cementation and placement of all 
components, but not after instillation of the study drug. 
b. The posterior capsular instillation will take place in 3 areas: the posterior medial 
capsule, the posterior lateral capsule and the central posterior capsule. For ideal 
posterior capsular placement, it is recommended the knee be placed at approximately 
90 degrees of flexion. An assistant may also gently translate the tibia forward a few 
millimeters if needed to better access the central posterior capsule and/or retract the 
relevant capsular tissues as needed.  
c. The first syringe with the Luer-lock applicator is inserted full-length behind the 
medial condyle, between the condyle and the medial capsule to reach the posterior 
capsule as far proximal and as deep as possible (flexion, slight forward translation, 
and retraction all help to attain this goal). Instill the first half of the syringe with the 
Luer-lock applicator in this area. 


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d. The remainder of study drug from the first syringe with the Luer-lock applicator is 
inserted full-length behind the lateral condyle between the condyle and the lateral 
capsule to reach the posterior capsule as far proximal and as deep as possible (again 
flexion, slight forward translation, and retraction all help attain this goal). The 
Luer-lock applicator may be placed either above or below the popliteus tendon to 
reach the posterior capsule. 
e. The second syringe is placed into the intracondylar notch, and study drug 
administered directly on to the central posterior capsule. Again, having the knee in 
flexion in slight forward translation and with appropriate retraction may help to 
visualize the area.   
i. If a cruciate retaining system is utilized, the syringe with Luer-lock applicator 
is placed full-length into the medial aspect of the femoral component notch (as 
far proximal and as deep as possible) and half the drug instilled at a 
posteromedial angle. The syringe is then moved to the lateral aspect of the 
femoral component notch (maintaining its deep position) and the remainder of 
study drug is instilled at a posterolateral angle. These maneuvers allow drug to 
be instilled directly to coat the entirety of the central posterior capsular region. 
Gravity will draw study drug distally toward the tibia as the drug is instilled. 
ii. If a posterior-stabilized design is utilized, best visualization will likely be over 
the top of the tibial post, so the entire contents of the syringe should be 
instilled from that point (with the syringe and Luer-lock applicator inserted 
full-length at the proximal and deepest aspect of the central region of the 
capsule, directly coating the entirety of the central region by moving from 
medial to lateral). Gravity will draw study drug distally toward the tibia as the 
drug is instilled. 
f. The knee is then brought out into full extension and kept in that position for the 
remainder of the case. The surgeon may choose to massage the back of the knee 
briefly to help distribute the drug. 
2. Anteromedial tissues and periosteum: The third syringe and Luer-lock applicator is used to 
instill the medial gutter, periosteum, and capsule. Be sure to evenly distribute the study drug 
onto all these surfaces. Retraction and elevation of the medial capsule by an assistant to best 
visualize these areas will be helpful to ensure even coating. 
3. Anterolateral tissues, periosteum, and closure: The final syringe and Luer-lock applicator 
is similarly used to instill study drug onto the lateral capsule, periosteum, lateral gutter, fat 
pad, and quadriceps tendon, which should all be coated evenly. Again, elevation of the lateral 
capsule and quadriceps will help with visualization. Wound closure of the arthrotomy, fascia, 
and dermis may then take place per surgeon preference. 
5.5.1.1.2. 
Combination of Periarticular Injection and Instillation 
The total volume of HTX-011 is to be administered intraoperatively. 


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For this administration assignment, HTX-011 will be prepared in 2 groups of syringes: 1 group 
of syringes with an 18G needle for periarticular injection and the other group of syringes without 
a needle for instillation. For example, in Cohort 1 each of those groups contains 3.4 mL for a 
total of 6.8 mL. See Section 3.1.2 for the specific volume of HTX-011 to be administered for 
each cohort. 
Combination Administration: Injection Steps 
Injection of the posterior capsule should occur prior to cementation and placement of 
components to allow adequate visualization. 
Posterior Capsule 
One half of the total volume of injectate is placed in the posterior capsule.  
 
The HTX-011 injection will be performed just prior to mixing of cement and placement of 
components. At this point, it is expected that the menisci have been resected and the posterior 
aspect of the joint debrided as needed, taking care to avoid injury to posterior neurovascular 
structures. Typically, mixing of cement may begin during the injection process once 
experienced in the technique. Initially, the knee is placed at 90 degrees using the lamina 
spreader to distract the joint. This will facilitate visualization of the posterior capsule. 
 
Injection should be done evenly with 4 to 6 injection points. 
 
 
The appropriate technique should include the following: 
 Insertion of the needle by a few millimeters 
 Aspiration to ensure the needle is not intravascular (this is mandatory due to the potential 
of unintended intravascular administration), then 
 Injection of a small amount of HTX-011. NOTE: Unintended intravascular injection 
may cause life-threatening central nervous system and cardiac sequelae. 
Combination Administration: Instillation Steps 
Instillation of the remaining tissues should then take place at the end of the case, prior to closure 
but after irrigation and suction have been completed. 


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Periosteum Administration and Remaining Capsular Administration 
 
Instill the remaining volume using the syringe with a Luer-lock applicator to all exposed 
intra-articular soft tissues, including the following: 
 Periosteum of the femur and tibia 
 Medial and lateral gutters including periosteum and capsular tissue 
 Anterior joint capsule including patellofemoral capsule, peripatellar region and any 
remaining anterior fat pad and tendinous structures 
 
Wound closure of the arthrotomy, fascia, and dermis may now take place per surgeon 
preference. Avoid HTX-011 administration into the shallow subdermal area. 
5.5.1.1.3. 
Periarticular Injection 
The total volume of HTX-011 is to be administered intraoperatively. 
Injection of the posterior, medial, and lateral capsule should occur prior to cementation and 
placement of components to allow adequate visualization. 
Posterior Capsule 
One half of the total volume of injectate is placed in the posterior capsule.  
 
The HTX-011 injection will be performed just prior to mixing of cement and placement of 
components. At this point, it is expected that the menisci have been resected and the posterior 
aspect of the joint debrided as needed, taking care to avoid injury to posterior neurovascular 
structures. Typically, mixing of cement may begin during the injection process once 
experienced in the technique. Initially, the knee is placed at 90 degrees using the lamina 
spreader to distract the joint. This will facilitate visualization of the posterior capsule. 
 
Injection should be done evenly with 4 to 6 injection points. 
 
 
The appropriate technique should include: 
 Insertion of the needle by a few millimeters 
 Aspiration to ensure the needle is not intravascular (this is mandatory due to the potential 
of unintended intravascular administration), then 


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 Injection of a small amount of HTX-011. NOTE: Unintended intravascular injection 
may cause life-threatening central nervous system and cardiac sequelae. 
Medial and Lateral Capsule 
One half of the remaining volume is divided equally into the medial and lateral capsule. 
 
In similar fashion to posterior capsule injection, inject an equal volume medially and laterally 
with multiple injection points to evenly distribute HTX-011 throughout both capsular 
regions, and periosteum of the femur and tibia. 
Peripatellar Area and Dermal Tissue 
The remainder of the injections should occur at the end of the case, after all irrigation and suction 
have occurred. 
 
Peripatellar Area 
 The peripatellar area includes all anterior joint capsular tissues and patellofemoral 
capsule. 
 Using approximately 2/3 of the remaining volume, inject at multiple points to evenly 
distribute HTX-011 throughout the area, including the quadriceps and patellar tendons. 
 
Dermal Tissue 
 Before surgical wound closure, administer the remaining HTX-011 into the deep tissue 
on either side of the skin incision. Avoid administration into the shallow subdermal area. 
5.5.1.2. 
Bupivacaine HCl and Saline Placebo 
The total volume of study drug is to be administered intraoperatively via periarticular injection. 
It is important to be cautious because the total volume of saline placebo will vary and is lower 
than the usual volume of bupivacaine HCl. For example, in Cohort 1 the total volume for 
bupivacaine HCl is 50 mL while the total volume for saline placebo is only 6.8 mL.  
5.5.1.2.1. 
Periarticular Injection (Bupivacaine HCl 0.25% Without Epinephrine, or 
Saline Placebo) 
Bupivacaine HCl Injection (Total Volume = 50 mL) 
Injection should occur prior to cementation and placement of components to allow adequate 
visualization. 
Posterior Capsule 
 
The bupivacaine HCl injection will be performed just prior to mixing of cement and 
placement of components. At this point, it is expected that the menisci have been resected 
and the posterior aspect of the joint debrided as needed, taking care to avoid injury to 
posterior neurovascular structures. Typically, mixing of cement may begin during the 


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injection process once experienced in the technique. Initially, the knee is placed at 90 degrees 
using the lamina spreader to distract the joint. This will facilitate visualization of the 
posterior capsule.  
 
Approximately 25 mL will be injected into the posterior capsule. This should be done evenly 
with at least 10 to 15 injection points. 
 
 
The appropriate technique should include: 
 Insertion of the needle by a few millimeters 
 Aspiration to ensure the needle is not intravascular (this is mandatory due to the potential 
of unintended intravascular administration), then 
 Injection of a small amount of bupivacaine HCl. NOTE: unintended intravascular 
injection may cause life-threatening central nervous system and cardiac sequelae. 
Medial and Lateral Capsule 
 
In similar fashion to posterior capsule injection, inject 7 mL medially and 7 mL laterally with 
multiple injection points to evenly distribute bupivacaine HCl throughout both capsular 
regions, and periosteum of the femur and tibia. 
Peripatellar Area 
 
The peripatellar area includes all anterior joint capsular tissues and patellofemoral capsule. 
 
Inject 8 mL with multiple injection points to evenly distribute bupivacaine HCl throughout 
the area. 
Dermal Tissue 
 
Before surgical wound closure, administer the remaining bupivacaine HCl into the deep 
tissue on either side of the skin incision. Avoid administration into the shallow subdermal 
area. 
Saline Placebo Injection 
Saline placebo injection will be performed as described above for bupivacaine HCl injection 
with adjustments made for volume. The volume of saline placebo will vary in each cohort. For 
example, in Cohort 1 the total volume is 6.8 mL. 


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5.5.2. 
Study Drug Administration in Cohort 2 
This section describes the administration technique of study drug in Cohort 2: HTX-011, 
ropivacaine, bupivacaine HCl, and saline placebo. HTX-011 will be administered with or 
without ropivacaine. 
HTX-011 will be administered via periarticular instillation to the surgical wound. 
Bupivacaine HCl and saline placebo will be administered by periarticular injection only. 
However, note the following difference in volume: 
 
The volume of bupivacaine HCl (0.25% without epinephrine) is 50 mL 
 
The volume of saline placebo is 13.7 mL 
Ropivacaine 0.5% (50 mg; 10 mL) will be administered by injection to the posterior capsule 
only.  
5.5.2.1. 
HTX-011 Without Ropivacaine 
5.5.2.1.1. 
Periarticular Instillation 
The total volume of HTX-011 is to be administered intraoperatively. It is important to be 
cautious because the total volume of HTX-011 is lower than the volume of bupivacaine HCl. In 
Cohort 2, the total volume of HTX-011 is only 13.7 mL. 
Instillation is the direct topical coating of the periosteum and joint capsule with HTX-011. This 
will be done using syringes with a Luer-lock applicator (without a needle). To avoid study drug 
interference with the properties of polymethylmethacrylate bone cement, care should be taken to 
avoid contact between study drug and the cement. 
For instillation to the posterior capsule, HTX-011 100 mg/3 mg will be prepared in 2 syringes 
each containing equal volumes of study drug. For instillation to the anteromedial and 
anterolateral tissues and periosteum, HTX-011 300 mg/9 mg will be prepared in 4 syringes each 
containing equal volumes of study drug. 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. 
1. Posterior Capsular Administration 
a. Drug instillation to the posterior capsule is performed after cementation of the 
components and placement of the tibial tray/spacer. It is expected that irrigation and 
suction will be complete before study drug administration. The surgeon may utilize 
pulsatile lavage and irrigate as desired after cementation and placement of all 
components, but not after instillation of the study drug. 
b. The posterior capsular instillation will take place in 3 areas: the posterior medial 
capsule, the posterior lateral capsule and the central posterior capsule. For ideal 
posterior capsular placement, it is recommended the knee be placed at approximately 


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90 degrees of flexion. An assistant may also gently translate the tibia forward a few 
millimeters if needed to better access the central posterior capsule and/or retract the 
relevant capsular tissues as needed.  
c. The first syringe for instillation to posterior capsule with the Luer-lock applicator is 
inserted full-length behind the medial condyle, between the condyle and the medial 
capsule to reach the posterior capsule as far proximal and as deep as possible (flexion, 
slight forward translation, and retraction all help to attain this goal). Instill the first 
half of the syringe with the Luer-lock applicator in this area. 
d. The remainder of study drug from the first syringe with the Luer-lock applicator is 
inserted full-length behind the lateral condyle between the condyle and the lateral 
capsule to reach the posterior capsule as far proximal and as deep as possible (again 
flexion, slight forward translation, and retraction all help attain this goal). The 
Luer-lock applicator may be placed either above or below the popliteus tendon to 
reach the posterior capsule. 
e. The second syringe for instillation to posterior capsule is placed into the intracondylar 
notch, and study drug administered directly on to the central posterior capsule. Again, 
having the knee in flexion in slight forward translation and with appropriate retraction 
may help to visualize the area.   
i. If a cruciate retaining system is utilized, the syringe with Luer-lock applicator 
is placed full-length into the medial aspect of the femoral component notch (as 
far proximal and as deep as possible) and half the drug instilled at a 
posteromedial angle. The syringe is then moved to the lateral aspect of the 
femoral component notch (maintaining its deep position) and the remainder of 
study drug is instilled at a posterolateral angle. These maneuvers allow drug to 
be instilled directly to coat the entirety of the central posterior capsular region. 
Gravity will draw study drug distally toward the tibia as the drug is instilled. 
ii. If a posterior-stabilized design is utilized, best visualization will likely be over 
the top of the tibial post, so the entire contents of the syringe should be 
instilled from that point (with the syringe and Luer-lock applicator inserted 
full-length at the proximal and deepest aspect of the central region of the 
capsule, directly coating the entirety of the central region by moving from 
medial to lateral). Gravity will draw study drug distally toward the tibia as the 
drug is instilled. 
f. The knee is then brought out into full extension and kept in that position for the 
remainder of the case. The surgeon may choose to massage the back of the knee 
briefly to help distribute the drug. 
2. Anteromedial tissues and periosteum: The first 2 of the remaining 4 syringes and 
Luer-lock applicator are used to instill the medial gutter, periosteum, and capsule. Be sure to 
evenly distribute the study drug onto all these surfaces. Retraction and elevation of the 


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medial capsule by an assistant to best visualize these areas will be helpful to ensure even 
coating.  
3. Anterolateral tissues, periosteum, and closure: The final 2 of the remaining 4 syringes and 
Luer-lock applicator are similarly used to instill study drug onto the lateral capsule, 
periosteum, lateral gutter, fat pad, and quadriceps tendon, which should all be coated evenly. 
Again, elevation of the lateral capsule and quadriceps will help with visualization. Wound 
closure of the arthrotomy, fascia, and dermis may then take place per surgeon preference. 
5.5.2.2. 
HTX-011 With Ropivacaine 
5.5.2.2.1. 
Periarticular Instillation of HTX-011 
Periarticular instillation of HTX-011 is described in Section 5.5.2.1.1. 
5.5.2.2.2. 
Injection of Ropivacaine in the Posterior Capsule 
 
The ropivacaine injection will be performed just prior to mixing of cement and placement of 
components. At this point, it is expected that the menisci have been resected and the posterior 
aspect of the joint debrided as needed, taking care to avoid injury to posterior neurovascular 
structures. Typically, mixing of cement may begin during the injection process once 
experienced in the technique. Initially, the knee is placed at 90 degrees using the lamina 
spreader to distract the joint. This will facilitate visualization of the posterior capsule.  
 
Ropivacaine should be injected in posterior capsule evenly with at least 10 to 15 injection 
points. 
 
 
The appropriate technique should include: 
 Insertion of the needle by a few millimeters 
 Aspiration to ensure the needle is not intravascular (this is mandatory due to the potential 
of unintended intravascular administration), then 
 Injection of a small amount of ropivacaine. NOTE: unintended intravascular injection 
may cause life-threatening central nervous system and cardiac sequelae. 
5.5.2.3. 
Bupivacaine HCl and Saline Placebo 
The total volume of study drug is to be administered intraoperatively via periarticular injection. 
It is important to be cautious because the total volume of saline placebo is lower than the usual 


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volume of bupivacaine HCl. In Cohort 2, the total volume for bupivacaine HCl is 50 mL while 
the total volume for saline placebo is only 13.7 mL.  
5.5.2.3.1. 
Periarticular Injection of Bupivacaine HCl 0.25% Without Epinephrine 
(Total Volume = 50 mL) 
Injection should occur prior to cementation and placement of components to allow adequate 
visualization. 
Posterior Capsule 
 
The bupivacaine HCl injection will be performed just prior to mixing of cement and 
placement of components. At this point, it is expected that the menisci have been resected 
and the posterior aspect of the joint debrided as needed, taking care to avoid injury to 
posterior neurovascular structures. Typically, mixing of cement may begin during the 
injection process once experienced in the technique. Initially, the knee is placed at 90 degrees 
using the lamina spreader to distract the joint. This will facilitate visualization of the 
posterior capsule.  
 
Approximately 25 mL will be injected into the posterior capsule. This should be done evenly 
with at least 10 to 15 injection points. 
 
 
The appropriate technique should include: 
 Insertion of the needle by a few millimeters 
 Aspiration to ensure the needle is not intravascular (this is mandatory due to the potential 
of unintended intravascular administration), then 
 Injection of a small amount of bupivacaine HCl. NOTE: unintended intravascular 
injection may cause life-threatening central nervous system and cardiac sequelae. 
Medial and Lateral Capsule 
 
In similar fashion to posterior capsule injection, inject 7 mL medially and 7 mL laterally with 
multiple injection points to evenly distribute bupivacaine HCl throughout both capsular 
regions, and periosteum of the femur and tibia. 
Peripatellar Area 
 
The peripatellar area includes all anterior joint capsular tissues and patellofemoral capsule. 


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 
Inject 8 mL with multiple injection points to evenly distribute bupivacaine HCl throughout 
the area. 
Dermal Tissue 
 
Before surgical wound closure, administer the remaining bupivacaine HCl into the deep 
tissue on either side of the skin incision. Avoid administration into the shallow subdermal 
area. 
5.5.2.3.2. 
Periarticular Injection of Saline Placebo 
Saline placebo injection will be performed as above described for bupivacaine HCl injection 
with adjustments made for volume. In Cohort 2, the total volume is 13.7 mL. 
5.6. 
Study Drug Compliance 
All study drug must be administered in accordance with the treatment assignment. Because study 
drug is being administered as a component of the surgical procedure, a lack of treatment 
compliance is not expected.  
5.7. 
Study Drug Accountability 
The IP 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 IP to permit reconciliation of study drug. 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 IP (ie, accountability or 
dispensing logs). 
All study drug records must be readily available for inspection by the site’s unblinded clinical 
monitor and/or auditor. No IP can be returned to the Sponsor or designee or disposed of at the 
study site until the unblinded clinical monitor has verified the accuracy of the study drug records 
at the study site. All returns, disposal, or destruction must be approved by the Sponsor in writing. 


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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. See 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 before randomization 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 Day 28 will be recorded in the 
subject’s eCRF. The name, dose, and route, as well as the start date and time, of concomitant 
medications must be recorded during the 72-hour postoperative period. 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 must have a start date recorded; “prn” should not be recorded on the 
eCRF. IV fluids and oxygen during surgery do not need to be recorded unless being used to treat 
an AE. 
6.3. 
Efficacy Assessments 
6.3.1. 
Pain Intensity Assessment 
Subjects will be asked to evaluate their current pain level at scheduled timepoints after surgery. 
Subjects will receive training by the site on how to provide pain intensity assessments. 
Pain intensity scores will be assessed using an 11-point NRS (0–10) where 0 represents “no 
pain” and 10 represents “worst pain imaginable” (see Appendix D). NRS scores will be recorded 
first at rest (NRS-R; in a dependent position [either seated comfortably or lying down]) and then 
with activity (NRS-A) where the prescribed activity is a straight leg raise of the surgical leg 
while the subject is lying down or recumbent. Continuous passive motion (CPM) 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 (see Section 9.3). 


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If a subject withdraws from the study before 72 hours, NRS-R and NRS-A pain intensity scores 
will be recorded at the time of withdrawal. 
6.3.2. 
Use of Opioid Rescue Medications 
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 from Time 0 through 72 hours. For more 
information on opioid rescue medications permitted, see Section 3.1.3. 
6.3.2.1. 
Subject Daily Diary 
Subjects will be provided a diary to record if they took any opioid medication for their pain that 
day. Subjects will be required to record their use of opioids from 72 hours through Day 28. 
6.3.3. 
Patient Global Assessment of Pain Control 
Subjects will be asked to evaluate the performance of study drug as a pain treatment at different 
intervals using a 4-point rating scale where 0 represents “poor” and 3 represents “excellent” 
(Rothman, 2009). See Appendix E for the PGA scale. 
6.3.4. 
Rehabilitation and Ambulation 
Sites will assess the subject’s ability to participate in rehabilitation sessions according to the 
site’s standard rehabilitation protocol. 
Sites will also assess the subject’s ability to ambulate. Ambulation is defined as the ability to 
walk more than 3 steps with an assisted device. 
6.3.5. 
Discharge Readiness 
Discharge readiness will be assessed using the MPADSS criteria (Chung, 1995). Discharge 
readiness assessments will be repeated for subjects who remain hospitalized at 96 and 120 hours. 
Refer to Appendix B. 
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 on whether or not to 
discharge a subject from the study. Subjects are required to remain in the hospital/research 
facility for 72 hours. 
6.3.6. 
Satisfaction With Postoperative Pain Control 
The subject will be questioned about his or her satisfaction with postoperative pain control. The 
subject’s response to the following statement “I am satisfied with postoperative pain control” 
will be recorded using a 5-point Likert scale where 1 represents “strongly disagree” and 
5 represents “strongly agree.” 


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6.3.7. 
Overall Benefit of Analgesia Assessment 
The subject 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 F for the OBAS scale. 
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 Day 28. See Section 8 for details. 
6.4.2. 
Local Anesthetic Systemic Toxicity Assessment 
Subjects should be assessed on a regular basis to identify early neurologic and cardiac signs and 
symptoms that may be attributed to local anesthetic systemic toxicity (LAST; eg, 
metallic/strange taste, perioral tingling, ringing in ears, visual disturbance, tremors, muscle 
twitching, dizziness/lightheadedness, convulsion/seizure, bradycardia, arrhythmia, hypotension) 
(Vasques, 2015). Additional monitoring of subjects for safety should be performed as needed 
(eg, vital signs, unscheduled PK blood draw). 
Signs and symptoms that are clinically significant and may be attributed to LAST should be 
recorded as AEs. 
6.4.3. 
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, and calculation of BMI (BMI = weight [kg]/height 
[m2]) will be conducted. 
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. 
6.4.4. 
Vital Signs 
Vital signs will include systolic and diastolic blood pressure, resting heart rate, and respiration 
rate. Subjects should be in a supine position (includes sitting in a recliner chair) for at least 
5 minutes before taking vital signs. Clinically significant post-treatment vital sign results should 
be recorded as AEs. 


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6.4.5. 
12-Lead Electrocardiograms and Holter Monitoring 
A Screening ECG will be obtained for all subjects. Standard digital 12-lead ECG results will be 
recorded in triplicate. Subjects should be in the supine position (includes sitting in a recliner 
chair) for at least 5 minutes before each ECG recording. The mean of the 3 ECGs will be used as 
the baseline result. 
Continuous Holter monitoring will be performed. Subjects will be provided with a Holter 
monitor at the Screening Visit and will receive training on how to activate it. Subjects will be 
required to have a continuous reading at least 24 hours before surgery and will wear the monitor 
for 72 hours after the start of study drug administration. 
The ECG and Holter monitor results will be reviewed by a central reader and the information 
will be provided to the sites. Refer to the Cardiac Manual for instructions on collecting and 
transmitting results. Clinically significant findings after study drug administration will be 
recorded as TEAEs. 
If a Holter monitor safety alert is received after study drug administration, obtain vital sign 
measurements and collect an unscheduled blood sample for PK analysis to evaluate for LAST.  
6.4.6. 
Wound Healing Assessment 
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. The findings will be graded according to the Southampton Wound Scoring 
System (Bailey, 1992); see Appendix C. 
6.4.7. 
Motor Function Assessment 
Subjects will be assessed on their ability to perform a timed 20-meter walk unassisted, but with 
the optional use of a 4-legged walker for balance, in an unobstructed, dedicated corridor. The 
time it takes the subject to complete the walk test will also be recorded. The subject should be 
accompanied during the walk test to ensure patient safety and to assist in preventing any falls. 
6.4.8. 
Clinical Laboratory Tests 
Blood and urine samples will be collected for diagnostic screening tests and for safety laboratory 
tests (hematology and serum chemistry). See Table 1 for a list of clinical laboratory tests and 
parameters. Urine samples will be tested by local laboratories. Blood samples will be tested by a 
central laboratory. 
Laboratory results will be reviewed by the Investigator. Any laboratory values outside of the 
normal reference range will be evaluated for clinical significance. Clinically significant findings 
after study drug administration will be recorded as AEs. 
Refer to the Laboratory Manual for detailed instructions on sample collection, processing, and 
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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. See Section 6 for information on study procedures and assessments. 
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 
Applicable.” Assessments that can be done without waking the subject (eg, blood collection for 
PK sample) 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: 
 
NRS-R pain intensity assessment (assessed in a dependent position, either seated comfortably 
or lying down) 
 
PGA of pain control 
 
OBAS assessment 
 
Vital signs 
 
12-lead ECG 
 
NRS-A pain intensity assessment (assessed while the subject is lying down or recumbent; the 
prescribed activity is a straight leg raise of the surgical leg) 
 
Blood sample collection 
 
Physical examination 
 
Wound healing assessment 
 
Timed 20-meter walk test 
 
Rehabilitation assessment 
 
Ambulation assessment 
 
Subject’s satisfaction with postoperative pain control 
7.1. 
Screening Period 
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 21 days prior to surgery. 
The Investigator must evaluate the subject’s medical history and the results of all Screening 
assessments to determine study eligibility before the subject is randomized. Screening laboratory 
test results that do not meet the eligibility criteria should not be repeated without the approval of 
the Sponsor’s Medical Monitor. 
Screening procedures and assessments will include the following: 
 
Medical history 
 
Demographic recording 
 
Physical examination (including weight, height, and BMI calculation) 


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 
Vital signs measurements 
 
12-lead ECG (triplicate) 
 
Urine collection for pregnancy test (female subjects of child-bearing potential only) 
 
Urine collection for drug screen 
 
Blood sample collection for the hematology and serum chemistry 
 
Timed 20-meter walk test 
 
Subject training for pain intensity assessments 
 
AE recording (from the time the subject signs the ICF) 
 
Prior and concomitant medication recording 
Subjects will be given a Holter monitor and provided training on how to activate it. Subjects will 
be instructed to turn on the monitor at least 24 hours before surgery (Day 0). 
All subjects who meet the Screening eligibility criteria will be randomized. Randomization may 
be done up to 1 business day prior to the day of surgery. Subjects do not need to be present for 
randomization to occur. 
7.2. 
Treatment and Postoperative Observation Period 
7.2.1. 
Day of Surgery (Day 0) 
7.2.1.1. 
Prior to Surgery 
Subjects will be admitted to the surgical unit on Day 0. Subjects will be reassessed for study 
eligibility. Subjects who continue to meet the eligibility criteria can continue on study and the 
following study procedures and assessments will be performed before surgery: 
 
Vital signs measurements 
 
Subject training for pain intensity assessments (refresher training) 
 
NRS-R pain intensity assessment 
 
Urine collection for pregnancy test (female subjects of child-bearing potential only) 
 
Urine collection for drug screen 
 
NRS-A pain intensity assessment 
 
Blood collection for PK 
 
Ambulation assessment 
 
AE recording  
 
Prior and concomitant medication assessment 
TXA 1 g IV will be administered prior to the start of surgery. In Cohort 2, subjects will also be 
administered pregabalin PO (150 mg) and acetaminophen IV (no more than 1 g [1000 mg] in a 
6-hour window, as per the approved prescribing information) just before being taken to the 
operating room prior to the start of surgery.  
7.2.1.2. 
Surgery and Study Drug Administration 
Subjects will undergo a primary unilateral TKA under general anesthesia. Sites should follow 
intraoperative safety monitoring in accordance with American Society of Anesthesiologists 


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Standards for Basic Anesthetic Monitoring (American Society of Anesthesiologists, 2015). The 
start and stop time of surgery and additional surgical details should be recorded in the eCRF.  
Subjects will be administered study drug 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 will be administered via 
infiltration to the surgical site (eg, periarticular instillation, periarticular injection, or a 
combination of periarticular injection and instillation). See Section 5.5 for complete details on 
the study drug administration technique. 
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 as Time 0 for all efficacy, safety, and PK assessments. 
The start of HTX-011 administration will be considered as Time 0, whether or not 
administered with ropivacaine. Placement of the last suture will be considered the end of 
surgery. 
During surgery, the use of fentanyl up to 4 μg/kg is permitted. All subjects will receive 75 µg 
fentanyl IV just prior to the end of the surgery. As the prescribing information for fentanyl citrate 
(Fentanyl Citrate USPI, 2012) specifies that for intraoperative use a “moderate dose” of 2 to 
20 μg/kg IV is necessary in order to allow the anesthesiologist to respond to any signal that the 
surgical stress is increasing or anesthesia lightening, this dose was chosen to be in the lowermost 
portion of that range and therefore not interfere with assessment of postoperative opioid load. As 
clinically appropriate, the minimum possible fentanyl dose should be used. 
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. 
A PK blood sample should be collected 30 minutes (±5 min) after the start of study drug 
administration even if the subject is still in the operating room. 
Subjects will receive a second dose of TXA 1 g IV up to approximately 8 hours after the initial 
dose (Dang, 2013; ICJR, 2014; Danninger, 2015). 
After immediate postoperative recovery, subjects will be transferred to the PACU. 
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. 
For the time period after study drug administration until hospital discharge, subjects should 
receive ASA 325 mg PO twice a day; surgeons may also use additional DVT prophylaxis as per 
their standard of care. 
Study procedures and assessments that will be performed during the postoperative assessment 
period are listed below. All timepoints are referenced to the start of study drug administration. 
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. 


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 
NRS-R pain intensity assessment: at 1 hour (±5 min); 2 and 4 hours (±15 min); 6, 8, and 
12 hours (±30 min); 24 hours (±1 hr); and 36, 48, 60, and 72 hours (±2 hr) 
 
NRS-A pain intensity assessment: at 1 hour (±5 min); 2 and 4 hours (±15 min); 6, 8, and 
12 hours (±30 min); 24 hours (±1 hr); and 36, 48, 60, and 72 hours (±2 hr) 
 
PGA of pain control assessment: 24 hours (±1 hr), 48 and 72 hours (±2 hr) 
 
Vital signs measurements: 24 hours (±1 hr), 48 and 72 hours (±2 hr) 
 
Physical examination: 72 hours (±2 hr; height and weight not required) 
 
Blood sample collection for PK: 1 hour (±5 min); 2 and 4 hours (±15 min); 6, 8, and 
12 hours (±30 min); 20, 22, 24, 26, and 28 hours (±1 hr); and 36, 48, 60, and 72 hours 
(±2 hr). Note: PK blood sample should be collected even if the subject is still in the operating 
room. 
 
Blood sample for hematology and serum chemistry tests: 24 hours (±1 hr; hematology 
only) and 72 hours (±2 hr; hematology and serum chemistry) 
 
Timed 20-meter walk test: 6 and 12 hours (±30 min), 24 hours (±1 hr), 48 and 72 hours 
(±2 hr) 
 
Wound healing assessment: 72 hours (±2 hr). Note: Wound healing assessment will be 
repeated for any subjects who remain hospitalized at 96 and 120 hours. 
 
Subject’s satisfaction with postoperative pain control: 24 hours (±1 hr), 48 and 72 hours 
(±2 hr) and Day 10 (±2 days) 
 
Rehabilitation assessment: 6 and 12 hours (±30 min); 24 hours (±1 hr); 36, 48, 60, and 
72 hours (±2 hr) 
 
Ambulation assessment: 6 and 12 hours (±30 min); 24 hours (±1 hr); 48 and 72 hours 
(±2 hr) 
 
Discharge readiness assessment per the MPADSS criteria: 2 and 4 hours (±15 min); 6, 8, 
and 12 hours (±30 min); 24 hours (±1 hr); and 36, 48, 60, and 72 hours (±2 hrs). Note: 
Discharge readiness assessment will be repeated for any subjects who remain hospitalized at 
96 and 120 hours. 
 
OBAS assessment: 24 hours (±1 hr), 48 and 72 hours (±2 hrs) 
 
AE recording: Any time between study drug administration and 72 hours 
 
Concomitant medication recording: Any time between study drug administration and 
72 hours 
 
Use of opioid rescue medication recording: Any time between study drug administration 
and 72 hours 
7.2.3. 
End of the Postoperative Assessment Period 
After the 72-hour assessments have been completed, the Holter monitor will be removed, and the 
subject may be discharged. The time of discharge will be recorded. If a subject is not ready to be 
discharged due to an AE, it should be recorded on the AE eCRF as per Section 6.4.1. If a subject 
is ready for discharge but is not discharged for any reason other than AE, it should be recorded 
on the eCRF. 
Subjects will be given a diary to record their use of opioids on a daily basis from 72 hours 
through Day 28. 


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7.3. 
Follow-Up Period 
7.3.1. 
Day 6 (±1 Day) 
Blood sample collection for PK. Samples may be collected by a visiting nurse or at the study 
site. 
7.3.2. 
Day 10 Visit (±2 Days) 
All subjects will return to the study site and will have the following procedures and assessments: 
 
NRS-R pain intensity assessment 
 
NRS-A pain intensity assessment 
 
Timed 20-meter walk test 
 
Wound healing assessment 
 
Blood sample collection for PK 
 
Blood sample collection for the hematology and serum chemistry 
 
Subject’s satisfaction with postoperative pain control 
 
Review subject daily diary 
 
AE recording 
 
Concomitant medication recording 
7.3.3. 
Day 28 Visit (±4 Days) 
All subjects will return to the study site and will have the following procedures and assessments: 
 
NRS-R pain intensity assessment 
 
NRS-A pain intensity assessment 
 
PGA of pain control assessment  
 
Return and review subject daily diary 
 
OBAS assessment 
 
Wound healing assessment 
 
AE recording 
 
Concomitant medication recording 
7.4. 
Early Termination Visit 
Subjects who withdraw from the study before their Day 28 Visit will be asked to complete Early 
Termination procedures, which will include the following: 
 
NRS-R pain intensity assessment (if withdrew prior to 72 hours) 
 
NRS-A pain intensity assessment (if withdrew prior to 72 hours) 
 
PGA of pain control assessment (if withdrew prior to Day 28 
 
Return and review subject daily diary (if withdrew between 72 hours and Day 28) 
 
Vital signs (if withdrew prior to 72 hours) 
 
Blood sample collection for hematology and serum chemistry (if withdrew prior to 72 hours) 
 
Physical examination (if withdrew prior to 72 hours [height and weight not required]) 
 
Timed 20-meter walk test (if withdrew prior to Day 10) 


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 
Wound healing assessment 
 
AE recording 
 
Concomitant medication recording 
7.5. 
Unscheduled Visits and Assessments 
Unscheduled visits and assessments should be performed if clinically indicated in the opinion of 
the Investigator. Except when urgent clinical evaluation is necessary, it is expected that the 
Investigator will have the subject return for an unscheduled visit rather than directing the subject 
to a hospital emergency room. The following procedures and assessments are examples of what 
may be performed at an unscheduled visit, depending on the clinical situation: 
 
Vital signs 
 
Physical examination 
 
ECG 
 
Wound healing assessment 
 
X-ray 
 
AE recording 
 
Concomitant medication recording 
 
Blood sample collection to determine plasma bupivacaine concentration (if the unscheduled 
visit is potentially related to a cardiac or neurological TEAE) 
 
Blood sample collection for hematology and chemistry 


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8. 
SAFETY MONITORING AND REPORTING 
Investigators are responsible for the detection and documentation of events that meet the 
definition of an AE, SAE, suspected adverse reaction, serious suspected adverse reaction, 
unanticipated adverse device effect, or unanticipated problem, as provided in this protocol. 
Investigators must review the HTX-011 IB so as to be aware of the safety-related events, which 
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 laboratory value, 
vital sign result, or ECG finding deemed clinically significant by the Investigator, regardless of 
causal relationship, must be reported as an AE. A clinical diagnosis, rather than the changes in 
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 IP interrupted or 
discontinued. 
 Any laboratory abnormality that required the subject to receive specific treatment for the 
abnormality. 
 Any laboratory abnormality that required additional monitoring and follow-up visits 
 Any laboratory abnormality requiring further diagnostic investigation 


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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 preexisting 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, 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, hospitalizations 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. 
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 
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. 


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8.1.3. 
Definition of a Suspected Adverse Reaction 
A suspected adverse reaction is defined as any AE for which there is a reasonable possibility that 
the AE was caused by the study drug.  
8.1.4. 
Definition of a Serious Suspected Adverse Reaction 
A serious suspected adverse reaction is any suspected adverse reaction that is determined to be 
serious, based on the outcomes of a SAE described in Section 8.1.2. 
8.1.5. 
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 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. 


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If there is any doubt as to whether a clinical observation is an AE, the event should be reported. 
All AEs must have their relationship to study agent assessed. In a clinical trial, the study drug 
must always be suspect. 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 Day 28. 
If an Investigator becomes aware of an SAE that occurs in a subject more than 28 days after 
study drug administration 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 outlined 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: 
 
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. 
 
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. 
 
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. 
 
Death 
SAEs will be followed until the event resolves (ie, when the event no longer meets any of the 
seriousness criteria), 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). 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 meets the protocol definition of an SAE due to any 
cause that occurs during the course of this study, 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 
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 


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 
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 preferred 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 entering the information into the eCRF within 
24 hours of the Investigator becoming aware of the problem. 
If EDC is not available, the Investigator must complete an unanticipated problem report form 
and email it to the Sponsor within 24 hours of the Investigator becoming aware of the problem. 
The Investigator must also enter the information into the eCRF as soon as possible thereafter. 
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 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 
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 


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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 
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 
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 within 24 hours after the Investigator 
becomes aware of it using the SAE reporting procedures outlined in Section 8.4.1. 
8.5. 
Safety Oversight 
The internal, blinded Product Safety and Risk Management Committee will monitor safety data 
on a periodic basis throughout the study, (ie, monthly unless more frequent monitoring is 
necessary due to high enrollment or safety concern), including regular review of ECG findings, 
Holter monitor safety alerts, AEs, and SAEs. ECGs and AEs will be reviewed to identify 
possible signs of LAST. 
The stopping criteria, enrollment suspension or study termination for safety issues, are provided 
in Section 13.5. 


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9. 
STUDY RESTRICTIONS 
9.1. 
Prohibited Medications 
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). 
With the exception of preoperative administration of pregabalin and acetaminophen (in Cohort 2 
only), intraoperative administration of study drug (including ropivacaine in 1 arm in Cohort 2) 
and fentanyl, opioid rescue medications specified in Section 3.1.3, and ASA for DVT 
prophylaxis, no other analgesic agents, including ketamine and NSAIDs, are permitted from 
signing the ICF through 72 hours after study drug administration, except under the following 
circumstances:  
 
To treat an AE. 
 
For pretreatment prior to needle placement. 
 
To decrease venous irritation caused by propofol (in which case, no more than a single 
administration of lidocaine 1% 20 mg IV may be administered). 
After 72 hours, the analgesic regimen may be adjusted for each subject individually as deemed 
appropriate by the physician responsible for the postoperative care. 
9.2. 
Contraception 
Female subjects of child-bearing potential with a non-surgically sterile partner must use an 
acceptable form of contraception in the event of sexual activity during the study and for 30 days 
after study drug administration. Acceptable forms of contraception include double-barrier 
contraception or an insertable, injectable, transdermal, or combination oral contraceptive. 
9.3. 
Prohibited Treatment 
CPM 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. Baseline is defined as the last observed 
measurement, whether scheduled or unscheduled, prior to study drug administration. All safety 
and efficacy endpoints will be summarized by treatment group and/or cohort, as appropriate. 
Continuous variables will be summarized using the number of subjects with data (n), mean, 
standard deviation (SD), median, minimum, and maximum. Selected continuous variable 
summaries will also include the standard error (SE). Categorical variables will be summarized 
using frequency counts and percentages. 
Unless otherwise specified, all statistical hypothesis testing will be two-sided using α = 0.05. 
10.2. Determination of Sample Size 
Cohort 1: The sample size of up to approximately 60 subjects was selected empirically without 
formal statistical assumptions. 
Cohort 2: The mean (SD) AUC0-48 in the saline placebo and HTX-011 400 mg groups after 
adjusting for opioid rescue medication use is expected to be approximately 425 (90) and 
365 (90), respectively. Using a 2-sample t-test, 50 subjects per treatment group results in 
approximately 90% power to detect a statistically significant treatment effect with α = 0.05, 
2-sided. 
10.3. Analysis Populations 
Intent-to-Treat (ITT) Population: All subjects who are randomized and receive study drug will be 
included in the ITT Population. This population will be used as the primary analysis population 
for all efficacy endpoints. The randomized treatment assignment will be used for analysis in this 
population.  
Safety Population: All subjects who receive study drug will be included in the Safety Population. 
This population will be used for all summaries of safety data. The actual treatment received will 
be used for analysis in this population. 
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, randomized, dosed, completing the 
72-hour postoperative observation period, completing Day 28, and not completing Day 28 by 
reason for withdrawal will be summarized for the ITT Population. Subject demographics and 
baseline characteristics will be summarized for the ITT Population and will include age, age 
category, sex, race, ethnicity, height, weight, and BMI. 


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10.4.2. 
Efficacy Analysis 
Cohorts 1 and 2 will be analyzed separately with no data pooling across cohorts. 
In Cohort 1, each arm of HTX-011 will be tested against each control arm.  
In Cohort 2, the following treatment comparisons will be performed in a hierarchical order for 
the primary and key secondary endpoints: 
1. Mean AUC0-48 of the NRS-R pain intensity scores for HTX-011 400 mg/12 mg (13.7 mL) via 
periarticular instillation and ropivacaine 50 mg via periarticular injection vs. saline placebo. 
2. Mean AUC0-48 of the NRS-R pain intensity scores for HTX-011 400 mg/12 mg (13.7 mL) via 
periarticular instillation vs. saline placebo. 
3. Mean AUC0-72 of the NRS-R pain intensity scores for HTX-011 400 mg/12 mg (13.7 mL) via 
periarticular instillation and ropivacaine 50 mg via periarticular injection vs. saline placebo. 
4. Mean AUC0-72 of the NRS-R pain intensity scores for HTX-011 400 mg/12 mg (13.7 mL) via 
periarticular instillation vs. saline placebo. 
In order to account for multiple treatment comparisons on the primary and key secondary 
endpoints in Cohort 2, a strict testing hierarchy will be applied to control study-wise alpha level 
at 0.05. If the first treatment comparison is statistically significant (p≤0.05), then the second 
treatment comparison will be tested. If the second treatment comparison is statistically 
significant, then the third treatment comparison will be tested. Sequential testing will continue in 
this manner down the hierarchical order until a treatment comparison fails to meet statistical 
significance, after which all subsequent treatment comparisons will be considered exploratory. 
10.4.2.1. 
Primary Efficacy Analysis 
The primary analysis of mean AUC0-48 of the NRS-R pain intensity scores will be carried out on 
the ITT Population using an analysis of variance (ANOVA) model with treatment as the main 
effect. Results will be expressed as mean AUCs and SDs, least-squares mean differences and 
SEs with associated 95% confidence intervals (CIs), and p-values. To account for the duration 
effect of opioid rescue medication, the windowed worst observation carried forward (wWOCF) 
method will be implemented as the primary analysis method for endpoints involving NRS 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 NRS pain intensity score observed prior to the rescue medication window, 
with the following exception: if the NRS pain intensity score for a windowed observation is 
higher than the worst pre-window score, then it will not be replaced. Sensitivity analyses for 
endpoints involving NRS pain intensity scores will analyze the data without adjustment for the 
effect of opioid rescue medications. 
10.4.2.2. 
Secondary Efficacy Analyses 
Continuous secondary efficacy endpoints will be analyzed similarly to that specified for the 
primary endpoint. 


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Categorical endpoints will be analyzed using Fisher’s exact test. Results will be expressed as the 
number and percentage of subjects meeting the relevant endpoint, differences in proportions with 
95% CIs, and p-values. 
Median time in hours to first opioid rescue administration will be analyzed using Kaplan-Meier 
methods. 
10.4.2.3. 
Handling of Missing Data 
Due to the required 72-hour inpatient post-surgery observation period, the amount of missing 
data is expected to be very low. For any missing data observed, NRS pain intensity scores will be 
imputed via last observation carried forward (LOCF), in which the most recent post-dose 
non-missing 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 in the same randomized treatment group will be 
used. Predose values will not be carried forward to postdose timepoints. Analyses that adjust for 
the effect of opioid rescue medication will perform wWOCF following LOCF (ie, perform 
LOCF first, then apply wWOCF). 
Other continuous efficacy endpoints with missing data will be handled using LOCF. In general, 
subjects with missing categorical data at a timepoint will be assumed to have not met the 
endpoint at that timepoint. For the analysis of time to first opioid rescue medication, subjects 
who withdraw from the study prior to completing the 72-hour postoperative observation period 
or complete the 72-hour postoperative observation period without having taken rescue 
medication will be censored at the time of study withdrawal or completion of the 72-hour 
postoperative observation period, whichever is earlier. 
10.4.3. 
Safety Analysis 
All safety analyses will be carried out on the Safety Population. All safety data will be listed and 
summarized by treatment group.  
AEs will be monitored during the study and the data analyzed with respect to incidence within 
each treatment group as well as severity and potential relationship of the AEs to study drug. 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. Incidence of TEAEs and SAEs will be summarized and presented in descending 
order of frequency according to the highest dose of HTX-011 studied. AEs 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 
values outside the standard reference range will be flagged and listed. 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. 


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The change from Baseline to each visit for each of the vital sign variables will be summarized. 
Abnormal vital sign values will be flagged and listed. 
Wound healing assessment and proportion of subjects able to complete a timed 20-meter walk 
test 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 parameter estimates will be calculated using 
noncompartmental analysis. 
10.5. Interim Analysis 
One interim analysis will be performed. An internal IRC will review unblinded summary-level 
data from Cohort 1 to make study design decisions, as outlined in Section 3.1.2. The interim 
analysis will be performed after at least 80% of the planned number of subjects in Cohort 1 have 
all of their pain intensity and opioid use data through the 72-hour postoperative assessments 
entered into electronic clinical database. The internal IRC will be composed of 1 Sponsor 
representative from the Clinical Research, Biometrics, Pharmacovigilance, Regulatory, and 
Pharmaceutical and Translational Sciences functions. The IRC will operate under a written, 
detailed IRC Charter. 
There will be no interim analyses on data collected during Cohort 2. 


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11. 
QUALITY ASSURANCE AND QUALITY CONTROL 
Quality assurance and quality control systems will be implemented and maintained with 
Standard Operating Procedures (SOPs) by the Sponsor and its designee(s), as appropriate, to 
ensure that the clinical study is conducted and the data are generated, documented (recorded), 
and reported in compliance with the protocol, GCP, International Conference on Harmonisation 
(ICH) E6 guidelines, and any other 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 copies of any 
audit or inspection reports received to the Sponsor. 


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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), IB, recruitment materials, 
information about study compensation to subjects, 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 are implemented to the study. 
All changes to the ICF will be approved by the EC; a determination will be made regarding 
whether previously consented participants need to be re-consented. If any other information 
approved by the EC for presentation to potential subjects is amended during the study, the 
Investigator is also responsible for ensuring EC review and approval. 
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 a multicenter 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 will include 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 re-consented, 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 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 


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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. 
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 (unblinded monitor only), 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 (see 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 Violations and Deviations 
The Investigator will not implement any protocol deviation without agreement by the Sponsor 
except where necessary to eliminate an immediate hazard to study subjects. 


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Protocol deviations fall into 2 categories: those with approval prior to the event (protocol 
exemptions) and those occurring during the course of the study without prior approval (protocol 
violations). If an exemption from the protocol design (eg, a missed study visit or an unmet 
inclusion or exclusion criterion) is desired for an individual subject, other than those to eliminate 
immediate hazard, the Investigator must request an exemption from the Sponsor or designee. The 
Investigator will notify the EC of exemptions and deviations, as required by EC guidelines and 
site requirements. Exemptions (with rationale) will be documented at the site and in the Sponsor 
files. For any protocol violation, the site will document the protocol violation in the subject’s 
source documents. In the event of a significant violation, the site will notify the Sponsor or 
designee. Significant violations include, but are not limited to, those that involve fraud or 
misconduct, increase the health risk to the subject, or confound interpretation of primary study 
assessments. The Sponsor is responsible for notifying the regulatory authorities, if required. 
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. Stopping Criteria: Suspension or Termination of Study or Investigational Site 
13.5.1. 
Suspension of Study 
Enrollment will be suspended if the Sponsor discovers the occurrence of either of the following: 
 
Any death for which a clear alternative cause (unrelated to study drug) is not readily apparent 
 
Three (3) non-fatal SAEs that are considered by the Sponsor to be possibly related to study 
drug, and that are either unexpected or for which a clear alternative cause is not readily 
apparent. 
13.5.2. 
Termination of Study or Investigational Site 
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 terminating the study early or closing a site include, but are not limited to, the 
following: 


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 
If there is a suspension of the study and further investigation shows that any death or 
3 non-fatal SAEs are determined by the Sponsor to be related to study drug and pose an 
unacceptable risk to the study subjects, the study will be terminated. 
 
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. 
 
Data are not sufficiently complete and/or evaluable.  
 
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. 
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 CONSORT (Consolidated 
Standards of Reporting Trials) 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. 
REFERENCE LIST 
Affas, F., E. B. Nygards, C. O. Stiller, P. Wretenberg and C. Olofsson (2011). "Pain control after 
total knee arthroplasty: a randomized trial comparing local infiltration anesthesia and continuous 
femoral block." Acta Orthop 82(4): 441-447. 
American Society of Anesthesiologists. (2015). "Standards for Basic Anesthetic Monitoring: 
Section 10.28.15." from http://www.asahq.org/quality-and-practice-management/standards-and-
guidelines. 
Bailey, I. S., S. E. Karran, K. Toyn, P. Brough, C. Ranaboldo and S. J. Karran (1992). 
"Community surveillance of complications after hernia surgery." BMJ 304(6825): 469-471. 
Busch, C. A., B. J. Shore, R. Bhandari, S. Ganapathy, S. J. MacDonald, R. B. Bourne, C. H. 
Rorabeck and R. W. McCalden (2006). "Efficacy of periarticular multimodal drug injection in 
total knee arthroplasty. A randomized trial." J Bone Joint Surg Am 88(5): 959-963. 
Buvanendran, A., J. S. Kroin, C. J. Della Valle, M. Kari, M. Moric and K. J. Tuman (2010). 
"Perioperative Oral Pregabalin Reduces Chronic Pain After Total Knee Arthroplasty: A 
Prospective, Randomized, Controlled Trial." Anesthesia & Analgesia 110(1): 199-207. 
Chung, F. (1995). "Discharge criteria--a new trend." Can J Anaesth 42(11): 1056-1058. 
Dang, P. and R. Schwarzkopf (2013). "Tranexamic Acid and Total Knee Arthroplasty." Annals 
Orthopedics Rheumatology 1(1): 1001. 
Danninger, T. and S. G. Memtsoudis (2015). "Tranexamic acid and orthopedic surgery—the 
search for the holy grail of blood conservation." Annals of Translational Medicine 3(6): 77. 
Essving, P., K. Axelsson, J. Kjellberg, O. Wallgren, A. Gupta and A. Lundin (2010). "Reduced 
morphine consumption and pain intensity with local infiltration analgesia (LIA) following total 
knee arthroplasty." Acta Orthop 81(3): 354-360. 
Fentanyl Citrate USPI (2012). Fentanyl Citrate injection. Lake Forest, IL 60045: Akorn, Inc. 
Gan, T. J., A. S. Habib, T. E. Miller, W. White and J. L. Apfelbaum (2014). "Incidence, patient 
satisfaction, and perceptions of post-surgical pain: results from a US national survey." Curr Med 
Res Opin 30(1): 149-160. 
ICJR. (2014). "Effects of Tranexamic Acid On Bleeding In Total Knee Arthroplasty." 
International Congress for Joint Reconstruction, from 
http://icjr.net/report_168_tranexamic_acid.htm. 
Kehlet, H. and L. O. Andersen (2011). "Local infiltration analgesia in joint replacement: the 
evidence and recommendations for clinical practice." Acta Anaesthesiol Scand 55(7): 778-784. 
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. 


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Li, F., J. Ma, M. Kuang, X. Jiang, Y. Wang, B. Lu, X. Zhao, L. Sun and X. Ma (2017). "The 
efficacy of pregabalin for the management of postoperative pain in primary total knee and hip 
arthroplasty: a meta-analysis." Journal of Orthopaedic Surgery and Research 12(1): 49. 
Lyrica USPI (2009). Lyrica (pregabalin) Capsules, CV. Vega Baja, PR 00694: Pfizer 
Pharmaceuticals LLC. 
MARCAIN SmPC (2016). MARCAIN Polyamp Steripack 0.25%. Dublin, IE: Aspen. 
MARCAINE USPI (2011). MARCAINE (Bupivacaine Hydrochloride Injection). Lake Forest, IL 
60045: Hospira, Inc. 
MOBIC SmPC (2015). MOBIC 7.5 mg tablets. Dublin, IE: Boehringer Ingelheim Limited. 
MOBIC Tablets USPI (2016). MOBIC (meloxicam) tablets, for oral use. Ridgefield, CT 06877: 
Boehringer Ingelheim Pharmaceuticals, Inc. 
Mont, M. A., W. B. Beaver, S. H. Dysart, J. W. Barrington and D. J. Del Gaizo (2017). "Local 
Infiltration Analgesia With Liposomal Bupivacaine Improves Pain Scores and Reduces Opioid 
Use After Total Knee Arthroplasty: Results of a Randomized Controlled Trial." The Journal of 
Arthroplasty. 
Moote, C. (1992). "Efficacy of nonsteroidal anti-inflammatory drugs in the management of 
postoperative pain." Drugs 44 Suppl 5: 14-29; discussion 29-30. 
Naropin SmPC (2017). Naropin 10 mg/ml solution for injection. Dublin, IE: Aspen. 
Naropin USPI (2012). Naropin (ropivacaine HCl) Injection. Schaumburg, IL 60173: APP 
Pharmaceuticals, LLC. 
Ortiz, M. I., G. Castañeda-Hernández, J. A. Izquierdo-Vega and H. A. Ponce-Monter (2011). 
"Peripheral synergistic interaction between lidocaine and lumiracoxib on the 1% formalin test in 
rats." The Open Pain Journal 4: 8-14. 
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. 
Surdam, J. W., D. J. Licini, N. T. Baynes and B. R. Arce (2015). "The use of exparel (liposomal 
bupivacaine) to manage postoperative pain in unilateral total knee arthroplasty patients." J 
Arthroplasty 30(2): 325-329. 
Vasques, F., A. U. Behr, G. Weinberg, C. Ori and G. Di Gregorio (2015). "A Review of Local 
Anesthetic Systemic Toxicity Cases Since Publication of the American Society of Regional 
Anesthesia Recommendations: To Whom It May Concern." Regional Anesthesia and Pain 
Medicine 40(6): 698-705. 
 








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Appendix D: 
Pain Intensity Assessments Using the Numeric Rating Scale (NRS) 
 
The following question will be answered by the subject for all NRS with activity (NRS-A) and 
NRS at rest (NRS-R) pain intensity assessments: 
 
“On a scale of 0–10, 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: Breivik, H., P. C. Borchgrevink, S. M. Allen, L. A. Rosseland, L. Romundstad, E. K. Hals, G. Kvarstein 
and A. Stubhaug (2008). "Assessment of pain." Br J Anaesth 101(1): 17-24. 


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Appendix E: 
Patient Global Assessment (PGA) of Pain Control 
 
The following question will be answered by the subject at each PGA assessment timepoint: 
“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: 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 F: 
Overall Benefit of Analgesia Assessment 
 
Sites will ask each subject the statements listed below, and the rating scale below will be used to 
calculate the overall OBAS score. 
 
 
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 hr  
(0=not at all to 4=very much) 
|__| 
3 Please grade any distress and bother from itching in the past 24 hr  
(0=not at all to 4=very much) 
|__| 
4 Please grade any distress and bother from sweating in the past 24 hr  
(0=not at all to 4=very much) 
|__| 
5 Please grade any distress and bother from freezing in the past 24 hr  
(0=not at all to 4=very much) 
|__| 
6 Please grade any distress and bother from dizziness in the past 24 hr  
(0=not at all to 4=very much) 
|__| 
7 How satisfied are you with your pain treatment during the past 24 hr  
(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: 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. 
 


Signature Page for VV-CLIN-000795 v7.0
Signature Page for VV-CLIN-000795 v7.0
Approval
22-Dec-2017 05:43:07 GMT+0000

SAP_001.pdf: 
Document Type:  
Statistical Analysis Plan 
Official Title:  
A Phase 2b, Randomized, Double-Blind, Saline Placebo- and Active-
Controlled, Multicenter Study of HTX-011 via Infiltration for 
Postoperative Analgesia in Subjects Undergoing Total Knee 
Arthroplasty 
NCT Number:  
NCT03015532 
Document Date:  
05-Jan-2018 
 


HTX-011-209 
 
A PHASE 2B, RANDOMIZED, DOUBLE-BLIND, SALINE PLACEBO- AND 
ACTIVE-CONTROLLED, MULTICENTER STUDY OF HTX-011 VIA 
INFILTRATION FOR POSTOPERATIVE ANALGESIA IN SUBJECTS 
UNDERGOING TOTAL KNEE ARTHROPLASTY 
 
05 January 2018 
 
Statistical Analysis Plan 
 
Version 4.0 
 
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:  ____________ 
 
 
 
 
 
Vice President, Biometrics 
 
 
                        Heron Therapeutics, Inc. 
 
 
 
 
 
Approved by: ____________________________  
 
Date:  ____________ 
 
 
 
 
 
 
 
                        Vice President, Clinical Research  
                        Heron Therapeutics, Inc. 
 
 
 


Heron Therapeutics, Inc. 
Statistical Analysis Plan, V 4.0
Protocol HTX-011-209 
05 January 2018
 
Confidential 
2 
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. 
Statistical Hypotheses and Multiple Endpoint Handling .............................................12 
5.4. 
Analysis Populations ....................................................................................................13 
5.4.1. 
Intent-to-Treat (ITT) Population ............................................................................13 
5.4.2. 
Safety Population ...................................................................................................13 
5.5. 
Other Important Considerations ...................................................................................14 
5.5.1. 
Definition of Baseline ............................................................................................14 
5.5.2. 
Calculation of Change and Percent Change from Baseline ...................................14 
5.5.3. 
Study Day Calculation for Reporting Purposes .....................................................14 
5.5.4. 
Visit Windows .......................................................................................................14 
5.5.5. 
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 
8.1. 
Prior and Concomitant Medications ............................................................................17 
8.2. 
Surgery Procedure ........................................................................................................17 
8.3. 
Study Drug ...................................................................................................................17 


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Statistical Analysis Plan, V 4.0
Protocol HTX-011-209 
05 January 2018
 
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3 
9. 
Efficacy Analysis ...........................................................................................................17 
9.1. 
Primary Efficacy Endpoint ..........................................................................................18 
9.1.1. 
Primary Analysis ....................................................................................................18 
9.1.2. 
Sensitivity Analyses ...............................................................................................19 
9.2. 
Secondary Efficacy Endpoints .....................................................................................19 
9.2.1. 
Analyses .................................................................................................................19 
9.3. 
Other Efficacy Analyses ..............................................................................................25 
10. 
Safety Analysis ...............................................................................................................26 
10.1.  Adverse Events ............................................................................................................26 
10.1.1. 
Incidence of Treatment Emergent Adverse Events ...............................................27 
10.1.2. 
Relationship of Adverse Events to Investigational drug ........................................27 
10.1.3. 
Severity of Adverse Event .....................................................................................27 
10.1.4. 
Serious Adverse Events .........................................................................................27 
10.1.5. 
Adverse Events Leading to Study Withdrawal ......................................................28 
10.1.6. 
Opioid-related Adverse Events ..............................................................................28 
10.1.7. 
Death ......................................................................................................................29 
10.2.  Clinical Laboratory Evaluations ..................................................................................29 
10.2.1. 
Hematology ............................................................................................................29 
10.2.2. 
Blood Chemistry ....................................................................................................30 
10.2.3. 
Urine Pregnancy Test and Urine Drug Screen .......................................................30 
10.3.  Vital Sign Measurements .............................................................................................30 
10.4.  Electrocardiogram ........................................................................................................31 
10.5.  Physical Examination...................................................................................................31 
10.6.  Wound Healing Assessment ........................................................................................31 
10.7.  Motor Function Assessment ........................................................................................31 
11. 
Interim Analysis .............................................................................................................31 
11.1.  Interim Analysis ...........................................................................................................31 
11.2.  Data Safety Monitoring Board .....................................................................................32 
12. 
References ......................................................................................................................32 
Appendix 1. 
Imputation of Partial and Missing Dates ...................................................33 
Appendix 2. 
Document Revision History .......................................................................34 
 


Heron Therapeutics, Inc. 
Statistical Analysis Plan, V 4.0
Protocol HTX-011-209 
05 January 2018
 
Confidential 
4 
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 
IRC 
Interim Revivew Committee 
IRS 
Integrated Rank of Silverman 
ITT 
Intent-to-Treat  
IWRS 
Interactive web response system 
IV 
Intravenous(ly) 
K-M 
Kaplan-Meier 
LDH 
Lactic dehydrogenase 
LLN 
Lower limit of normal 
LOCF 
Last observation carried forward 
LSMD 
Least-squares mean difference 
MedDRA 
Medical Dictionary for Regulatory Activities 
MME 
Morphine milligram equivalency 
MPADSS 
Modified Postanaesthetic Discharge Scoring System 
NRI 
Non-responder imputation 
NRS 
Numeric Rating Scale 
NRS-A 
Numeric Rating Scale with activity 
NRS-R 
Numeric Rating Scale at rest 
NSAID 
Nonsteroidal anti-inflammatory drug 
OBAS 
Overall benefit of analgesia score 
ORAE 
Opioid-related adverse event 
PACU 
Post-Anesthesia Care Unit 
PGA 
Patient’s Global Assessment 
PK 
Pharmacokinetic(s) 


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Statistical Analysis Plan, V 4.0
Protocol HTX-011-209 
05 January 2018
 
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5 
Abbreviation 
Term 
PO 
Administered orally 
PR 
Per rectum 
PRN 
As needed 
PT 
Preferred term 
RBC 
Red blood cell 
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 
SEM 
Standard error of the mean 
SI 
Standard international 
SOC 
System Organ Class 
SPI 
Summed pain intensity 
TEAE 
Treatment-emergent adverse event 
TKA 
Total knee arthroplasty 
ULN 
Upper limit of normal 
US 
United States 
WBC 
White blood cell 
WHODrug 
World Health Organization Drug classification dictionary 
wWOCF 
Windowed worst observation carried forward 


Heron Therapeutics, Inc. 
Statistical Analysis Plan, V 4.0
Protocol HTX-011-209 
05 January 2018
 
Confidential 
6 
1. 
ADMINISTRATIVE STRUCTURE 
1.1. 
Sponsor and Oversight 
This study is being conducted under the sponsorship of Heron Therapeutics, Inc. (Heron).  
 
 
 
 
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 blinded 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 the pharmacokinetic (PK) 
assessments and the Holter assessments in the study.  Planned PK analyses will be presented 
in a separate PK analysis plan and planned Holter analyses will be presented in a separate 
Holter analysis plan. 
This SAP was prepared based on protocol version 6, issued 21 December 2017 and 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. See 
Appendix 1 for revision history of the SAP. 
This SAP should be read in conjunction with the study protocol and the electronic Case 
Report Forms (eCRFs).   


Heron Therapeutics, Inc. 
Statistical Analysis Plan, V 4.0
Protocol HTX-011-209 
05 January 2018
 
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7 
3. 
OBJECTIVES 
The primary objective of the study is: 
 To compare the efficacy and duration of analgesia achieved following periarticular 
infiltration of HTX-011 with that of saline placebo in subjects undergoing unilateral 
total knee arthroplasty (TKA) 
The secondary objectives are: 
 To compare the efficacy and duration of analgesia for HTX-011 with that of 
bupivacaine hydrochloride (HCl) without epinephrine in this study population. 
 To evaluate additional efficacy parameters, including opioid load, in this study 
population. 
 To evaluate the efficacy and duration of analgesia for HTX-011 administered using 
different techniques in this study population. 
 To characterize the bupivacaine and meloxicam PK profiles following administration 
of HTX-011 in this study population. 
 To assess the safety and tolerability of HTX-011 in this study population. 
4. 
INVESTIGATIONAL PLAN 
4.1. 
Overall Study Design and Plan 
HTX-011-209 is a Phase 2b, randomized, double-blind, saline placebo- and active-controlled, 
multicenter study in subjects undergoing primary unilateral TKA.  This study will evaluate 
the efficacy and safety profile of HTX-011 on clinical outcomes (eg, level of pain, duration 
of analgesia, avoidance of opioids, etc.) in subjects treated with a single intraoperative dose 
of study drug administered via infiltration to the surgical site. 
Cohort 1 
Approximately 60 subjects will be randomized to 1 of the following 4 treatment groups in a 
2:2:1:1 ratio: 
 HTX-011 200 mg (6.8 mL) via periarticular instillation into the surgical site (20 
subjects) 
 HTX-011 200 mg (6.8 mL) via a combination of periarticular injection and 
instillation into the surgical site (20 subjects) 
 Saline placebo (6.8 mL) via periarticular injection into the surgical site (10 subjects) 
 Bupivacaine HCl without epinephrine 0.25% (125 mg, 50 mL) via periarticular 
injection into the surgical site (10 subjects) 
 


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After at least 80% of the planned subjects in Cohort 1 have completed their 72-hour 
postoperative assessments and have their pain intensity and opioid use data entered into the 
eCRF, an interim analysis will be performed.  An internal Interim Review Committee (IRC), 
composed of 1 Sponsor representative from each of the Clinical Research, Biometrics, 
Pharmacovigilance, Regulatory, and Pharmaceutical and Translational Sciences functions 
will review unblinded summary-level data in order to make a determination to proceed with 
the next cohort and to select the dose of HTX-011 that will be studied in the next cohort.  
Detailed responsibilities of the IRC will be presented in an IRC charter. 
Cohort 2  
Cohort 2 was planned as an optional cohort. Following a review of the results from Cohort 1, 
the IRC recommended initiating enrollment in Cohort 2 with a single dose level of HTX-011 
400 mg/12 mg (bupivacaine/meloxicam doses; 13.7 mL) in each HTX-011 treatment group.  
Approximately 200 subjects will be randomized to 1 of the following 4 treatment groups in a 
1:1:1:1 ratio: 
 HTX-011 400 mg/12 mg (13.7 mL) via periarticular instillation into the surgical site 
(50 subjects) 
 HTX-011 400 mg/12 mg (13.7 mL) via periarticular instillation into the surgical site 
and ropivacaine 0.5% (50 mg, 10 mL) via periarticular injection into the surgical site 
(posterior capsule) (50 subjects) 
 Saline placebo (13.7 mL) via periarticular injection into the surgical site (50 subjects) 
 Bupivacaine HCl without epinephrine 0.25% (125 mg, 50 mL) via periarticular 
injection into the surgical site (50 subjects) 
 
Just before being taken to the operating room prior to the start of surgery, each subject in 
Cohort 2 will be administered pregabalin 150 mg orally (PO) and acetaminophen 1000 mg 
intravenously (IV) to reduce initial postoperative pain.  There will be no interim analyses on 
data collected during Cohort 2. 
It is anticipated that this trial will be performed at approximately 30 sites in the United States 
(US). 
4.2. 
Assessments 
Efficacy assessments will include the following: 
 Pain intensity scores using the Numeric Rating Scale (NRS) at rest (NRS-R) 
 Pain intensity scores using the NRS with activity (NRS-A) 
 Use of opioid rescue medication 
 Patient’s Global Assessment (PGA) of pain control 
 Assessment of ability to participate in rehabilitation sessions 
 Assessment of ability to ambulate 






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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 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, and CI will have one 
decimal place and SD and SEM will have 2 decimal places. 
 If the original value has 1 decimal place: mean, median, and CI will have 2 decimal 
places and SD and SEM will have 3 decimal places. 
 If the original value has 2 or more decimal places: mean, median, CI, SD, and SEM 
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. 1.3 or higher, conforming to the SDTM 
Implementation Guide (SDTMIG) v. 3.1.3 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 
Cohort 1: The sample size of up to approximately 60 subjects was selected empirically 
without formal statistical assumptions. 
Cohort 2: The mean (SD) AUC0-48 in the saline placebo and HTX-011 400 mg/12 mg groups 
after adjusting for opioid rescue medication use is expected to be approximately 425 (90) and 
365 (90), respectively. Using a 2-sample t-test, 50 subjects per treatment group results in 
approximately 90% power to detect a statistically significant treatment effect with α = 0.05, 
2-sided. 
5.2. 
Randomization, Stratification, and Blinding 
Subjects will be randomized to receive HTX-011 (with or without ropivacaine), bupivacaine 
HCl, or saline placebo.  The randomization will not be stratified.  Any subject who is 
randomized but withdraws from the study prior to study drug administration will be replaced 
by the next eligible subject. The replacement subject will be assigned to the same treatment 
group as the subject who withdrew. Subjects will not be aware of the study drug they are 


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receiving.  The site’s pharmacy and surgical staff will not be blinded to the treatment 
assignments because HTX-011 is a colored and viscous liquid in contrast to bupivacaine HCl 
and saline placebo, and the volume of study drug to be administered varies by treatment 
group.  Once surgery is completed and the subject is transferred to the Postanesthesia Care 
Unit (PACU), the Investigator and all site staff involved in the safety and efficacy 
assessments, as well as the clinical staff at the CRO involved with study conduct and data 
collection will be blinded to treatment assignments until after database lock.  For Cohort 1, 
the Sponsor’s study team will also be blinded to the treatment assignments with the exception 
of the clinical trial materials (CTM) staff and an unblinded statistician (from Agility Clinical) 
who will perform the randomization and interim analysis data review, but will otherwise be 
uninvolved in the conduct of the study. For Cohort 2, the Sponsor’s study team will also be 
blinded to the treatment assignments with the exception of the CTM staff, Clinical Research 
Specialists (observers in surgery), and an unblinded statistician (from Agility Clinical) who 
will perform the randomization, but will otherwise be uninvolved in the conduct of the study. 
An internal IRC consisting of 1 Sponsor representative from each of the Clinical Research, 
Biometrics, Pharmacovigilance, Regulatory, and Pharmaceutical and Translational Sciences 
functions will be unblinded to summary-level data during the interim analyses conducted in 
Cohort 1.  The IRC will operate under a written, detailed IRC charter. 
The randomization will be based on a blocked algorithm and will be done centrally via an 
interactive web response system (IWRS).   
A subject’s treatment group assignment will not be broken until the end of the study unless 
emergency medical treatment of that subject depends upon knowledge of the assigned 
treatment.   
The Sponsor retains the right to break a subject’s treatment code for SAEs that are 
unexpected and are suspected to be causally related to an investigational product and that 
potentially require expedited reporting to regulatory authorities. 
5.3. 
Statistical Hypotheses and Multiple Endpoint Handling 
Cohort 1 and Cohort 2 will be analyzed separately with no data pooling across cohorts. 
In Cohort 1, each arm of HTX-011 will be tested against each control arm.  The primary 
comparison on the primary endpoint for each HTX-011 group will be against the saline 
placebo group under the following hypotheses: 
H0: µHTX-011 = µSaline Placebo 
Ha: µHTX-011 ≠ µSaline Placebo 
Comparisons of HTX-011 against bupivacaine HCl will be considered secondary 
comparisons.  As there is no prospective statistical power calculation of Cohort 1, there will 


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be no adjustments made to any hypothesis test due to multiple comparisons or multiple 
endpoints. 
In Cohort 2, the following treatment comparisons will be performed in a hierarchical order 
for the primary and key secondary endpoints:  
1. Mean AUC0-48 of the NRS-R pain intensity scores for HTX-011 400 mg/12 mg (13.7 mL) 
via periarticular instillation and ropivacaine 50 mg via periarticular injection vs. saline 
placebo.  
2. Mean AUC0-48 of the NRS-R pain intensity scores for HTX-011 400 mg/12 mg (13.7 mL) 
via periarticular instillation vs. saline placebo.  
3. Mean AUC0-72 of the NRS-R pain intensity scores for HTX-011 400 mg/12 mg (13.7 mL) 
via periarticular instillation and ropivacaine 50 mg via periarticular injection vs. saline 
placebo.  
4. Mean AUC0-72 of the NRS-R pain intensity scores for HTX-011 400 mg/12 mg (13.7 mL) 
via periarticular instillation vs. saline placebo.  
In order to account for multiple treatment comparisons on the primary and key secondary 
endpoints in Cohort 2, a strict testing hierarchy will be applied to control study-wise alpha 
level at 0.05.  If the first treatment comparison is statistically significant (p≤0.05), then the 
second treatment comparison will be tested.  If the second treatment comparison is 
statistically significant, then the third treatment comparison will be tested.  Sequential testing 
will continue in this manner down the hierarchical order until a treatment comparison fails to 
meet statistical significance, after which all subsequent treatment comparisons will be 
considered exploratory. 
5.4. 
Analysis Populations 
5.4.1. 
Intent-to-Treat (ITT) Population 
The ITT Population will consist of all subjects who are randomized and receive study drug.  
This analysis population will be used as the primary analysis population for all efficacy 
endpoints.  The randomized treatment assignment will be used for analysis in this population. 
5.4.2. 
Safety Population 
The Safety Population will consist of all subjects who receive study drug.  This population 
will be used for all summaries of safety data.  The actual treatment received will be used for 
analysis in this population. 


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5.5. 
Other Important Considerations 
5.5.1. 
Definition of Baseline 
Baseline data are defined as the last data collected, whether scheduled or unscheduled, prior 
to the start of study drug administration.   
5.5.2. 
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) 
5.5.3. 
Study Day Calculation for Reporting Purposes 
The start of HTX-011 administration will be considered as Time 0 whether or not 
administered with ropivacaine.  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. 
5.5.4. 
Visit Windows 
Due to the short duration of the study and the primary efficacy analyses occurring during the 
3-day postoperative period of subject hospitalization, no programmatically calculated visit 
windows are defined for this study. 
5.5.5. 
Handling of Missing and Partial Data 
The amount of missing data during the 3-day postoperative primary efficacy analysis period 
is expected to be very low due to the protocol-required 3-day hospitalization of all subjects 
following surgery.  For any data that is missing, the NRS pain intensity scores 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 


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available prior to the first missing value, then the median of values from subjects with 
nonmissing values within the same treatment group at the relevant timepoint will be used.  
Predose values will not be carried forward to postdose timepoints.   
For binary endpoints (those involving proportions of subjects) not involving the NRS-R or 
NRS-A, any subject with missing data at a timepoint will be considered as not meeting the 
endpoint at that timepoint.  This is known as nonresponder imputation (NRI).  Binary 
endpoints involving the NRS-R or NRS-A (such as proportion of subjects who are pain-free) 
through 72 hours will be constructed following windowed worst observation carried forward 
(wWOCF) (see Section 9.1.1 for details). Binary endpoints involving NRS-R or NRS-A on 
Day 10 or Day 28 (such as proportion of subjects with NRS score < 4 on Day 10) will be 
constructed using NRI. 
A table displaying the number and percentage of subjects with missing NRS-R pain intensity 
scores at each nominal timepoint 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. 
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 
who failed screening with reasons for screen failure, subjects randomized, subjects in the ITT 
Population, subjects in the Safety Population, subjects completing the 72-hour postoperative 
observation period, subjects completing study (Day 28), subjects withdrawn from study with 
the primary 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 
The demographics and baseline characteristics will be presented in tables using descriptive 
statistics.  The demographics consist of age, age category, sex, race, and ethnicity.  The 
baseline characteristics consist of weight, height, body mass index (BMI), nicotine status, 
and alcohol use.  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 
years old. 
Demographics and baseline characteristics will be presented for the Safety Population and 
demographics only will be presented for all subjects enrolled who fail screening. 
7.2. 
Medical History 
Medical history will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA®) version 19.1.  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 body system.   
7.3. 
Protocol Deviations 
Deviations and violations from the protocol will be recorded.  Protocol deviations will be 
classified into, but not necessarily limited to, the following categories: 
 ICF procedures 
 Eligibility criteria 
 Prohibited concomitant medication/therapy 
 Laboratory assessment  
 Study procedure (eg, efficacy ratings, ECG, PE, etc.) 
 Safety reporting 
 Randomization/blinding 
 Study drug dosing/administration 
 Visit schedule/windows 
Classification of deviations as important protocol violations will be decided on a case-by-
case basis without knowledge of the treatment assigned and before database lock.  Protocol 
deviations will be presented in a summary table by protocol deviation category and 
treatment.  Important protocol deviations will also be listed separately from all protocol 
deviations. 


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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 Study Day 1.  
Concomitant medications are defined as medications that are ongoing on Study Day 1 or with 
a start date occurring on or after Study Day 1.  Medications with start and stop dates which 
bracket Study 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 classification 
dictionary (WHODrug). 
Prior and concomitant medications will be summarized separately by drug class and 
preferred term (PT).  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 medications and concomitant medications will be summarized for the Safety 
Population. 
8.2. 
Surgery Procedure 
The knee subject to the surgical procedure (left or right) and the duration of surgery will be 
summarized.  Duration will be calculated as completion time minus start time, reported in 
minutes. 
8.3. 
Study Drug 
For all subjects, treatment will consist of a single intraoperative dose of study drug.  As such, 
extent of exposure will be reported in the CSR as the number of subjects by treatment 
received in the Safety Population.  A summary of treatment compliance will not be produced, 
as by definition it will be 100% for the Safety Population.  
9. 
EFFICACY ANALYSIS 
All efficacy analyses will be performed on the ITT Population. Table 1 displays the planned 
cohorts and treatment groups being studied. 
Table 1.  Planned Cohorts and Treatment Group Designations 
Cohort 
Treatment 
Sample Size 
1 
HTX-011 200 mg/6 mg (6.8 mL) Instillation 
20 
 
HTX-011 200 mg/6 mg (6.8 mL) Combination 
20 
 
Saline placebo (6.8 mL) Injection 
10 
 
Bupivacaine HCl 125 mg (50 mL) Injection 
10 


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Cohort 
Treatment 
Sample Size 
 
 
 
2 
HTX-011 400 mg/12 mg (13.7 mL) Instillation + Ropivacaine 50 mg 
Injection 
50 
 
HTX-011 400 mg/12 mg (13.7 mL) Instillation 
50 
 
Saline placebo (13.7 mL) Injection 
50 
 
Bupivacaine HCl 125 mg (50 mL) Injection 
50 
 
See Section 5.3 for details on hypothesis tests and multiple hypothesis handling for primary 
and key secondary endpoints in Cohort 2.  
9.1. 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the mean AUC of the NRS-R pain intensity scores through 
48 hours (AUC0-48). 
9.1.1. 
Primary Analysis 
During the first 48 hours following surgery, the NRS-R is measured at hours 1, 2, 4, 6, 8, 12, 
24, 36, and 48 hours.  Using the trapezoidal rule and letting Pt = the NRS-R pain intensity 
score at time t, then:  
ሺݐെݐିଵሻܲ௧షభ൅ܲ௧
2
 
 
is the trapezoidal area between times t and t-1.  The AUC0-48 is thus calculated as follows: 
 
ܣܷܥ଴ିସ଼ൌන݂ሺݐሻ݀ݐൎ෍ሺݐ௜െݐ௜ିଵሻܲ௜ିଵ൅ܲ௜
2
ସ଼
௜ୀଶ
ସ଼
ଵ
 
 
The primary endpoint of mean AUC0-48 of the NRS-R pain intensity scores will be analyzed 
using an analysis of variance (ANOVA) model with randomized treatment as the main effect.  
In Cohort 1, each HTX-011 group will be tested against each of the control groups.  In 
Cohort 2, treatment comparisons will be performed in a hierarchical order as described in 
Section 5.3. Results will be expressed as mean AUCs, SDs, and least-squares mean 
differences (LSMD) and standard errors (SE) with associated 95% CIs, and p-values.   
To adjust for the duration effect of opioid rescue medication, the windowed worst 
observation carried forward (wWOCF) method will be implemented as the primary analysis 
method for endpoints involving NRS 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 NRS pain intensity score 
observed prior to the rescue medication window, with the following exception: if the NRS 
pain intensity score for a windowed observation is higher than the worst pre-window score, 
then it will not be replaced.  wWOCF will be performed following LOCF (ie, perform LOCF 


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first, and then apply wWOCF).  See Table 2 in Section 9.2 for predefined analgesic windows 
for each opioid medication. 
The mean AUC0-48 of the NRS-R pain intensity scores using wWOCF will also be plotted 
with associated SEM in a bar chart. 
9.1.2. 
Sensitivity Analyses 
One sensitivity analysis (using LOCF only) will be performed on the primary endpoint: 
reproducing the primary analysis but without adjusting the NRS-R pain intensity scores for 
the use of opioid rescue medications. 
 
 
 
9.2.1. 
Analyses 
Key Secondary Endpoint: Mean AUC of the NRS-R pain intensity scores through 72 
hours (AUC0-72) 
During the first 72 hours following surgery, the NRS-R is measured at hours 1, 2, 4, 6, 8, 12, 
24, 36, 48, 60 and 72 hours. The AUC0-72 is thus calculated as follows: 
 
ܣܷܥ଴ି଻ଶൌන݂ሺݐሻ݀ݐൎ෍ሺݐ௜െݐ௜ିଵሻܲ௜ିଵ൅ܲ௜
2
଻ଶ
௜ୀଶ
଻ଶ
ଵ
 
Similar statistical methods as the primary endpoint will be used for the analysis of this 
endpoint. See Sections 4.3.1 and 4.3.1 for detail. 
The mean AUC0-72 of the NRS-R pain intensity scores using wWOCF will also be plotted 
with associated SEM in a bar chart. 
Secondary Endpoint: Mean total postoperative opioid consumption (in morphine 
equivalents) through 24, 48, and 72 hours 
Determination of morphine equivalents 
Use of opioid rescue medication will be examined by unique preferred terms.  All opioids  
used will have the morphine milligram equivalency (MME) calculated (Opioid Morphine 
Equivalent Conversion Factors, Centers for Disease Control and Prevention, Atlanta, GA, 
May 2014) based on the conversion factor for each preferred term and the route of the opioid.  
Protocol-allowed postoperative rescue medications consist of IV morphine and oral (PO) 
immediate-release oxycodone. For the first 2 hours in the PACU, the subject may receive up 
to 15 mg IV morphine, as needed. Thereafter, the subject may receive up to 10 mg in a 2-


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hour period, as needed. In addition, the subject may also receive up to 10 mg of PO 
immediate-release oxycodone within any 4-hour period as needed, from after study drug 
administration through 72 hours. No other analgesic agents, including ketamine and 
nonsteroidal anti-inflammatory drugs (NSAIDs), are permitted during the 72-hour 
postoperative observation period.  
Table 2 displays the MME along with the analgesic windows of selected opioid rescue 
medications for wWOCF purposes.  Protocol-allowed postoperative rescue medications are 
checked.  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 Intravenous Morphine Milligram Equivalents for 
Opioid Rescue Medications 
Medication 
Route 
Window (hr) 
MME Factor 
Protocol Allowed 
CODEINE 
PO 
6 
0.05 
 
 
HYDROMOPHONE 
HYDOCHLORIDE 
PO 
4 
1.33 
 
 
HDROMORPHONE 
HYDOCHLORIDE 
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 
Intramuscular (IM) 
4 
1.00 
 
 
MORPHINE 
Per rectum (PR) 
4 
1.00 
 
 
OXYCODONE 
IV 
4 
1.00 
 
 
OXYCODONE 
IM 
4 
1.00 
 
 
OXYCODONE 
PO 
6 
0.50 
 
 
TRAMADOL 
IV 
6 
0.06 
 
 
TRAMADOL 
PO 
6 
0.04 
 
 
 
Analysis method 
Opioid rescue medication use is collected from hours 0-72.  Average daily use and total use 
will be tabulated using descriptive statistics for each opioid and overall during the following 
periods: hours 0-24, hours 0-48, and hours 0-72.  Subjects who did not use a specific opioid 
rescue medication during a period of interest will have their dose set to 0 for that period.   
The Shapiro-Wilk test will be used to examine the assumption of normality.  If this test is 
statistically significant (ie, p<0.05) then the assumption of normality is violated and the total 
postoperative opioid consumption during each period of interest will be analyzed using 
Wilcoxon rank sum test. Results will be expressed as median (range) and p-values. However, 
if assumption of normality holds (ie, Shapiro-Wilk p-value ≥ 0.05), then the total 
postoperative opioid consumption during each period of interest will be analyzed using an 
ANOVA model with randomized treatment as the main effect.  Results will be expressed as 
means, SDs, and LSMD and SE with associated 95% CI, and p-values.   






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෍
 
 
 
 






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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 in the HTX-011 total column.  For tables showing incidence by PT only, the PTs 
will be sorted in descending order of incidence in the HTX-011 total column.   
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 possibly related TEAE 
 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 opioid-related TEAE (ORAE) 
 Number of SAEs 
 Number of subjects with at least 1 SAE 
 Number of subjects with at least 1 possibly related SAE 
 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 Investigational drug 
Incidence of possibly related TEAEs to study drug will be presented in a table by SOC and 
PT.  The potential relationships are “Unlikely Related” and “Possibly Related”. TEAEs that 
are missing relationship will be presented in the summary table as “Possibly Related” but 
will be presented in the data listing with a missing relationship.     
10.1.3. 
Severity of Adverse Event 
Incidence of severe TEAEs will be presented in a table by SOC and PT.  TEAEs that are 
missing severity will be presented in summary tables as “severe” but will be presented in the 
data listing with a missing severity.   
10.1.4. 
Serious Adverse Events 
The seriousness of a TEAE should be assessed by the Investigator independently from the 
severity of the TEAE.  A SAE is an AE occurrence that results in death, is life-threatening, 


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requires inpatient hospitalization or prolongation of existing inpatient hospitalization, results 
in persistent or significant disability/incapacity, or is a congenital abnormality/birth defect. 
Important medical events that may not be immediately life-threatening or result in death, or 
require hospitalization may be considered SAEs when, based upon medical judgment, they 
may jeopardize the subject or may require intervention to prevent one of the outcomes listed 
above. 
Incidence of treatment-emergent SAEs will be presented in a table by SOC and PT.  
Incidence of possibly related SAEs will also be presented by PT.  The incidence of SAE 
tables will include only 1 occurrence of a PT per subject.  If a subject reports the same SAE 
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 SAEs within the same SOC, then that 
SOC will only be incremented by 1 since subject counts will be presented.  SAEs will also be 
listed separately. 
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. 
Opioid-related Adverse Events 
Incidence of TEAEs that are potentially opioid-related, regardless of whether a subject 
actually received an opioid medication, will be presented by PT.  Prespecified PTs that may 
be opioid-related include the following: 
 Nausea 
 Vomiting 
 Constipation 
 Pruritus 
 Somnolence 
 Respiratory depression 
 Urinary retention 
 
Incidence of ORAEs will be presented separately as follows: 
 
 Incidence of ORAEs through Day 28 
 Incidence of ORAEs through 72 hours 
 Incidence of ORAEs through Day 28 in the subset of subjects who received at least 1 
opioid rescue medication through 72 hours 
 Incidence of ORAEs through 72 hours in the subset of subjects who received at least 
1 opioid rescue medication through 72 hours 


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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. 
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, hour 24 [hematology only], hour 72), 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 an abnormal 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 abnormal 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). 


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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.   
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 abnormalities in Liver Function Tests (ALT, AST) will be 
summarized at each visit for each treatment group for the following categories:  
 > 1 x ULN  
 ≥ 2 x ULN 
 ≥ 3 x ULN 
 ≥ 4 x ULN 
 ≥ 5 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), and respiration rate will be collected at screening, on Study Day 1 before 
study drug administration, and at 24, 48, and 72 hours.   
Summary tables including actual values and changes from Baseline will be presented for 
vital signs.   
The number and percentage of subjects with clinically relevant abnormalities will be 
presented using data from any postdose visit (including unscheduled visits). The criteria for 
clinically relevant abnormalities are shown in   Table 3:  


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  Table 3.  Clinically Relevant Vital Signs Abnormalities 
Vital Sign 
Low 
High 
HR 
≤50 bpm and ≥15 bpm decrease from 
Baseline 
≥120 bpm and ≥15 bpm increase from 
Baseline 
SBP 
≤90 mmHg and ≥20 mmHg decrease from 
Baseline 
≥160 mmHg and ≥20 mmHg increase from 
Baseline 
DBP 
≤50 mmHg and ≥15 mmHg decrease from 
Baseline 
≥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 
12-lead ECG (triplicate) is performed at screening.  Screening ECG results will be listed 
only, and will include each of the 3 triplicate ECGs as well as the mean values from the 
triplicate assessments. 
10.5. 
Physical Examination 
Physical examination is performed at Screening, 72 hours, and early termination.  Physical 
examination results will be listed only. 
10.6. 
Wound Healing Assessment 
Wound healing assessment according to the Southampton Wound Scoring System (Bailey, 
Karran et al. 1992) is performed at 72, and 120 hours, and on Days 10 and 28.  A summary of 
wound healing assessment results will be produced, showing the number and percentage of 
subjects at each visit by grade with subgrade breakdown.  Wound healing assessment results 
will also be listed. 
10.7. 
Motor Function Assessment 
Motor function assessment is performed at Screening, at 6, 12, 24, 48, and 72 hours, and on 
Day 10.  The proportion of subjects able to complete a timed 20-meter walk test unassisted (a 
successful motor function assessment) will be summarized at each timepoint.  
11. 
INTERIM ANALYSIS 
11.1. 
Interim Analysis 
One interim analysis will be performed.  An internal IRC composed of 1 Sponsor 
representative from each of the Clinical Research, Biometrics, Pharmacovigilance, 
Regulatory, and Pharmaceutical and Translational Sciences functions will review unblinded 
summary-level data from Cohort 1 in order to make a determination to proceed with the next 
cohort and to select the dose(s) of HTX-011 that will be studied in the next cohort.  The 
interim analysis will be performed after at least 80% of the planned subjects in Cohort 1 have 


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had their pain intensity and opioid use data through the 72-hour postoperative assessments 
entered into the eCRF.  Detailed responsibilities of the IRC will be presented in an IRC 
charter.  No adjustments to the type-1 error rate will be made in the efficacy hypothesis 
testing as a result of this interim analysis. 
There will be no interim analyses for Cohort 2. 
11.2. 
Data Safety Monitoring Board 
An independent Data Safety Monitoring Board (DSMB) will not be involved with the 
conduct of this study.  The Sponsor will review blinded tables and listings of accumulating 
data approximately bi-weekly to check enrollment, adherence to follow-up schedule, and 
ongoing safety results.   
12. 
REFERENCES 
Bailey, I. S., S. E. Karran, K. Toyn, P. Brough, C. Ranaboldo and S. J. Karran (1992). 
"Community surveillance of complications after hernia surgery." BMJ 304(6825): 469-471. 
Chan, I. S. and Z. Zhang (1999). "Test-based exact confidence intervals for the difference of 
two binomial proportions." Biometrics 55(4): 1202-1209. 
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. 
Silverman, D. G., T. Z. O'Connor and S. J. Brull (1993). "Integrated assessment of pain 
scores and rescue morphine use during studies of analgesic efficacy." Anesth Analg 77(1): 
168-170. 
 


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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 
Set month to month 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 first dose 
Missing 
Set day as day of 1st dose 
year = year of SDA 
Month < month of first dose 
Missing 
Set day as last day of onset month 
year = year of SDA 
Month > month of first dose 
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, there is 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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Version 
Date 
Notes/Revisions 
 
 
Revised the analysis plan for Cohort 2 to include a hierarchical 
order for the primary and key secondary endpoints 
 
Revised the sample size calculation statement in Cohort 2