Conditions: Postoperative Pain
Keywords: bunion bunionectomy bunion surgery postoperative pain
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 412
Healthy volunteers: no

Brief summary:
This is a Phase 3, randomized, double-blind, saline placebo- and active-controlled, multicenter study to evaluate the analgesic efficacy and safety of HTX 011 administered via local administration into the surgical site in subjects undergoing bunionectomy.

Detailed description:

Arms:
arm 1: HTX 011 (bupivacaine/meloxicam) arm 2: Saline placebo arm 3: Bupivacaine HCl

Interventions: intervention 1: HTX-011 intervention 2: Saline Placebo intervention 3: Bupivacaine HCl intervention 4: Luer-lock applicator intervention 5: Vial access device
Intervention descriptions: intervention 1: HTX 011 (bupivacaine/meloxicam), 60 mg/1.8 mg by instillation intervention 2: Saline placebo by instillation intervention 3: Bupivacaine HCl without epinephrine, 50 mg by injection intervention 4: Applicator for instillation intervention 5: Device for withdrawal of drug product

Protocol document:
Prot_000.pdf: 
Document Type:  
Study Protocol 
Official Title:  
A Phase 3, Randomized, Double-Blind, Saline Placebo- and Active 
Controlled, Multicenter Study of HTX-011 via Local Administration for 
Postoperative Analgesia and Decreased Opioid Use Following 
Unilateral Simple Bunionectomy 
NCT Number:  
NCT03295721 
Document Date:  
24-Sep-2017 
 


 
Confidentiality Statement 
This document contains confidential information of Heron Therapeutics, Inc. 
Do not copy or distribute without prior written permission of the Sponsor. 
Any unauthorized use, reproduction, publication, or dissemination is strictly prohibited. 
 
 
CLINICAL STUDY PROTOCOL: HTX-011-301 
 
Protocol Title: 
A Phase 3, Randomized, Double-Blind, Saline Placebo- and 
Active-Controlled, Multicenter Study of HTX-011 via Local 
Administration for Postoperative Analgesia and Decreased Opioid 
Use Following Unilateral Simple Bunionectomy 
Brief Title: 
Phase 3 bunionectomy study for postoperative analgesia (EPOCH 1) 
Investigational Product: HTX-011 (bupivacaine and meloxicam extended-release solution) 
2.5%/0.075% 
Phase of Development: 
3 
EudraCT number: 
2017-001637-81 
Sponsor: 
Heron Therapeutics, Inc. 
4242 Campus Point Court, Suite 200 
San Diego, CA 92121 
1-858-251-4400 
Medical Monitors: 
Primary 
 
 
 
Secondary 
 
 
 
Medical Project 
Leader: 
  
 
 
 
Protocol Version: 
Version 3 
Version 2 
Version 1 
24 September 2017 
29 June 2017 
21 April 2017 


Protocol No: HTX-011-301 Version 3 
Heron Therapeutics, Inc. 
Phase 3 bunionectomy study for postoperative analgesia (EPOCH 1) 
Confidential 
2 
INVESTIGATOR AGREEMENT 
CLINICAL STUDY PROTOCOL: HTX-011-301 
TITLE: A Phase 3, Randomized, Double-Blind, Saline Placebo- and Active-Controlled, 
Multicenter Study of HTX-011 via Local Administration for Postoperative Analgesia and 
Decreased Opioid Use Following Unilateral Simple Bunionectomy 
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-011-301 Version 3 
Heron Therapeutics, Inc. 
Phase 3 bunionectomy study for postoperative analgesia (EPOCH 1) 
Confidential 
3 
PROTOCOL SYNOPSIS 
Sponsor: Heron Therapeutics, Inc. 
Protocol Number: HTX-011-301 
Name of Investigational Product: 
HTX-011 (bupivacaine and meloxicam 
extended-release solution) 2.5%/0.075%  
Protocol Title:  
A Phase 3, Randomized, Double-Blind, Saline 
Placebo- and Active-Controlled, Multicenter Study of 
HTX-011 via Local Administration for Postoperative 
Analgesia and Decreased Opioid Use Following 
Unilateral Simple Bunionectomy 
Name of Active Ingredients: 
bupivacaine and meloxicam 
Phase of Development: 3 
Study Objectives: 
Primary Objective: 
 To compare the efficacy and duration of analgesia following local administration of HTX-011 with 
that of saline placebo during the first 72 hours following unilateral simple bunionectomy. 
Secondary Objectives: 
 To compare the efficacy and duration of analgesia for HTX-011 with bupivacaine HCl without 
epinephrine during the first 72 hours following surgery in this study population. 
 To compare the effect of HTX-011 with saline placebo and bupivacaine HCl without epinephrine 
on opioid load during the first 72 hours following surgery in this study population.  
 To assess the safety and tolerability of HTX-011 in this study population. 
 To further establish the pharmacokinetic (PK) parameters of bupivacaine and meloxicam in 
HTX-011 in this study population. 
Methodology: This is a Phase 3, randomized, double-blind, saline placebo- and active-controlled, 
multicenter study in subjects undergoing unilateral simple bunionectomy. 
Subjects will be screened within 28 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 surgery. On the day 
of surgery (Day 1), subjects who continue to meet the eligibility criteria will undergo a unilateral simple 
bunionectomy under regional anesthesia with no more than 20 mL of 1% lidocaine without epinephrine 
administered as a Mayo block. Epidural or spinal anesthesia is not permitted. During surgery, the use of 
intravenous (IV) fentanyl up to 4 μg/kg will be permitted for intraoperative pain control. Intraoperative 
administration of other opioids or any other analgesics (including ketamine), local anesthetics, or 
anti-inflammatory agents (except as specified by the protocol) is prohibited, unless needed to treat an 
adverse event (AE) that occurs after signing the Informed Consent Form (ICF), for pretreatment prior to a 
needle placement, or to decrease venous irritation (eg, caused by propofol, in which case no more than a 
single administration of lidocaine 1% 20 mg IV may be administered).  
Near the completion of surgery and after irrigation and suction have been completed, a single dose of 
study drug (HTX-011, saline placebo, or bupivacaine HCl without epinephrine) will be given 
intraoperatively via local administration into the surgical site.  
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 the start of study drug administration to undergo postoperative assessments. After the 
72-hour assessments have been completed, subjects may be discharged. Subjects will return to the study 


Protocol No: HTX-011-301 Version 3 
Heron Therapeutics, Inc. 
Phase 3 bunionectomy study for postoperative analgesia (EPOCH 1) 
Confidential 
4 
Sponsor: Heron Therapeutics, Inc. 
Protocol Number: HTX-011-301 
Name of Investigational Product: 
HTX-011 (bupivacaine and meloxicam 
extended-release solution) 2.5%/0.075%  
Protocol Title:  
A Phase 3, Randomized, Double-Blind, Saline 
Placebo- and Active-Controlled, Multicenter Study of 
HTX-011 via Local Administration for Postoperative 
Analgesia and Decreased Opioid Use Following 
Unilateral Simple Bunionectomy 
Name of Active Ingredients: 
bupivacaine and meloxicam 
Phase of Development: 3 
site on Days 10 and 28 to complete follow-up assessments. In addition, subjects will return for a Safety 
Follow-Up on Day 42. 
Treatment Groups  
Approximately 400 subjects will be randomized to 1 of the following 3 treatment groups in a 3:3:2 ratio: 
 HTX-011, 60 mg/1.8 mg (bupivacaine/meloxicam doses), 2.1 mL, via instillation into the surgical 
site (150 subjects) 
 Bupivacaine HCl without epinephrine 0.5%, 50 mg (10 mL), via injection into the surgical site 
(150 subjects) 
 Saline placebo, 2.1 mL, via instillation into the surgical site (100 subjects) 
Blinding 
The study will use a double-blind design. 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 saline placebo and 
bupivacaine HCl 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 PACU, the assessor and all staff involved in efficacy and safety 
assessments will be blinded to treatment assignments until after database lock. 
Postoperative 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 treating postoperative pain. Prior to the administration of the first dose of rescue medication, 
if the subject has not already had at least 1 postoperative pain score assessed, then a Numeric Rating 
Scale (NRS) score at rest (NRS-R) followed by an NRS score with activity (NRS-A) must be obtained. 
Postoperative rescue medication will consist of oral (PO) immediate-release oxycodone (no more than 
10 mg within a 4-hour period as needed), IV morphine (no more than 10 mg within a 2-hour period as 
needed), and/or oral acetaminophen (no more than 1 gram [1000 mg] in a 6-hour window). For subjects 
administered any acetaminophen-containing product, the total combined daily dose must not exceed 
4 grams (4000 mg) as severe liver damage may occur. No other analgesic agents, including nonsteroidal 
anti-inflammatory drugs (NSAIDs), are permitted during the 72-hour postoperative observation period.  
Subjects who are not medically ready for discharge at 72 hours may receive the same rescue medication 
as above to treat postoperative pain until discharge.  
For subjects who are medically ready for discharge at 72 hours, oral acetaminophen (no more than 
1000 mg every 6 hours as needed) should be recommended for postoperative pain. If a subject received 
10 mg or more of oxycodone in the 12 hours prior to discharge, the subject should be provided with a 
prescription for oxycodone (up to 10 mg PO q4h as needed). Subjects will complete a daily diary to 
record if they take an opioid medication between 72 hours and Day 28. 
Number of Planned Subjects: Approximately 400 subjects will be randomized and dosed. 


Protocol No: HTX-011-301 Version 3 
Heron Therapeutics, Inc. 
Phase 3 bunionectomy study for postoperative analgesia (EPOCH 1) 
Confidential 
5 
Sponsor: Heron Therapeutics, Inc. 
Protocol Number: HTX-011-301 
Name of Investigational Product: 
HTX-011 (bupivacaine and meloxicam 
extended-release solution) 2.5%/0.075%  
Protocol Title:  
A Phase 3, Randomized, Double-Blind, Saline 
Placebo- and Active-Controlled, Multicenter Study of 
HTX-011 via Local Administration for Postoperative 
Analgesia and Decreased Opioid Use Following 
Unilateral Simple Bunionectomy 
Name of Active Ingredients: 
bupivacaine and meloxicam 
Phase of Development: 3 
Study Sites: Up to approximately 25 sites. 
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 a primary unilateral, distal, first metatarsal bunionectomy with osteotomy 
and internal fixation under regional anesthesia. 
4. Has an American Society of Anesthesiologists Physical Status of I, II, or III. 
5. Female subjects are eligible only if all of the following apply: 
a. Not pregnant (female subjects of child-bearing potential must have a negative urine 
pregnancy test at screening and on Day 1 before surgery). 
b. Not lactating. 
c. Not planning to become pregnant during the study. 
d. Is surgically sterile; or is at least 2 years post-menopausal; or is in a monogamous 
relationship with a partner who is surgically sterile; or is practicing abstinence or agrees to 
use double-barrier contraception in the event of sexual activity; or is using an insertable, 
injectable, transdermal, or combination oral contraceptive approved by applicable regulatory 
authorities 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 who meets any of the following criteria will be excluded from the study: 
1. Has had a contralateral foot bunionectomy in the past 3 months. 
2. Has a planned concurrent surgical procedure (eg, bilateral bunionectomy or collateral procedures 
on the surgical foot). 
3. 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 
bunionectomy and which may confound the postoperative assessments. 
4. Has a contraindication or a known or suspected history of hypersensitivity or clinically significant 
idiosyncratic reaction to bupivacaine (or other local anesthetics), meloxicam (or other NSAIDs), 
oxycodone, morphine, or acetaminophen. 


Protocol No: HTX-011-301 Version 3 
Heron Therapeutics, Inc. 
Phase 3 bunionectomy study for postoperative analgesia (EPOCH 1) 
Confidential 
6 
Sponsor: Heron Therapeutics, Inc. 
Protocol Number: HTX-011-301 
Name of Investigational Product: 
HTX-011 (bupivacaine and meloxicam 
extended-release solution) 2.5%/0.075%  
Protocol Title:  
A Phase 3, Randomized, Double-Blind, Saline 
Placebo- and Active-Controlled, Multicenter Study of 
HTX-011 via Local Administration for Postoperative 
Analgesia and Decreased Opioid Use Following 
Unilateral Simple Bunionectomy 
Name of Active Ingredients: 
bupivacaine and meloxicam 
Phase of Development: 3 
5. Has known or suspected daily use of opioids for 7 or more consecutive days within the previous 
6 months. 
6. Has taken any NSAIDs (including meloxicam) within at least 10 days prior to the scheduled 
surgery with the exception of subjects on low-dose (≤100 mg) daily acetylsalicylic acid for 
cardioprotection. 
7. Has taken long-acting opioids within 3 days prior to the scheduled surgery. 
8. Has taken any opioids within 24 hours prior to the scheduled surgery. 
9. Has been administered bupivacaine within 5 days prior to the scheduled surgery.  
10. Has been administered any local anesthetic within 72 hours prior to the scheduled surgery, other 
than for pretreatment prior to a needle placement, to treat an AE that occurs after signing the ICF, 
or to decrease venous irritation (eg, caused by propofol, in which case no more than a single 
administration of lidocaine 1% 20 mg IV may be administered). 
11. Has initiated treatment with any of the following medications within 1 month prior to study drug 
administration or is taking any of these medications to control pain: selective serotonin reuptake 
inhibitors (SSRIs), selective norepinephrine reuptake inhibitors (SNRIs), gabapentin, pregabalin, 
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.  
12. Has been administered systemic steroids within 5 half-lives or 10 days prior to administration of 
study drug (whichever is longer).  
13. Has a medical condition such that, in the opinion of the Investigator, participating in the study 
would pose a health risk to the subject or confound the postoperative assessments. Conditions 
may include, but are not limited to, any of the following: 
a. History of clinically significant cardiac abnormality such as myocardial infarction within 
6 months prior to signing the ICF, New York Heart Association class III or IV, or clinically 
significant abnormalities in cardiac function or on electrocardiogram (ECG; including but not 
limited to a PR interval >200 msec, a QT corrected by Fridericia’s formula [QTcF] 
>480 msec, or 3rd degree heart block). 
b. History of coronary artery bypass graft surgery within 12 months prior to 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 


Protocol No: HTX-011-301 Version 3 
Heron Therapeutics, Inc. 
Phase 3 bunionectomy study for postoperative analgesia (EPOCH 1) 
Confidential 
7 
Sponsor: Heron Therapeutics, Inc. 
Protocol Number: HTX-011-301 
Name of Investigational Product: 
HTX-011 (bupivacaine and meloxicam 
extended-release solution) 2.5%/0.075%  
Protocol Title:  
A Phase 3, Randomized, Double-Blind, Saline 
Placebo- and Active-Controlled, Multicenter Study of 
HTX-011 via Local Administration for Postoperative 
Analgesia and Decreased Opioid Use Following 
Unilateral Simple Bunionectomy 
Name of Active Ingredients: 
bupivacaine and meloxicam 
Phase of Development: 3 
>2 × ULN. 
e. History of known or suspected coagulopathy or uncontrolled anticoagulation. 
f. Loss of sensation in extremities or significant peripheral neuropathy. 
14. 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). 
15. Has uncontrolled anxiety, psychiatric, or neurological disorder that, in the opinion of the 
Investigator, might interfere with study assessments. 
16. 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. 
17. 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. 
18. Previously participated in an HTX-011 study.  
19. 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 within 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 long-acting, immediate-release local anesthetic as the free base) and low-dose meloxicam (an NSAID) 
incorporated in a proprietary bioerodible polymer (termed Biochronomer®). HTX-011 will be supplied by 
the Sponsor as a sterile, viscous liquid in 10 mL or 20 mL clear glass vials.  
A single dose of HTX-011 60 mg/1.8 mg (bupivacaine/meloxicam doses) will be administered via 
instillation into the surgical site using a Luer-lock applicator. The Luer-lock applicator will also be 
supplied by the Sponsor.  
Reference Therapy, Dose, and Mode of Administration: 
A single dose of saline placebo (0.9% sodium chloride solution) or bupivacaine HCl without epinephrine 
0.5% (50 mg) will be administered into the surgical site. Saline placebo will be administered by 
instillation using the same method as for HTX-011. Bupivacaine HCl will be administered via injection 


Protocol No: HTX-011-301 Version 3 
Heron Therapeutics, Inc. 
Phase 3 bunionectomy study for postoperative analgesia (EPOCH 1) 
Confidential 
8 
Sponsor: Heron Therapeutics, Inc. 
Protocol Number: HTX-011-301 
Name of Investigational Product: 
HTX-011 (bupivacaine and meloxicam 
extended-release solution) 2.5%/0.075%  
Protocol Title:  
A Phase 3, Randomized, Double-Blind, Saline 
Placebo- and Active-Controlled, Multicenter Study of 
HTX-011 via Local Administration for Postoperative 
Analgesia and Decreased Opioid Use Following 
Unilateral Simple Bunionectomy 
Name of Active Ingredients: 
bupivacaine and meloxicam 
Phase of Development: 3 
evenly throughout the tissue planes to ensure equal distribution across the surgical field. 
Saline placebo and bupivacaine HCl will be supplied by the Sponsor. 
Duration of Treatment: 
Subjects will receive a single dose of study drug. The total duration of study participation for each subject 
(from Screening through the Safety Follow-Up on Day 42) will be up to 77 days. The overall duration of 
the study is anticipated to be approximately 7 months. 
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 timepoints. 
Efficacy Assessments: 
 Pain intensity scores using NRS-R and NRS-A at 1, 2, 4, 8, 12, 24, 36, 48, 60, 72 hours, and on 
Day 10 and Day 28.  
 
NRS-R: Subjects should be seated/recumbent with the surgically attended leg elevated or lying 
supine. Measurements should be obtained after the subject is in the resting position for at least 
5 minutes.  
 
NRS-A: Subjects should be seated with the plantar surface of the ball of the surgically 
attended foot touching the floor (no weight-bearing). 
 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. 
 Discharge readiness assessment per the Modified Postanaesthetic Discharge Scoring System 
(MPADSS) criteria at 2, 4, 8, 12, 24, 36, 48, 60, and 72 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 at least 72 hours.) 
 Patient Global Assessment (PGA) of pain control at 24, 48, and 72 hours and on Day 28. 
Safety Assessments: 
 AEs from the time the subject signs the ICF through the Safety Follow-Up on Day 42. 
 Local Anesthetic Systemic Toxicity (LAST) assessments at 30 minutes (±5 min), 1 hour (±5 min), 
2 hours (±15 min), 4 hours (±15 min), 18 hours (±30 min), 24 hours (±1 h), and 72 hours (±4 h). If 
symptoms are present at 30 minutes, 1 hour, or 2 hours, an unscheduled blood sample will be 
collected for PK and a 12-lead ECG will be performed. If symptoms are present at 72 hours, an 
unscheduled blood sample will be collected for PK. 
 Clinical safety laboratory tests (hematology and serum chemistry) at the Screening Visit, at 


Protocol No: HTX-011-301 Version 3 
Heron Therapeutics, Inc. 
Phase 3 bunionectomy study for postoperative analgesia (EPOCH 1) 
Confidential 
9 
Sponsor: Heron Therapeutics, Inc. 
Protocol Number: HTX-011-301 
Name of Investigational Product: 
HTX-011 (bupivacaine and meloxicam 
extended-release solution) 2.5%/0.075%  
Protocol Title:  
A Phase 3, Randomized, Double-Blind, Saline 
Placebo- and Active-Controlled, Multicenter Study of 
HTX-011 via Local Administration for Postoperative 
Analgesia and Decreased Opioid Use Following 
Unilateral Simple Bunionectomy 
Name of Active Ingredients: 
bupivacaine and meloxicam 
Phase of Development: 3 
24 hours (hematology only), at 72 hours, and on Day 10. 
 Physical examination at Screening Visit and 72 hours; the Screening Visit will also include height, 
weight, and BMI calculation. 
 Wound healing assessment at 72 hours, on Day 10 and Day 28, and at the Safety Follow-Up on 
Day 42. 
 X-ray for bone healing assessment on Day 28 and at the Safety Follow-Up on Day 42. 
 Vital signs (resting heart rate, blood pressure, respiration rate, and body temperature) at the 
Screening Visit, on Day 1 before surgery, and post-treatment at 30 minutes and at 1, 1.5, 2, 4, 8, 12, 
18, 24, 36, 48, 60, and 72 hours. 
 ECG at the Screening Visit and at 4, 18, 24, 48, and 72 hours. 
PK Assessments: 
 Blood samples for bupivacaine and meloxicam PK analysis will be collected at 4, 18, 24, and 
48 hours post-treatment. (Note: when PK and NRS pain intensity assessments coincide, the NRS 
pain intensity assessments should be conducted before the blood draw.) 
Study Endpoints:  
Primary Efficacy Endpoint: 
 Mean area under the curve (AUC) of the Numeric Rating Scale of pain intensity scores with 
activity (NRS-A) through 72 hours (AUC0-72) for HTX-011 compared with saline placebo. 
Key Secondary Efficacy Endpoints (Hierarchical Testing): 
1. Mean AUC0-72 of the NRS-A pain intensity scores for HTX-011 compared with bupivacaine HCl.  
2. Mean total postoperative opioid consumption (in morphine equivalents) through 72 hours for 
HTX-011 compared with saline placebo. 
3. Proportion of subjects who are opioid-free through 72 hours for HTX-011 compared with 
bupivacaine HCl. 
4. Mean total postoperative opioid consumption (in morphine equivalents) through 72 hours for 
HTX-011 compared with bupivacaine HCl. 
 
 
 
 
 
 
 
 
 
 


Protocol No: HTX-011-301 Version 3 
Heron Therapeutics, Inc. 
Phase 3 bunionectomy study for postoperative analgesia (EPOCH 1) 
Confidential 
10 
Sponsor: Heron Therapeutics, Inc. 
Protocol Number: HTX-011-301 
Name of Investigational Product: 
HTX-011 (bupivacaine and meloxicam 
extended-release solution) 2.5%/0.075%  
Protocol Title:  
A Phase 3, Randomized, Double-Blind, Saline 
Placebo- and Active-Controlled, Multicenter Study of 
HTX-011 via Local Administration for Postoperative 
Analgesia and Decreased Opioid Use Following 
Unilateral Simple Bunionectomy 
Name of Active Ingredients: 
bupivacaine and meloxicam 
Phase of Development: 3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety Endpoints 
 Incidence of treatment-emergent AEs (TEAEs), serious TEAEs (SAEs), and opioid-related AEs 
(ORAEs) through the Safety Follow-Up on Day 42. 
 Change from baseline in clinical laboratory results. 
 Change from baseline in ECG data. 
 Change from baseline in vital signs. 
 Wound healing assessment at 72 hours, on Day 10 and Day 28, and at the Safety Follow-Up on 
Day 42. 
 Bone healing assessment on Day 28 and at the Safety Follow-Up on Day 42. 
PK Endpoints 
 Calculated maximum plasma concentration (Cmax). 
 Calculated time to reach maximum plasma concentration (Tmax). 
Statistical Methods: 
Efficacy Analyses 
The primary estimand to address the efficacy objectives is the mean AUC of NRS-A pain intensity scores 
through 72 hours (AUC0-72) adjusted for use of opioid rescue medication via windowed worst observation 
carried forward (wWOCF), comparing the estimated treatment difference between HTX-011 and saline 
placebo using analysis of variance (ANOVA) with missing data imputed via last observation carried 
forward (LOCF) for interval censored pain intensity scores and worst observation carried forward 
(WOCF) for right-censored pain intensity scores in the Intent-to-Treat Population. 
The primary analysis of AUC0-72 of the NRS-A pain intensity scores will be carried out using an ANOVA 
model with treatment as the main effect, comparing HTX-011 with saline placebo at a significance level 
of 5%. Results will be expressed as mean AUCs and SDs, least-squares mean differences and SEs with 
associated 95% CIs, and p-values. To account for the duration effect of opioid rescue medication, the 


Protocol No: HTX-011-301 Version 3 
Heron Therapeutics, Inc. 
Phase 3 bunionectomy study for postoperative analgesia (EPOCH 1) 
Confidential 
11 
Sponsor: Heron Therapeutics, Inc. 
Protocol Number: HTX-011-301 
Name of Investigational Product: 
HTX-011 (bupivacaine and meloxicam 
extended-release solution) 2.5%/0.075%  
Protocol Title:  
A Phase 3, Randomized, Double-Blind, Saline 
Placebo- and Active-Controlled, Multicenter Study of 
HTX-011 via Local Administration for Postoperative 
Analgesia and Decreased Opioid Use Following 
Unilateral Simple Bunionectomy 
Name of Active Ingredients: 
bupivacaine and meloxicam 
Phase of Development: 3 
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. 
To account for multiple hypothesis testing on the primary endpoint and on each of the 4 key secondary 
endpoints, a strict testing hierarchy will be applied to control study-wise alpha level at 0.05. If the primary 
endpoint is statistically significant (p≤0.05), then the first key secondary endpoint will be tested. If the 
first key secondary endpoint is statistically significant, then the second key secondary endpoint will be 
tested. Sequential testing will continue in this manner down the key secondary endpoint list until an 
endpoint fails to meet statistical significance, after which all subsequent key secondary endpoints will be 
considered exploratory. If the primary endpoint is not statistically significant, then all key secondary 
endpoints will be considered exploratory. 
Continuous endpoints will be analyzed using an ANOVA model with treatment as the main effect. 
Results will be expressed as means and SDs, least-squares mean differences and SEs with associated 
95% CIs, and p-values. 
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 with Kaplan-Meier methods. 
Handling of Missing Data  
Due to the required 72-hour inpatient postoperative observation period, the amount of missing data is 
expected to be very low. For any missing data observed through 72 hours in subjects who complete the 
72-hour postoperative observation period, NRS pain intensity scores will be imputed via LOCF, in which 
the most recent postdose value is used for a subsequent missing value. For subjects who do not have a 
postdose value prior to their first missing value, the median of the postdose values at the relevant 
timepoint from subjects with observed data in the same randomized treatment group will be used. Predose 
values will not be carried forward to postdose timepoints. In subjects who withdraw from the study prior 
to 72 hours, missing NRS pain intensity scores through 72 hours that were to be collected following 
withdrawal will be imputed via WOCF, in which the worst (highest) NRS pain intensity score observed 
prior to withdrawal will be used for post-withdrawal values through 72 hours. Analyses that adjust for the 
effect of opioid rescue medication will perform wWOCF following LOCF/WOCF (ie, perform 
LOCF/WOCF first, then apply wWOCF). The number and percentage of missing NRS pain intensity 
scores will be summarized. 
Safety Analyses 
All safety data will be listed and summarized by treatment group; no statistical hypothesis testing will be 






Protocol No: HTX-011-301 Version 3 
Heron Therapeutics, Inc. 
Phase 3 bunionectomy study for postoperative analgesia (EPOCH 1) 
Confidential 
14 
Abbreviations: D, day; ECG, electrocardiogram; ET, Early Termination; F/up, follow-up; h, hour; LAST, Local Anesthetic Systemic Toxicity; min, minutes; MPADSS, Modified 
Postanaesthetic Discharge Scoring System; NRS-A, Numeric Rating Scale with activity; NRS-R, Numeric Rating Scale at rest; OR, operating room; PGA, Patient Global 
Assessment; PK, pharmacokinetic; Preop, preoperative assessments; WOCBP, women of childbearing potential; D10, Day 10; D28, Day 28; D42, Day 42. 
* The start of study drug administration will be considered as Time 0 for all efficacy, safety, and PK assessments. For assessments at timepoints when the subject is asleep, an 
attempt should be made to wake the subject. If there is no response, the assessments at these timepoints may be recorded as “Not Done.” Assessments that can be done without 
waking the subject (eg, blood collection for PK) should be completed. When PK and NRS pain intensity assessments coincide, the NRS pain intensity assessments should be 
conducted before the blood draw. See Section 6 for more information on study procedures and assessments. 
a Subjects who withdraw from the study will be asked to complete Early Termination procedures based on the timing of withdrawal (ie, prior to the Day 28 Visit, or after the Day 
28 Visit and prior to the Safety Follow-Up on Day 42). 
b The urine drug screen and urine pregnancy test should be performed first. Results should be confirmed negative prior to performing any additional assessments and prior to 
initiation of surgery. 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 body mass index calculation. 
d Only if subject withdraws prior to 72 hours. 
e If early neurologic and cardiac signs and symptoms of LAST are observed, unscheduled vital sign measurements, 12-lead ECG, and blood sample collection for PK must be 
performed. 
f 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. 
g Hematology only. 
h The length of the surgical incision should be recorded. 
i NRS-R should be assessed while the subject is seated/recumbent with the surgically attended leg elevated or lying supine. Measurements should be obtained after the subject is in 
the resting position for at least 5 minutes. 
j If a subject requires rescue medication before the 1-hour pain intensity assessments, then an unscheduled NRS-R pain score followed by an NRS-A pain score must be obtained 
before administering the first dose of rescue medication. These do not replace the 1-hour NRS-R and NRS-A assessments.  
k Only if subject withdraws prior to Day 28. 
l The prescribed activity for NRS-A is sitting with the plantar surface of the ball of the surgically attended foot touching the floor (no weight-bearing). 
m Subjects will complete a daily diary from 72 hours through Day 28 to record if they take any opioid medication. Subject diary results will be reviewed at each site visit up to and 
including the Day 28 Visit. 
n This study instrument assesses a subject’s potential readiness to be discharged and should be repeated at all scheduled timepoints. It is not meant to be used to decide on whether 
or not to discharge a subject from the study.  
o An X-ray finding of delayed healing should be followed with a repeat X-ray every 2 to 4 weeks until resolution (ie, signs of normal healing are evident). 
p Only if the subject withdrew from the study after 72 hours. 
q At the Screening Visit, ensure subject is not taking any prohibited medications. Record all medications taken from the time the subject signs the Informed Consent Form (ICF) 
through the Safety Follow-Up on Day 42. 
r Adverse events will be collected from the time the subject signs the ICF through the Safety Follow-Up on Day 42. 
 


Protocol No: HTX-011-301 Version 3 
Heron Therapeutics, Inc. 
Phase 3 bunionectomy study for postoperative analgesia (EPOCH 1) 
Confidential 
15 
TABLE OF CONTENTS 
INVESTIGATOR AGREEMENT...................................................................................................2 
PROTOCOL SYNOPSIS ................................................................................................................3 
SCHEDULE OF EVENTS ............................................................................................................13 
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 ...........................................23 
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 .......................................................................................................28 
3.1.3. 
Postoperative Rescue Medications .............................................................................29 
3.1.4. 
Postoperative Assessments .........................................................................................29 
3.2. 
Study Endpoints ..........................................................................................................30 
3.2.1. 
Efficacy Endpoints ......................................................................................................30 
3.2.1.1. 
Primary Efficacy Endpoint .........................................................................................30 
3.2.1.2. 
Key Secondary Efficacy Endpoints (Hierarchical Testing) ........................................30 
 
 
3.2.2. 
Safety Endpoints .........................................................................................................31 
3.2.3. 
Pharmacokinetic Endpoints ........................................................................................31 
3.3. 
Study Duration ............................................................................................................31 
4. 
STUDY ENROLLMENT AND WITHDRAWAL ....................................................32 
4.1. 
Study Population .........................................................................................................32 
4.1.1. 
Inclusion Criteria ........................................................................................................32 
4.1.2. 
Exclusion Criteria .......................................................................................................32 
4.2. 
Method of Assigning Subjects to Treatment Groups .................................................34 
4.2.1. 
Procedures for Handling Randomized Subjects Who Do Not Meet the Study 
Eligibility Criteria .......................................................................................................34 


Protocol No: HTX-011-301 Version 3 
Heron Therapeutics, Inc. 
Phase 3 bunionectomy study for postoperative analgesia (EPOCH 1) 
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16 
4.3. 
Blinding ......................................................................................................................35 
4.3.1. 
Breaking the Blind ......................................................................................................35 
4.4. 
Subject Withdrawal and Replacement ........................................................................35 
4.4.1. 
Subject Withdrawal ....................................................................................................35 
4.4.2. 
Subject Replacement ..................................................................................................36 
5. 
STUDY TREATMENT ..............................................................................................37 
5.1. 
Description of Investigational Product .......................................................................37 
5.2. 
Manufacturing, Packaging, and Labeling ...................................................................37 
5.3. 
Storage ........................................................................................................................37 
5.4. 
Preparation ..................................................................................................................37 
5.5. 
Study Drug Administration.........................................................................................37 
5.5.1. 
Instillation: HTX-011 and Saline Placebo ..................................................................37 
5.5.2. 
Injection: Bupivacaine HCl ........................................................................................38 
5.6. 
Study Drug Compliance .............................................................................................39 
5.7. 
Study Drug Accountability .........................................................................................39 
6. 
STUDY PROCEDURES AND ASSESSMENTS......................................................40 
6.1. 
Medical History and Demographics ...........................................................................40 
6.1.1. 
Medical History ..........................................................................................................40 
6.1.2. 
Demographics .............................................................................................................40 
6.2. 
Prior and Concomitant Therapy ..................................................................................40 
6.2.1. 
Allowed Concomitant Medications ............................................................................40 
6.2.2. 
Prohibited Medications ...............................................................................................41 
6.2.2.1. 
Medications Prohibited Prior to Surgery ....................................................................41 
6.2.2.2. 
Medications Prohibited During Surgery .....................................................................41 
6.2.2.3. 
Medications Prohibited From Time 0 Through 72 Hours ..........................................41 
6.3. 
Efficacy Assessments .................................................................................................41 
6.3.1. 
Pain Intensity Assessment ..........................................................................................41 
6.3.2. 
Use of Opioid Medications .........................................................................................42 
6.3.2.1. 
Opioid Rescue Medication Through 72 Hours ...........................................................42 
6.3.2.2. 
Subject Daily Diary of Opioid Use From 72 Hours Through Day 28 ........................42 
6.3.3. 
Discharge Readiness ...................................................................................................42 
6.3.4. 
Patient Global Assessment (PGA) of Pain Control ....................................................42 
6.4. 
Safety Assessments .....................................................................................................43 


Protocol No: HTX-011-301 Version 3 
Heron Therapeutics, Inc. 
Phase 3 bunionectomy study for postoperative analgesia (EPOCH 1) 
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17 
6.4.1. 
Adverse Events ...........................................................................................................43 
6.4.2. 
Local Anesthetic Systemic Toxicity Assessment .......................................................43 
6.4.3. 
Physical Examinations ................................................................................................43 
6.4.4. 
Vital Signs ..................................................................................................................43 
6.4.5. 
12-Lead Electrocardiograms .......................................................................................43 
6.4.6. 
Wound Healing Assessment .......................................................................................44 
6.4.7. 
Bone Healing Assessment ..........................................................................................44 
6.4.8. 
Clinical Laboratory Tests ...........................................................................................44 
6.5. 
Pharmacokinetic Assessments ....................................................................................45 
7. 
TIMING OF PROCEDURES AND ASSESSMENTS ..............................................46 
7.1. 
Screening Period .........................................................................................................46 
7.2. 
Treatment and Postoperative Observation Period ......................................................47 
7.2.1. 
Day of Surgery (Day 1) ..............................................................................................47 
7.2.1.1. 
Prior to Surgery ...........................................................................................................47 
7.2.1.2. 
Surgery and Study Drug Administration ....................................................................47 
7.2.2. 
Postoperative Assessment Period (Up to 72 Hours) ...................................................48 
7.2.3. 
End of the Postoperative Assessment Period ..............................................................49 
7.3. 
Follow-Up Period .......................................................................................................50 
7.3.1.1. 
Day 10 Visit (±3 Days) ...............................................................................................50 
7.3.1.2. 
Day 28 Visit (±4 Days) ...............................................................................................50 
7.3.1.3. 
Safety Follow-Up (Day 42 ±7 Days) ..........................................................................50 
7.4. 
Early Termination Visit ..............................................................................................50 
7.4.1. 
Withdrawal Prior to the Day 28 Visit .........................................................................51 
7.4.2. 
Withdrawal After the Day 28 Visit and Prior to the Safety Follow-Up on 
Day 42 .........................................................................................................................51 
7.5. 
Unscheduled Visits and Assessments .........................................................................51 
8. 
SAFETY MONITORING AND REPORTING .........................................................53 
8.1. 
Definition of Safety Parameters..................................................................................53 
8.1.1. 
Definition of an Adverse Event ..................................................................................53 
8.1.2. 
Definition of a Serious Adverse Event .......................................................................54 
8.1.3. 
Definition of a Suspected Adverse Reaction ..............................................................55 
8.1.4. 
Definition of a Serious Suspected Adverse Reaction .................................................55 
8.1.5. 
Definition of Unanticipated Problems ........................................................................55 


Protocol No: HTX-011-301 Version 3 
Heron Therapeutics, Inc. 
Phase 3 bunionectomy study for postoperative analgesia (EPOCH 1) 
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8.2. 
Classification of Adverse Events ................................................................................55 
8.2.1. 
Severity of Adverse Events ........................................................................................55 
8.2.2. 
Relationship to Study Drug ........................................................................................56 
8.3. 
Time Period and Frequency for Event Assessment and Follow Up ...........................56 
8.3.1. 
Adverse Event and Serious Adverse Event Monitoring .............................................56 
8.3.2. 
Follow-Up of Events ...................................................................................................57 
8.4. 
Reporting Procedures ..................................................................................................57 
8.4.1. 
Reporting Serious Adverse Events to the Sponsor .....................................................57 
8.4.2. 
Reporting Unanticipated Problems to the Sponsor .....................................................58 
8.4.3. 
Regulatory Reporting Requirements ..........................................................................59 
8.4.4. 
Pregnancy Reporting ..................................................................................................59 
8.5. 
Safety Oversight .........................................................................................................59 
9. 
OTHER STUDY RESTRICTIONS ...........................................................................60 
9.1. 
Contraception ..............................................................................................................60 
10. 
STATISTICAL CONSIDERATIONS .......................................................................61 
10.1. 
General Considerations ...............................................................................................61 
10.2. 
Determination of Sample Size ....................................................................................61 
10.3. 
Analysis Populations ..................................................................................................61 
10.4. 
Statistical Analysis Methods.......................................................................................62 
10.4.1. 
Disposition and Demographics ...................................................................................62 
10.4.2. 
Efficacy Analysis ........................................................................................................62 
10.4.2.1. 
Primary Efficacy Analysis ..........................................................................................62 
10.4.2.2. 
Key Secondary Efficacy Analyses ..............................................................................62 
10.4.2.3. 
Study-Wise Type I Error Control ...............................................................................63 
 
63 
10.4.2.5. 
Handling of Missing Data ...........................................................................................63 
10.4.3. 
Safety Analysis ...........................................................................................................63 
10.4.4. 
Pharmacokinetic Analysis ..........................................................................................64 
10.5. 
Interim Analysis ..........................................................................................................64 
11. 
QUALITY ASSURANCE AND QUALITY CONTROL .........................................65 
12. 
REGULATORY AND ETHICAL CONSIDERATIONS ..........................................66 
12.1. 
Regulatory Authority Approval ..................................................................................66 
12.2. 
Ethical Conduct of the Study ......................................................................................66 


Protocol No: HTX-011-301 Version 3 
Heron Therapeutics, Inc. 
Phase 3 bunionectomy study for postoperative analgesia (EPOCH 1) 
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12.3. 
Ethics Committee Approval .......................................................................................66 
12.4. 
Informed Consent Process ..........................................................................................66 
12.5. 
Confidentiality ............................................................................................................67 
13. 
STUDY ADMINISTRATION ...................................................................................69 
13.1. 
Clinical Monitoring ....................................................................................................69 
13.2. 
Source Documents and Record Retention ..................................................................69 
13.3. 
Management of Protocol Amendments and Deviations .............................................69 
13.3.1. 
Protocol Modification .................................................................................................69 
13.3.2. 
Protocol Violations and Deviations ............................................................................69 
13.4. 
Financial Disclosure ...................................................................................................70 
13.5. 
Stopping Criteria: Suspension or Termination of Study or Investigational 
Site ..............................................................................................................................70 
13.5.1. 
Suspension of Study ...................................................................................................70 
13.5.2. 
Termination of Study or Investigational Site ..............................................................70 
13.6. 
Publication and Information Disclosure Policy ..........................................................71 
14. 
REFERENCE LIST ....................................................................................................72 
APPENDIX A. AMERICAN SOCIETY OF ANESTHESIOLOGISTS PHYSICAL 
STATUS CLASSIFICATION SYSTEM ...................................................................75 
APPENDIX B. BMI CALCULATION ......................................................................................76 
APPENDIX C. PAIN INTENSITY ASSESSMENTS USING THE NUMERIC 
RATING SCALE (NRS) ............................................................................................77 
APPENDIX D. PATIENT GLOBAL ASSESSMENT (PGA) OF PAIN CONTROL ...............78 
APPENDIX E. DISCHARGE READINESS ASSESSMENT – MODIFIED 
POSTANAESTHETIC DISCHARGE SCORING SYSTEM CRITERIA ................79 
APPENDIX F. WOUND HEALING ASSESSMENT ...............................................................80 
APPENDIX G. INSTRUCTIONS FOR POSTOPERATIVE PAIN MANAGEMENT 
FOR SUBJECTS MEDICALLY READY FOR DISCHARGE ................................81 
APPENDIX H. LOCAL ANESTHETIC SYSTEMIC TOXICITY ASSESSMENT .................82 
 
 
LIST OF TABLES 
Table 1: 
Clinical Laboratory Tests ...........................................................................................44 
 


Protocol No: HTX-011-301 Version 3 
Heron Therapeutics, Inc. 
Phase 3 bunionectomy study for postoperative analgesia (EPOCH 1) 
Confidential 
20 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
AE 
Adverse event 
ANOVA 
Analysis of variance 
API 
Active pharmaceutical ingredient 
AUC 
Area under the curve  
BMI 
Body mass index 
CFR 
Code of Federal Regulations 
CHMP 
Committee for Medicinal Products for Human Use 
CI 
Confidence interval 
Cmax 
Maximum observed plasma concentration 
CONSORT 
Consolidated Standards of Reporting Trials 
COX-2 
Cyclooxygenase-2 
CPMP 
Committee for Proprietary Medicinal Products 
CTM 
Clinical trial material 
CV 
Cardiovascular  
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 
h 
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 
IRB 
Institutional Review Board 


Protocol No: HTX-011-301 Version 3 
Heron Therapeutics, Inc. 
Phase 3 bunionectomy study for postoperative analgesia (EPOCH 1) 
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IRT 
Interactive response technology 
ITT 
Intent-to-Treat  
IV 
Intravenous(ly)  
LAST 
Local Anesthetic Systemic Toxicity 
LOCF 
Last observation carried forward 
min 
Minute 
MPADSS 
Modified Postanaesthetic Discharge Scoring System 
NONMEM 
Non-linear mixed effects modeling 
NRS 
Numeric Rating Scale 
NRS-A 
NRS scores with activity  
NRS-R 
NRS scores at rest  
NSAID 
Nonsteroidal anti-inflammatory drug 
ORAE 
Opioid-related adverse event 
PACU 
Postanesthesia care unit 
PGA 
Patient Global Assessment 
PK 
Pharmacokinetic(s) 
PO 
By mouth, orally 
REB 
Research Ethics Board 
SAE 
Serious adverse event 
SD 
Standard deviation 
SE 
Standard error 
SNRI 
Selective norepinephrine reuptake inhibitor 
SOP 
Standard Operating Procedure 
SSRI 
Selective serotonin reuptake inhibitor 
TEAE 
Treatment-emergent adverse event 
Tmax 
Time to maximum plasma concentration 
ULN 
Upper limit of normal 
US 
United States 
WOCF 
Worst observation carried forward 
wWOCF 
Windowed worst observation carried forward 


Protocol No: HTX-011-301 Version 3 
Heron Therapeutics, Inc. 
Phase 3 bunionectomy study for postoperative analgesia (EPOCH 1) 
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1. 
INTRODUCTION 
1.1. 
Background Information and Study Rationale 
Up to 70% of patients have moderate to severe pain after surgery, and the most severe pain 
occurs within the first 72 hours (Lynch, 1997;  Svensson, 2000;  Apfelbaum, 2003;  Gan, 2014;  
Misiolek, 2014;  Singla, 2014;  Meissner, 2015). Administering a local anesthetic (eg, 
bupivacaine, ropivacaine, or levobupivacaine) is a relatively simple and safe means of providing 
postoperative pain relief. A major limitation of current local anesthetics is their short duration of 
effect (6 to 12 hours following surgery) (Kehlet, 2011). Consequently, many patients are given 
opioids for pain management. The requirement for opioids postoperatively is a serious 
manifestation of ineffective pain relief. Exposure to opioids can lead to opioid-related adverse 
events (ORAEs) resulting in worse patient outcomes and increased hospital costs (Coley, 2002;  
Wheeler, 2002;  Stephens, 2003;  Cashman, 2004;  Shirakami, 2005;  Jarzyna, 2011;  
Ramachandran, 2011;  Chan, 2013;  Kessler, 2013;  Oderda, 2013;  Lee, 2015;  Lee, 2016). 
Furthermore, transition from acute opioid use to chronic use can occur quickly. A recent review 
of a random sample of records from patients who had at least 1 opioid prescription between 2006 
and 2015 showed that the probability of chronic opioid use begins to increase after the third day 
supplied and rises rapidly thereafter (Shah, 2017). The United States (US) is facing a national 
opioid crisis that has led to a public health epidemic with multiple national and state responses. 
In 2015, 2 million Americans had a substance use disorder involving prescription pain relievers, 
and over 20,000 accidental overdose deaths were related to prescription pain relievers (Bose, 
2016;  Rudd, 2016). Reduced exposure to opioids and better pain management is associated with 
improved patient outcomes and reduced risk for the development of persistent pain and 
consequent opioid abuse (Barnett, 2017). Therefore, there is a medical need for clinical 
alternatives to prescription opioids to manage ambulatory nonmalignant pain. The development 
of an extended-release local anesthetic applicable for a broad range of surgeries that could 
significantly reduce both pain and opioid use after surgery and can be easily administered with a 
favorable safety profile would address an important public health need. 
Heron Therapeutics, Inc. (Heron) is developing HTX-011 for local administration into the 
surgical site to reduce postoperative pain and the need for opioid analgesics through 72 hours. 
HTX-011 is an extended-release, fixed-ratio combination product that contains 2 active 
pharmaceutical ingredients (APIs), bupivacaine as the main or disease-active ingredient and 
low-dose meloxicam to enhance the effectiveness of bupivacaine, incorporated in a proprietary 
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 over 3 days. Bupivacaine HCl is an amide-type, long-acting, immediate-release, local 
anesthetic and meloxicam is a nonsteroidal anti-inflammatory drug (NSAID). Both have been 
approved by the US Food and Drug Administration (FDA) and in many countries outside the US 
and have a long history of clinical use. Bupivacaine is available as a solution for injection and is 
approved for surgical anesthesia and for acute pain management (nerve block) in adults and 
children (MARCAINE, SENSORCAINE®, and VIVACAINETM). Meloxicam is available as a 
tablet for oral use and approved for short-term symptomatic treatment of exacerbations of 
osteoarthrosis and long-term symptomatic treatment of rheumatoid arthritis or ankylosing 


Protocol No: HTX-011-301 Version 3 
Heron Therapeutics, Inc. 
Phase 3 bunionectomy study for postoperative analgesia (EPOCH 1) 
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spondylitis in adults. 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 3, randomized, double-blind, saline placebo- and active-controlled, multicenter 
study in subjects undergoing unilateral simple bunionectomy to evaluate the analgesic efficacy, 
safety, and pharmacokinetics (PK) of HTX-011 administered via local administration into the 
surgical site. 
1.2. 
Rationale for Study Design, Doses, and Control Groups 
Bunionectomy is an accepted model of postoperative pain. Bunionectomy produces generally 
reliable and persistent pain symptoms for a period typically lasting over 72 hours from the 
surgery, which allows for analysis of acute analgesia over an extended period of time. 
The study will compare HTX-011 via local administration into the surgical site with 2 controls: a 
saline placebo control and an active control, bupivacaine HCl without epinephrine. 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. 
One dose level of HTX-011 will be evaluated in this study, 60 mg/1.8 mg 
(bupivacaine/meloxicam doses) administered via instillation. The dose and administration 
technique were selected based on a previous Phase 2, dose-finding study in bunionectomy 
(Study 208). In Study 208, HTX-011 doses ranging from 30 mg/0.9 mg to 200 mg/6 mg 
administered via different local administration techniques (injection, injection using a Mayo 
block, instillation) were evaluated. The 60 mg/1.8 mg dose was determined to be the minimally 
effective dose for producing postoperative analgesia through 72 hours. An evaluation of pain 
intensity scores by local administration technique for HTX 011 60 mg/1.8 mg demonstrated a 
significant reduction in mean pain intensity over 72 hours when HTX-011 was administered via 
instillation compared with saline placebo and bupivacaine HCl. HTX-011 60 mg/1.8 mg had a 
favorable safety profile. No serious adverse events (SAEs) were observed for this dose. Based on 
these findings, 60 mg/1.8 mg administered via instillation was selected for this Phase 3 study. 
The primary endpoint for this study, mean area under the curve (AUC) of the Numeric Rating 
Scale of pain intensity scores with activity (NRS-A) through 72 hours (AUC0-72) for HTX-011 
compared with saline placebo, was selected based on FDA and Committee for Medicinal 
Products for Human Use (CHMP) guidances as well as regulatory precedent. Draft FDA 
Guidance for Industry on Analgesic Indications: Developing Drug and Biological Products 
(February 2014) states that “pain intensity is the fundamental measure that defines the efficacy of 
an analgesic drug.” In addition, the FDA agreed to a primary endpoint of AUC of the NRS pain 
intensity scores over the first 24-hour period in a bony model (bunionectomy) for EXPAREL® 
(EXPAREL USPI, 2016). The timepoint of 72 hours selected for this study is considered 


Protocol No: HTX-011-301 Version 3 
Heron Therapeutics, Inc. 
Phase 3 bunionectomy study for postoperative analgesia (EPOCH 1) 
Confidential 
24 
clinically relevant for patients as literature shows that the most severe postoperative pain occurs 
within the first 72 hours after surgery (Lynch 1997;  Svensson 2000;  Apfelbaum 2003;  Gan 
2014;  Misiolek 2014;  Singla 2014;  Meissner 2015). NRS-A was selected for the primary 
endpoint because activity is known to be a more sensitive measure of pain control (Breivik, 
2008), and the prescribed activity reflects a simple daily activity for patients (sitting with the 
plantar surface of the ball of the surgically attended foot touching the floor [no weight-bearing]). 
The primary comparator is saline placebo, as recommended in the February 2014 FDA draft 
Guidance for Industry on Analgesic Indications: Developing Drug and Biological Products and 
the Committee for Proprietary Medicinal Products (CPMP’s) Note for Guidance on Clinical 
Investigation of Medicinal Products For Treatment of Nociceptive Pain (Doc. Ref. 
CPMP/EWP/612/00). Bupivacaine HCl is included as an active comparator. Bupivacaine HCl is 
the widely accepted standard for local analgesia. Bupivacaine is the disease-active ingredient in 
the HTX-011 fixed-ratio combination product with low-dose meloxicam included to enhance the 
effectiveness of bupivacaine. Discussions with experts confirmed that bupivacaine doses 
commonly used for bunionectomy range from 8 to 10 mL using 0.25% or 0.5% solution 
delivered into the wound. The dose of bupivacaine solution selected for this Phase 3 study, 
50 mg (10 mL of 0.5% solution), reflects the maximum dose and maximum concentration that is 
commonly used and allows for appropriate comparisons within the study. This dose is within the 
range of dosing provided in bupivacaine labeling (MARCAINE USPI, 2011;  MARCAIN SmPC, 
2016) and is further supported by a clinical study of EXPAREL in bunionectomy, which used a 
volume of 8 mL for both EXPAREL and placebo (Golf, 2011), and by published literature with 
active comparators (Ptaszek, 1999;  Baxter, 2013). All subjects with inadequately controlled pain 
will have access to prespecified rescue medication, including both non-opioid (acetaminophen) 
and opioid (morphine and/or oxycodone) options. 
The study includes 4 prespecified key secondary endpoints with a strict statistical hypothesis 
testing hierarchy to preserve the study-wise alpha level at 5%. Given the importance of 
comparison to the bupivacaine active control arm in order to satisfy the Combination Rule, 
21 Code of Federal Regulations (CFR) 300.50 Fixed-Combination Prescription Drugs for 
Humans, the first key secondary endpoint will evaluate the mean AUC0-72 of the NRS-A pain 
intensity scores compared with an active control, bupivacaine HCl. The 2nd, 3rd, and 4th key 
secondary endpoints will evaluate opioid consumption through 72 hours compared with saline 
placebo, proportion of subjects who are opioid-free through 72 hours compared with bupivacaine 
HCl, and opioid consumption through 72 hours compared with bupivacaine HCl, respectively. 
Given the concern for misuse and abuse of opioids, a reduction in opioid load and an increase in 
the number of subjects who are opioid free are considered clinically meaningful endpoints and 
are in alignment with the February 2014 FDA draft Guidance for Industry on Analgesic 
Indications: Developing Drug and Biological Products. Opioid sparing endpoints were also 
included in recently approved labels for EXPAREL, OFIRMEV®, and CALDOLOR®, and 
NAROPIN®. 
1.3. 
Potential Risks and Benefits 
As of 23 March 2017, 665 subjects have been exposed to 1 of the 3 different formulations of 
HTX-011 in 6 clinical studies. This includes 2 Phase 1 studies in healthy volunteers 
(subcutaneous study drug administration [Studies 02 and 102]) and 4 Phase 2 local 




Protocol No: HTX-011-301 Version 3 
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Use of HTX-011 in subjects with hypersensitivity to bupivacaine, meloxicam, or any of the 
components of HTX-011 is contraindicated. 
The analgesic efficacy of HTX-011 has been evaluated in Phase 2. In a Phase 2 study in subjects 
undergoing unilateral simple bunionectomy, single-dose administration of the Phase 3 HTX-011 
formulation ranging from 60 mg/1.8 mg to 200 mg/6 mg resulted in a significant reduction in 
mean AUC of pain intensity scores through 72 hours. HTX-011 was also associated with 
decreased total opioid consumption, and resulted in more subjects who were opioid-free and a 
longer time to first opioid use compared with saline placebo. Similar efficacy results were 
observed in a second Phase 2 study in subjects undergoing unilateral open inguinal 
herniorrhaphy, where single-dose administration of the current HTX-011 formulation at doses of 
200 mg/6 mg to 400 mg/12 mg also significantly decreased the mean AUC of pain intensity 
scores through 72 hours compared with saline placebo. 
For more information on HTX-011, refer to the Investigator’s Brochure (IB). For more 
information on the APIs, bupivacaine and meloxicam, refer to the local product labels. 


Protocol No: HTX-011-301 Version 3 
Heron Therapeutics, Inc. 
Phase 3 bunionectomy study for postoperative analgesia (EPOCH 1) 
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2. 
STUDY OBJECTIVES 
2.1. 
Primary Objective 
The primary objective is to compare the efficacy and duration of analgesia following local 
administration of HTX-011 with saline placebo during the first 72 hours following unilateral 
simple bunionectomy. 
2.2. 
Secondary Objectives 
The secondary objectives are as follows: 
 To compare the efficacy and duration of analgesia for HTX-011 with bupivacaine 
HCl without epinephrine during the first 72 hours following surgery in this study 
population. 
 To compare the effect of HTX-011 with saline placebo and bupivacaine HCl without 
epinephrine on opioid load during the first 72 hours following surgery in this study 
population. 
 To assess the safety and tolerability of HTX-011 in this study population. 
 To further establish the PK parameters of bupivacaine and meloxicam in HTX-011 in 
this study population. 


Protocol No: HTX-011-301 Version 3 
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Phase 3 bunionectomy study for postoperative analgesia (EPOCH 1) 
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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 3, randomized, double-blind, saline placebo- and active-controlled, multicenter 
study to evaluate the analgesic efficacy, safety, and PK of HTX-011 administered via local 
administration into the surgical site in subjects undergoing unilateral simple bunionectomy. 
All subjects will be screened within 28 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 1), subjects who continue to meet the eligibility 
criteria will undergo a unilateral simple bunionectomy under regional anesthesia with no more 
than 20 mL of 1% lidocaine without epinephrine administered as a Mayo block. Epidural or 
spinal anesthesia is not permitted. During surgery, the use of intravenous (IV) fentanyl up to 
4 μg/kg will be permitted for intraoperative pain control. Intraoperative administration of other 
opioids or other analgesics, local anesthetics, or anti-inflammatory agents (except as specified by 
the protocol) is prohibited, unless needed to treat an adverse event (AE) that occurs after signing 
the Informed Consent Form (ICF), for pretreatment prior to a needle placement, or to decrease 
venous irritation (eg, caused by propofol, in which case no more than a single administration of 
lidocaine 1% 20 mg IV may be administered). 
Near the completion of surgery and after irrigation and suction have been completed, a single 
dose of study drug (HTX-011, saline placebo, or bupivacaine HCl without epinephrine) will be 
given intraoperatively via local administration into the surgical site, as described in Section 5.5. 
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 the 
start of study drug 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. In addition, subjects will return for a 
Safety Follow-Up on Day 42. 
3.1.2. 
Treatment Groups 
Approximately 400 subjects will be randomized to 1 of the following 3 treatment groups in a 
3:3:2 ratio: 
 HTX-011, 60 mg/1.8 mg (bupivacaine/meloxicam doses), 2.1 mL, via instillation into 
the surgical site (150 subjects) 
 Bupivacaine HCl without epinephrine 0.5%, 50 mg (10 mL), via injection into the 
surgical site (150 subjects) 
 Saline placebo, 2.1 mL, via instillation into the surgical site (100 subjects) 


Protocol No: HTX-011-301 Version 3 
Heron Therapeutics, Inc. 
Phase 3 bunionectomy study for postoperative analgesia (EPOCH 1) 
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3.1.3. 
Postoperative 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 treating postoperative pain. Prior to the administration of the first dose 
of rescue medication, if the subject has not already had at least 1 postoperative pain score 
assessed, then 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 oral (PO) immediate-release oxycodone (no more 
than 10 mg within a 4-hour period as needed), IV morphine (no more than 10 mg within a 2-hour 
period as needed), and/or oral acetaminophen (no more than 1 gram [1000 mg] in a 6-hour 
window). For subjects administered any acetaminophen-containing product, the total combined 
daily dose must not exceed 4 grams (4000 mg) as severe liver damage may occur. No other 
analgesic agents, including NSAIDs, are permitted during the 72-hour postoperative observation 
period. 
Subjects who are not medically ready for discharge at 72 hours may receive the same rescue 
medication as above to treat postoperative pain until discharge. 
For subjects who are medically ready for discharge at 72 hours, oral acetaminophen (no more 
than 1000 mg every 6 hours as needed) should be recommended for postoperative pain. If a 
subject received 10 mg or more of oxycodone in the 12 hours prior to discharge, the subject 
should be provided with a prescription for oxycodone (up to 10 mg PO q4h as needed). See 
Appendix G for instructions on postoperative pain management for subjects medically ready for 
discharge. 
Subjects will complete a daily diary to record if they take an opioid medication between 72 hours 
and Day 28. 
3.1.4. 
Postoperative Assessments 
Efficacy assessments will include pain intensity scores using NRS-R and NRS-A, use of opioid 
medication, discharge readiness as assessed by the Modified Postanaesthetic Discharge Scoring 
System (MPADSS), and Patient Global Assessment (PGA) of pain control. 
Safety assessments will include AE recording, local anesthetic systemic toxicity (LAST) 
assessments, physical examinations, vital signs, electrocardiograms (ECGs), hematology and 
serum chemistry, wound healing, and bone healing (X-ray) assessments. 
PK assessments will include the collection of blood samples for bupivacaine and meloxicam PK 
analysis. See Section 7.2.2 for instructions regarding unscheduled PK blood sample collection 
for signs and symptoms associated with potential LAST. 
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. 


Protocol No: HTX-011-301 Version 3 
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Phase 3 bunionectomy study for postoperative analgesia (EPOCH 1) 
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3.2. 
Study Endpoints 
3.2.1. 
Efficacy Endpoints 
3.2.1.1. 
Primary Efficacy Endpoint 
 Mean area under the curve (AUC) of the Numeric Rating Scale of pain intensity 
scores with activity (NRS-A) through 72 hours (AUC0-72) for HTX-011 compared 
with saline placebo. 
3.2.1.2. 
Key Secondary Efficacy Endpoints (Hierarchical Testing) 
1. Mean AUC0-72 of the NRS-A pain intensity scores for HTX-011 compared with 
bupivacaine HCl. 
2. Mean total postoperative opioid consumption (in morphine equivalents) through 72 hours 
for HTX-011 compared with saline placebo. 
3. Proportion of subjects who are opioid-free through 72 hours for HTX-011 compared with 
bupivacaine HCl. 
4. Mean total postoperative opioid consumption (in morphine equivalents) through 72 hours 
for HTX-011 compared with bupivacaine HCl. 
3.2.1.3. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol No: HTX-011-301 Version 3 
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3.2.2. 
Safety Endpoints 
 Incidence of TEAEs, SAEs, and ORAEs through the Safety Follow-Up on Day 42. 
 Change from baseline in clinical laboratory results. 
 Change from baseline in ECG data. 
 Change from baseline in vital signs. 
 Wound healing assessment at 72 hours, on Day 10 and Day 28, and at the Safety 
Follow-Up on Day 42. 
 Bone healing assessment on Day 28 and at the Safety Follow-Up on Day 42. 
3.2.3. 
Pharmacokinetic Endpoints 
 Calculated maximum plasma concentration (Cmax). 
 Calculated time to reach maximum plasma concentration (Tmax). 
3.3. 
Study Duration 
The overall duration of the study is anticipated to be approximately 7 months. The total duration 
of study participation for each subject (from Screening through the Safety Follow-Up on Day 42) 
will be up to 77 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). 


Protocol No: HTX-011-301 Version 3 
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Phase 3 bunionectomy study for postoperative analgesia (EPOCH 1) 
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4. 
STUDY ENROLLMENT AND WITHDRAWAL 
4.1. 
Study Population 
Approximately 400 subjects will be randomized in this study at up to approximately 25 study 
sites. 
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 a primary unilateral, distal, first metatarsal bunionectomy with 
osteotomy and internal fixation under regional anesthesia. 
4. Has an American Society of Anesthesiologists Physical Status of I, II, or III. 
5. Female subjects are eligible only if all of the following apply: 
a. Not pregnant (female subjects of child-bearing potential must have a negative urine 
pregnancy test at screening and on Day 1 before surgery). 
b. Not lactating. 
c. Not planning to become pregnant during the study. 
d. Is surgically sterile; or is at least 2 years post-menopausal; or is in a monogamous 
relationship with a partner who is surgically sterile; or is practicing abstinence or 
agrees to use double-barrier contraception in the event of sexual activity; or is using 
an insertable, injectable, transdermal, or combination oral contraceptive approved by 
applicable regulatory authorities 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 who meets any of the following criteria will be excluded from the study: 
1. Has had a contralateral foot bunionectomy in the past 3 months. 
2. Has a planned concurrent surgical procedure (eg, bilateral bunionectomy or collateral 
procedures on the surgical foot). 
3. 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 bunionectomy and which may confound the postoperative 
assessments. 


Protocol No: HTX-011-301 Version 3 
Heron Therapeutics, Inc. 
Phase 3 bunionectomy study for postoperative analgesia (EPOCH 1) 
Confidential 
33 
4. Has a contraindication or a known or suspected history of hypersensitivity or clinically 
significant idiosyncratic reaction to bupivacaine (or other local anesthetics), meloxicam 
(or other NSAIDs), oxycodone, morphine, or acetaminophen. 
5. Has known or suspected daily use of opioids for 7 or more consecutive days within the 
previous 6 months. 
6. Has taken any NSAIDs (including meloxicam) within at least 10 days prior to the 
scheduled surgery with the exception of subjects on low dose (≤100 mg) daily 
acetylsalicylic acid for cardioprotection. 
7. Has taken long-acting opioids within 3 days prior to the scheduled surgery. 
8. Has taken any opioids within 24 hours prior to the scheduled surgery. 
9. Has been administered bupivacaine within 5 days prior to the scheduled surgery. 
10. Has been administered any local anesthetic within 72 hours prior to the scheduled 
surgery, other than for pretreatment prior to a needle placement, to treat an AE that 
occurs after signing the ICF, or to decrease venous irritation (eg, caused by propofol, in 
which case no more than a single administration of lidocaine 1% 20 mg IV may be 
administered). 
11. Has initiated treatment with any of the following medications within 1 month prior to 
study drug administration or is taking any of these medications to control pain: selective 
serotonin reuptake inhibitors (SSRIs), selective norepinephrine reuptake inhibitors 
(SNRIs), gabapentin, pregabalin, 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. 
12. Has been administered systemic steroids within 5 half-lives or 10 days prior to 
administration of study drug (whichever is longer). 
13. Has a medical condition such that, in the opinion of the Investigator, participating in the 
study would pose a health risk to the subject or confound the postoperative assessments. 
Conditions may include, but are not limited to, any of the following: 
a. History of clinically significant cardiac abnormality such as myocardial infarction 
within 6 months prior to signing the ICF, New York Heart Association class III or IV, 
or clinically significant abnormalities in cardiac function or on ECG (including but 
not limited to a PR interval >200 msec, a QT corrected by Fridericia’s formula 
[QTcF] >480 msec, or 3rd degree heart block). 
b. History of coronary artery bypass graft surgery within 12 months prior to 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-011-301 Version 3 
Heron Therapeutics, Inc. 
Phase 3 bunionectomy study for postoperative analgesia (EPOCH 1) 
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f. Loss of sensation in extremities or significant peripheral neuropathy. 
14. 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). 
15. Has uncontrolled anxiety, psychiatric, or neurological disorder that, in the opinion of the 
Investigator, might interfere with study assessments. 
16. 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. 
17. 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. 
18. Previously participated in an HTX-011 study. 
19. 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 within 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 
centralized computer-generated blocked randomization algorithm created by an interactive 
response technology (IRT) provider. 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 1 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. 


Protocol No: HTX-011-301 Version 3 
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Phase 3 bunionectomy study for postoperative analgesia (EPOCH 1) 
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4.3. 
Blinding 
The study will use a double-blind design to minimize potential bias in subject selection as well as 
efficacy and safety assessments. 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 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) and clinical observer staff. 
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 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 
 Ineligible at Day 1 
The date and the primary reason for early withdrawal will be recorded on the electronic case 
report form (eCRF). At the time of withdrawal from the study, every attempt should be made to 
complete the Early Termination Visit assessments (see Section 7.3.1.3). 


Protocol No: HTX-011-301 Version 3 
Heron Therapeutics, Inc. 
Phase 3 bunionectomy study for postoperative analgesia (EPOCH 1) 
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4.4.2. 
Subject Replacement 
Randomized subjects who withdraw from study will not be replaced. To account for withdrawal 
of subjects who are ineligible at Day 1 or are otherwise randomized but not dosed, enrollment 
will continue until at least 400 subjects have been randomized and dosed. 


Protocol No: HTX-011-301 Version 3 
Heron Therapeutics, Inc. 
Phase 3 bunionectomy study for postoperative analgesia (EPOCH 1) 
Confidential 
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5. 
STUDY TREATMENT 
All subjects will receive a single dose of study drug intraoperatively while undergoing a 
bunionectomy. Study drug is defined as HTX-011 (investigational product), saline placebo 
(control), or bupivacaine HCl without epinephrine (active control). 
HTX-011, saline placebo, and bupivacaine HCl will be supplied by the Sponsor. 
5.1. 
Description of Investigational Product 
HTX-011 is a slightly yellow, viscous, semi-solid gel liquid. HTX-011 is supplied in 10 mL or 
20 mL clear glass vials. The vials serve only as a closed container for the drug product. For 
administration of study drug, the formulation in the vials will be aseptically transferred to sterile 
syringes. 
5.2. 
Manufacturing, Packaging, and Labeling 
HTX-011 will be manufactured according to Good Manufacturing Practices. 
Study drug will be packaged and labeled by the Sponsor or designee and will be packed and 
dispatched to comply with shipping and storage conditions. Study drug labeling will comply with 
all applicable national and local laws and regulations. 
5.3. 
Storage 
At the study site, HTX-011 should be stored at a controlled room temperature of 20 to 25°C 
(with excursions permitted from 15 to 30°C). The room should be locked with restricted access. 
A temperature log must be maintained to monitor the room’s temperature. 
Saline placebo and bupivacaine HCl will be stored as per the prescribing information. 
5.4. 
Preparation 
Study drug will be prepared at the study site. HTX-011 and saline placebo will be prepared in a 
group of syringes without a needle. Bupivacaine HCl will be prepared in a group of syringes 
with a needle. Refer to the Pharmacy Manual for details on study drug preparation. 
5.5. 
Study Drug Administration 
Study drug will be given via local administration into the surgical wound prior to wound closure, 
after irrigation and suction of each layer are complete. “Infiltration” is a regulatory term for 
product labels to describe local administration via instillation or injection. 
5.5.1. 
Instillation: HTX-011 and Saline Placebo 
HTX-011 and saline placebo will be administered via instillation using a Luer-lock applicator 
supplied by the Sponsor. 
Following irrigation and suction of each fascial layer, study drug will be administered evenly so 
that all tissues receive adequate coverage. Care should be taken to ensure adequate exposure of 
the proximal and distal ends (ie, beyond the bony incision) of the wound to study drug. Study 


Protocol No: HTX-011-301 Version 3 
Heron Therapeutics, Inc. 
Phase 3 bunionectomy study for postoperative analgesia (EPOCH 1) 
Confidential 
38 
drug should form rings of anesthetic around both the proximal and distal aspects of the 
metatarsal. To ensure adequate saturation of all exposed tissues in the surgical field, study drug 
may be administered in layers. Note that the shallow subdermal layer is to be avoided and that all 
study drug should be utilized (ie, there should be no residual study drug left). Thereafter, skin 
closure will commence to complete the surgical procedure (ie, there should be no betadine wash 
until after skin closure at the end of the case). 
5.5.2. 
Injection: Bupivacaine HCl 
Bupivacaine HCl will be administered via injection. Study drug should be administered 
throughout the tissue planes to ensure equal distribution across the surgical field. The medication 
should form rings of anesthetic around both the proximal and distal aspects of the metatarsal. An 
appropriate way of doing this is as follows: 
 Start proximal to the bony incision and administer half the contents of the syringe 
distally past the bony incision (blue arrows in photo below). 
 Repeat the procedure with the rest of the syringe but now start distally and inject 
proximally (red arrows in photo below). 
 Ensure adequate saturation of all exposed tissues in the surgical field. 
 Thereafter, commence skin closure to complete the surgical procedure (ie, there 
should be no betadine wash until after skin closure at the end of the case). 
 


Protocol No: HTX-011-301 Version 3 
Heron Therapeutics, Inc. 
Phase 3 bunionectomy study for postoperative analgesia (EPOCH 1) 
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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 study drugs 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 study drug to permit reconciliation. The Investigator or designee 
must maintain adequate records of distribution, including the date received, number and units 
received, lot numbers, dispensing, and return or destruction of all study drug (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 study drug 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. 


Protocol No: HTX-011-301 Version 3 
Heron Therapeutics, Inc. 
Phase 3 bunionectomy study for postoperative analgesia (EPOCH 1) 
Confidential 
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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 the Safety Follow-Up on Day 42 
will be recorded in the subject’s eCRF. The dosing regimen of “prn” should not be recorded on 
the eCRF. 
During the 72-hour postoperative period, the name, dose, and route, as well as the start date and 
time, of concomitant medications must be recorded. Medications include prescription or 
over-the-counter medications (including herbal products and vitamins). For subjects entering on 
a stable dose of permitted medication, any change in dose should also be recorded. Note: All 
medications received during this period must have a start time recorded, except for IV fluids and 
oxygen during surgery, which do not need to be recorded unless being used to treat an AE. 
After the 72-hour period until the Safety Follow-Up on Day 42, at least the start date of each 
concomitant medication should be recorded. 
6.2.1. 
Allowed Concomitant Medications 
All treatments that the Investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the Investigator’s in keeping with the standard of medical care. 
Antiemetic medications may be given to treat nausea and/or vomiting, but should not be 
administered prophylactically (ie, as a routine preventative in the absence of signs or symptoms 
of nausea or vomiting). 
During surgery, the use of IV fentanyl up to 4 μg/kg is permitted for intraoperative pain control. 
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. 


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See Section 3.1.3 for information on rescue medications permitted. 
See Appendix G for information on postoperative pain management for subjects who are 
medically ready for discharge. 
6.2.2. 
Prohibited Medications 
6.2.2.1. 
Medications Prohibited Prior to Surgery 
Refer to exclusion criteria 5 through 11 and 17 for medications that are prohibited prior to the 
scheduled surgery (Section 4.1.2). Of note, for exclusion criterion 12, oral, parenteral, and 
topical steroids are considered systemic steroids, but inhaled and ophthalmic steroids are not 
considered systemic steroids. 
6.2.2.2. 
Medications Prohibited During Surgery 
Epidural or spinal anesthesia is not permitted. 
Intraoperative administration of opioids or any other analgesics (including ketamine), local 
anesthetics, or anti-inflammatory agents except as specified by the protocol (ie, HTX-011, 
bupivacaine HCl, and fentanyl) is prohibited, unless needed to treat an AE that occurs after 
signing the ICF, for pretreatment prior to a needle placement, or to decrease venous irritation (eg, 
caused by propofol, in which case no more than a single administration of lidocaine 1% 20 mg 
IV may be administered). 
6.2.2.3. 
Medications Prohibited From Time 0 Through 72 Hours 
With the exception of rescue medications specified in Section 3.1.3, no other analgesic agents, 
including NSAIDs, are permitted during the 72-hour postoperative observation period. 
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” (Breivik 2008). NRS scores will be recorded 
first at rest (NRS-R) and then with activity (NRS-A). 
For NRS-R assessments, subjects should be seated/recumbent with the surgically attended leg 
elevated or lying supine. Measurements should be obtained after the subject is in the resting 
position for at least 5 minutes. 
For NRS-A assessments, subjects should be seated with the plantar surface of the ball of the 
surgically attended foot touching the floor (no weight-bearing; see photo below). 


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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. See Appendix C. 
6.3.2. 
Use of Opioid Medications 
6.3.2.1. 
Opioid Rescue Medication Through 72 Hours 
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. 
6.3.2.2. 
Subject Daily Diary of Opioid Use From 72 Hours Through Day 28 
Subjects will be provided a daily diary to record if they take any opioid medication from 
72 hours through Day 28 (yes or no).  
6.3.3. 
Discharge Readiness 
Discharge readiness will be assessed using the MPADSS criteria (Chung, 1995). See 
Appendix E. 
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. 
6.3.4. 
Patient Global Assessment (PGA) of Pain Control 
Subjects will be asked to evaluate their pain control over the preceding 24 hours using a 4-point 
PGA scale where 0 represents “poor” and 3 represents “excellent” (Rothman, 2009). See 
Appendix D for the PGA scale. 


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6.4. 
Safety Assessments 
6.4.1. 
Adverse Events 
All AEs regardless of causality or seriousness will be recorded from the time the subject signs 
the ICF through the Safety Follow-Up on Day 42. See Section 8 for details. Clinically significant 
post-treatment findings for laboratory results, vital signs, ECGs, or X-rays should be recorded as 
AEs. LAST signs or symptoms, abnormal physical examination findings and wound healing 
abnormalities should also be recorded as AEs. 
6.4.2. 
Local Anesthetic Systemic Toxicity Assessment 
A LAST assessment questionnaire is provided (see Appendix H) to monitor for early neurologic 
and cardiac signs and symptoms of LAST (Vasques, 2015). 
Subjects should be assessed with this questionnaire on a regular basis to identify early stages of 
toxicity to determine whether treatment should be initiated. If a subject has signs or symptoms 
that may be attributed to LAST, vital sign measurements, 12-lead ECG, and blood sample 
collection for PK must be performed. If symptoms are present at a timepoint when 1 of these 
assessments is not scheduled, an unscheduled assessment must be performed. 
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 (see Appendix B) 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, respiration rate, 
and body temperature. Subjects should be in a supine position (includes sitting in a recliner 
chair) for at least 5 minutes before taking vital signs.  
6.4.5. 
12-Lead Electrocardiograms 
Screening and post-treatment ECGs will be obtained for all subjects. Standard digital 12-lead 
ECGs will be performed in triplicate. Subjects should be in the supine position (includes sitting 
in a recliner chair) for at least 5 minutes before each initial ECG recording. The mean of the 
3 ECGs will be used as the baseline result. 
The ECG tracings will be reviewed by a central reader. Refer to the Cardiac Safety Study 
Manual for instructions on collecting and transmitting results. 




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Glucose  
Lactate dehydrogenase 
Magnesium  
Phosphorus  
Potassium  
Sodium  
Total bilirubin 
Total protein 
Uric acid 
6.5. 
Pharmacokinetic Assessments 
Limited blood samples for bupivacaine and meloxicam PK analysis will be collected from 
subjects. Blood samples may be drawn using a properly maintained indwelling cannula. Samples 
will be sent to a central laboratory for analysis. Refer to the Laboratory Manual for detailed 
instructions on sample collection, processing, storage, and shipping procedures. 


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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 
pain assessments at timepoints when the subject is asleep, an attempt should be made to wake the 
subject. If there is no response, the assessments at these timepoints may be recorded as “Not 
Done.” Assessments that can be done without waking the subject (eg, blood collection for PK) 
should be completed. Additional visits and/or assessments are permitted if clinically indicated in 
the opinion of the Investigator. 
When the following assessments are scheduled at the same timepoint, it is recommended that 
they be performed in this order: 
 NRS-R pain intensity assessment (subjects should be seated/recumbent with the 
surgically attended leg elevated or lying supine; measurements should be obtained 
after the subject is in the resting position for at least 5 minutes) 
 PGA of pain control assessment 
 Vital signs 
 12-lead ECG 
 NRS-A pain intensity assessment (subjects should be seated with the plantar surface 
of the ball of the surgically attended foot touching the floor [no weight bearing]) 
 LAST assessment 
 Blood sample collection 
 Physical examination 
 Wound healing assessment 
 Bone healing assessment (X-ray) 
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 28 days prior to surgery. The Investigator must evaluate the subject’s medical 
history and the results of all Screening assessments to determine study eligibility before the 
subject is randomized. 
Screening procedures and assessments will include the following: 
 Urine drug screen 
 Urine pregnancy test (female subjects of child-bearing potential only) 
 Medical history 
 Demographic recording 


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 Physical examination (including weight, height, and BMI calculation) 
 Vital signs measurements 
 12-lead ECG (in triplicate) 
 Blood sample collection for the hematology and serum chemistry 
 Subject training for pain intensity assessments 
 AE recording (from the time the subject signs the ICF) 
 Prior and concomitant medication recording (from the time the subject signs the ICF) 
The urine drug screen and urine pregnancy test should be performed first, and the results should 
be confirmed as negative prior to performing any additional assessments. 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. Any other 
screening laboratory test result that does not meet the eligibility criteria may not be repeated 
without the Sponsor's approval. 
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 1) 
7.2.1.1. 
Prior to Surgery 
On Day 1, subjects will be reassessed for study eligibility. This includes a urine drug screen test 
(all subjects) and urine pregnancy test (female subjects of child-bearing potential only). Results 
should be confirmed as negative prior to performing any additional assessments. 
Subjects who continue to meet the eligibility criteria can continue on study and will be admitted 
to the surgical unit. The following additional study procedures and assessments will be 
performed before surgery: 
 Vital signs measurements 
 Subject training for pain intensity assessments (refresher training) 
 AE recording 
 Prior and concomitant medication assessment 
7.2.1.2. 
Surgery and Study Drug Administration 
Subjects will undergo a unilateral simple bunionectomy under regional anesthesia (no more than 
20 mL of 1% lidocaine without epinephrine administered as a Mayo block; epidural or spinal 
anesthesia is not permitted). Sites should follow intraoperative safety monitoring in accordance 


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with ASA Standards for Basic Anesthetic Monitoring (American Society of Anesthesiologists, 
2015), which is consistent with the European Board of Anaesthesiology (EBA) recommendations 
for minimal monitoring during Anaesthesia and Recovery (for review in 2018) (EBA UEMS, 
2016). The start and stop time of surgery and additional surgical details (including the length of 
the surgical incision) 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 
local administration into the surgical site at the end of the surgical procedure, but prior to wound 
closure. 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. 
Placement of the last suture will be considered the end of surgery. 
Concomitant medications used during surgery will be recorded (note that IV fluids and oxygen 
are not required to be recorded unless being used to treat an AE). AEs will also be recorded. 
After immediate postoperative recovery, subjects will be transferred to the 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. 
Study procedures and assessments that will be performed 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. 
 NRS-R and NRS-A pain intensity assessments: at 1 hour (±5 min), 2 and 4 hours 
(±15 min), 8 and 12 hours (±30 min), 24 hours (±1 h), 36 and 48 hours (±2 h), 60 and 
72 hours (±4 h) 
 Note: If a subject requires rescue medication before the 1-hour pain intensity 
assessments, then an unscheduled NRS-R pain score followed by an NRS-A pain 
score must be obtained before administering the first dose of rescue medication. 
These do not replace the 1-hour NRS-R and NRS-A assessments. 
 PGA of pain control assessment: 24 hours (±1 h), 48 hours (±2 h), and 72 hours 
(±4 h) 
 Vital signs measurements: 30 minutes (±5 min), 1 hour (±5 min), 1.5 hours 
(±10 min), 2 hours (±15 min), 4 hours (±15 min), 8 hours (±30 min), 12 hours 
(±30 min), 18 hours (±30 min), 24 hours (±1 h), 36 hours (±2 h), 48 hours (±2 h), 
60 hours (±4 h), and 72 hours (±4 h) 
 LAST assessments: 30 minutes (±5 min), 1 hour (±5 min), 2 hours (±15 min), 
4 hours (±15 min), 18 hours (±30 min), 24 hours (±1 h), and 72 hours (±4 h). If 
symptoms are present at 30 minutes, 1 hour, or 2 hours, an unscheduled blood sample 


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will be collected for PK and a 12-lead ECG will be performed. If symptoms are 
present at 72 hours, an unscheduled blood sample will be collected for PK. 
 12-lead ECG (in triplicate): 4 hours (±15 min), 18 hours (±30 min), 24 hours (±1 h), 
48 hours (±2 h), and 72 hours (±4 h) 
 Physical examination: 72 hours (±4 h; height and weight not required) 
 Blood sample for hematology and serum chemistry tests: 24 hours (±1 h; 
hematology only) and 72 hours (±4 h; hematology and serum chemistry)  
 Blood sample collection for PK: 4 hours (±15 min), 18 hours (±30 min), 24 hours 
(±1 h), and 48 hours (±2 h)  
 Wound healing assessment: 72 hours (±4 h)  
 Discharge readiness assessment per the MPADSS criteria: 2 and 4 hours 
(±15 min), 8 and 12 hours (±30 min), 24 hours (±1 h), 36 and 48 hours (±2 h), 60 and 
72 hours (±4 h)  
 AE recording: (Note: the start date and time of all AEs during this timeframe must 
be recorded) 
 Concomitant medication recording: (Note: the start date and time of all 
concomitant medications during this timeframe must be recorded) 
 Use of rescue medication recording: Any time between study drug administration 
and 72 hours (Note: the start date and time of all rescue medications during this 
timeframe must be recorded.) 
7.2.3. 
End of the Postoperative Assessment Period 
After the 72-hour assessments have been completed, the subject may be discharged if medically 
ready. 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 8.3.1. If a subject is ready for 
discharge but is not discharged for any reason other than AE, the reason should be recorded on 
the eCRF. 
Subjects who are not medically ready for discharge at 72 hours may receive the same rescue 
medication as outlined in Section 3.1.3 to treat postoperative pain until discharge. 
For subjects who are medically ready for discharge at 72 hours, oral acetaminophen (no more 
than 1000 mg every 6 hours as needed) should be recommended for postoperative pain. If a 
subject received 10 mg or more of oxycodone in the 12 hours prior to discharge, the subject 
should be provided with a prescription for oxycodone (up to 10 mg PO q4h as needed, #15, no 
substitutions). See Appendix G for instructions on postoperative pain management for subjects 
medically ready for discharge. 
Subjects will be given a diary to complete daily and record if they take any opioid medication 
from 72 hours through Day 28. 


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7.3. 
Follow-Up Period 
7.3.1.1. 
Day 10 Visit (±3 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 
 Wound healing assessment 
 Blood sample collection for the hematology and serum chemistry 
 Review subject diary results 
 AE recording 
 Concomitant medication recording 
7.3.1.2. 
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 
 Wound healing assessment 
 Review subject diary results 
 AE recording 
 Concomitant medication recording 
 Bone healing assessment (X-ray) 
7.3.1.3. 
Safety Follow-Up (Day 42 ±7 Days) 
All subjects will return to the study site and will have the following procedures and assessments: 
 Wound healing assessment 
 AE recording 
 Concomitant medication recording 
 Bone healing assessment (X-ray) 
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 items listed in Section 7.4.1. Subjects who 
withdraw from the study after the Day 28 Visit but prior to the Safety Follow-Up on Day 42 will 


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be asked to complete Early Termination procedures, which will include the items listed in 
Section 7.4.2. 
7.4.1. 
Withdrawal Prior to the Day 28 Visit 
 NRS-R pain intensity assessment 
 NRS-A pain intensity assessment 
 PGA of pain control assessment 
 Vital signs (if withdrew prior to 72 hours) 
 Blood sample collection for hematology and serum chemistry (if withdrew prior to 
72 hours) 
 12-lead ECG (triplicate) (if withdrew prior to 72 hours) 
 Physical examination (if withdrew prior to 72 hours [height and weight not required]) 
 Wound healing assessment 
 Bone healing assessment (X-ray; if clinically indicated and withdrew after 72 hours) 
 LAST assessment (if withdrew prior to 72 hours) 
 Review subject diary results 
 AE recording 
 Concomitant medication recording 
7.4.2. 
Withdrawal After the Day 28 Visit and Prior to the Safety Follow-Up on Day 42 
 AE recording 
 Concomitant medication recording 
 Wound healing assessment 
 Bone healing assessment (X-ray) 
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 


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 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 
 X-ray of the surgical site (if clinical concern) 


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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 or X-ray findings deemed clinically significant by the Investigator, 
regardless of causal relationship, must be reported as an AE. LAST signs or symptoms, abnormal 
physical examination findings and wound healing abnormalities should also be recorded as AEs. 
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 investigational 
product interrupted or discontinued. 
 Any laboratory abnormality that required the subject to receive specific treatment 
for the lab abnormality. 


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 Any laboratory abnormality that required additional monitoring and follow-up 
visits. 
 Any laboratory abnormality requiring further diagnostic investigation. 
The following examples are not considered AEs: 
 Medical or surgical procedure (eg, endoscopy, appendectomy), although the condition 
that leads to the procedure is an AE. 
 Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) 
(including laboratory values) present or detected at the start of the study that do not 
worsen. 
 The disease or disorder being studied, or expected progression, signs, or symptoms of 
the disease or disorder being studied, unless they become more severe or occur with a 
greater frequency than expected for the subject’s condition. 
 Transient paresthesia that is considered to be clinically normal (would be expected to 
occur as a long-acting local anesthetic wears off). 
8.1.2. 
Definition of a Serious Adverse Event 
An AE or suspected adverse reaction is considered “serious” if, in the view of either the 
Investigator or Sponsor, it results in any of the following outcomes: 
 Death. 
 A life-threatening AE (ie, 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 


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occurrence of an AE, or hospitalization or an emergency room visit that lasts less than 24 hours 
that does not meet the criteria of an important medical or a life-threatening event. 
According to 21 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. 
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. 


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 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. 
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 the Safety Follow-Up on Day 42. Note: the AE start time, as well as the date, 
must be recorded during the 72-hour postoperative period. After this period, only the start date 
must be recorded. 
For subjects who received study drug, if an Investigator becomes aware of an SAE that occurs 
after the subject’s study participation and the Investigator considers the event to be possibly 
related to the study drug, the Investigator needs to report the SAE to the Sponsor as described in 
Section 8.4.1. 


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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). 
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 


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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 
 Prior and concomitant medications 
Also, the following documents are to be forwarded: any laboratory results, diagnostic test results, 
or medical reports relevant to the SAE. 
EDC is the primary method for notification of SAE information. In rare circumstances and in the 
absence of email capacity, notification by fax or telephone is acceptable, with a copy of the SAE 
reporting form sent by overnight mail. Initial notification via telephone does not replace the need 
for the Investigator to complete the SAE information in the eCRF within the time frames 
outlined. 
If the Investigator does not have all information regarding an SAE, he/she must not wait to 
receive additional information before notifying the Sponsor of the event. The SAE must be 
updated when additional information is received. Follow-up information received on all SAEs 
must be forwarded to the Sponsor using the same timelines as for an initial report. 
The Investigator must notify the Sponsor by reporting any unanticipated adverse device effect 
within 24 hours of the Investigator becoming aware of the effect. 
8.4.2. 
Reporting Unanticipated Problems to the Sponsor 
If the Investigator determines that an event meets the protocol definition of an unanticipated 
problem, he/she must notify the Sponsor by completing an Unanticipated Problem Form and 
emailing it to the Sponsor within 24 hours of the Investigator becoming aware of the 
problem. 
Email Address: 
Heron_PV@ubc.com 
The following information will be included with unanticipated problem reporting: 
 Protocol identifying information: protocol title, protocol number, and Investigator’s 
name. 
 A detailed description of the event, incident, experience, or outcome. 
 An explanation of the basis for determining that the event, incident, experience, or 
outcome represents an unanticipated problem.  


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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 
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 by completing a Pregnancy Form and 
emailing it to the Sponsor within 24 hours after the Investigator becomes aware of the 
pregnancy. 
Email Address: 
Heron_PV@ubc.com 
8.5. 
Safety Oversight 
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, 
AEs, LAST assessments, wound healing assessments, bone healing assessments, and SAEs. 
The stopping criteria, enrollment suspension or study termination for safety issues, are provided 
in Section 13.5.  


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9. 
OTHER STUDY RESTRICTIONS 
9.1. 
Contraception 
Female subjects of child-bearing potential 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 approved by applicable regulatory 
authorities. Note: The does not apply to women in only a same-sex relationship or women in a 
monogamous relationship with a surgically sterile partner. 


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10. 
STATISTICAL CONSIDERATIONS 
10.1. 
General Considerations 
All efficacy and safety data will be listed by subject. Unless otherwise specified, Baseline is 
defined as the last observed measurement, whether scheduled or unscheduled, prior to study drug 
administration. All safety and efficacy endpoints will be summarized by treatment group. 
Continuous variables will be summarized using the number of subjects with data (n), mean, SD, 
median, minimum, and maximum. Selected continuous variable summaries will also include the 
SE. Categorical variables will be summarized using frequency counts and percentages. 
Unless otherwise specified, all statistical hypothesis testing will be two-sided using α = 0.05. 
10.2. 
Determination of Sample Size 
Based on a previous Phase 2 study of HTX-011 in subjects undergoing unilateral simple 
bunionectomy, estimates of the relevant parameters for each of the primary and key secondary 
endpoints are as follows: 
Parameter 
Saline 
Placebo 
Bupivacaine 
HCl 
HTX-011  
60 mg/1.8 mg 
Pain intensity AUC0-72: Mean (SD) 
425 (175) 
425 (175) 
325 (175) 
Opioid consumption (mg): Mean (SD) 
30 (25) 
30 (25) 
20 (20) 
Proportion of opioid-free subjects  
5% 
10% 
25% 
Assuming these estimates and using Satterthwaite’s t-test with α = 0.05, 2-sided for the 
continuous endpoints and Fisher’s exact test with α = 0.05, 2-sided for the categorical endpoints, 
150 subjects in the HTX-011 group, 150 subjects in the bupivacaine HCl active control group, 
and 100 subjects in the saline placebo control group provide at least 90% power to detect a 
statistically significant difference between the HTX-011 group and each of the control groups for 
each of the primary and key secondary endpoints. 
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. 
Per Protocol Population: All subjects in the ITT Population who do not receive a prohibited 
rescue medication prior to 72 hours and who have no important protocol violations prior to 
72 hours will be included in the Per Protocol Population. This population will be used for 
sensitivity analyses on the primary and key secondary endpoints. 
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. 


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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, completing the Safety Follow-up 
on Day 42, and not completing the Safety Follow-up on Day 42 by reason for withdrawal will be 
summarized for the ITT Population. Subject demographics and baseline characteristics will also 
be summarized for the ITT Population and will include age, age category, sex, race, ethnicity, 
height, weight, and BMI. 
10.4.2. 
Efficacy Analysis 
10.4.2.1. Primary Efficacy Analysis 
The primary estimand to address the efficacy objectives is the mean AUC of NRS-A pain 
intensity scores through 72 hours (AUC0-72) adjusted for use of opioid rescue medication via 
windowed worst observation carried forward (wWOCF), comparing the estimated treatment 
difference between HTX-011 and saline placebo using analysis of variance (ANOVA) with 
missing data imputed via last observation carried forward (LOCF) for interval censored pain 
intensity scores and worst observation carried forward (WOCF) for right-censored pain intensity 
scores in the ITT Population. 
The primary analysis of AUC0-72 of the NRS-A pain intensity scores will be carried out using an 
ANOVA model with treatment as the main effect, comparing HTX-011 with saline placebo at a 
significance level of 5%. Results will be expressed as mean AUCs and SDs, least-squares mean 
differences (LSMD) and SEs with associated 95% CIs, and p-values. To account for the duration 
effect of opioid rescue medication, the 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. Key Secondary Efficacy Analyses 
Key secondary endpoints involving AUC of NRS-A will be analyzed similarly to the methods 
described for the primary endpoint. 
Total opioid consumption through 72 hours will be summarized using descriptive statistics. 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 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 
period of interest will be analyzed using an ANOVA model with randomized treatment as the 


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main effect. Results will be expressed as means, SDs, and LSMD and SE with associated 95% 
CI, and p-values. 
The proportion of subjects who are opioid-free through 72 hours 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.  
10.4.2.3. Study-Wise Type I Error Control 
To account for multiple hypothesis testing on the primary endpoint and on each of the 4 key 
secondary endpoints, a strict testing hierarchy will be applied to control study-wise alpha level at 
0.05. If the primary endpoint is statistically significant (p ≤0.05), then the first key secondary 
endpoint will be tested. If the first key secondary endpoint is statistically significant, then the 
second key secondary endpoint will be tested. Sequential testing will continue in this manner 
down the key secondary endpoint list until an endpoint fails to meet statistical significance, after 
which all subsequent key secondary endpoints will be considered exploratory. If the primary 
endpoint is not statistically significant, then all key secondary endpoints will be considered 
exploratory. 
 
 
 
 
 
10.4.2.5. Handling of Missing Data 
Due to the required 72-hour inpatient postoperative observation period, the amount of missing 
data is expected to be very low. For any missing data observed through 72 hours in subjects who 
complete the 72-hour postoperative observation period, NRS pain intensity scores will be 
imputed via LOCF, in which the most recent postdose value is used for a subsequent missing 
value. For subjects who do not have a postdose value prior to their first missing value, the 
median of the postdose values at the relevant timepoint from subjects with observed data in the 
same randomized treatment group will be used. Predose values will not be carried forward to 
postdose timepoints. In subjects who withdraw from the study prior to 72 hours, missing NRS 
pain intensity scores through 72 hours that were to be collected following withdrawal will be 
imputed via WOCF, in which the worst (highest) NRS pain intensity score observed prior to 
withdrawal will be used for post-withdrawal values through 72 hours. Analyses that adjust for 
the effect of opioid rescue medication will perform wWOCF following LOCF/WOCF (ie, 
perform LOCF/WOCF first, then apply wWOCF). The number and percentage of missing NRS 
pain intensity scores will be summarized. 
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 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 


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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 HTX-011 group. 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 
subject values will be listed and values outside of the standard reference range will be flagged. 
Shift tables will be produced showing the frequency of shifts from Baseline to the lowest and to 
the highest on-study value in and out of the normal range as well as by visit. Laboratory 
parameters will also be summarized by visit. 
The change from Baseline to each visit for each of the vital sign variables will be summarized. 
Abnormal vital sign values will be flagged and listed. Changes from baseline in ECG results will 
be summarized. 
Wound healing assessment results will be summarized at each timepoint. Bone healing 
assessment X-ray results will also be summarized. 
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. An estimated Cmax and Tmax will be calculated using 
population PK modeling, which will be developed in non-linear mixed effects modeling 
(NONMEM) using data from previous HTX-011 clinical studies. 
10.5. 
Interim Analysis 
No formal interim analyses are planned. 


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11. 
QUALITY ASSURANCE AND QUALITY CONTROL 
Quality assurance and quality control systems will be implemented and maintained 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, International Conference on Harmonisation (ICH) 
Guideline for Good Clinical Practice E6, and applicable regulatory requirements. The accuracy, 
completeness, and reliability of the study data presented to the Sponsor, however, are the 
responsibility of the Investigator. The Investigator or designee must record all required data 
using the prespecified data collection method defined by the Sponsor or its designee. 
The study will be monitored regularly by the Sponsor (Section 13.1) and may be audited or 
inspected by the Sponsor (or designee), EC, and/or regulatory authorities at any time during the 
study or after study completion. In the event of an audit, the Investigator agrees to allow the 
Sponsor, representatives of the Sponsor, the competent authority, or other regulatory agencies 
direct access to all study records. The Investigator will immediately notify the Sponsor of all 
audits or inspections scheduled by any regulatory authority and promptly forward 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, and any information for presentation to 
potential subjects by ECs. 
The Investigator is responsible for providing the Sponsor with the written EC approval prior to 
commencing the study (ie, before shipment of study drug to the site). All amendments to the 
protocol require review and approval by the EC before the changes 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 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 the Health Insurance Portability and Accountability Act (HIPAA) 
and in a form satisfactory to the Sponsor. 
The subject’s contact information will be securely stored at each clinical site for internal use 
during the study. Throughout the study, a subject’s source data will only be linked to the 
Sponsor’s clinical study database or documentation via a unique identification number. Copies of 
any subject source documents that are provided to the Sponsor must have certain personally 
identifiable information removed (ie, subject name, address, and other identifier fields not 
collected in the subject’s eCRF). At the end of the study, all records will continue to be kept in a 
secure location for as long a period as dictated by the EC and institutional regulations. 


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


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13. 
STUDY ADMINISTRATION 
13.1. 
Clinical Monitoring 
The Sponsor (or its designee) is responsible for ensuring the proper conduct of the study. This 
includes ensuring the subjects’ rights and well-being are protected, the conduct of the study is 
within compliance of an approved protocol and GCPs, and the integrity of the data are accurate, 
complete and verifiable from source documentation. At regular intervals during the study, the 
Sponsor’s study monitors will contact the study site via site visits, telephone calls, emails, and 
letters in order to review study progress and the eCRF completion and to address any concerns or 
questions regarding the study conduct. During monitoring visits, the following aspects of study 
conduct will be carefully reviewed: subjects’ informed consent documents, subject recruitment 
procedures, subjects’ compliance with the study procedures, source-data verification, drug 
accountability (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. 
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 


Protocol No: HTX-011-301 Version 3 
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Phase 3 bunionectomy study for postoperative analgesia (EPOCH 1) 
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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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Phase 3 bunionectomy study for postoperative analgesia (EPOCH 1) 
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14. 
REFERENCE LIST 
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. 
Apfelbaum, J. L., C. Chen, S. S. Mehta and T. J. Gan (2003). "Postoperative Pain Experience: 
Results from a National Survey Suggest Postoperative Pain Continues to Be Undermanaged." 
Anesthesia & Analgesia 97(2). 
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. 
Barnett, M. L., A. R. Olenski and A. B. Jena (2017). "Opioid-Prescribing Patterns of Emergency 
Physicians and Risk of Long-Term Use." New England Journal of Medicine 376(7): 663-673. 
Baxter, R., K. Bramlett, E. Onel and S. Daniels (2013). "Impact of local administration of 
liposome bupivacaine for postsurgical analgesia on wound healing: a review of data from ten 
prospective, controlled clinical studies." Clin Ther 35(3): 312-320 e315. 
Bose, J., S. L. Hedden, R. N. Lipari and E. Park-Lee (2016) "Center for Behavioral Health 
Statistics and Quality (2016). Key Substance Use and Mental Health Indicators in the United 
States: Results from the 2015 National Survey on Drug Use and Health (HHS Publication No. 
SMA 16-4984, NSDUH Series H-51). Retrieved from http://www.samhsa.gov/data." 
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. 
Cashman, J. N. and S. J. Dolin (2004). "Respiratory and haemodynamic effects of acute 
postoperative pain management: evidence from published data." Br J Anaesth 93(2): 212-223. 
Chan, E. Y., F. M. Blyth, L. Nairn and M. Fransen (2013). "Acute postoperative pain following 
hospital discharge after total knee arthroplasty." Osteoarthritis and Cartilage 21(9): 1257-1263. 
Chung, F. (1995). "Discharge criteria--a new trend." Can J Anaesth 42(11): 1056-1058. 
Coley, K. C., B. A. Williams, S. V. DaPos, C. Chen and R. B. Smith (2002). "Retrospective 
evaluation of unanticipated admissions and readmissions after same day surgery and associated 
costs." Journal of Clinical Anesthesia 14(5): 349-353. 
EBA UEMS. (2016). "European Board of Anaesthesiology (EBA) Recommendations for 
Minimal Monitoring During Anaesthesia and Recovery." from http://www.eba-
uems.eu/PS/PS.html. 
EXPAREL USPI (2016). EXPAREL (Bupivacaine Liposome Injectable Suspension). San Diego, 
CA 92121: Pacira Pharmaceuticals, Inc. 
Fentanyl Citrate USPI (2012). Fentanyl Citrate injection. Lake Forest, IL 60045: Akorn, Inc. 


Protocol No: HTX-011-301 Version 3 
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Phase 3 bunionectomy study for postoperative analgesia (EPOCH 1) 
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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. 
Golf, M., S. E. Daniels and E. Onel (2011). "A phase 3, randomized, placebo-controlled trial of 
DepoFoam(R) bupivacaine (extended-release bupivacaine local analgesic) in bunionectomy." 
Adv Ther 28(9): 776-788. 
Jarzyna, D., C. Jungquist, C. Pasero, J. Willens, A. Nisbet, L. Oakes, S. Dempsey, D. Santangelo 
and R. Polomano (2011). "American Society for Pain Management Nursing guidelines on 
monitoring for opioid-induced sedation and respiratory depression." Pain management nursing : 
official journal of the American Society of Pain Management Nurses 12(3): 118-145.e110. 
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. 
Kessler, E. R., M. Shah, S. K. Gruschkus and A. Raju (2013). "Cost and Quality Implications of 
Opioid-Based Postsurgical Pain Control Using Administrative Claims Data from a Large Health 
System: Opioid-Related Adverse Events and Their Impact on Clinical and Economic Outcomes." 
Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy 33(4): 383-391. 
Lee, L. A., R. A. Caplan, L. S. Stephens, K. L. Posner, G. W. Terman, T. Voepel-Lewis and K. 
B. Domino (2015). "Postoperative Opioid-induced Respiratory DepressionA Closed Claims 
Analysis." Anesthesiology 122(3): 659-665. 
Lee, M. J., S. L. Daniels, J. R. L. Wild, T. R. Wilson, A. Jackson, C. K. Shun, A. Wheeler, R. 
West, E. M. Nofal, V. K. Proctor, M. Rigby, H. Burnett, R. Gaikwad, K. Madhbak, E. Flatt and 
F. Akram (2016). "Readmissions after general surgery: a prospective multicenter audit." Journal 
of Surgical Research 209: 53-59. 
Lynch, E. P., M. A. Lazor, J. E. Gellis, J. Orav, L. Goldman and E. R. Marcantonio (1997). 
"Patient Experience of Pain After Elective Noncardiac Surgery." Anesthesia & Analgesia 85(1). 
MARCAIN SmPC (2016). MARCAIN Polyamp Steripack 0.25%. Dublin, IE: Aspen. 
MARCAINE USPI (2011). MARCAINE (Bupivacaine Hydrochloride Injection). Lake Forest, IL 
60045: Hospira, Inc. 
Meissner, W., F. Coluzzi, D. Fletcher, F. Huygen, B. Morlion, E. Neugebauer, A. M. Pérez and 
J. Pergolizzi (2015). "Improving the management of post-operative acute pain: priorities for 
change." Current Medical Research and Opinion 31(11): 2131-2143. 
Misiolek, H., M. Cettler, J. Woron, J. Wordliczek, J. Dobrogowski and E. Mayzner-Zawadzka 
(2014). "The 2014 guidelines for post-operative pain management." Anaesthesiol Intensive Ther 
46(4): 221-244. 
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. 


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Oderda, G. M., T. J. Gan, B. H. Johnson and S. B. Robinson (2013). "Effect of Opioid-Related 
Adverse Events on Outcomes in Selected Surgical Patients." Journal of Pain & Palliative Care 
Pharmacotherapy 27(1): 62-70. 
Ptaszek, A. J., S. G. Morris and J. W. Brodsky (1999). "Midfoot Field Block Anesthesia with 
Monitored Intravenous Sedation in Forefoot Surgery." Foot & Ankle International 20(9): 583-
586. 
Ramachandran, S. K., N. Haider, K. A. Saran, M. Mathis, J. Kim, M. Morris and M. O'Reilly 
(2011). "Life-threatening critical respiratory events: a retrospective study of postoperative 
patients found unresponsive during analgesic therapy." Journal of Clinical Anesthesia 23(3): 
207-213. 
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. 
Rudd, R. A., P. Seth, F. David and L. Scholl (2016). "Increases in Drug and Opioid-Involved 
Overdose Deaths - United States, 2010-2015." MMWR Morb Mortal Wkly Rep 65(5051): 1445-
1452. 
Shah, A., C. J. Hayes and B. C. Martin (2017). "Characteristics of Initial Prescription Episodes 
and Likelihood of Long-Term Opioid Use - United States, 2006-2015." MMWR Morb Mortal 
Wkly Rep 66(10): 265-269. 
Shirakami, G., Y. Teratani, T. Namba, H. Hirakata, M. Tazuke-Nishimura and K. Fukuda 
(2005). "Delayed discharge and acceptability of ambulatory surgery in adult outpatients 
receiving general anesthesia." Journal of Anesthesia 19(2): 93-101. 
Singla, N. K., P. J. Desjardins and P. D. Chang (2014). "A comparison of the clinical and 
experimental characteristics of four acute surgical pain models: Dental extraction, bunionectomy, 
joint replacement, and soft tissue surgery." PAIN 155(3): 441-456. 
Stephens, J., B. Laskin, C. Pashos, B. Pena and J. Wong (2003). "The burden of acute 
postoperative pain and the potential role of the COX-2-specific inhibitors." Rheumatology 
42(90003): 40-52. 
Svensson, I., B. Sjöström and H. Haljamäe (2000). "Assessment of Pain Experiences after 
Elective Surgery." Journal of Pain and Symptom Management 20(3): 193-201. 
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. 
Wheeler, M., G. M. Oderda, M. A. Ashburn and A. G. Lipman (2002). "Adverse events 
associated with postoperative opioid analgesia: A systematic review." The Journal of Pain 3(3): 
159-180. 
 




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APPENDIX B. BMI CALCULATION 
Body Mass Index = Weight in kilograms / (height in meters)2 
Meters = inches × 0.0254 
Kilograms = pounds × 0.45 
 
Example: 
For a man who weighs 165 pounds and is 71 inches tall: 
165 lbs. × 0.45 = 74.25 kg 
71 in. × 0.0254 = 1.8 m 
74.25 / (1.8 × 1.8) = 22.92 kg/m2 
 


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APPENDIX C. 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 D. 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., Vallow, S., Damaraju, C.V., and Hewitt, D.J. (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, 1433-1443. 
 
 




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Appendix F. 
WOUND HEALING ASSESSMENT 
Record “Present” or “Absent” for each of the following symptoms in relationship to the wound. 
Signs and symptoms that are present should be entered on the electronic case report form (eCRF) 
as adverse events (AEs). Note that if an event qualifies as a serious adverse event (SAE; see 
Section 8.4.1), the Sponsor must be notified within 24 hours of when the Investigator is first 
aware of the event. 
Bruising 
Present 
Absent 
Erythema 
Present 
Absent 
Edema 
Present 
Absent 
Heat 
Present 
Absent 
Drainage 
Present 
Absent 
Cellulitis 
Present 
Absent 
Delayed healing 
Present 
Absent 
Dehiscence 
Present 
Absent 


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APPENDIX G. INSTRUCTIONS FOR POSTOPERATIVE PAIN 
MANAGEMENT FOR SUBJECTS MEDICALLY READY 
FOR DISCHARGE  
The following text should be read by the Investigator or designee to the subject at the time of 
discharge: 
You have completed the initial part of the study which required you to stay at the facility. You 
are now being discharged to go home. You will come back here again for check-up visits on 
Day 10 (approximately 1 week from now), Day 28 (approximately 3½ weeks from now), and for 
a Safety Follow-Up on Day 42 (approximately 5½ weeks from now). 
While you are at home, if you experience any pain from your operation, please take up to 
2 over-the-counter extra-strength (500 mg) acetaminophen tablets (eg, Tylenol) every 6 hours as 
needed. Do not take more than 8 tablets (4000 mg) in a 24-hour period. If this does not control 
your pain, please call <<insert name and contact information>> so that we can talk about 
providing you with a prescription for something stronger, if needed. 
Do not take other acetaminophen-containing products that are available over the counter 
without first checking with your doctor. As an example, cold medicine over the counter may 
contain acetaminophen and may result in exceeding the daily dose limit of acetaminophen and 
can cause liver damage. 
NOTE: If a subject required 10 mg or more of oxycodone in the 12 hours prior to discharge, the 
subject should be provided with a prescription for oxycodone up to 10 mg PO q4h, #15, as 
needed. Pharmacists should be instructed that substitutions for any other opioid-containing 
product are not permitted. 




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Phase 3 bunionectomy study for postoperative analgesia (EPOCH 1) 
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Local Anesthetic Systemic Toxicity (LAST) Questionnaire 
Record “Present” or “Absent” for each of the following symptoms. Signs and symptoms that are present 
should be entered on the electronic case report form (eCRF) as adverse events. Note that if an event 
qualifies as an SAE (see Section 8.4.1), the Sponsor must be notified within 24 hours of when the 
Investigator is first aware of the event. 
Metallic/strange taste 
Present 
Absent 
Perioral tingling 
Present 
Absent 
Ringing in ears 
Present 
Absent 
Visual disturbance 
Present 
Absent 
Tremors 
Present 
Absent 
Muscle twitching 
Present 
Absent 
Dizziness/lightheadedness 
Present 
Absent 
Convulsion/seizure 
Present 
Absent 
Bradycardia 
Present 
Absent 
Arrhythmia 
Present 
Absent 
Hypotension 
Present 
Absent 
Cardiac arrest 
Present 
Absent 
Respiratory arrest 
Present 
Absent 
 
Reference: Vasques, F., A.U. Behr, G. Weinberg, C. Ori, 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.” Reg Anesth Pain Med 40(6): 698-705. 


Signature Page for VV-CLIN-000397 v1.0
Signature Page for VV-CLIN-000397 v1.0
Approval
25-Sep-2017 00:31:06 GMT+0000

SAP_001.pdf: 
Document Type:  
Statistical Analysis Plan 
Official Title:  
A Phase 3, Randomized, Double-Blind, Saline Placebo- and 
Active-Controlled, Multicenter Study of HTX-011 via Local 
Administration for Postoperative Analgesia and Decreased Opioid Use 
Following Unilateral Simple Bunionectomy 
NCT Number:  
NCT03295721 
Document Date:  
10-Oct-2017 
 


 
Confidentiality Statement 
This document contains confidential information of Heron Therapeutics, Inc. 
Do not copy or distribute without written permission of the Sponsor. 
Any authorized use, reproduction, publication, or dissemination is strictly prohibited. 
STUDY HTX-011-301 
 
A PHASE 3, RANDOMIZED, DOUBLE-BLIND, SALINE PLACEBO- AND ACTIVE-
CONTROLLED, MULTICENTER STUDY OF HTX-011 VIA LOCAL 
ADMINISTRATION FOR POSTOPERATIVE ANALGESIA AND DECREASED 
OPIOID USE FOLLOWING UNILATERAL SIMPLE BUNIONECTOMY (EPOCH 1) 
 
10 October 2017 
 
Statistical Analysis Plan 
 
Version 1  
 
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, V1 
Protocol HTX-011-301 (EPOCH 1) 
10 October 2017
 
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TABLE OF CONTENTS 
1. 
Administrative Structure ..................................................................................................7 
1.1. 
Sponsor and Oversight ...................................................................................................7 
1.2. 
Data Quality Assurance .................................................................................................7 
2. 
Introduction ......................................................................................................................7 
3. 
Objectives .........................................................................................................................8 
4. 
Investigational Plan ..........................................................................................................8 
4.1. 
Overall Study Design and Plan ......................................................................................8 
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 ...............................................................12 
5.3. 
Statistical Hypotheses and Multiple Endpoint Handling .............................................12 
5.4. 
Analysis Populations ....................................................................................................14 
5.4.1. 
Intent-to-Treat (ITT) Population ............................................................................14 
5.4.2. 
Per Protocol Population .........................................................................................14 
5.4.3. 
Safety Population ...................................................................................................14 
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. 
72 Hour Postoperative Observation Period............................................................15 
5.5.5. 
Visit Windows .......................................................................................................15 
5.5.6. 
Handling of Missing and Partial Data ....................................................................15 
6. 
Subject Disposition ........................................................................................................16 
7. 
Demographics, Characteristics, and Medical History ....................................................16 
7.1. 
Demographics and Baseline Characteristics ................................................................16 
7.2. 
Medical History ...........................................................................................................17 
7.3. 
Protocol Deviations ......................................................................................................17 
8. 
Treatments and Medications ..........................................................................................17 
8.1. 
Prior and Concomitant Medications ............................................................................17 


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10 October 2017
 
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8.2. 
Rescue Medication .......................................................................................................18 
8.3. 
Surgery Procedure ........................................................................................................18 
8.4. 
Study Drug ...................................................................................................................18 
9. 
Efficacy Analysis ...........................................................................................................18 
9.1. 
Primary Efficacy Endpoint ..........................................................................................19 
9.1.1. 
Primary Analysis ....................................................................................................20 
9.1.2. 
Sensitivity Analyses ...............................................................................................21 
9.2. 
Key Secondary Efficacy Endpoints .............................................................................21 
 
 
9.3.1. 
Analyses .................................................................................................................23 
 
 
10. 
Safety Analysis ...............................................................................................................27 
10.1. Adverse Events ............................................................................................................27 
10.1.1. 
Incidence of Treatment Emergent Adverse Events ...............................................28 
10.1.2. 
Relationship of Adverse Events to Investigational Drug .......................................29 
10.1.3. 
Severity of Adverse Event .....................................................................................29 
10.1.4. 
Serious Adverse Events .........................................................................................29 
10.1.5. 
Adverse Events Leading to Study Withdrawal ......................................................29 
10.1.6. 
Opioid-related Adverse Events ..............................................................................29 
10.1.7. 
Local Inflammatory Adverse Events .....................................................................30 
10.1.8. 
Local Anesthetic System Toxicity (LAST) related Adverse Events .....................31 
10.1.9. 
Death ......................................................................................................................31 
10.2. Local Anesthetic System Toxicity Assessment ...........................................................31 
10.3. Clinical Laboratory Evaluations ..................................................................................31 
10.3.1. 
Hematology ............................................................................................................32 
10.3.2. 
Blood Chemistry ....................................................................................................32 
10.3.3. 
Urine Pregnancy Test and Urine Drug Screen .......................................................33 
10.4. Vital Sign Measurements .............................................................................................33 
10.5. Electrocardiogram ........................................................................................................34 
10.6. Physical Examination...................................................................................................34 
10.7. Wound Healing Assessment ........................................................................................35 
10.8. Bone Healing Assessment............................................................................................35 
11. 
Interim Analysis .............................................................................................................35 
11.1. Interim Analysis ...........................................................................................................35 


Heron Therapeutics, Inc. 
Statistical Analysis Plan, V1 
Protocol HTX-011-301 (EPOCH 1) 
10 October 2017
 
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11.2. Data Safety Monitoring Board .....................................................................................35 
12. 
References ......................................................................................................................36 
Appendix 1. 
Imputation of Partial and Missing Dates ...................................................37 
Appendix 2. 
Document Revision History .......................................................................38 


Heron Therapeutics, Inc. 
Statistical Analysis Plan, V1 
Protocol HTX-011-301 (EPOCH 1) 
10 October 2017
 
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List of Abbreviations 
Abbreviation 
Term 
AE 
Adverse event  
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANOVA 
Analysis of variance 
AST 
Aspartate aminotransferase 
ATC 
Anatomic Therapeutic Classification 
AUC 
Area under the curve 
bpm 
Beats per minute 
BMI 
Body mass index 
BUN 
Blood urea nitrogen 
CI 
Confidence interval 
CRO 
Contract Research Organization 
CSR 
Clinical Study Report 
CTM 
Clinical trial materials 
DBP 
Diastolic blood pressure 
DM 
Data management 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
eDISH 
Evaluation of drug-induced serious hepatotoxicity 
GGT 
Gamma glutamyltransferase 
HCl 
Hydrochloride 
HR 
Heart rate 
IM 
Intramuscular 
IRS 
Integrated Rank of Silverman 
IRT 
Interactive response technology 
ITT 
Intent-to-Treat  
IV 
Intravenous(ly) 
K-M 
Kaplan-Meier 
LAST 
Local Anesthetic System Toxicity 
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 
Nonresponder imputation 
NRS 
Numeric Rating Scale 
NRS-A 
Numeric Rating Scale with activity 
NRS-R 
Numeric Rating Scale at rest 
NSAID 
Nonsteroidal anti-inflammatory drug 
ORAE 
Opioid-related adverse event 
PACU 
Post-Anesthesia Care Unit 
PGA 
Patient’s Global Assessment 
PGIC 
Patient’s Global Impresson of Change 
PK 
Pharmacokinetic(s) 


Heron Therapeutics, Inc. 
Statistical Analysis Plan, V1 
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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 
SI 
Standard international 
SOC 
System Organ Class 
TEAE 
Treatment-emergent adverse event 
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, V1 
Protocol HTX-011-301 (EPOCH 1) 
10 October 2017
 
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1. 
ADMINISTRATIVE STRUCTURE 
1.1. 
Sponsor and Oversight 
This study is being conducted under the sponsorship of Heron Therapeutics, Inc. (Heron).  
 
 
 
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 pharmacokinetics (PK) 
assessments in the study. Planned PK analysis will be presented in a separate PK analysis 
plan. 
This SAP was prepared prior to data analysis to provide full details of analyses to be 
presented in the Clinical Study Report (CSR), including a technical and detailed elaboration 
of the statistical analysis methods presented in the protocol.  Revisions can be made to this 
SAP while the study is ongoing; however, it must be finalized prior to database lock.  Any 
deviations from the analysis plan provided in the SAP will be fully documented in the final 
CSR. 
This SAP should be read in conjunction with the study protocol and the electronic Case 
Report Forms (eCRFs). 
   


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3. 
OBJECTIVES 
The primary objective of the study is as follows: 
 To compare the efficacy and duration of analgesia following local administration of 
HTX-011 with saline placebo during the first 72 hours following unilateral simple 
bunionectomy 
The secondary objectives are as follows: 
 To compare the efficacy and duration of analgesia for HTX-011 with bupivacaine 
HCl without epinephrine during the first 72 hours following surgery in this study 
population  
 To compare the effect of HTX-011 with saline placebo and bupivacaine HCl without 
epinephrine on opioid load during the first 72 hours following surgery in this study 
population  
 To assess the safety and tolerability of HTX-011 in this study population 
 To further establish the pharmacokinetic (PK) parameters of bupivacaine and 
meloxicam in HTX-011 in this study population 
4. 
INVESTIGATIONAL PLAN 
4.1. 
Overall Study Design and Plan 
This is a Phase 3, randomized, double-blind, saline placebo- and active-controlled, 
multicenter study in subjects undergoing unilateral simple bunionectomy. This study will 
evaluate the efficacy and safety profile of HTX-011 on clinical outcomes (eg, level of pain, 
avoidance of opioids, etc.) in subjects treated with a single intraoperative dose of study drug 
administered via instillation into the surgical site. 
Approximately 400 subjects will be randomized to 1 of the following 3 treatment group in a 
3:3:2 ratio: 
 HTX-011, 60 mg/1.8 mg (bupivacaine/meloxicam doses), 2.1 mL, via instillation into the 
surgical site (150 subjects) 
 Bupivacaine HCl without epinephrine 0.5%, 50 mg (10 mL), via injection into the 
surgical site (150 subjects) 
 Saline placebo, 2.1 mL, via instillation into the surgical site (100 subjects) 
4.2. 
Assessments 
Efficacy assessments will include the following: 
 Pain intensity scores using the NRS with activity (NRS-A) and using the NRS at rest 
(NRS-R)  
 Use of opioid rescue medication 




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4.3.2. 
Safety Endpoints 
The safety endpoints are: 
 
 Incidence of treatment-emergent AEs (TEAEs), serious TEAEs (SAEs), and 
opioid-related AEs (ORAEs) through the Safety Follow-up on Day 42 
 Change from baseline in clinical laboratory results 
 Change from baseline in ECG data 
 Change from baseline in vital signs 
 Wound healing assessment at 72 hours and, on Day 10 and Day 28, and at the Safety 
Follow-up on Day 42 
 Bone healing assessment on Day 28 and at the Safety Follow-up on Day 42 
5. 
GENERAL STATISTICAL CONSIDERATIONS 
Unless specified otherwise, all statistical analyses will be performed using a two-sided 
hypothesis test at the 5% level of significance. All p-values will be rounded to 4 decimal 
places.  If a p-value is less than 0.0001, it will be reported as “< 0.0001”.  If a p-value is 
greater than 0.9999, it will be reported as “> 0.9999”. 
Continuous data will be presented using descriptive statistics: number of subjects (n), mean, 
standard deviation (SD), median, minimum and maximum.  Descriptive statistics on efficacy 
measures will also include the standard error (SE).  Categorical data will be summarized by 
the number and percent of subjects.  Confidence intervals (CI) will be 95% and two-sided, 
unless otherwise stated.  Data will be displayed in all listings sorted by treatment group, 
subject number and visit/study day.  When count data are presented, the percent will be 
suppressed when the count is zero in order to draw attention to the non-zero counts.  A row 
denoted “Missing” will be included in count tabulations where necessary to account for 
dropouts and missing values.  The denominator for all percentages will be the number of 




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5.2. 
Randomization, Stratification, and Blinding 
Subjects will be randomized to receive HTX-011, bupivacaine HCl, or saline placebo.  The 
randomization will not be stratified.  Subjects will not be aware of the study drug they are 
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.  However, subjects will not be aware of the study drug they are 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) and clinical observer 
staff. 
The randomization will be based on a centralized computer-generated blocked randomization 
algorithm created by an IRT provider.   
A subject’s treatment group assignment will not be broken until database lock 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 
The primary endpoint of AUC0-72 of NRS-A will be a comparison of HTX-011 with saline 
placebo under the following hypothesis: 
H0: µHTX-011 = µsaline placebo 
Ha: µHTX-011 ≠ µsaline placebo  
The primary endpoint will be carried out using an analysis of variance (ANOVA) model with 
treatment as the main effect, comparing HTX-011 with saline placebo at a significance level 
of 5%.  Results will be expressed as mean AUCs and SDs, least-square mean differences 
(LSMD) and SEs with associated 95% CI, and p-values.  
The first key secondary endpoint involving AUC0-72 of NRS-A comparing HTX-011 with 
bupivacaine HCl will be analyzed similarly to the methods described for the primary 
endpoint.  
Total postoperative opioid consumption through 72 hours will be summarized using 
descriptive statistics. 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 


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is violated and the total postoperative opioid consumption through 72 hours will be analyzed 
using a Wilcoxon rank sum test. Results will be expressed as median (range) and p-values. 
However, if the assumption of normality holds (ie, Shapiro-Wilk p-value >0.05), then the 
total postoperative opioid consumption through 72 hours will be analyzed using an ANOVA 
model with treatment as the main effect. Results will be expressed as means, SDs, and 
LSMD and SEs with associated 95% CI, and p-values.  
The proportion of subjects who are opioid-free postoperatively through 72 hours 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% CI, and p-values. 
In order to account for multiple hypothesis testing on the primary endpoint and on each of the 
4 key secondary endpoints, a strict testing hierarchy will be applied to control study-wise 
alpha level at 0.05.  If the primary endpoint is statistically significant (p ≤ 0.05), then the first 
key secondary endpoint will be tested. If the first key secondary endpoint is statistically 
significant, then the second key secondary endpoint will be tested. Sequential testing will 
continue in this manner down the key secondary endpoint list until an endpoint fails to meet 
statistical significance, after which all subsequent key secondary endpoints will be 
considered exploratory (Figure 1). If the primary endpoint is not statistically significant, then 
all key secondary endpoints will be considered exploratory. 
Figure 1. Hierarchical test procedure for primary and key secondary endpoints 
 
 
 
Abbreviations: BPV, bupivacaine HCl; PBO, saline placebo 


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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. 
Per Protocol Population 
The Per Protocol Population will consists of all subjects in the ITT Population who do not 
receive a prohibited rescue medication prior to 72 hours and who have no important protocol 
violations prior to 72 hours. This population will be used for sensitivity analyses on the 
primary and key secondary endpoints. 
5.4.3. 
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. 
5.5. 
Other Important Considerations 
5.5.1. 
Definition of Baseline 
Baseline data are defined as the last observed measurement collected, whether scheduled or 
unscheduled, prior to the start of study drug administration.   
5.5.2. 
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 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 


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 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. 
72 Hour Postoperative Observation Period 
The 72 hour postoperative observation period will be defined as the period of time from the 
start date/time of study drug administration to the date/time of NRS-A pain intensity score 
assessment at the nominal 72-hour postoperative timepoint.  
Subjects who have a reported NRS-A pain intensity score at the nominal 72-hour 
postoperative timepoint will be considered as completing the 72 hour postoperative 
observation period. 
5.5.5. 
Visit Windows 
Due to the short duration of the study and the primary efficacy analyses occurring during the 
72-hour postoperative period of subject hospitalization, no programmatically calculated visit 
windows are defined for this study. 
5.5.6. 
Handling of Missing and Partial Data 
The amount of missing data during the primary efficacy analysis period is expected to be 
very low due to the protocol-required 72-hour hospitalization of all subjects following 
surgery.   
For any data that is missing through 72 hours in subjects who complete the 72-hour 
postoperative observation period, the 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 available prior to the first 
missing value, then the median of values from subjects with observed values within the same 
treatment group at the relevant timepoint will be used.  Predose values will not be carried 
forward to postdose timepoints.   
In subjects who withdraw from the study prior to 72 hours, missing NRS pain intensity 
scores through 72 hours that were to be collected following withdrawal will be imputed via 
worst observation carried forward (WOCF), in which the worst (highest) NRS pain intensity 
score observed prior to withdrawal will be used for post-withdrawal values through 72 hours. 
Any missing NRS pain intensity scores prior to the point of withdrawal will be imputed via 
LOCF. 
For binary endpoints (those involving proportions of subjects) not involving the 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 


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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). Analyses 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-A 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 Per Protocol Population, subjects in the Safety Population, 
subjects completing the 72-hour postoperative observation period, subjects completing 
Day 28, subjects completing the Safety Follow-up on Day 42, and subjects not completing 
the Safety Follow-up on Day 42 by reason for withdrawal.  Only 1 reason for study 
withdrawal will be recorded for each subject.   
7. 
DEMOGRAPHICS, CHARACTERISTICS, AND MEDICAL 
HISTORY 
7.1. 
Demographics and Baseline Characteristics 
Demographics and baseline characteristics will be presented in tables using descriptive 
statistics.  Demographics consist of age, age category, sex, race, and ethnicity.  Baseline 
characteristics consist of weight, height, and body mass index (BMI).  A subject’s age in 
years is calculated using the integer part of the difference in number of days between the date 
that informed consent is signed and date of birth divided by 365.25, or is recorded directly on 


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the eCRF.  The number and percentage of subjects in the following age categories will be 
presented: 18-44, 45-54, 55-64, 65-74, 75-84, and ≥ 85. 
Demographics and baseline characteristics will be presented for the ITT Population, the 
Safety Population, and the Per Protocol Population. Demographics will also 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 System Organ Class (SOC) and preferred term (PT).   
7.3. 
Protocol Deviations 
Deviations and violations from the protocol will be recorded.  Protocol deviations will be 
classified into, 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.  Reasons for excluding subjects from the Per Protocol Population will be 
summarized for the ITT population by treatment and overall. 
8. 
TREATMENTS AND MEDICATIONS 
8.1. 
Prior and Concomitant Medications 
Prior medications are defined as medications with a stop date occurring before Day 1.  
Concomitant medications are defined as medications that are ongoing on Day 1 or with a 
start date occurring on or after Day 1.  Medications with start and stop dates which bracket 
Day 1, or for which missing start and/or stop dates make it impossible to determine the prior 
or concomitant status, will be summarized as concomitant medications. 


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All medications will be coded with the World Health Organization Drug classification 
dictionary (WHODrug), September 1, 2016. 
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 and concomitant medications will be summarized for the Safety Population.   
8.2. 
Rescue Medication 
The following steps will be implemented to identify rescue medication in the study. 
1. Select concomitant medication with indication of “Post Operative Pain” 
2. Identify rescue medications from step 1 in which the start date/time of medication is 
within the 72-hour postoperative observation period (see Section 5.5.4 for details)   
Opioid rescue medication in morphine milligram equivalency (MME) dose (see Section 9.2 
for details) and non-opioid rescue medication dose will be summarized for 0-24 hours, 0-48 
hours, and 0-72 hours.  In addition, proportions of subjects who received no rescue 
medication, who received opioid rescue medication only, who received non-opioid rescue 
medication only, and who received both opioid and non-opioid rescue medication will be 
summarized through 72 hours for the ITT population.  
8.3. 
Surgery Procedure 
The foot subject to the surgical procedure (left or right), length of incision in centimeters, and 
the duration of surgery will be summarized.  Duration will be calculated as completion time 
minus start time, reported in minutes.  
8.4. 
Study Drug 
For all subjects, treatment will consist of a single 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 
treatment groups being studied. 
 


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Table 1. 
Planned Treatment Groups 
Treatment 
Planned Sample Size 
HTX-011 60 mg/1.8 mg (2.1 mL) 
150 
Saline placebo (2.1 mL) 
100 
Bupivacaine HCl 50 mg (10 mL) 
150 
       
See Section 5.3 for details on multiple endpoint handling for primary and key secondary 
endpoints. 
The following treatment comparisons will be tested for each efficacy endpoint. 
1. HTX-011 60 mg/1.8 mg vs. saline placebo 
2. HTX-011 60 mg/1.8 mg vs. bupivacaine HCl 50 mg 
 
In addition, the following comparison will be tested for AUC of NRS-A and NRS-R pain 
intensity scores only: bupivacaine HCl 50 mg vs. saline placebo. 
 
Subgroup analyses will be performed for the primary and key secondary efficacy endpoints 
where applicable.  The following are the pre-defined subgroups: 
 
 Age at screening (18-44, 45-54, 55-64, 65-74, 75-84, and ≥ 85) 
 Sex (female, male) 
 Race (black, white, other) 
 Ethnicity (Hispanic or Latino, not Hispanic or Latino) 
 
If any of the subgroups has fewer than 20 total subjects, then that subgroup will either not be 
performed (eg, if there are fewer than 20 males) or will be pooled with another subgroup (eg, 
if there are fewer than 20 subjects in the 55-64 age group). 
9.1. 
Primary Efficacy Endpoint 
The primary estimand to address the efficacy objectives is the mean AUC of NRS-A pain 
intensity scores through 72 hours (AUC0-72) adjusted for use of opioid rescue medication via 
wWOCF, comparing the estimated treatment difference between HTX-011 and saline 
placebo using ANOVA with missing data imputed using LOCF for interval censored pain 
intensity scores and WOCF for right-censored pain intensity scores in the ITT Population. 
The primary efficacy endpoint is the mean AUC of the NRS-A pain intensity scores through 
72 hours (AUC0-72) for HTX-011 compared with saline placebo. 


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9.1.1. 
Primary Analysis 
During the first 72 hours following surgery, the NRS-A is measured at hours 1, 2, 4, 8, 12, 
24, 36, 48, 60, and 72.  Using the trapezoidal rule and letting Pt = the NRS-A pain intensity 
score at time t, then:  
(𝑡−𝑡−1) 𝑃𝑡−1 + 𝑃𝑡
2
 
 
is the trapezoidal area between times t and t-1.  The AUC0-72 is thus calculated as follows: 
 
𝐴𝑈𝐶0−72 = ∫𝑓(𝑡)𝑑𝑡≈∑(𝑡𝑖−𝑡𝑖−1) 𝑃𝑖−1 + 𝑃𝑖
2
72
𝑖=2
72
1
 
 
The primary endpoint of mean AUC0-72 of the NRS-A pain intensity scores will be analyzed 
using an ANOVA model with randomized treatment as the main effect, comparing HTX-011 
with saline placebo at a significance level of 5%.  Results will be expressed as mean AUCs, 
SDs, and LSMD and SEs with associated 95% CI, and p-values.   
To adjust for the duration effect of opioid rescue medication, 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.  wWOCF will be performed 
following LOCF/WOCF (ie, perform LOCF/WOCF first, then apply wWOCF).  See Table 2 
in Section 9.2 for predefined analgesic windows for each opioid medication.  
The mean AUC0-72 of the NRS-A pain intensity scores using wWOCF will also be plotted 
with associated SEs in a bar chart.  A forest plot showing the overall result and the result for 
each of the subgroups will also be presented. 
The AUC0-12, AUC0-24, AUC24-48, AUC0-48, and AUC48-72 of the NRS-A pain intensity scores 
will be analyzed similarly as for the AUC0-72 of the NRS-A pain intensity scores, with 
appropriate adjustments to the calculations to reflect the time periods of interest.  Mean 
AUC0-24, and mean AUC0-48 of NRS-A will also be plotted with associated SEs in a bar chart. 
In addition, the mean NRS-A pain intensity scores will be summarized at each assessed 
timepoint through Day 28. Mean NRS-A pain intensity scores will also be plotted in a line 
graph over time through 72 hours, with associated SEs at each timepoint. 


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9.1.2. 
Sensitivity Analyses 
The following sensitivity analyses will be performed on the primary endpoint:  
1. Reproducing the primary analysis but without adjusting the NRS-A pain intensity 
scores for the use of opioid rescue medications (ie, without applying wWOCF) 
2. Reproducing the primary analysis on the Per Protocol Population 
9.2. 
Key Secondary Efficacy Endpoints 
The key secondary efficacy endpoints via hierarchical testing are: 
1. Mean AUC of the NRS-A scores through 72 hours (AUC0-72) for HTX-011 compared 
with bupivacaine HCl 
2. Mean total postoperative opioid consumption (in morphine equivalents) through 
72 hours for HTX-011 compared with saline placebo 
3. Proportion of subjects who are opioid-free through 72 hours for HTX-011 compared 
with bupivacaine HCl 
4. Mean total postoperative opioid consumption (in morphine equivalents) through 
72 hours for HTX-011 compared with bupivacaine HCl 
The endpoint involving AUC of NRS-A will be analyzed similarly to the methods described 
for the primary endpoint in Sections 9.1.1 and 9.1.2.   
Subjects who have a total MME postoperative opioid dose = 0 through 72 hours will be 
characterized as “opioid-free” through 72 hours.  The proportion of subjects who are opioid-
free through 72 hours will be compared with bupivacaine HCl using Fisher’s exact test.  
Descriptive statistics, differences in proportions, p-values, and exact 95% CI based on 
Farrington-Manning score statistics (Chan and Zhang 1999) will be presented.  
The endpoints involving postoperative opioid consumption will be analyzed as follows: 
Determination of morphine equivalents 
Use of opioid rescue medication will be summarized by preferred term.  All opiate dosages 
and formulations will have the MME calculated (Opioid Morphine Equivalent Conversion 
Factors, Centers for Disease Control and Prevention, Atlanta, GA, May 2014).  
Protocol-allowed postoperative rescue medications consist of oral (PO) immediate-release 
oxycodone (no more than 10 mg within a 4-hour period as needed), intravenous (IV) 
morphine (no more than 10 mg within a 2-hour period as needed), and/or oral acetaminophen 
(no more than 1 gram [1000 mg] in a 6-hour window). For subjects administered any 
acetaminophen-containing product, the total combined daily dose must not exceed 4 grams 
(4000 mg) as severe liver damage may occur.  No other analgesic agents, including 


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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 opioid rescue 
medications are checked.  Opioid medications that are not protocol-allowed will be logged as 
protocol violations, but will still be subject to MME conversion for analysis. 
Table 2.   Analgesic Windows and Morphine Milligram Equivalents for Opioid 
Rescue Medications 
Medication 
Route 
Window 
(hr) 
MME Factor 
Protocol Allowed 
CODEINE 
PO 
6 
0.05 
 
 
DILAUDID 
PO 
4 
1.33 
 
 
DILAUDID 
IV 
4 
6.67 
 
 
FENTANYL 
IV 
1 
50.00 
 
 
HYDROCODONE 
PO 
6 
0.40 
 
 
MORPHINE 
IV 
4 
1.00 
 
 
MORPHINE 
PO 
4 
0.33 
 
 
MORPHINE 
IM 
4 
1.00 
 
 
MORPHINE 
PR 
4 
1.00 
 
 
OXYCODONE 
IV 
4 
1.00 
 
 
OXYCODONE 
IM 
4 
1.00 
 
 
OXYCODONE 
PO 
6 
0.50 
 
 
SUFENTANIL 
PO 
2 
500.00 
 
 
TRAMADOL 
IV 
6 
0.06 
 
 
TRAMADOL 
PO 
6 
0.04 
 
 
Abbreviations: hr, hour; IM, intramuscular; IV, intravenous; MME, morphine milligram equivalency; PO, by 
mouth (orally); PR, per rectum. 
             
Analysis method 
Rescue medication use is collected from hours 0-72.  Average daily use and total use will be 
tabulated using descriptive statistics for each opiate, for overall opioids, and for 
acetaminophen during the following periods: hours 0-24, hours 24-48, hours 0-48, hours 48-
72, and hours 0-72.  Subjects who did not use a specific rescue medication during a period of 
interest will have their dose set to 0 for that period.  Only postoperative opioid consumption 
will be subject to hypothesis testing for the relevant key secondary endpoints. 
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 a 
Wilcoxon rank sum test. Results will be expressed as median (range) and p-values. However, 
1if the 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 


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ANOVA model with randomized treatment as the main effect.  Results will be expressed as 
means, SDs, and LSMD and SEs with associated 95% CI, and p-values.   
The mean total postoperative opioid consumption will also be plotted in a bar chart for hours 
0-24, hours 0-48 and hours 0-72 with associated SEs.  
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
    
 
 
 
 
 
 




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10. 
SAFETY ANALYSIS 
All analyses of safety data will be conducted using the Safety Population.  Statistical 
hypothesis testing will not be performed on any safety results.  No imputation of missing 
safety data will be performed except in the case of partial AE and concomitant medication 
onset dates (Appendix 1). 
10.1. 
Adverse Events 
An AE is defined as any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related.  A TEAE is any AE which occurs any time 
during or after study drug administration, or any AE with an onset prior to study drug 
administration that worsens during or after study drug administration.  An AE may be any 
unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a study drug, whether or not considered 
causally associated with the use of the study drug. Any abnormal laboratory value, vital sign 


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result, or ECG finding deemed clinically significant by the Investigator, regardless of causal 
relationship, must be reported as an AE.  
For an event to be a TEAE, it must meet one of the following conditions: 
 Begins on Study Day 1, during or after administration of study drug 
 Begins after Study Day 1 
 Begins before Study Day 1 and worsens in severity during or after the Study Day 1 
administration of study drug 
AEs with unknown onset dates or unknown end dates will be counted as TEAEs unless the 
event resolves before Study Day 1.   
AEs will be coded using MedDRA version 19.1.  Only TEAEs will be presented in AE 
tables, according to the SOC and PT.  Any AEs that occur and resolve prior to Study Day 1 
or are ongoing but do not worsen on or after Study Day 1 will be considered pretreatment 
AEs and will appear in the AE listing but not in TEAE tables. 
10.1.1. 
Incidence of Treatment Emergent Adverse Events 
The incidence of TEAEs table will include only 1 occurrence of a PT per subject.  If a 
subject reports the same PT multiple times, then that PT will only be incremented by 1 since 
subject counts will be presented.  As with the PT, if a subject reports multiple TEAEs within 
the same SOC, then that SOC will only be incremented by 1 since subject counts will be 
presented.  For tables showing incidence by SOC and PT, SOCs will be sorted by the 
internationally agreed order and PTs will be sorted within SOC in descending order of 
incidence in the HTX-011 column.  For tables showing incidence by PT only, the PTs will be 
sorted in descending order of incidence in the HTX-011 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 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.   


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10.1.2. 
Relationship of Adverse Events to Investigational Drug 
The incidence of possibly related TEAEs will be presented in a table by SOC and PT.  
TEAEs that are missing relationship will be considered “Possibly Related” for the purpose of 
this incidence table but will be presented in the data listing with a missing relationship.   
10.1.3. 
Severity of Adverse Event 
The incidence of severe TEAEs will be presented in a table by SOC and PT.  TEAEs that are 
missing severity will be considered “severe” for the purpose of this incidence table 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, 
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.  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 


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 Somnolence 
 Respiratory depression 
 Urinary retention 
 
Incidence of ORAEs will be presented separately as follows: 
 Incidence of ORAEs  
 Incidence of ORAEs through the 72-hour postoperative observation period 
 Incidence of ORAEs in the subset of subjects who received at least 1 opioid rescue 
medication during the 72-hour postoperative observation period 
 Incidence of ORAEs through the 72-hour postoperative observation period in the 
subset of subjects who received at least 1 opioid rescue medication during the 72-
hour postoperative observation period 
10.1.7. 
Local Inflammatory Adverse Events 
To enable a broad and comprehensive analysis of TEAEs potentially related to 
adverse effects on wound healing, local inflammatory TEAEs were reviewed by 
searching the safety database using a custom list of PTs created by Heron from 
4 MedDRA SOCs (Table 3). 
Table 3. Local Inflammatory Adverse Events by System Organ Class and 
Preferred Term 
General disorders 
and administration 
site condition 
Infections and infestations 
Injury, poisoning and 
procedural complications 
Skin and 
subcutaneous 
tissue disorders 
 Impaired healing 
 Cellulitis 
 Incision site cellulitis 
 Incision site infection       
 Infection       
 Medical device site 
cellulitis        
 Post procedural 
cellulitis        
 Postoperative wound 
infection  
 Purulent discharge  
 Wound infection 
 Incision site 
complication  
 Incision site 
erythema       
 Incision site 
haemorrhage  
 Incision site 
vesicles         
 Postoperative wound 
complication  
 Wound complication  
 Wound dehiscence 
 Blister    
 Blood blister 
 Erythemaa 
a The Preferred Term of erythema was included in addition to incision site erythema for the most 
comprehensive review. 
 
Incidence of local inflammatory TEAEs will be presented in a table by SOC and PT. Local 
inflammatory TEAEs will also be listed separately. 


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10.1.8. 
Local Anesthetic System Toxicity (LAST) related Adverse Events 
The symptoms that may attribute to LAST were reviewed by searching the safety database 
using a custom list of PTs created by Heron (Table 4). 
Table 4. LAST-Related Adverse Events by System Organ Class and Preferred Term 
 Nervous system 
disorder 
Cardiac disorder 
Vascular 
disorder 
Respiratory, thoracic 
and mediastinal 
disorder 
 Dysguesia 
 Paresthesia oral 
 Tinnitus 
 Visual impairment 
 Tremor 
 Muscle twitching 
 Dizziness 
 Seizure 
 Bradycardia 
 Arrhythmia 
 Cardiac arrest 
 Hypotension 
 Respiratory arrest 
 
Incidence of LAST-related TEAEs will be presented in a table by SOC and PT. LAST 
TEAEs will also be listed separately.  
10.1.9. 
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. 
Local Anesthetic System Toxicity Assessment 
A LAST assessment questionnaire will be provided on a regular basis to monitor for early 
neurologic and cardiac signs and symptoms of LAST.  A summary of LAST assessment 
results will be produced, showing the number and percentage of subjects with any sign of 
LAST symptom with breakdown of each symptom for overall and by each visit.  LAST 
assessment results will also be listed. 
10.3. 
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 


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tables will include each visit (Baseline, hour 24 [hematology only], hour 72, and Day 10), 
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.  
10.3.1. 
Hematology 
The following laboratory tests will be included in hematology summary tables: hematocrit, 
hemoglobin, platelet count, red blood cell (RBC) count, and total and differential white blood 
cell (WBC) count (basophils, eosinophils, lymphocytes, monocytes, and neutrophils). 
10.3.2. 
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 


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highest postdose AST vs. total bilirubin observed at the same draw as the high AST value, 
will be produced. 
The incidence of subjects with clinically relevant abnormalities in Liver Function Tests will 
be summarized at each visit for each treatment group for the following categories. Subjects 
with clinical relevant abnormalities in Liver Function Tests will be presented in data listing 
as well. 
 ALT or AST: 
o > 1 x ULN  
o ≥ 2 x ULN 
o ≥ 3 x ULN 
o ≥ 4 x ULN 
o ≥ 5 x ULN  
 
 Total bilirubin ≥ 2 x ULN 
 
 ALP: 
o ≥ 1.5 x ULN 
o ≥ 2 x ULN 
 
 ALT ≥ 3 x ULN and AST ≥ 3 x ULN 
 
 ALT ≥ 3 x ULN and total bilirubin ≥ 2 x ULN 
 
 AST ≥ 3 x ULN and total bilirubin ≥ 2 x ULN 
 
 Potential Hy’s Law: (ALT or AST ≥ 3 x ULN) and ALP < 2 x ULN and total 
bilirubin ≥ 2 x ULN 
10.3.3. 
Urine Pregnancy Test and Urine Drug Screen 
Urine pregnancy test results (women of child-bearing potential) and urine drug screen results 
will be listed. 
10.4. 
Vital Sign Measurements 
Vital signs including systolic blood pressure (SBP), diastolic blood pressure (DBP), heart 
rate/pulse (HR), body temperature, and respiration rate will be collected at screening, on Day 
1 before surgery, and post-treatment at 30 minutes and at 1, 1.5, 2, 4, 8, 12, 18, 24, 36, 48, 
60, and 72 hours.   
Summary tables including actual values and changes from Baseline will be presented for 
vital signs.   


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The number and percentage of subjects with clinically relevant abnormalities will be 
presented using data from any postdose visit (including unscheduled visits). Subjects with 
clinical relevant abnormalities in vital signs will be presented in data listing as well. The 
criteria for clinically relevant abnormalities are shown in Table 5:  
Table 5.  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. 
10.5. 
Electrocardiogram 
12-lead ECG (triplicate) is performed at screening and at 4, 18, 24, 48, and 72 hours.   ECG 
parameters include heart rate (beats/min), PR interval (ms), RR interval (ms), QRS interval 
(ms), QT interval (ms), and QTcF interval (ms). Overall interpretations of ECG results are 
also included.  
ECG assessments will be performed in triplicate, and the mean value of the observed 
triplicates will be used for each ECG parameter. Summary statistics of ECG parameters and 
change from Baseline in ECG parameters will be presented using descriptive statistics at 
each scheduled visit by treatment group. Shift from baseline of overall ECG interpretation at 
each postoperative timepoint will also be provided.  
The number and percentage of subjects with clinically relevant abnormalities will be 
presented using summary table as well as data listing at each postoperative timepoint. 
 QTcF values > 450 ms, > 480 ms, and > 500 ms 
 Change from Baseline in QTcF values > 30 ms and > 60 ms 
 QT values > 500 ms 
All ECG assessments will be listed. 
10.6. 
Physical Examination 
Physical examination is performed at Screening, 72 hours, and early termination.  Physical 
examination data will be listed only. 


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10.7. 
Wound Healing Assessment 
Surgical wound healing will be assessed using a wound healing assessment questionnaire at 
72 hours and on Day 10, Day 28 and Safety Follow-up on Day 42.  A summary of wound 
healing assessment results will be produced, showing the number and percentage of subjects 
with abnormal wound healing symptoms at each visit.  Wound healing assessment results 
will also be listed. 
10.8. 
Bone Healing Assessment 
An X ray of surgical site will be obtained to evaluate the status of bone healing process on 
Day 28 and Safety Follow-up on Day 42.  Bone healing assessment results will be 
summarized and presented in data listing.  
11. 
INTERIM ANALYSIS 
11.1. 
Interim Analysis 
No formal interim analyses are planned. 
11.2. 
Data Safety Monitoring Board 
An independent Data Safety Monitoring Board (DSMB) will not be involved with the 
conduct of this study.  The Sponsor will review blinded tables and listings of accumulating 
data approximately monthly to check enrollment, adherence to follow-up schedule, and 
ongoing safety results.   
 
 
 


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12. 
REFERENCES 
Chan, I. S. and Z. Zhang (1999). "Test-based exact confidence intervals for the difference of 
two binomial proportions." Biometrics 55(4): 1202-1209. 
Dai, F., D. G. Silverman, J. E. Chelly, J. Li, I. Belfer and L. Qin (2013). "Integration of Pain 
Score and Morphine Consumption in Analgesic Clinical Studies." The Journal of Pain 14(8): 
767-777.e768. 
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. 
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 
Date of SDA 
year = year of SDA 
Missing 
Missing 
Set month and day to those of SDA 
year < year of SDA 
Missing 
Nonmissing 
set month to December 
year < year of SDA 
Missing 
Missing 
set month and day to December 31 
year > year of SDA 
Missing 
Nonmissing 
set month to January 
year > year of SDA 
Missing 
Missing 
set month and day to January 1 
year = year of SDA 
Month = month of SDA 
Missing 
Set day as day of SDA 
year = year of SDA 
Month < month of SDA 
Missing 
Set day as last day of onset month 
year = year of SDA 
Month > month of SDA 
Missing 
Set day as first day of onset month 
year < year of SDA 
Nonmissing 
Missing 
Set day as last day of onset month 
year > year of SDA 
Nonmissing 
Missing 
Set day as first day of onset month 
SDA = study drug administration. 
 
If AE resolution date is present and prior to study drug administration, no need to impute 
incomplete AE start date, as the AE is not treatment emergent and the event should be in the 
medical history. 
 
Concomitant Medications 
 If year and month are present and day is missing then set day to first day of month for 
start date, and set day to last day of month for end date 
 If year and day are present and month is missing then set month to January for start 
date, and set month to December for end date 
 If year is present and month and day are missing then set month and day to January 1 
for start date, and set month and day to December 31 for end date 
 Completely missing dates will not be imputed 
If start date is completely missing and end date is not prior to study drug administration, then 
the medication will be classified as concomitant; if the end date is missing, then the 
medication will be classified as ongoing.  Medications for which the start and end dates are 
completely missing will be classified as concomitant. 
 


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APPENDIX 2. DOCUMENT REVISION HISTORY 
Version 
Date 
Notes/Revisions 
1 
28 September 2017 
Initial version, based on protocol version 3 (24SEP2017) 
 
 
 


Signature Page for VV-CLIN-000399 v1.0
Signature Page for VV-CLIN-000399 v1.0
Approval
10-Oct-2017 18:57:38 GMT+0000
Approval
13-Oct-2017 20:43:55 GMT+0000