Conditions: Postoperative Pain
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 243
Healthy volunteers: no

Brief summary:
This is a Phase 2B, randomized, assessor-blind, active- and saline placebo-controlled, multicenter study in subjects undergoing augmentation mammoplasty to evaluate the analgesic efficacy, safety, and pharmacokinetics (PK) of HTX-011 when administered via ultrasound-guided lateral and medial pectoral nerve block before surgery.

Detailed description:

Arms:
arm 1: HTX-011 (bupivacaine/meloxicam), 60 mg/1.8 mg via nerve block. arm 2: HTX-011(bupivacaine/meloxicam), 120 mg/3.6 mg via nerve block. arm 3: HTX-011(bupivacaine/meloxicam), 240 mg/7.2 mg via nerve block. arm 4: HTX-011 (bupivacaine/meloxicam), 400 mg/12 mg via nerve block. arm 5: HTX-011 (bupivacaine/meloxicam), 400 mg/ 12 mg via instillation. arm 6: Bupivacaine HCl without epinephrine, 50 mg via nerve block. arm 7: Saline placebo via nerve block.

Interventions: intervention 1: HTX-011 intervention 2: Bupivacaine HCl without epinephrine intervention 3: Saline Placebo
Intervention descriptions: intervention 1: HTX-011 (bupivacaine/meloxicam) via nerve block or instillation. intervention 2: Bupivacaine HCl without epinephrine, 50 mg via nerve block. intervention 3: Saline placebo via nerve block.

Protocol document:
Prot_000.pdf: 
Document Type:  
Study Protocol 
Official Title:  
A Phase 2B, Randomized, Controlled Study of HTX-011 Administered 
Via Pectoral Nerve Block in Subjects Undergoing Upper Extremity 
Surgery for Augmentation Mammoplasty 
NCT Number:  
NCT03011333 
Document Date:  
15-Nov-2017 
 


Confidentiality Statement 
This document contains confidential information of Heron Therapeutics, Inc. 
Do not copy or distribute without written permission of the Sponsor. 
Any unauthorized use, reproduction, publication, or dissemination is strictly prohibited. 
 
 
CLINICAL STUDY PROTOCOL: HTX-011-211 
Protocol Title: 
A Phase 2B, Randomized, Controlled Study of HTX-011 
Administered Via Pectoral Nerve Block in Subjects 
Undergoing Upper Extremity Surgery for Augmentation 
Mammoplasty 
Brief Title: 
Phase 2B upper extremity nerve block study 
Investigational Product: 
HTX-011 (extended-release 2.5% bupivacaine and 0.075% 
meloxicam) 
Phase of Development: 
2B 
Sponsor: 
Heron Therapeutics, Inc. 
4242 Campus Point Court, Suite 200 
San Diego, CA 92121 
1-858-251-4400 
Medical Monitor: 
 
 
 
Medical Project Leader: 
 
  
 
 
Protocol Version: 
Version 6 
15 November 2017 
 
Version 5 
07 August 2017 
 
Version 4 
04 April 2017 
 
Version 3 
02 February 2017 
 
Version 2 
16 December 2016 
 
Version 1 
20 September 2016 


Protocol No: HTX-011-211 
Page 2 of 73 
Version 6 
 
Heron Therapeutics, Inc. 
Confidential 
INVESTIGATOR AGREEMENT 
CLINICAL STUDY PROTOCOL: HTX-011-211 
TITLE: A Phase 2B, Randomized, Controlled Study of HTX-011 Administered Via 
Pectoral Nerve Block in Subjects Undergoing Upper Extremity Surgery for 
Augmentation Mammoplasty 
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-011-211 
Page 3 of 73 
Version 6 
 
Heron Therapeutics, Inc. 
Confidential 
PROTOCOL SYNOPSIS 
Sponsor: Heron Therapeutics, Inc. 
Protocol Number: HTX-011-211 
Name of Investigational Product: 
HTX-011 (extended-release 2.5% bupivacaine and 
0.075% meloxicam) 
Protocol Title: 
A Phase 2B, Randomized, Controlled Study of 
HTX-011 Administered Via Pectoral Nerve Block in 
Subjects Undergoing Upper Extremity Surgery for 
Augmentation Mammoplasty 
Name of Active Ingredients: 
Bupivacaine and meloxicam 
Phase of Development: 2B 
Study Objectives: 
Primary Objective: 
 To compare the efficacy and duration of analgesia following bilateral ultrasound-guided lateral and medial 
pectoral nerve block with HTX-011 to bupivacaine HCl without epinephrine and saline placebo in subjects 
undergoing upper extremity surgery. 
Secondary Objectives: 
 To evaluate the efficacy and duration of analgesia for HTX-011 administered using different techniques in this 
study population. 
 To evaluate additional efficacy parameters in this study population. 
 To characterize the bupivacaine and meloxicam pharmacokinetic (PK) profiles of HTX-011 in this study 
population. 
 To determine the optimal administration technique of HTX-011 in this surgical model. 
 To further assess the safety and tolerability of HTX-011 in this study population. 
Methodology: This is a Phase 2B, randomized, double-blind, active- and saline placebo-controlled multicenter 
study in subjects undergoing bilateral submuscular augmentation mammoplasty under general anesthesia.  
Subjects will be screened within 21 days prior to study drug administration. Subjects who meet the Screening 
eligibility criteria will be randomized. Randomization may be done up to 1 business day prior to study drug 
administration. Subjects will be administered a single dose of study drug (HTX-011, bupivacaine HCl without 
epinephrine, or saline placebo) via bilateral ultrasound-guided lateral and medial pectoral nerve block and/or 
instillation into the surgical site. For subjects receiving study drug via ultrasound-guided lateral and medial pectoral 
nerve block, study drug will be administered within 4 hours prior to undergoing mammoplasty. For subjects 
receiving study drug via instillation, study drug will be administered prior to the end of surgery. 
Dexamethasone cannot to be administered prophylactically before surgery. During surgery, the use of fentanyl up to 
4 µg/kg will be permitted. In order to decrease the inherent variability in pain control on postoperative pain 
perception, subjects in Cohorts 2 and 4 will receive protocol-specified fentanyl 50 µg intravenously (IV) just prior to 
the end of the surgery. Intraoperative administration of other opioids or any other analgesics (including ketamine), 
local anesthetics (except for ropivacaine HCl), 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) 
or for pretreatment prior to a needle placement. 
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 end of surgery to 
undergo postoperative assessments. After the 72-hour assessments have been completed, subjects may be 
discharged. Subjects will return to the study site at 120 ±6 hours, and on Day 10 and Day 28 to complete follow-up 
assessments. 
An internal Interim Review Committee (IRC) will review unblinded, summary-level efficacy, safety, and PK data 
from each cohort to determine if enrollment should be initiated in the next cohort and to guide Phase 3 study design. 
Each interim analysis will be performed after at least 80% of the planned number of subjects have all of their pain 
intensity and opioid use data through the 72-hour postoperative assessments entered into the electronic clinical 


Protocol No: HTX-011-211 
Page 4 of 73 
Version 6 
 
Heron Therapeutics, Inc. 
Confidential 
Sponsor: Heron Therapeutics, Inc. 
Protocol Number: HTX-011-211 
Name of Investigational Product: 
HTX-011 (extended-release 2.5% bupivacaine and 
0.075% meloxicam) 
Protocol Title: 
A Phase 2B, Randomized, Controlled Study of 
HTX-011 Administered Via Pectoral Nerve Block in 
Subjects Undergoing Upper Extremity Surgery for 
Augmentation Mammoplasty 
Name of Active Ingredients: 
Bupivacaine and meloxicam 
Phase of Development: 2B 
database for that cohort. The IRC will operate under a written, detailed IRC Charter. 
The study will include up to 4 cohorts. 
Cohort 1 
Approximately 24 subjects will be randomized to 1 of the following 3 treatment groups in a 2:1:1 ratio: 
 HTX-011 60 mg (2.1 mL) via bilateral ultrasound-guided lateral and medial pectoral nerve block (12 subjects) 
 Bupivacaine HCl without epinephrine 0.25% (50 mg, 20 mL) via bilateral ultrasound-guided lateral and medial 
pectoral nerve block (6 subjects) 
 Saline placebo (2.1 mL) via bilateral ultrasound-guided lateral and medial pectoral nerve block (6 subjects) 
Cohort 2 
Cohort 2 was planned as an optional cohort. Following a review of the results from Cohort 1, the IRC recommended 
initiating enrollment in Cohort 2 and randomizing approximately 48 subjects to 1 of the following 3 treatment 
groups in a 2:1:1 ratio: 
 HTX-011 (a single dose recommended by IRC of 120 mg/3.6 mg [bupivacaine/meloxicam doses], 4.1 mL) via 
bilateral ultrasound-guided lateral and medial pectoral nerve block (24 subjects) 
 Bupivacaine HCl without epinephrine 0.25% (50 mg, 20 mL) via bilateral ultrasound-guided lateral and medial 
pectoral nerve block (12 subjects) 
 Saline placebo (volume matching HTX-011 in Cohort 2) via bilateral ultrasound-guided lateral and medial 
pectoral nerve block (12 subjects) 
Cohort 3 
Cohort 3 was planned as an optional cohort. Following a review of the results from Cohort 2, the IRC recommended 
initiating enrollment in Cohort 3 and randomizing approximately 48 subjects to 1 of the following 3 treatment 
groups in a 2:1:1 ratio: 
 HTX-011 (a single dose recommended by IRC of 240 mg/7.2 mg [bupivacaine/meloxicam doses], 8.2 mL) via 
bilateral ultrasound-guided lateral and medial pectoral nerve block (24 subjects) 
 Bupivacaine HCl without epinephrine 0.25% (50 mg, 20 mL) via bilateral ultrasound-guided lateral and medial 
pectoral nerve block (12 subjects) 
 Saline placebo (volume matching HTX-011 in Cohort 3) via bilateral ultrasound-guided lateral and medial 
pectoral nerve block (12 subjects) 
Cohort 4 
Cohort 4 was planned as an optional cohort. Following a review of the results from Cohort 3, the IRC recommended 
initiating enrollment in Cohort 4 and randomizing approximately 120 subjects to 1 of the following 4 treatment 
groups in a 4:4:1:1 ratio: 
 HTX-011 (a single dose recommended by IRC of 400 mg/12 mg [bupivacaine/meloxicam doses], 13.7 mL) via 
bilateral ultrasound-guided lateral and medial pectoral nerve block (48 subjects) 
 HTX-011 (a single dose recommended by IRC of 400 mg/12 mg [bupivacaine/meloxicam doses], 13.7 mL) via 
instillation into the intended space for the implant, with 200 mg/6 mg, 6.8 mL per side, and saline placebo 
(volume matching HTX-011 in Cohort 4) via bilateral ultrasound-guided lateral and medial pectoral nerve block 
for masking (48 subjects) 
 Bupivacaine HCl without epinephrine 0.25% (50 mg, 20 mL) via bilateral ultrasound-guided lateral and medial 


Protocol No: HTX-011-211 
Page 5 of 73 
Version 6 
 
Heron Therapeutics, Inc. 
Confidential 
Sponsor: Heron Therapeutics, Inc. 
Protocol Number: HTX-011-211 
Name of Investigational Product: 
HTX-011 (extended-release 2.5% bupivacaine and 
0.075% meloxicam) 
Protocol Title: 
A Phase 2B, Randomized, Controlled Study of 
HTX-011 Administered Via Pectoral Nerve Block in 
Subjects Undergoing Upper Extremity Surgery for 
Augmentation Mammoplasty 
Name of Active Ingredients: 
Bupivacaine and meloxicam 
Phase of Development: 2B 
pectoral nerve block (12 subjects) 
 Saline placebo (volume matching HTX-011 in Cohort 4) via bilateral ultrasound-guided lateral and medial 
pectoral nerve block (12 subjects) 
Postoperative Opioid Rescue Medications 
Subjects should only receive rescue medication upon request for pain control as needed during the 72-hour 
postoperative observation period. 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) and 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) and/or intravenous morphine (no more than 10 mg within a 2-hour period as needed). No 
other analgesic agents, including nonsteroidal anti-inflammatory drugs (NSAIDs) and acetaminophen, are permitted 
during the 72-hour postoperative observation period. 
After 72 hours, the analgesic regimen may be adjusted for each subject individually as deemed appropriate by the 
physician responsible for the postoperative care. Subjects will complete a daily diary to record if they take an opioid 
medication between 72 hours and Day 28. 
Number of Planned Subjects: Up to approximately 240 subjects will be randomized and dosed 
Study Sites: Approximately 5 study sites in the United States (US) 
Study Population: 
Inclusion Criteria 
Each subject must meet all of the following criteria to be enrolled in this study: 
1. Is able to provide written informed consent, adhere to the study visit schedule, and complete all study 
assessments. 
2. Is female ≥18 years of age at screening. 
3. Is scheduled to undergo primary bilateral submuscular augmentation mammoplasty with saline or silicone 
smooth implants with a volume of 300 to 500 cc, inclusive. Note: textured implants are not allowed. 
4. Has an American Society of Anesthesiologists Physical Status of I, II, or III. 
5. Is suitable for a nerve block procedure. 
6. Is able to demonstrate motor function by raising both arms above the head unassisted. 
7. Is able to assess sensory function by exhibiting sensitivity to cold in the pectoral area (upper outer quadrant). 
8. Subjects are eligible only if all of the following apply: 
a. 
Not pregnant (subjects of child-bearing potential must have a negative urine pregnancy test at screening 
and on Day 0 before study drug administration). 
b. Not lactating. 
c. 
Not planning to become pregnant during the study. 
d. Surgically sterile; or at least 2 years post-menopausal; or have a monogamous partner who is surgically 
sterile; or is practicing double-barrier contraception; or practicing abstinence (must agree to use double-
barrier contraception in the event of sexual activity); or using an insertable, injectable, transdermal, or 
combination oral contraceptive approved by the US Food and Drug Administration (FDA) for greater than 
2 months prior to screening and commits to the use of an acceptable form of birth control for the duration 
of the study and for 30 days after study drug administration. Note: women in only a same-sex relationship 
do not need to meet this criterion. 


Protocol No: HTX-011-211 
Page 6 of 73 
Version 6 
 
Heron Therapeutics, Inc. 
Confidential 
Sponsor: Heron Therapeutics, Inc. 
Protocol Number: HTX-011-211 
Name of Investigational Product: 
HTX-011 (extended-release 2.5% bupivacaine and 
0.075% meloxicam) 
Protocol Title: 
A Phase 2B, Randomized, Controlled Study of 
HTX-011 Administered Via Pectoral Nerve Block in 
Subjects Undergoing Upper Extremity Surgery for 
Augmentation Mammoplasty 
Name of Active Ingredients: 
Bupivacaine and meloxicam 
Phase of Development: 2B 
Exclusion Criteria 
A subject who meets any of the following criteria will be excluded from the study: 
1. Has a planned concurrent surgical procedure (eg, mastopexy). 
2. Has a planned concurrent reconstructive procedure status post breast cancer therapy. 
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 augmentation 
mammoplasty 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 
fentanyl. 
5. Has known or suspected daily use of opioids for 7 or more consecutive days within the previous 6 months. 
6. Has taken NSAIDs (including meloxicam) within at least 10 days prior to 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 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 to treat an 
AE that occurs after signing the ICF and prior to study drug administration or for pretreatment prior to a needle 
placement. 
11. Has initiated treatment with any of the following medications within 1 month prior to study drug administration 
or is taking any of these medications to control pain: selective serotonin reuptake inhibitors (SSRIs), selective 
norepinephrine reuptake inhibitors (SNRIs), gabapentin, pregabalin, duloxetine, or cyclooxygenase-2 (COX-2) 
inhibitors. (Note: If a subject is taking one of these medications for a reason other than pain control, she 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 a medical condition such that, in the opinion of the Investigator, participating in the study would pose a 
health risk to the subject or confound the postoperative assessments. Conditions may include, but are not limited 
to, any of the following: 
a. 
History of clinically significant cardiac abnormality such as myocardial infarction within 6 months prior to 
signing the informed consent, New York Heart Association class III or IV, or clinically significant 
abnormalities of electrocardiogram (ECG) or cardiac function. 
b. History of coronary artery bypass graft surgery within 12 months of signing the ICF. 
c. 
History of severe liver function impairment, as defined by Child-Pugh Class C, having an aspartate 
aminotransferase >3 × the upper limit of normal (ULN), or having an alanine aminotransferase >3 × ULN. 
d. History of severe kidney function impairment as defined by creatinine clearance (Cockcroft Gault) 
<30 mL/min, being on dialysis, and/or having a serum creatinine >2 × ULN. 
e. 
History of known or suspected coagulopathy or uncontrolled anticoagulation. 
f. 
Loss of sensation in extremities or significant peripheral neuropathy. 
13. As per subject history and/or medical records, has active infection or is currently undergoing treatment for 
Hepatitis B, Hepatitis C, or human immunodeficiency virus (HIV). 
14. Has uncontrolled anxiety, psychiatric, or neurological disorder that might interfere with study assessments. 
15. Has any chronic neuromuscular deficit of either pectoral nerve function or arm/shoulder/truncal musculature. 
16. Has any chronic condition or disease that would compromise neurological or vascular assessments. 
17. Had a malignancy in the last year, with the exception of non-metastatic basal cell or squamous cell carcinoma 


Protocol No: HTX-011-211 
Page 7 of 73 
Version 6 
 
Heron Therapeutics, Inc. 
Confidential 
Sponsor: Heron Therapeutics, Inc. 
Protocol Number: HTX-011-211 
Name of Investigational Product: 
HTX-011 (extended-release 2.5% bupivacaine and 
0.075% meloxicam) 
Protocol Title: 
A Phase 2B, Randomized, Controlled Study of 
HTX-011 Administered Via Pectoral Nerve Block in 
Subjects Undergoing Upper Extremity Surgery for 
Augmentation Mammoplasty 
Name of Active Ingredients: 
Bupivacaine and meloxicam 
Phase of Development: 2B 
of the skin or localized carcinoma in situ of the cervix. 
18. Has a known or suspected history of drug abuse, a positive drug screen on the day of surgery, or a recent history 
of alcohol abuse. Note: Subjects with a positive drug screen who are taking an allowed, prescribed medication 
that is known to result in a positive drug test (eg, amphetamine and dextroamphetamine for attention-
deficit/hyperactivity disorder, benzodiazepine for anxiety disorder) may be eligible for participation in the 
study. Subjects taking medical marijuana are not allowed to participate in the study. 
19. Previous participation in an HTX-011 study or received an investigational product or device in a clinical trial 
within 30 days or within 5 elimination half-lives (whichever is longer) prior to surgery, or is planning to take 
part in another clinical trial while participating in this study. 
20. Has undergone 3 or more surgeries in 12 months prior to signing the ICF, other than for diagnostic procedures 
(eg, colonoscopy). 
21. Has a body mass index (BMI) >35 kg/m2. 
Investigational Product, Dose, and Mode of Administration: 
HTX-011 is an extended-release, fixed-ratio combination product that contains bupivacaine (a local anesthetic as the 
free base) and low-dose meloxicam (an NSAID) incorporated in a bioerodible polymer (termed Biochronomer®). 
HTX-011 will be supplied by the Sponsor as a sterile, viscous liquid. 
A single dose of HTX-011 will be administered by bilateral ultrasound-guided lateral and medial pectoral nerve 
block and/or instillation within the pectoral pocket. Doses between 60 and 400 mg, inclusive, may be evaluated in 
this study. 
Reference Therapy, Dose, and Mode of Administration: 
Bupivacaine HCl without epinephrine 0.25% (50 mg) and saline placebo (0.9% sodium chloride solution) will be 
administered by bilateral ultrasound-guided lateral and medial pectoral nerve block. 
Bupivacaine HCl and saline placebo will be supplied by sites. 
Duration of Treatment: Subjects will receive a single dose of study drug. The overall duration of the study is 
anticipated to be approximately 18 months. The total duration of study participation for each subject (from 
Screening through Day 28) will be up to 53 days. 
Criteria for Evaluation: 
Efficacy, safety, and PK assessments will be performed. The end of surgery will be considered as Time 0 for all 
efficacy and safety assessments, except where otherwise specified. The start of study drug administration will be 
considered as Time 0 for all PK timepoints. 
Efficacy Assessments: 
 Pain intensity scores using the Numeric Rating Scale at rest (NRS-R) on Day 0 before study drug administration; 
at 1, 2, 4, 6, 8, 12, 24, 36, 48, 60, and 72 hours; and on Day 10 and Day 28. 
 Pain intensity scores using the NRS-A (with the elbows at the side and against the body, raise hands in front of 
abdomen, clasp hands together, and hold that position for at least 5 seconds) on Day 0 before study drug 
administration; at 1, 2, 4, 6, 8, 12, 24, 36, 48, 60, and 72 hours; and on Day 10 and Day 28. 
 Date, time of administration, and amount of all opioid rescue medication taken through 72 hours. 
 Subject daily diary to record if any opioids were taken from 72 hours through Day 28. 
 Patient Global Assessment (PGA) of pain control at 24, 48, and 72 hours, and on Day 28. 
 Discharge readiness assessment per the Modified Postanaesthetic Discharge Scoring System (MPADSS) criteria 


Protocol No: HTX-011-211 
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Heron Therapeutics, Inc. 
Confidential 
Sponsor: Heron Therapeutics, Inc. 
Protocol Number: HTX-011-211 
Name of Investigational Product: 
HTX-011 (extended-release 2.5% bupivacaine and 
0.075% meloxicam) 
Protocol Title: 
A Phase 2B, Randomized, Controlled Study of 
HTX-011 Administered Via Pectoral Nerve Block in 
Subjects Undergoing Upper Extremity Surgery for 
Augmentation Mammoplasty 
Name of Active Ingredients: 
Bupivacaine and meloxicam 
Phase of Development: 2B 
at 2, 4, 6, 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 72 hours.) 
 Subject’s satisfaction with postoperative pain control at 24, 48, and 72 hours, and on Day 10 using a 5-point 
Likert scale. 
 Overall benefit of analgesia score (OBAS) at 24, 48, and 72 hours, and on Day 28. 
Safety Assessments: 
 AEs from the time the subject signs the Informed Consent Form through Day 28. 
 Clinical laboratory tests at the Screening visit (hematology and serum chemistry), 24 hours (hematology only), 
and at 72 hours and Day 10 (hematology and serum chemistry). 
 Physical examination at the Screening visit and 72 hours; the Screening visit should include height, weight, and 
BMI calculation. 
 Wound healing assessment at 72 hours and on Day 10 and Day 28. 
 Vital signs (resting heart rate, blood pressure, and respiration rate) at the Screening visit, on Day 0 before study 
drug administration, and post-treatment at 24, 48, and 72 hours. 
 ECG at the Screening visit. 
 Continuous Holter monitoring beginning at least 24 hours prior to surgery through 72 hours. 
 Motor function assessment (ie, with the elbows at the side and against the body, raise hands in front of abdomen, 
clasp hands together, and hold that position for at least 5 seconds) at the Screening visit; 6, 12, 24, 48, and 
72 hours; and on Day 10. 
 Sensory function assessment (ie, cold alcohol swab test on the upper outer quadrant of the breast on the side of 
the dominant hand) at the Screening visit; at 15, 30, and 60 minutes after the start of ultrasound-guided study 
drug administration; at 6, 12, 24, 48, and 72 hours after the end of surgery; and on Day 10. 
 Blinded assessor’s satisfaction with return of sensory and motor function at 24, 48, and 72 hours and on Day 10 
using a 5-point Likert scale. 
Pharmacokinetic Assessments: 
Blood samples for bupivacaine and meloxicam PK analysis will be collected at the following timepoints: prior to 
study drug administration and at 30 minutes and 1, 2, 4, 6, 8, 12, 20, 22, 24, 26, 28, 36, 48, 60, 72, and 120 hours 
after the start of study drug administration. (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 NRS-A pain intensity scores through 24 hours (AUC0-24).  
Secondary Efficacy Endpoints 
 Mean total postoperative opioid consumption (in morphine equivalents) through 24, 48, and 72 hours. 
 Median time in hours to first opioid rescue administration through 72 hours. 
 Mean AUC of the NRS-A pain intensity scores at the following intervals: 0-6, 0-12, 12-24, 24-48, 0-48, 48-72, 


Protocol No: HTX-011-211 
Page 9 of 73 
Version 6 
 
Heron Therapeutics, Inc. 
Confidential 
Sponsor: Heron Therapeutics, Inc. 
Protocol Number: HTX-011-211 
Name of Investigational Product: 
HTX-011 (extended-release 2.5% bupivacaine and 
0.075% meloxicam) 
Protocol Title: 
A Phase 2B, Randomized, Controlled Study of 
HTX-011 Administered Via Pectoral Nerve Block in 
Subjects Undergoing Upper Extremity Surgery for 
Augmentation Mammoplasty 
Name of Active Ingredients: 
Bupivacaine and meloxicam 
Phase of Development: 2B 
and 0-72 hours. 
 Mean AUC of the NRS-R pain intensity scores at the following intervals: 0-6, 0-12, 12-24, 0-24, 24-48, 0-48, 
48-72, and 0-72 hours. 
 Mean NRS-R pain intensity scores at each assessed timepoint. 
 Mean NRS-A pain intensity scores at each assessed timepoint. 
 Integrated Rank Analysis of Silverman using the NRS-A pain intensity AUC scores and total opioid 
consumption through 24, 48, and 72 hours. 
 Proportion of subjects achieving a score of “good” or better (>1) pain control based on PGA at 24, 48, and 72 
hours, and on Day 28. 
 Proportion of subjects who are pain-free at rest (defined as an NRS-R pain intensity score of 0 or 1) at each 
assessed timepoint. 
 Proportion of subjects who are pain-free with activity (defined as an NRS-A pain intensity score of 0 or 1) at 
each assessed timepoint. 
 Proportion of subjects who are opioid-free through 24, 48, and 72 hours. 
 Proportion of subjects who are opioid-free from 72 hours through Day 10 and Day 28. 
 Proportion of subjects who first achieve an MPADSS score ≥9 at 2, 4, 6, 8, 12, 24, 36, 48, 60, and 72 hours. 
 Mean subject’s satisfaction with postoperative pain control at 24, 48, and 72 hours and on Day 10. 
 Mean OBAS at 24, 48, and 72 hours, and on Day 28. 
Safety Endpoints 
 Incidence of treatment-emergent AEs (TEAEs), serious TEAEs (SAEs), and opioid-related AEs (ORAEs) 
through Day 28. 
 Change from baseline in clinical laboratory results. 
 Change from baseline in vital signs at each assessed timepoint. 
 Change from baseline in Holter data. 
 Wound healing assessment at 72 hours and on Day 10 and Day 28. 
 Time to return of motor function. 
 Loss of sensation in the breast at 15, 30, and 60 minutes after the start of ultrasound-guided study drug 
administration. 
 Time to return of sensory function. 
 Blinded assessor’s satisfaction with return of sensory and motor function at 24, 48, and 72 hours, and on Day 10. 
Pharmacokinetic Endpoints 
 Maximum observed plasma concentration (Cmax). 
 AUC from Time 0 to the last collection time after study drug administration (AUC0-last). 
 AUC from Time 0 extrapolated to infinity (AUC0-∞). 
 Time to maximum plasma concentration (Tmax). 
 Apparent terminal elimination rate constant (λz). 


Protocol No: HTX-011-211 
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Heron Therapeutics, Inc. 
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Sponsor: Heron Therapeutics, Inc. 
Protocol Number: HTX-011-211 
Name of Investigational Product: 
HTX-011 (extended-release 2.5% bupivacaine and 
0.075% meloxicam) 
Protocol Title: 
A Phase 2B, Randomized, Controlled Study of 
HTX-011 Administered Via Pectoral Nerve Block in 
Subjects Undergoing Upper Extremity Surgery for 
Augmentation Mammoplasty 
Name of Active Ingredients: 
Bupivacaine and meloxicam 
Phase of Development: 2B 
 Apparent terminal elimination half-life (t½el). 
Statistical Methods: 
Efficacy Analyses: 
For the purposes of statistical hypothesis testing, data for saline placebo subjects will be pooled across cohorts into a 
single saline placebo treatment group, and data for bupivacaine HCl subjects will be pooled across cohorts into a 
single bupivacaine HCl treatment group. The primary endpoint of mean AUC0-24 of the NRS-A pain intensity scores 
will be analyzed using an analysis of variance (ANOVA) model with treatment as the main effect. Each dose of 
HTX-011 will be tested against each of the pooled control arms. Results will be expressed as mean AUCs and 
standard deviations (SDs), least-squares mean differences and standard errors (SEs) with associated 95% confidence 
intervals (CIs), and p-values. Other continuous efficacy endpoints will be analyzed similarly to the primary 
endpoint. 
Categorical endpoints will be analyzed using Fisher’s exact test. Results will be expressed as the number and 
percentage of subjects meeting the relevant endpoint, differences in proportions with 95% CIs, and p-values. Median 
time in hours to first opioid rescue administration will be analyzed using Kaplan-Meier methods. 
Safety Analyses: 
All safety data will be listed and summarized by treatment group, with data for each control group pooled across 
cohorts, and no statistical hypothesis testing will be performed. All TEAEs will be coded and tabulated by System 
Organ Class and Preferred Term. Incidence of TEAEs, SAEs, and ORAEs will be summarized and presented in 
descending order of frequency according to the highest dose of HTX-011 studied. Associated clinical laboratory 
parameters such as hepatic enzymes, renal function, and hematology values will be grouped and presented together 
in summary tables. Individual subject values will be listed and values outside of the standard reference range will be 
flagged. Changes in vital sign parameters will be summarized. 
Interim Analysis: 
Up to 4 interim analyses are planned. An internal IRC will review unblinded, summary-level data from each cohort 
to make study design decisions. Each interim analysis will be performed after at least 80% of the planned number of 
subjects have all of their pain intensity and opioid use data through the 72-hour postoperative assessments entered 
into the electronic clinical database for that cohort. The internal IRC will be composed of 1 Sponsor representative 
from the Clinical Research, Biometrics, Pharmacovigilance, Regulatory, and Pharmaceutical and Translational 
Sciences functions. The IRC will operate under a written, detailed IRC Charter. 
Determination of Sample Size: 
The sample size of up to approximately 240 subjects in this study was selected empirically without formal statistical 
assumptions. 
 




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Global Assessment; PK, pharmacokinetic; Preop, preoperative assessments; WOCBP, women of childbearing potential; D10, Day 10; D28, Day 28. 
* The start of study drug administration will be considered as Time 0 for all PK timepoints. The end of surgery (defined as placement of last suture) will be 
considered as Time 0 for all efficacy and safety timepoints. For assessments at timepoints when the subject is asleep, an attempt should be made to wake the 
subject. If there is no response, the assessments at these timepoints may be recorded as “Not Done.”  Assessments that can be done without awakening the 
subject (eg, blood collection for PK sample) should be completed. See Section 6 for more information on study procedures and assessments. 
a Subjects who withdraw from the study before their Day 28 Visit will be asked to complete Early Termination procedures. 
b Before study drug administration. 
c Result must be negative and confirmed prior to study drug administration. 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. 
d Includes height, weight, and body mass index (BMI) calculation. 
e Only if subject withdraws prior to 72 hours. 
f Only if subject withdraws prior to Day 28. 
g A sensory function test (cold alcohol swab test on the upper outer quadrant of the breast on the side of the dominant hand) should be performed at 15, 30, and 
60 minutes after the start of ultrasound-guided study drug administration. Assessments do not need to be performed if the subject is in or on the way to the 
operating room. 
h Only if subject withdraws prior to Day 10. 
i Having the subject keep her elbows at her side and against her body and then raise her hands in front of her abdomen, clasp hands together, and hold that 
position for at least 5 seconds. 
j 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. 
k Subjects will be required to have continuous reading of the Holter monitor at least 24 hours before surgery.  
l Hematology at 24 hours; hematology and serum chemistry at all other timepoints. 
m For subjects receiving study drug via ultrasound-guided lateral and medial pectoral nerve block, study drug will be administered within 4 hours prior to 
undergoing mammoplasty. For subjects receiving study drug via instillation into the surgical site, study drug will be administered prior to the end of surgery. 
n NRS-R pain intensity scores will be assessed in a dependent position. NRS-A pain intensity scores will be assessed by having the subject keep her elbows at 
her side and against her body and then raise her hands in front of her abdomen, clasp hands together, and hold that position for at least 5 seconds. 
o 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. 
p Subjects will complete a daily diary to record the use of opioids from 72 hours through Day 28. 
q At the Screening Visit, ensure subject is not taking any prohibited medications. Record all medications taken between the day of signing the Informed Consent 
Form and Day 28. 
r Adverse events will be collected from the time the subject signs the Informed Consent Form through Day 28. 
s If a cardiac or neurological treatment-emergent adverse event occurs during the study, a blood sample should be collected at the time that the event is noted to 
determine the plasma bupivacaine concentration. 
t A PK sample should be collected 30 minutes (±5 min) after the start of study drug administration. 


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TABLE OF CONTENTS 
INVESTIGATOR AGREEMENT.............................................................................................2 
PROTOCOL SYNOPSIS ..........................................................................................................3 
SCHEDULE OF EVENTS ......................................................................................................11 
TABLE OF CONTENTS .........................................................................................................13 
LIST OF TABLES ...................................................................................................................17 
LIST OF APPENDICES ..........................................................................................................17 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ............................................18 
1. 
INTRODUCTION ..........................................................................................................20 
1.1. 
Background Information and Study Rationale ............................................................20 
1.2. 
Rationale for Study Design, Doses, and Control Groups ............................................20 
1.3. 
Potential Risks and Benefits ........................................................................................22 
2. 
STUDY OBJECTIVES ..................................................................................................24 
2.1. 
Primary Objective ........................................................................................................24 
2.2. 
Secondary Objectives...................................................................................................24 
3. 
INVESTIGATIONAL PLAN AND ENDPOINTS .......................................................25 
3.1. 
Description of the Study Design ..................................................................................25 
3.1.1. 
Overall Study Design .............................................................................................25 
3.1.2. 
Treatment Groups ..................................................................................................26 
3.1.3. 
Postoperative Opioid Rescue Medications ............................................................27 
3.1.4. 
Postoperative Assessments ....................................................................................27 
3.2. 
Study Endpoints ...........................................................................................................28 
3.2.1. 
Efficacy Endpoints .................................................................................................28 
3.2.2. 
Safety Endpoints ....................................................................................................28 
3.2.3. 
Pharmacokinetic Endpoints ...................................................................................29 
3.3. 
Study Duration .............................................................................................................29 
4. 
STUDY ENROLLMENT AND WITHDRAWAL ........................................................30 
4.1. 
Study Population ..........................................................................................................30 
4.1.1. 
Inclusion Criteria ...................................................................................................30 
4.1.2. 
Exclusion Criteria ..................................................................................................30 
4.2. 
Method of Assigning Subjects to Treatment Groups ...................................................32 
4.2.1. 
Procedures for Handling Randomized Subjects Who Do Not Meet the Study 
Eligibility Criteria ..................................................................................................32 


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4.3. 
Blinding........................................................................................................................32 
4.3.1. 
Breaking the Blind .................................................................................................33 
4.4. 
Subject Withdrawal and Replacement .........................................................................33 
4.4.1. 
Subject Withdrawal ................................................................................................33 
4.4.2. 
Subject Replacement ..............................................................................................34 
5. 
STUDY TREATMENT .................................................................................................35 
5.1. 
Description of Investigational Product ........................................................................35 
5.2. 
Manufacturing, Packaging, and Labeling ....................................................................35 
5.3. 
Storage .........................................................................................................................35 
5.4. 
Preparation ...................................................................................................................35 
5.5. 
Study Drug Administration ..........................................................................................35 
5.5.1. 
Nerve Block ...........................................................................................................35 
5.5.2. 
HTX-011 Instillation and Saline Placebo Nerve Block .........................................36 
5.6. 
Study Drug Compliance ...............................................................................................36 
5.7. 
Study Drug Accountability ..........................................................................................36 
6. 
STUDY PROCEDURES AND ASSESSMENTS .........................................................37 
6.1. 
Medical History and Demographics ............................................................................37 
6.1.1. 
Medical History .....................................................................................................37 
6.1.2. 
Demographics ........................................................................................................37 
6.2. 
Prior and Concomitant Therapy ...................................................................................37 
6.3. 
Efficacy Assessments...................................................................................................37 
6.3.1. 
Pain Intensity Assessment......................................................................................37 
6.3.2. 
Use of Opioid Rescue Medications ........................................................................38 
6.3.3. 
Subject Daily Diary................................................................................................38 
6.3.4. 
Patient Global Assessment of Pain Control ...........................................................38 
6.3.5. 
Discharge Readiness ..............................................................................................38 
6.3.6. 
Satisfaction With Postoperative Pain Control and With Return of Sensory and 
Motor Function ......................................................................................................38 
6.3.7. 
Overall Benefit of Analgesia Assessment..............................................................38 
6.4. 
Safety Assessments ......................................................................................................39 
6.4.1. 
Adverse Events ......................................................................................................39 
6.4.2. 
Local Anesthetic Systemic Toxicity Assessment ..................................................39 
6.4.3. 
Physical Examinations ...........................................................................................39 
6.4.4. 
Vital Signs ..............................................................................................................39 


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6.4.5. 
12-Lead Electrocardiograms and Holter Monitoring .............................................39 
6.4.6. 
Wound Healing Assessment ..................................................................................40 
6.4.7. 
Motor Function Assessment ..................................................................................40 
6.4.8. 
Sensory Function Assessment................................................................................40 
6.4.9. 
Clinical Laboratory Tests .......................................................................................40 
6.5. 
Pharmacokinetic Assessments .....................................................................................41 
7. 
TIMING OF PROCEDURES AND ASSESSMENTS ..................................................42 
7.1. 
Screening Period ..........................................................................................................42 
7.2. 
Study Drug Administration, Surgery, and Observational Period ................................43 
7.2.1. 
Day 0, Prior to Surgery ..........................................................................................43 
7.2.2. 
Pharmacokinetic Sampling After Study Drug Administration ..............................44 
7.2.3. 
Surgery (Day 0)......................................................................................................44 
7.2.4. 
Postoperative Observation Period (72 Hours) .......................................................44 
7.2.5. 
End of the Postoperative Assessment Period .........................................................45 
7.3. 
Follow-Up Period.........................................................................................................45 
7.3.1. 
120 hours (±6 Hours) After Start of Study Drug Administration ..........................45 
7.3.2. 
Day 10 Visit (±2 Days) ..........................................................................................45 
7.3.3. 
Day 28 Visit (±4 Days) ..........................................................................................46 
7.4. 
Early Termination Visit ...............................................................................................46 
7.5. 
Unscheduled Visits and Assessments ..........................................................................47 
8. 
SAFETY MONITORING AND REPORTING .............................................................48 
8.1. 
Definition of Safety Parameters ...................................................................................48 
8.1.1. 
Definition of an Adverse Event .............................................................................48 
8.1.2. 
Definition of a Serious Adverse Event ..................................................................49 
8.1.3. 
Definition of a Suspected Adverse Reaction .........................................................50 
8.1.4. 
Definition of a Serious Suspected Adverse Reaction ............................................50 
8.1.5. 
Definition of Unanticipated Problems ...................................................................50 
8.2. 
Classification of Adverse Events .................................................................................50 
8.2.1. 
Severity of Adverse Events ....................................................................................50 
8.2.2. 
Relationship to Study Drug ....................................................................................50 
8.3. 
Time Period and Frequency for Event Assessment and Follow Up ............................51 
8.3.1. 
Adverse Event and Serious Adverse Event Monitoring ........................................51 
8.3.2. 
Follow-Up of Events ..............................................................................................51 


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8.4. 
Reporting Procedures ...................................................................................................52 
8.4.1. 
Reporting Serious Adverse Events to the Sponsor ................................................52 
8.4.2. 
Reporting Unanticipated Problems to the Sponsor ................................................53 
8.4.3. 
Regulatory Reporting Requirements ......................................................................53 
8.4.4. 
Pregnancy Reporting ..............................................................................................54 
8.5. 
Safety Oversight...........................................................................................................54 
9. 
STUDY RESTRICTIONS .............................................................................................55 
9.1. 
Prohibited Medications ................................................................................................55 
9.2. 
Contraception ...............................................................................................................55 
10. 
STATISTICAL CONSIDERATIONS ...........................................................................56 
10.1. General Considerations ................................................................................................56 
10.2. Determination of Sample Size .....................................................................................56 
10.3. Analysis Populations ....................................................................................................56 
10.4. Statistical Analysis Methods ........................................................................................56 
10.4.1. 
Disposition and Demographics ..............................................................................56 
10.4.2. 
Efficacy Analysis ...................................................................................................56 
10.4.3. 
Safety Analysis ......................................................................................................58 
10.4.4. 
Pharmacokinetic Analysis ......................................................................................58 
10.5. Interim Analysis ...........................................................................................................58 
11. 
QUALITY ASSURANCE AND QUALITY CONTROL .............................................60 
12. 
REGULATORY AND ETHICAL CONSIDERATIONS .............................................61 
12.1. Regulatory Authority Approval ...................................................................................61 
12.2. Ethical Conduct of the Study .......................................................................................61 
12.3. Ethics Committee Approval .........................................................................................61 
12.4. Informed Consent Process ...........................................................................................61 
12.5. Confidentiality .............................................................................................................62 
13. 
STUDY ADMINISTRATION .......................................................................................64 
13.1. Clinical Monitoring ......................................................................................................64 
13.2. Source Documents and Record Retention ...................................................................64 
13.3. Management of Protocol Amendments and Deviations ..............................................64 
13.3.1. 
Protocol Modification ............................................................................................64 
13.3.2. 
Protocol Violations and Deviations .......................................................................64 
13.4. Financial Disclosure.....................................................................................................65 
13.5. Stopping Criteria: Suspension or Termination of Study or Investigational Site .........65 


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13.5.1. 
Suspension of Study ...............................................................................................65 
13.5.2. 
Termination of Study or Investigational Site .........................................................65 
13.6. Publication and Information Disclosure Policy ...........................................................66 
14. 
REFERENCE LIST ........................................................................................................67 
 
LIST OF TABLES 
Table 1. 
Clinical Laboratory Tests .....................................................................41 
 
LIST OF APPENDICES 
Appendix A. 
American Society of Anesthesiologists Physical Status 
Classification System ...........................................................................69 
Appendix B. 
Discharge Readiness Assessment - Modified Postanaesthetic 
Discharge Scoring System Criteria ......................................................70 
Appendix C. 
Wound Healing Assessment - Southampton Wound Scoring 
System ..................................................................................................71 
Appendix D. 
Patient Global Assessment (PGA) of Pain Control .............................72 
Appendix E. 
Overall Benefit of Analgesia Assessment............................................73 
 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
AE 
Adverse event 
ANOVA 
Analysis of variance 
ASA 
American Society of Anesthesiologists 
AUC 
Area under the curve 
BMI 
Body mass index 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
Cmax 
Maximum observed plasma concentration 
CONSORT 
Consolidated Standards of Reporting Trials 
CTM 
Clinical trial material 
CV 
Cardiovascular  
EC 
Ethics Committee  
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EDC 
Electronic data capture 
ET 
Early termination 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GPP 
Good Publication Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human immunodeficiency virus 
hr(s) 
Hour(s) 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
IEC 
Independent Ethics Committee 
ICH 
International Conference on Harmonisation 
ICMJE 
International Committee of Medical Journal Editors 
IP 
Investigational product  
IRB 
Institutional Review Board 
IRC 
Interim Review Committee 
ITT 
Intent-to-Treat  
LAST 
Local anesthetic systemic toxicity 
LOCF 
Last observation carried forward 
min 
Minute 


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mITT 
Modified Intent-to-Treat 
MPADSS 
Modified Postanaesthetic Discharge Scoring System 
NRS 
Numeric Rating Scale 
NRS-A 
NRS scores with activity  
NRS-R 
NRS scores at rest (in a dependent position) 
NSAID 
Nonsteroidal anti-inflammatory drug 
OBAS 
Overall benefit of analgesia score 
ORAE 
Opioid-related adverse event 
PACU 
Postanesthesia care unit 
PGA 
Patient Global Assessment 
PK 
Pharmacokinetic(s) 
PO 
By mouth, orally 
Preop 
Preoperative 
PRN 
As needed 
REB 
Research Ethics Board 
SAE 
Serious adverse event 
SD 
Standard deviation 
SE 
Standard error 
SNRI 
Selective norepinephrine reuptake inhibitors 
SOP 
Standard Operating Procedures 
SPI 
Summed pain intensity 
SSRI 
Selective serotonin reuptake inhibitors 
t½el 
Apparent terminal elimination half-life 
TEAE 
Treatment-emergent adverse event 
Tmax 
Time to maximum plasma concentration 
ULN 
Upper limit of normal 
US 
United States 
WOCBP 
Women of child-bearing potential 
wWOCF 
Windowed worst observation carried forward 
λz 
Apparent terminal elimination rate constant 


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1. 
INTRODUCTION 
1.1. 
Background Information and Study Rationale 
It is estimated that up to 80% of patients suffer from moderate to severe pain during the first 
24 to 48 hours after surgery (Gan 2014). Consequently, many are given narcotic analgesics for 
pain management. Administering a local anesthetic is a relatively simple and safe means of 
providing postoperative pain relief and promoting a quicker recovery; however, a major 
limitation of local anesthetics is their short duration of effect (6 to 12 hours following surgery) 
(Kehlet 2011). The development of an extended release local anesthetic that would provide pain 
relief during this critical postoperative timeframe and reduce the need for narcotics would be of 
clinical significance. 
Nonsteroidal anti-inflammatory drugs (NSAIDs) have long been used in the treatment of 
postoperative pain (Moote 1992), and there is evidence that there may be a synergistic 
interaction between local anesthetics and NSAIDs when locally administered together (Ortiz 
2011). 
In the past decade, the use of regional anesthesia in general, in particular peripheral nerve blocks, 
has increased dramatically. These techniques may allow for more rapid discharge from the 
hospital and decrease opioid load. Developing a long-acting agent that can be used in nerve 
block would help to further facilitate this trend. 
Heron is developing HTX-011 for the management of postoperative pain. HTX-011 is an 
extended-release, fixed-ratio combination product that contains bupivacaine (a local anesthetic as 
the free base) and low-dose meloxicam (an NSAID) incorporated in a bioerodible polymer 
(termed Biochronomer®). When HTX-011 is administered, the polymer undergoes controlled 
hydrolysis in the tissue, resulting in the extended release of bupivacaine and meloxicam. 
The extended release is achieved using a proprietary vehicle formulation consisting of the novel 
tri[ethylene glycol]-based poly[orthoester] polymer (AP135) in combination with different 
excipients approved for human use (dimethyl sulfoxide, glycerol triacetate [triacetin], and 
maleic acid). 
This is a Phase 2B, randomized, double-blind, active- and saline placebo-controlled, multicenter 
study in subjects undergoing augmentation mammoplasty to evaluate the analgesic efficacy, 
safety, and pharmacokinetics (PK) of HTX-011 when administered via bilateral 
ultrasound-guided lateral and medial pectoral nerve block before surgery and/or instillation into 
the surgical site. 
1.2. 
Rationale for Study Design, Doses, and Control Groups 
Augmentation mammoplasty is an accepted model of postoperative pain. Augmentation 
mammoplasty produces generally reliable and persistent pain symptoms for a period typically 
lasting longer than 72 hours from the surgery, which allows for analysis of acute analgesia over 
an extended period of time. 


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HTX-011 will be administered by bilateral ultrasound-guided lateral and medial pectoral nerve 
block. A pectoral nerve block is commonly used for surgical anesthesia and the management of 
postoperative pain for upper extremity surgeries and is associated with a low risk of 
complications. HTX-011 may also be administered via instillation within the pectoral pocket. 
Nonclinical studies demonstrated that HTX-011 is compatible with the silicone membranes used 
to fabricate implants, and does not significantly affect the tensile properties of the membrane or 
extract significant amounts of silicone or other leachables. Bupivacaine HCl without epinephrine 
and saline placebo will be used as active control and placebo control, respectively, for efficacy 
and safety evaluations. 
Initially, single doses of HTX-011 from 60 to 300 mg, inclusive, were to be evaluated in this 
study. Doses up to 600 mg have been evaluated in previous HTX-011 Phase 2 clinical studies. A 
Phase 1, saline placebo-controlled study evaluated single doses of 100, 200, and 400 mg of 
HTX-011 administered to healthy volunteers via subcutaneous injection. All doses were well 
tolerated, and demonstrated therapeutically relevant plasma bupivacaine levels were sustained 
for 2 to 3 days in the absence of the large initial peak observed with commercially available 
formulations of the drug (bupivacaine HCl). The analgesic effects of HTX-011 persisted through 
96 hours, which closely correlated with plasma bupivacaine concentrations. HTX-011 doses up 
to 600 mg have also been administered in concluded and ongoing Phase 2 studies; current data 
show that they have been generally well tolerated. 
Nonclinical and clinical data support a dose of HTX-011 400 mg/12 mg (bupivacaine/meloxicam 
doses) administered as a 100 mg dose to each of the lateral and medial pectoral nerves 
bilaterally. These data include results from a femoral nerve block toxicity study in the dog with 
HTX-011 doses of 60 mg and 120 mg via ultrasound guided administration that showed no gross 
or microscopic changes related to HTX-011. Moreover, the summary PK results from the 
HTX-011 doses of 120 mg/3.6 mg and 240 mg/7.2 mg in Cohorts 2 and 3 reviewed by the IRC 
in the present clinical study showed that the bupivacaine Cmax was relatively linear with dose. 
Thus, extrapolation to a dose of 400 mg/12 mg is reasonable and yields a projected mean 
bupivacaine Cmax of approximately 700 ng/mL. Further, mean bupivacaine Cmax values for the 
120 mg/3.6 mg and 240 mg/7.2 mg dose groups in the present study are consistent with 
dose-adjusted Cmax values observed in the HTX-011 Phase 2 program following local 
administration of HTX-011. 
The 28-day duration of postoperative assessments is considered appropriate for determining the 
analgesic effect-time curve, safety, and PK profiles for HTX-011. 
Interim analyses will be performed after at least 80% of the planned number of subjects have all 
of their pain intensity and opioid use data through the 72-hour postoperative assessments entered 
into the electronic clinical database for that cohort. The choice of 72 hours was based on results 
from all HTX-011 clinical studies to date, which showed that the time to maximum plasma 
concentration for bupivacaine is less than 24 hours. An interim analysis after the 72-hour 
assessments will therefore include maximal exposure to study drug.  
The study will employ a randomized and double-blind design to minimize potential bias in 
subject selection as well as efficacy and safety assessments. Specific members of the site’s 
pharmacy staff and surgical staff will not be blinded to the treatment assignments because 


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HTX-011 is colored and viscous whereas bupivacaine HCl and saline placebo are not, and the 
volume of study drug to be administered varies by treatment group. However, subjects will also 
not be aware of the study drug they are receiving, and once surgery is complete and the subject is 
transferred to the postanesthesia care unit (PACU), the Investigator and all staff involved in 
efficacy and safety assessments will be blinded to treatment assignments until after database 
lock.  
As a postoperative pain study, the primary endpoint is the area under the curve (AUC) of the 
Numeric Rating Scale (NRS) pain intensity scores with activity (NRS-A) from the start of study 
drug administration through 24 hours. Secondary efficacy endpoints will be assessed through 
72 hours and beyond and will include assessments of opioid use, including the time to first use of 
opioid rescue medication, as recommended by draft Food and Drug Administration (FDA) 
guidelines (FDA Draft Guidance for Industry, Analgesic Indications: Developing Drug and 
Biological Products [February 2014]). 
1.3. 
Potential Risks and Benefits 
As of 28 February 2017, more than 600 subjects have been exposed to 1 of 3 different 
formulations of HTX-011 in 6 clinical studies. Studies included healthy volunteers and subjects 
undergoing elective surgery (bunionectomy, herniorrhaphy, and abdominoplasty). In healthy 
volunteer studies, the 2 most common adverse events (AEs) when HTX-011 was administered 
subcutaneously were contusion and erythema at the site of administration. 
All subjects undergoing surgery received a single dose of an HTX-011 formulation ranging from 
30 mg to 600 mg (based on bupivacaine dose) via local administration into the surgical site 
(injection, instillation, a combination of injection and instillation, or injection using a Mayo 
block). HTX-011 was generally well tolerated. Most of the treatment-related AEs (TEAEs) were 
mild or moderate in severity and resolved without sequelae. When administered to subjects 
undergoing surgery, the 2 most common TEAEs were nausea and constipation. 
 
 
 
 
 
 In a bunionectomy study with the 
current formulation at doses up to 200 mg, 1 SAE of non-healing postoperative wound was 
reported in a subject who received the 200 mg dose. 
An identified risk for HTX-011 is incision site erythema, which was observed primarily in 
bunionectomy. Most events were self-limiting, mild or moderate in severity, and resolved 
without intervention or sequelae. 
Potential risks for bupivacaine include dose-related cardiovascular (CV) and central nervous 
system toxicity (MARCAINE USPI 2011; MARCAIN SmPC 2016). Close attention should be 
given to conditions that may represent reported toxicities associated with bupivacaine including, 
but not limited to, perioral tingling, metallic taste, visual and auditory disturbances, muscle 
twitching, seizure, acidosis, shortness of breath, bradycardia (heart rate <50 beats per minute 


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with symptoms), hypotension (systolic blood pressure <90 mmHg or symptomatic decrease from 
baseline), low oxygen saturation (≤90% for ≥1 minute), and cardiac arrest. 
Potential risks for meloxicam include CV adverse reactions and gastrointestinal bleeding 
(MOBIC SmPC 2015; MOBIC USPI 2016). NSAIDs may cause an increased risk of serious CV 
thrombotic events, myocardial infarction, and stroke, which can be fatal, and this risk may 
increase with duration of use. Patients with CV disease or risk factors for CV disease may be at 
greater risk. NSAIDs may also cause an increased risk of serious gastrointestinal AEs including 
bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. Elderly 
patients are at greater risk for serious gastrointestinal events. It is unclear how applicable these 
potential risks are for meloxicam when given as a single local administration (a novel 
administration method for meloxicam) for postoperative pain as part of a fixed-ratio combination 
(eg, HTX-011). 
The analgesic efficacy with the current HTX-011 formulation is being evaluated in ongoing 
Phase 2 studies. In one Phase 2 study in subjects undergoing unilateral open inguinal 
herniorrhaphy, single-dose administration of the current HTX-011 formulation at doses of 
200 mg to 400 mg resulted in a significant reduction in mean AUC of pain intensity scores 
through 72 hours compared with saline placebo. Similar efficacy results were observed in a 
second Phase 2 study in subjects undergoing simple unilateral bunionectomy, where single-dose 
administration of the current HTX-011 formulation at doses ranging from 60 mg to 200 mg also 
significantly decreased the 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. 
For more information on HTX-011, refer to the HTX-011 Investigator’s Brochure (IB). For more 
information on the active pharmaceutical ingredients, bupivacaine and meloxicam, refer to the 
local product labels. 


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2. 
STUDY OBJECTIVES 
2.1. 
Primary Objective 
The primary objective is to compare the efficacy and duration of analgesia following bilateral 
ultrasound-guided lateral and medial pectoral nerve block with HTX-011 to bupivacaine HCl 
without epinephrine and saline placebo in subjects undergoing upper extremity surgery. 
2.2. 
Secondary Objectives 
The secondary objectives are as follows: 
 
To evaluate the efficacy and duration of analgesia for HTX-011 administered using different 
techniques in this study population. 
 
To evaluate additional efficacy parameters in this study population. 
 
To characterize the bupivacaine and meloxicam PK profiles of HTX-011 in this study 
population. 
 
To determine the optimal administration technique of HTX-011 in this surgical model. 
 
To further assess the safety and tolerability of HTX-011 in this study population. 


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3. 
INVESTIGATIONAL PLAN AND ENDPOINTS 
3.1. 
Description of the Study Design 
3.1.1. 
Overall Study Design 
This is a Phase 2B, randomized, double-blind, active- and saline placebo-controlled, multicenter 
study to evaluate the analgesic efficacy, safety, and PK of HTX-011 administered by pectoral 
nerve block and/or instillation into the surgical site in subjects undergoing bilateral submuscular 
augmentation mammoplasty under general anesthesia.  
Subjects will be screened within 21 days prior to study drug administration. Subjects who meet 
the Screening eligibility criteria will be randomized. Randomization may be done up to 
1 business day prior to study drug administration. Subjects will be administered a single dose of 
study drug (HTX-011, bupivacaine HCl without epinephrine, or saline placebo) via bilateral 
ultrasound-guided lateral and medial pectoral nerve block and/or instillation into the surgical 
site. For subjects receiving study drug via ultrasound-guided lateral and medial pectoral nerve 
block, study drug will be administered within 4 hours prior to undergoing mammoplasty. For 
subjects receiving study drug via instillation, study drug will be administered prior to the end of 
surgery (see Section 5.5 for details on study drug administration). 
Dexamethasone cannot be administered prophylactically before surgery. During surgery, the use 
of fentanyl up to 4 µg/kg will be permitted. In order to decrease the inherent variability in pain 
control on postoperative pain perception, subjects in Cohorts 2 and 4 will receive 
protocol-specified fentanyl 50 µg intravenously (IV) just prior to the end of the surgery. 
Intraoperative administration of other opioids or any other analgesics (including ketamine), local 
anesthetics (except for ropivacaine HCl), or anti-inflammatory agents (except as specified by the 
protocol) is prohibited, unless needed to treat an AE that occurs after signing the Informed 
Consent Form (ICF) or for pretreatment prior to a needle placement. 
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 
end of surgery to undergo postoperative assessments. After the 72-hour assessments have been 
completed, subjects may be discharged. Subjects will return to the study site at 120 ±6 hours, and 
on Day 10 and Day 28 to complete follow-up assessments. 
An internal Interim Review Committee (IRC) will review unblinded, summary level efficacy, 
safety, and PK data from each cohort to determine if enrollment should be initiated in the next 
cohort and to guide Phase 3 study design. Each interim analysis will be performed after at least 
80% of the planned number of subjects have all of their pain intensity and opioid use data 
through the 72-hour postoperative assessments entered into the electronic clinical database for 
that cohort. The IRC will operate under a written, detailed IRC Charter. 


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3.1.2. 
Treatment Groups 
The study will include up to 4 cohorts. 
Cohort 1 
Approximately 24 subjects will be randomized to 1 of the following 3 treatment groups in a 
2:1:1 ratio: 
 
HTX-011 60 mg (2.1 mL) via bilateral ultrasound-guided lateral and medial pectoral nerve 
block (12 subjects) 
 
Bupivacaine HCl without epinephrine 0.25% (50 mg, 20 mL) via bilateral ultrasound-guided 
lateral and medial pectoral nerve block (6 subjects) 
 
Saline placebo (2.1 mL) via bilateral ultrasound-guided lateral and medial pectoral nerve 
block (6 subjects) 
Cohort 2 
Cohort 2 was planned as an optional cohort. Following a review of the results from Cohort 1, the 
IRC recommended initiating enrollment in Cohort 2 and randomizing approximately 48 subjects 
to 1 of the following 3 treatment groups in a 2:1:1 ratio: 
 
HTX-011 (a single dose recommended by IRC of 120 mg/3.6 mg [bupivacaine/meloxicam 
doses], 4.1 mL) via bilateral ultrasound-guided lateral and medial pectoral nerve block (24 
subjects) 
 
Bupivacaine HCl without epinephrine 0.25% (50 mg, 20 mL) via bilateral ultrasound-guided 
lateral and medial pectoral nerve block (12 subjects) 
 
Saline placebo (volume matching HTX-011 in Cohort 2) via bilateral ultrasound-guided 
lateral and medial pectoral nerve block (12 subjects). 
Cohort 3 
Cohort 3 was planned as an optional cohort. Following a review of the results from Cohort 2, the 
IRC recommended initiating enrollment in Cohort 3 and randomizing approximately 48 subjects 
to 1 of the following 3 treatment groups in a 2:1:1 ratio: 
 
HTX-011 (a single dose recommended by IRC of 240 mg/7.2 mg [bupivacaine/meloxicam 
doses], 8.2 mL) via bilateral ultrasound-guided lateral and medial pectoral nerve block 
(24 subjects) 
 
Bupivacaine HCl without epinephrine 0.25% (50 mg, 20 mL) via bilateral ultrasound-guided 
lateral and medial pectoral nerve block (12 subjects) 
 
Saline placebo (volume matching HTX-011 in Cohort 3) via bilateral ultrasound-guided 
lateral and medial pectoral nerve block (12 subjects) 


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Cohort 4 
Cohort 4 was planned as an optional cohort. Following a review of the results from Cohort 3, the 
IRC recommended initiating enrollment in Cohort 4 and randomizing approximately 
120 subjects to 1 of the following 4 treatment groups in a 4:4:1:1 ratio: 
 HTX-011 (a single dose recommended by IRC of 400 mg/12 mg [bupivacaine/meloxicam 
doses], 13.7 mL) via bilateral ultrasound-guided lateral and medial pectoral nerve block 
(48 subjects) 
 HTX-011 (a single dose recommended by IRC of 400 mg/12 mg [bupivacaine/meloxicam 
doses], 13.7 mL) via instillation into the intended space for the implant, with 200 mg/6 mg, 
6.8 mL per side, and saline placebo (volume matching HTX-011 in Cohort 4) via bilateral 
ultrasound-guided lateral and medial pectoral nerve block for masking (48 subjects) 
 Bupivacaine HCl without epinephrine 0.25% (50 mg, 20 mL) via bilateral ultrasound-guided 
lateral and medial pectoral nerve block (12 subjects) 
 Saline placebo (volume matching HTX-011 in Cohort 4) via bilateral ultrasound-guided 
lateral and medial pectoral nerve block (12 subjects) 
3.1.3. 
Postoperative Opioid Rescue Medications 
Subjects should only receive rescue medication upon request for pain control, as needed, during 
the 72-hour postoperative observation period. 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 NRS scores at rest (NRS-R) and with activity (NRS-A) must be obtained. 
Postoperative rescue medication will consist of oral (PO) immediate-release oxycodone (no more 
than 10 mg in a 4-hour period as needed) and/or intravenous morphine (no more than 10 mg in a 
2-hour period as needed). No other analgesic agents, including NSAIDs and acetaminophen, are 
permitted during the 72-hour postoperative observation period.  
After 72 hours, the analgesic regimen may be adjusted for each subject individually as deemed 
appropriate by the physician responsible for the postoperative care. 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 the NRS-R and NRS-A; use of 
opioid recue medication; Patient Global Assessment (PGA) of pain control; assessments of 
discharge readiness; assessment of persistent postsurgical pain; subject’s satisfaction with 
postoperative pain control; and the subject’s assessment of overall benefit of analgesia. 
Safety assessments will include AE recording, physical examinations, vital signs, motor function 
assessment, sensory function assessment, clinical safety laboratory tests (hematology and serum 
chemistry), wound healing assessment, and blinded assessor’s satisfaction with return of sensory 
and motor function. Holter monitoring will also be assessed. 


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PK assessments will include the collection of blood samples to evaluate the bupivacaine PK 
profile for HTX-011 and bupivacaine HCl, and the meloxicam PK profile of HTX-011. 
See Section 6 for more information on the study procedures and assessments, and Section 7 and 
the Schedule of Events table for the timing of procedures and assessments. 
3.2. 
Study Endpoints 
3.2.1. 
Efficacy Endpoints 
Primary Efficacy Endpoint: 
 
Mean area under the curve (AUC) of the NRS-A pain intensity scores through 24 hours 
(AUC0-24). 
Secondary Efficacy Endpoints: 
 
Mean total postoperative opioid consumption (in morphine equivalents) through 24, 48, and 
72 hours. 
 
Median time in hours to first opioid rescue administration through 72 hours. 
 
Mean AUC of the NRS-A pain intensity scores at the following intervals: 0-6, 0-12, 12-24, 
24-48, 0-48, 48-72, and 0-72 hours.  
 
Mean AUC of the NRS-R pain intensity scores at the following intervals: 0-6, 0-12, 12-24, 0-
24, 24-48, 0-48, 48-72, and 0-72 hours. 
 
Mean NRS-R pain intensity scores at each assessed timepoint. 
 
Mean NRS-A pain intensity scores at each assessed timepoint. 
 
Integrated Rank Analysis of Silverman using the NRS-A pain intensity AUC scores and total 
opioid consumption through 24, 48, and 72 hours. 
 
Proportion of subjects achieving a score of “good” or better (>1) pain control based on PGA 
at 24, 48, and 72 hours and on Day 28. 
 
Proportion of subjects who are pain-free (defined as an NRS-R pain intensity score of 0 or 1) 
at each assessed timepoint. 
 
Proportion of subjects who are pain-free (defined as an NRS-A pain intensity score of 0 or 1) 
at each assessed timepoint. 
 
Proportion of subjects who are opioid-free through 24, 48, and 72 hours. 
 
Proportion of subjects who are opioid-free from 72 hours through Day 10 and Day 28. 
 
Proportion of subjects who first achieve a Modified Postanaesthetic Discharge Scoring 
System (MPADSS) score ≥9 at 2, 4, 6, 8, 12, 24, 36, 48, 60, and 72 hours. 
 
Mean subject’s satisfaction with postoperative pain control at 24, 48, and 72 hours, and on 
Day 10. 
 
Mean overall benefit of analgesia score (OBAS) at 24, 48, and 72 hours, and on Day 28. 
3.2.2. 
Safety Endpoints 
 
Incidence of TEAEs, SAEs, and opioid-related AEs (ORAEs) through Day 28. 
 
Change from baseline in clinical laboratory results. 
 
Change from baseline in vital signs at each assessed timepoint. 
 
Change from baseline in Holter data. 


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 
Wound healing assessment at 72 hours and on Day 10 and Day 28. 
 
Time to return of motor function. 
 
Loss of sensation in the breast at 15, 30, and 60 minutes after the start of ultrasound-guided 
study drug administration. 
 
Time to return of sensory function. 
 
Blinded assessor’s satisfaction with return of sensory and motor function at 24, 48, and 
72 hours, and on Day 10. 
3.2.3. 
Pharmacokinetic Endpoints 
 
Maximum observed plasma concentration (Cmax). 
 
AUC from Time 0 to the last collection time after study drug administration (AUC0-last). 
 
AUC from Time 0 extrapolated to infinity (AUC0-∞). 
 
Time to maximum plasma concentration (Tmax). 
 
Apparent terminal elimination rate constant (λz). 
 
Apparent terminal elimination half-life (t½el). 
3.3. 
Study Duration 
The overall duration of the study is anticipated to be approximately 18 months. The total 
duration of study participation for each subject (from Screening through Day 28) will be up to 
53 days. 
For regulatory reporting purposes, the end of the study is defined as the date of the last subject’s 
last assessment (scheduled or unscheduled). 


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4. 
STUDY ENROLLMENT AND WITHDRAWAL 
4.1. 
Study Population 
Up to approximately 240 subjects will be enrolled in this study in approximately 5 study sites in 
the United States (US). 
4.1.1. 
Inclusion Criteria 
Each subject must meet all of the following criteria to be enrolled in this study: 
1. Is able to provide written informed consent, adhere to the study visit schedule, and 
complete all study assessments. 
2. Is female ≥18 years of age at screening. 
3. Is scheduled to undergo bilateral submuscular augmentation mammoplasty with saline or 
silicone smooth implants with a volume of 300 to 500 cc, inclusive. Note: textured 
implants are not allowed. 
4. Has an American Society of Anesthesiologists Physical Status of I, II, or III. 
5. Is suitable for a nerve block procedure.  
6. Is able to demonstrate motor function by raising both arms above the head unassisted. 
7. Is able to assess sensory function by exhibiting sensitivity to cold in the pectoral area 
(upper outer quadrant). 
8. Subjects are eligible only if all of the following apply: 
a. Not pregnant (subjects of child-bearing potential must have a negative urine 
pregnancy test at screening and on Day 0 before study drug administration). 
b. Not lactating. 
c. Not planning to become pregnant during the study. 
d. Surgically sterile; or at least 2 years post-menopausal; or have a monogamous partner 
who is surgically sterile; or is practicing double-barrier contraception; or practicing 
abstinence (must agree to use double barrier contraception in the event of sexual 
activity); or using an insertable, injectable, transdermal, or combination oral 
contraceptive approved by the US Food and Drug Administration (FDA) for greater 
than 2 months prior to screening and commits to the use of an acceptable form of 
birth control for the duration of the study and for 30 days after study drug 
administration. Note: women in only a same-sex relationship do not need to meet this 
criterion. 
4.1.2. 
Exclusion Criteria 
A subject who meets any of the following criteria will be excluded from the study: 
1. Has a planned concurrent surgical procedure (eg, mastopexy). 
2. Has a planned reconstructive procedure status post breast cancer therapy. 
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 


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strictly related to the augmentation mammoplasty 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 fentanyl. 
5. Has known or suspected daily use of opioids for 7 or more consecutive days within the 
previous 6 months. 
6. Has taken NSAIDs (including meloxicam) within at least 10 days prior to 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 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 to treat an AE that occurs after signing the ICF or for pretreatment prior to a 
needle placement. 
11. Has initiated treatment with any of the following medications within 1 month prior to 
study drug administration or is taking any of these medications to control pain: selective 
serotonin reuptake inhibitors (SSRIs), selective norepinephrine reuptake inhibitors 
(SNRIs), gabapentin, pregabalin, duloxetine, or cyclooxygenase-2 (COX-2) inhibitors. 
(Note: If a subject is taking one of these medications for a reason other than pain control, 
she 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 a medical condition that, in the opinion of the Investigator, participating in the study 
would pose a health risk to the subject or confound the postoperative assessments. 
Conditions may include, but are not limited to, any of the following: 
a. History of clinically significant cardiac abnormality such as myocardial infarction 
within 6 months prior to signing the informed consent, New York Heart Association 
class III or IV, or clinically significant abnormalities of electrocardiogram (ECG) or 
cardiac function. 
b. History of coronary artery bypass graft surgery within 12 months of signing the ICF. 
c. History of severe liver function impairment, as defined by Child-Pugh Class C, 
having an aspartate aminotransferase >3 × the upper limit of normal (ULN), or 
having an alanine aminotransferase >3 × ULN. 
d. History of severe kidney function impairment as defined by creatinine clearance 
(Cockcroft Gault) <30 mL/min, being on dialysis, and/or having a serum creatinine 
>2 × ULN. 
e. History of known or suspected coagulopathy or uncontrolled anticoagulation. 
f. Loss of sensation in extremities or significant peripheral neuropathy. 
13. As per subject history and/or medical records, has active infection or is currently 
undergoing treatment for Hepatitis B, Hepatitis C, or human immunodeficiency virus 
(HIV). 
14. Has uncontrolled anxiety, psychiatric, or neurological disorder that might interfere with 
study assessments 


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15. Has any chronic neuromuscular deficit of either pectoral nerve function or 
arm/shoulder/truncal musculature. 
16. Has any chronic condition or disease that would compromise neurological or vascular 
assessments. 
17. Had a malignancy in the last year, with the exception of non-metastatic basal cell or 
squamous cell carcinoma of the skin or localized carcinoma in situ of the cervix. 
18. Has a known or suspected history of drug abuse, a positive drug screen on the day of 
surgery, or a recent history of alcohol abuse. Note: Subjects with a positive drug screen 
who are taking an allowed, prescribed medication that is known to result in a positive 
drug test (eg, amphetamine and dextroamphetamine for attention-deficit/hyperactivity 
disorder, benzodiazepine for anxiety disorder) may be eligible for participation in the 
study. Subjects taking medical marijuana are not allowed to participate in the study. 
19. Previous participation in an HTX-011 study or received an investigational product or 
device in a clinical trial within 30 days or within 5 elimination half-lives (whichever is 
longer) prior to surgery, or is planning to take part in another clinical trial while 
participating in this study. 
20. Has undergone 3 or more surgeries in 12 months prior to signing the ICF, other than for 
diagnostic procedures (eg, colonoscopy). 
21. Has a body mass index (BMI) >35 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 study drug administration. Subjects will be randomized using 
a computer-generated randomization scheme. All randomization information will be kept in a 
secure location accessible only by the randomization personnel, the assigned Pharmacist(s) and 
his/her verifier, and the unblinded clinical monitor. No subject may receive study drug prior to 
randomization. 
4.2.1. 
Procedures for Handling Randomized Subjects Who Do Not Meet the Study 
Eligibility Criteria 
Subjects who fail to meet the eligibility criteria should not, under any circumstances, receive 
study drug. 
Subjects who meet the Screening eligibility criteria and are randomized, but who do not meet the 
eligibility criteria on Day 0 prior to study drug administration will be withdrawn from the study 
without receiving study drug. In the event a subject does not meet the eligibility criteria but is 
randomized and receives study drug, the Investigator should inform the Sponsor immediately. 
The Sponsor’s Medical Monitor and the Investigator will discuss whether to allow the subject to 
continue on study. 
4.3. 
Blinding 
The study will use a double-blind design. Specific members of the site’s pharmacy and surgical 
staff will not be blinded to the treatment assignments because HTX-011 is colored and viscous in 
contrast to bupivacaine HCl and saline placebo, and the volume of study drug to be administered 


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varies by treatment group. However, the subject will not be told of her treatment assignment. In 
order to maintain the blind for the subject, the subject must not be allowed to see the color of the 
injectate, and the anesthesiologist must ensure he/she does not impress upon the subjects any 
visual or verbalized cues as to the treatment. 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 assignments until after database lock. The Sponsor’s 
study team will also be blinded to the treatment assignments with the exception of the clinical 
trial material (CTM) staff, the clinical observers, the bioanalytical staff, and an unblinded 
statistician who will perform the randomization and interim analysis data reviews, but will 
otherwise be uninvolved in the conduct of the study. In addition, an internal IRC will be 
unblinded during the interim reviews of summary-level efficacy, safety, and PK data from the 
study. 
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 she received. An attempt 
should be made to contact the Sponsor before breaking the blind. If the Sponsor cannot be 
reached and the blind is broken by the Investigator, the reason for unblinding must be 
documented and the Sponsor must be contacted within 24 hours. 
The Sponsor retains the right to break the treatment code for SAEs that are unexpected and are 
suspected to be causally related to an investigational product (IP) and that potentially require 
expedited reporting to regulatory authorities.  
All circumstances leading to the premature unblinding must be clearly documented. 
4.4. 
Subject Withdrawal and Replacement 
4.4.1. 
Subject Withdrawal 
Subjects are free to withdraw from the study at any time without prejudice to further treatment. 
A subject may also be withdrawn from the study by the Investigator or the Sponsor at any time if 
either determines that it is not in the subject’s best interest to continue participation. 
Possible reasons for early withdrawal include the following: 
 
Adverse event 
 
Consent withdrawal 
 
Death 
 
Lost to follow up 
 
Investigator’s decision 
 
Sponsor’s decision 
 
Screen fail on Day 0 
The date and the primary reason for early withdrawal will be recorded on the electronic Case 
Report Form (eCRF). At the time of withdrawal from the study, every attempt should be made to 
complete the Early Termination Visit assessments (see Section 7.4). 


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4.4.2. 
Subject Replacement 
Any subject who is randomized but withdraws from the study prior to study drug administration 
will be replaced by the next eligible study subject. The replacement subject will be assigned to 
the same treatment group as the subject who withdrew. 


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5. 
STUDY TREATMENT 
All subjects will receive a single dose of study drug. Study drug is defined as HTX-011 (IP), 
bupivacaine HCl without epinephrine (active control), or saline placebo (control). 
HTX-011 will be supplied by the Sponsor. Bupivacaine HCl and saline placebo will be supplied 
by study sites. 
5.1. 
Description of Investigational Product 
HTX-011 is a slightly yellow, viscous, semi-solid gel liquid. HTX-011 is supplied in prefilled 
sterile syringes and/or vials. The prefilled syringe and vials serve only as a closed container for 
the drug product. For administration of study drug, the formulation in the prefilled syringes 
and/or vials will be aseptically transferred to sterile syringes. 
5.2. 
Manufacturing, Packaging, and Labeling 
HTX-011 will be manufactured according to Good Manufacturing Practices, and packaged and 
labeled by the Sponsor or designee. HTX-011 will be packed and dispatched to comply with 
shipping and storage conditions. HTX-011 labeling will comply with all applicable federal and 
local laws and regulations. 
5.3. 
Storage 
HTX-011 should be stored at the study site in a refrigerator at 2ºC to 8ºC. The refrigerator should 
be in a locked area with restricted access. A temperature log should be maintained to monitor the 
refrigerator’s temperature. 
Saline placebo and bupivacaine HCl will be stored as per the prescribing information 
5.4. 
Preparation 
Study drug will be prepared at the study site by unblinded study personnel. Refer to the 
Pharmacy Manual for details on study drug preparation. 
5.5. 
Study Drug Administration 
Study drug should be prepared and study drug administration equipment should be assembled 
and primed as outlined in the Pharmacy Manual. 
Study personnel who are present during the administration of study drug are unblinded and 
cannot perform postoperative assessments. 
5.5.1. 
Nerve Block 
For bilateral ultrasound-guided lateral and medial pectoral nerve block, approximately half the 
total volume of study drug should be administered to each side and equal amounts should be 
administered per nerve. 


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Investigators will use ultrasound guidance to locate the lateral pectoral and medial pectoral 
nerves. The ultrasound machine may have capacity for color and needle localization software, if 
needed for ease of needle placement. With a linear array transducer in a sterile sleeve, the nerve 
will be identified in a transverse (short-axis) view below where it comes off at the brachial 
plexus; the internal appearance of the peripheral nerve bundle should appear to be a mixture of 
hypoechoic neural tissue (fascicles) and hyperechoic connective tissue (perineurium and 
epineurium). Once the optimal image of the nerve is obtained, a local anesthetic skin wheal (1% 
lidocaine) may be raised near the ultrasound transducer. A needle will be inserted through the 
skin wheal and directed medially in plane beneath the ultrasound transducer toward the nerves; 
the study drug will be injected around the nerves. 
The surgeon should administer 5 mL of 0.5% ropivacaine HCl in each of the surgical incision 
lines at closure. 
5.5.2. 
HTX-011 Instillation and Saline Placebo Nerve Block 
To maintain the study blind for instillation only administration, a nerve block will be performed 
as described in Section 5.5.1 using saline placebo. In addition, the Investigator will instill HTX-
011 into the surgical site in a manner to be specified by the Sponsor in the Pharmacy/Study 
Manual. Note: HTX-011 is to be instilled, not injected, into the tissue. 
The surgeon should administer 5 mL of 0.5% ropivacaine HCl in each of the surgical incision 
lines at closure. 
5.6. 
Study Drug Compliance 
All study drug must be administered in accordance with the treatment assignment.  
5.7. 
Study Drug Accountability 
The IP provided for this study will be used only as directed in the study protocol. In accordance 
with GCP, Investigators are required to maintain accurate and up-to-date records of all IP to 
permit reconciliation of study drug. The Investigator or designee must maintain adequate records 
of distribution, including the date received, number and units received, lot numbers, dispensing, 
and return or destruction of all IP (ie, accountability or dispensing logs). 
All study drug records must be readily available for inspection by the site’s unblinded clinical 
monitor and/or auditor. No IP can be returned to the Sponsor or designee or disposed of at the 
study site until the unblinded clinical monitor has verified the accuracy of the study drug records 
at the study site. All returns, disposal, or destruction must be approved by the Sponsor in writing. 


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6. 
STUDY PROCEDURES AND ASSESSMENTS 
The following sections describe the study procedures and assessments that will be performed 
during the study. See Section 7 and the Schedule of Events table. 
6.1. 
Medical History and Demographics 
6.1.1. 
Medical History 
A complete medical history will be obtained before randomization to ensure subjects qualify for 
the study. Medical history will be obtained through subject interview. A review of the subject’s 
medical records from their primary care physician is not required. 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 the day of signing the ICF and Day 28 will be 
recorded in the subject’s eCRF. For subjects entering on a stable dose of permitted medication, 
any change in dose should also be recorded. 
Medications include prescription or over-the-counter medications (including herbal products and 
vitamins). 
During surgery, the use of fentanyl up to 4 μg/kg is permitted. In addition, subjects in Cohorts 2 
and 4 will receive protocol-specified fentanyl 50 µg intravenously (IV) just prior to the end of 
the surgery. As the prescribing information for fentanyl citrate (Fentanyl Citrate USPI 2012) 
specifies that for intraoperative use a “moderate dose” of 2 to 20 μg/kg IV is necessary in order 
to allow the anesthesiologist to respond to any signal that the surgical stress is increasing or 
anesthesia lightening, this dose was chosen to be in the lowermost portion of that range and 
therefore not interfere with assessment of postoperative opioid load. As clinically appropriate, 
the minimum possible fentanyl dose should be used. 
Medications that are prohibited during the study are described in Section 9.1. 
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.” NRS scores will be recorded at rest (NRS-R; 
in a dependent position) and with activity (NRS-A). For the prescribed activity, the subject will 


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keep her elbows at her side and against her body and will then raise her hands in front of her 
abdomen, clasp hands together, and hold that position for at least 5 seconds (Smoot 2012). 
If a subject withdraws from the study before 72 hours, NRS-R and NRS-A pain intensity scores 
will be recorded at the time of withdrawal. 
6.3.2. 
Use of Opioid Rescue Medications 
The name, dose, and route as well as the date and time of administration of any opioid rescue 
medication taken 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. 
6.3.3. 
Subject Daily Diary 
Subjects will be provided a diary to record if they took any opioid medication that day. Subjects 
will be required to record their use of opioids on a daily basis from 72 hours through Day 28. 
6.3.4. 
Patient Global Assessment of Pain Control 
Subjects will be asked to evaluate the performance of study drug as a pain treatment at different 
intervals using a 4-point rating scale where 0 represents “poor” and 3 represents “excellent” 
(Rothman 2009). See Appendix D for the PGA scale. 
6.3.5. 
Discharge Readiness 
Discharge readiness will be assessed using the MPADSS criteria (Chung 1995). Refer to 
Appendix B. 
Note: This study instrument assesses a subject’s potential readiness to be discharged and should 
be repeated at all scheduled timepoints. It is not meant to be used to decide on whether or not to 
discharge a subject from the study. Subjects are required to remain in the hospital/research 
facility for 72 hours.  
6.3.6. 
Satisfaction With Postoperative Pain Control and With Return of Sensory and 
Motor Function 
The subject will be questioned about her satisfaction with postoperative pain control. The 
subject’s response to the following statement “I am satisfied with postoperative pain control” 
will be recorded using a 5-point Likert scale where 1 represents “strongly disagree” and 5 
represents “strongly agree.” 
The blinded assessor will also be questioned about his/her satisfaction with return of sensory and 
motor function using a 5-point Likert scale. 
6.3.7. 
Overall Benefit of Analgesia Assessment 
The subject will be questioned about their overall benefit of analgesia using a 7-item, 
multidimensional, quality assessment questionnaire (Lehmann 2010). The 7 items address pain, 


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vomiting, itching, sweating, freezing, dizziness, and overall satisfaction with postoperative pain 
and make up the OBAS. See Appendix E for the OBAS scale. 
6.4. 
Safety Assessments 
6.4.1. 
Adverse Events 
All AEs regardless of causality or seriousness will be recorded from the time the subject signs 
the ICF through Day 28. See Section 8 for details. 
6.4.2. 
Local Anesthetic Systemic Toxicity Assessment 
Subjects should be assessed on a regular basis to identify early neurologic and cardiac signs and 
symptoms that may be attributed to local anesthetic systemic toxicity (LAST; eg, 
metallic/strange taste, perioral tingling, ringing in ears, visual disturbance, tremors, muscle 
twitching, dizziness/lightheadedness, convulsion/seizure, bradycardia, arrhythmia, hypotension) 
(Vasques 2015). Additional monitoring of subjects for safety should be performed as needed (eg, 
vital signs, ECGs). 
Signs and symptoms that are clinically significant and may be attributed to LAST should be 
recorded as AEs. 
6.4.3. 
Physical Examinations 
Scheduled physical examinations will include an evaluation of the following: head, eyes, ears, 
nose, and throat as well as CV, respiratory, gastrointestinal, neurological, dermatological, and 
musculoskeletal systems. 
Baseline height and weight measurements, and calculation of BMI (BMI = weight [kg]/height 
[m2]) will be conducted. 
Unscheduled physical examinations may also be performed (the extent of which is to be 
determined by the Investigator) at any time during the study if indicated by a change in the 
subject’s medical history or condition. 
6.4.4. 
Vital Signs 
Vital signs will include systolic and diastolic blood pressure, resting heart rate, and respiration 
rate. Subjects should be in a supine position (includes sitting in a recliner chair) for at least 
5 minutes before taking vital signs. Clinically significant post-treatment vital sign results should 
be recorded as AEs. 
6.4.5. 
12-Lead Electrocardiograms and Holter Monitoring 
A Screening ECG will be obtained for all subjects. Standard digital 12-lead ECG results will be 
recorded in triplicate. Subjects should be in the supine position (includes sitting in a recliner 
chair) for at least 5 minutes before each ECG recording. The mean of the 3 ECGs will be used as 
the baseline result. 


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Continuous Holter monitoring will be performed. Subjects will be required to have a continuous 
reading at least 24 hours before surgery and will wear the monitor for 72 hours after the start of 
study drug administration. While the limb leads will be kept on until the 72-hour timepoint, the 
chest leads may be removed just prior to the operation and replaced immediately after the 
operation, if needed. The limb leads should not be removed during the operation. 
The ECG and Holter monitor results will be reviewed by a central reader and the information 
provided to the sites. Refer to the Cardiac Manual for instructions on collecting and transmitting 
results. Clinically significant findings after study drug administration will be recorded as TEAEs. 
6.4.6. 
Wound Healing Assessment 
Surgical wound healing will be evaluated by the Investigator or other medically qualified clinical 
site personnel; every attempt should be made by the site to use the same assessor for individual 
subject assessments. The findings will be graded according to the Southampton Wound Scoring 
System (Bailey 1992); see Appendix C. 
6.4.7. 
Motor Function Assessment 
Motor function will be assessed by having the subject keep her elbows at her side and against her 
body and then raise her hands in front of her abdomen, clasp hands together, and hold that 
position for at least 5 seconds. The results will be recorded on the eCRF. 
6.4.8. 
Sensory Function Assessment 
Sensory function will be evaluated using a cold alcohol swab test. An alcohol pad will be placed 
on the upper outer quadrant of the breast on the side of the dominant hand. The subject will not 
see when the pad is applied. The subject will be asked “Can you detect cold?” The results (Yes 
or No) will be recorded on the eCRF. 
6.4.9. 
Clinical Laboratory Tests 
Blood and urine samples will be collected for diagnostic screening tests and for safety laboratory 
tests (hematology and serum chemistry). See Table 1 for a list of clinical laboratory tests and 
parameters. Blood samples will be tested by a central laboratory. Urine samples will be tested by 
local laboratories. 
Laboratory results will be reviewed by the Investigator. Any laboratory values outside of the 
normal reference range will be evaluated for clinical significance. Clinically significant findings 
after study drug administration will be recorded as AEs. 
Refer to the Laboratory Manual for detailed instructions on sample collection, processing, and 
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7. 
TIMING OF PROCEDURES AND ASSESSMENTS 
This section lists the study procedures and assessments that will be performed at scheduled 
timepoints during the study. See Section 6 for information on study procedures and assessments. 
Unless there is a safety concern, every effort should be made to avoid protocol deviations. For 
assessments at timepoints when the subject is asleep, an attempt should be made to wake 
the subject. If there is no response, the assessments at these timepoints may be recorded as 
“Not Done.” Assessments that can be done without awakening the subject (eg, blood collection 
for PK sample) should be completed. Additional visits and/or assessments are permitted if 
clinically indicated in the opinion of the Investigator. 
When the following assessments are scheduled at the same timepoint, it is recommended that 
they be performed in this order: 
 
NRS-R pain intensity assessment (assessed in a dependent position) 
 
PGA of pain control 
 
OBAS assessment 
 
Vital signs 
 
12-lead ECG 
 
NRS-A pain intensity assessment (assessed by having the subject keep her elbows at her side 
and against her body and then raise her hands in front of her abdomen, clasp hands together, 
and hold that position for at least 5 seconds) 
 
Blood sample collection 
 
Physical examination 
 
Wound healing assessment 
 
Subject’s satisfaction with postoperative pain control 
7.1. 
Screening Period 
After providing written informed consent, potential study subjects will undergo Screening 
procedures to confirm eligibility to participate in the study. Screening procedures must be 
performed within 21 days prior to study drug administration. 
The Investigator must evaluate the subject’s medical history and the results of all Screening 
assessments to determine study eligibility before the subject is randomized. Screening laboratory 
test results that do not meet the eligibility criteria may not be repeated without the Sponsor's 
approval. 
Screening procedures and assessments will include the following: 
 
Medical history 
 
Demographic recording 
 
Physical examination including weight, height, and BMI calculation 
 
Vital signs measurements 
 
12-lead ECG (triplicate) 
 
Urine collection for pregnancy test (female subjects of child bearing potential only) 


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 
Urine collection for drug screen 
 
Blood sample collection for the hematology and serum chemistry 
 
Sensory function assessment  
 
Motor function assessment  
 
Subject training for pain intensity assessments 
 
AE recording (from signing the ICF) 
 
Prior and concomitant medication recording 
Subjects will be required to have a continuous reading of the Holter monitor at least 24 hours 
before surgery (Day 0). 
Subjects who meet the eligibility criteria may be randomized up to 1 business day prior to study 
drug administration. Subjects do not need to be present for randomization to occur. 
7.2. 
Study Drug Administration, Surgery, and Observational Period 
7.2.1. 
Day 0, Prior to Surgery 
On the day of surgery (Day 0), subjects will be reassessed for study eligibility. Subjects who 
continue to meet the eligibility criteria can continue on study and the following study procedures 
and assessments will be performed before study drug administration: 
 
Vital signs measurements 
 
Urine sample collection for the following assessments: 
 Drug screen 
 Pregnancy test (female subjects of childbearing potential only) 
 
Subject training for pain intensity assessments (refresher training) 
 
NRS-R pain intensity assessment 
 
Blood collection for PK 
 
NRS-A pain intensity assessment 
 
AE recording 
 
Prior and concomitant medication assessment 
After all assessments have been completed, study drug will be administered within 4 hours prior 
to surgery for subjects receiving study drug via ultrasound-guided lateral and medial pectoral 
nerve block. See Section 5.5 for complete details on the method of study drug administration. 
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. 
A sensory function assessment (cold test) will be performed on the upper outer quadrant of the 
breast on the side of the dominant hand at 15, 30, and 60 minutes after the start of 
ultrasound-guided study drug administration. If the subject is already on her way to or in the 
operating room, the assessment may be avoided and “Not Done” recorded on the eCRF. 


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7.2.2. 
Pharmacokinetic Sampling After Study Drug Administration 
Note: The start of study drug administration will be considered as Time 0 for all PK 
timepoints. 
Blood samples for PK analysis will be collected at the following timepoints: 30 minutes 
(±5 min); 1 hour (±5 min); 2 and 4 hours (±15 min); 6, 8, and 12 hours (±30 min); 20, 22, 24, 
26, and 28 hours (±1 hr); 36, 48, 60, 72 hours (±2 hr); and 120 hours (±6 hr) after the start of 
study drug administration. 
PK blood sample should be collected according to the above schedule even if the subject is still 
in the operating room. 
7.2.3. 
Surgery (Day 0) 
Subjects will be admitted to the surgical unit and will undergo a bilateral submuscular 
augmentation mammoplasty under general anesthesia. Sites should follow intraoperative safety 
monitoring in accordance with American Society of Anesthesiologists (ASA) Standards for 
Basic Anesthetic Monitoring (American Society of Anesthesiologists 2015). The start and stop 
time of surgery and additional surgical details should be recorded in the eCRF. Concomitant 
medications used during surgery and AEs will be recorded.  
For subjects receiving study drug via instillation, study drug will be administered prior to the end 
of surgery. See Section 5.5 for complete details on the method of study drug administration. 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 end of surgery (defined as placement of last suture) will be considered as Time 0 
for all efficacy and safety assessments. 
After immediate postoperative recovery, subjects will be transferred to the PACU.  
7.2.4. 
Postoperative Observation Period (72 Hours) 
Subjects will remain in the hospital/research facility for 72 hours after surgery. Study procedures 
and assessments that will be performed are listed below. 
Timepoints are generally referenced to the end of surgery (with the exception of PK and the 
initial sensory assessments). 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 pain intensity assessment: at 1 hour (±5 min); 2 and 4 hours (±15 min); 6, 8, and 12 
hours (±30 min); 24 hours (±1 hr); and 36, 48, 60, and 72 (±2 hr)  
 NRS-A pain intensity assessment: at 1 hour (±5 min); 2 and 4 hours (±15 min); 6, 8, and 12 
hours (±30 min); 24 hours (±1 hr); and 36, 48, 60, and 72 hours (±2 hr) 
 PGA of pain control assessment: 24 hours (±1 hr), 48 and 72 hours (±2 hr) 
 Vital signs measurements: 24 hours (±1 hr), 48 and 72 hours (±2 hr) 


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 Physical examination: 72 hours (±2 hr; height and weight not required) 
 Blood sample for clinical safety laboratory tests: 24 hours (±1 hr; hematology only) and 
72 hours (±2 hr; hematology and serum chemistry) 
 Sensory function test: 6 and 12 hours (±30 min); 24 hours (±1 hr); 48 and 72 hours (±2 hr) 
 Motor function test: 6 and 12 hours (±30 min); 24 hours (±1 hr); 48 and 72 hours (±2 hr) 
 Discharge readiness assessment per the MPADSS criteria: 2 and 4 hours (±15 min); 6, 8, 
and 12 hours (±30 min); 24 hours (±1 hr); and 36, 48, 60, and 72 hours (±2 hr) 
 Wound healing assessment: 72 hours (±2 hr) 
 Subject’s satisfaction with postoperative pain control: 24 hours (±1 hr), 48 and 72 hours 
(±2 hr) 
 Blinded assessor’s satisfaction with return of sensory and motor function: 24 hours 
(±1 hr), 48 and 72 hours (±2 hr) 
 
OBAS assessment: 24 hours (±1 hr), 48 and 72 hours (±2 hr) 
 AE recording: Any time between study drug administration and 72 hours 
 Concomitant medication recording: Any time between study drug administration and 
72 hours 
 Use of opioid rescue medication recording: Any time between study drug administration 
and 72 hours 
7.2.5. 
End of the Postoperative Assessment Period 
After the 72-hour postoperative assessments have been completed, the Holter monitor will be 
removed if applicable, and the subject may be discharged. The time of discharge will be 
recorded. If a subject is not ready to be discharged due to an AE, it should be recorded on the AE 
eCRF as per Section 6.4.1. If a subject is ready for discharge but is not discharged for any reason 
other than AE, it should be recorded on the eCRF. 
Subjects will be given a diary to record their use of opioids on a daily basis from 72 hours 
through Day 28. 
7.3. 
Follow-Up Period 
7.3.1. 
120 hours (±6 Hours) After Start of Study Drug Administration 
Subjects will return to the study site and will have the following procedures and assessments: 
 
Blood sample collection for PK 
 
Review subject daily diary 
 
AE recording 
 
Concomitant medication recording 
7.3.2. 
Day 10 Visit (±2 Days) 
All subjects will return to the study site and will have the following procedures and assessments: 
 
NRS-R pain intensity assessment 
 
NRS-A pain intensity assessment 


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 
Sensory function test 
 
Motor function assessment 
 
Wound healing assessment 
 
Blood sample collection for hematology and serum chemistry 
 
Subject’s satisfaction with postoperative pain control 
 
Blinded assessor’s satisfaction with return of sensory and motor function 
 
Review subject daily diary 
 
AE recording 
 Note: A blood sample to determine plasma bupivacaine concentration should be collected 
if the Investigator thinks the AE is potentially related to the cardiac or neurologic systems 
 
Concomitant medication recording  
7.3.3. 
Day 28 Visit (±4 Days) 
All subjects will return to the study site and will have the following procedures and assessments: 
 
NRS-R pain intensity assessment 
 
NRS-A pain intensity assessment 
 
PGA of pain control assessment  
 
OBAS assessment 
 
Wound healing assessment 
 
Return and review subject daily diary 
 
AE recording 
 Note: A blood sample to determine plasma bupivacaine concentration should be collected 
if the Investigator thinks the AE is potentially related to the cardiac or neurologic systems 
 
Concomitant medication recording 
7.4. 
Early Termination Visit 
Subjects who withdraw from the study before their Day 28 Visit will be asked to complete Early 
Termination procedures, which will include the following: 
 
NRS-R pain intensity assessment (if withdrew prior to 72 hours) 
 
NRS-A pain intensity assessment (if withdrew prior to 72 hours) 
 
PGA of pain control assessment (if withdrew prior to Day 28) 
 
Return and review subject daily diary (if withdrew between 72 hours and Day 28) 
 
Vital signs (if withdrew prior to 72 hours) 
 
Blood sample collection for clinical safety laboratory tests (hematology and serum 
chemistry) (if withdrew prior to Day 10) 
 
Physical examination (if withdrew prior to 72 hours [height and weight not required]) 
 
Sensory function test (if withdrew prior to Day 10) 
 
Motor function assessment (if withdrew prior to Day 10) 
 
Wound healing assessment 
 
AE recording 


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 
Concomitant medication recording 
7.5. 
Unscheduled Visits and Assessments 
Unscheduled visits and assessments should be performed if clinically indicated in the opinion of 
the Investigator. Except when urgent clinical evaluation is necessary, it is expected that the 
Investigator will have the subject return for an unscheduled visit rather than directing the subject 
to a hospital emergency room. The following procedures and assessments are examples of what 
may be performed at an unscheduled visit, depending on the clinical situation: 
 
Vital signs 
 
Physical examination 
 
ECG 
 
Wound healing assessment 
 
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 clinical safety laboratory tests (hematology and chemistry) 


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


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


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8.1.3. 
Definition of a Suspected Adverse Reaction 
A suspected adverse reaction is defined as any AE for which there is a reasonable possibility that 
the AE was caused by the study drug. 
8.1.4. 
Definition of a Serious Suspected Adverse Reaction 
A serious suspected adverse reaction is any suspected adverse reaction that is determined to be 
serious, based on the outcomes of an SAE described in Section 8.1.2. 
8.1.5. 
Definition of Unanticipated Problems 
Unanticipated problems are incidents, experiences, or outcomes that meet all of the following 
criteria: 
 
Unexpected in terms of nature, severity, or frequency given (a) the research procedures that 
are described in the protocol-related documents, such as the research protocol and informed 
consent document approved by the Ethics Committee (EC; includes Institutional Review 
Boards [IRBs], Independent Ethics Committees [IECs], and Research Ethics Boards [REBs]) 
and (b) the characteristics of the participant population being studied. 
 
Related or possibly related to participation in the research (“possibly related” means there is 
a reasonable possibility that the incident, experience, or outcome may have been caused by 
the procedures involved in the research). 
 
Suggest that the research places subjects or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized. 
An unanticipated adverse device effect is defined in Section 8.1.2. 
8.2. 
Classification of Adverse Events 
8.2.1. 
Severity of Adverse Events 
The Investigator will assess the severity of each AE based on his/her clinical judgment using one 
of the following categories: 
 
Mild: Event is easily tolerated by the subject, causes minimal discomfort, and does not 
interfere with everyday activities.  
 
Moderate: Event results in a low level of inconvenience or concern with the therapeutic 
measures. Moderate events may cause some interference with functioning.  
 
Severe: Event interrupts a participant’s usual daily activity and may require systemic drug 
therapy or other treatment. Severe events are usually potentially life-threatening or 
incapacitating.  
8.2.2. 
Relationship to Study Drug 
The Investigator will assess the relationship of each AE to study drug based on his/her clinical 
judgment. The Investigator’s assessment of an AE’s relationship to study drug is part of the 
documentation process, but it is not a factor in determining what is or is not reported in the study. 


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If there is any doubt as to whether a clinical observation is an AE, the event should be reported. 
All AEs must have their relationship to study agent assessed. In a clinical trial, the study drug 
must always be suspect. The Sponsor’s assessment of relationship may differ from the 
Investigator’s assessment. 
Relationship to study drug will be assessed according to the following guidelines: 
 
Possibly related: The AE is known to occur with the study drug, there is a reasonable 
possibility that the study drug caused the AE, or there is a temporal relationship between the 
study drug and event. Reasonable possibility means that there is evidence to suggest a causal 
relationship between the study drug and the AE. 
 
Unlikely Related: There is not a reasonable possibility that the administration of the study 
drug caused the event, there is no temporal relationship between the study drug and event 
onset, or an alternate etiology has been established. 
Even in situations in which minimal information is available for initially reporting an SAE, it is 
important that the Investigator always make an assessment of causality for every event before 
entering the information into the eCRF or completing the SAE reporting form, in the event 
electronic data capture (EDC) is not available. The causality assessment is one of the criteria 
used when determining regulatory reporting requirements. The Investigator may change his or 
her opinion of causality in light of follow-up information and amend the SAE information 
accordingly in the eCRF or the SAE reporting form, as applicable. 
8.3. 
Time Period and Frequency for Event Assessment and Follow Up 
8.3.1. 
Adverse Event and Serious Adverse Event Monitoring  
All AEs regardless of causality or seriousness will be recorded from the time the subject signs 
the ICF through Day 28. 
If an Investigator becomes aware of an SAE that occurs in a subject more than 28 days after 
study drug administration and the Investigator considers the event to be possibly related to the 
study drug, the Investigator should report the SAE to the Sponsor as outlined in Section 8.4.1. 
8.3.2. 
Follow-Up of Events 
After the occurrence of an AE or SAE, the Investigator is required to follow each subject 
proactively and provide further information on the subject’s condition. All AEs and SAEs 
documented at a previous visit or contact and designated as ongoing and 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: 


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 Resolved: The event resolved or the subject recovered without sequelae. An event (either 
serious or nonserious) occurred and had an endpoint, and the subject experienced no 
restrictions. Examples include stent placement for coronary artery disease (a device 
implanted is not a sequela), an appendectomy (a scar is not a sequela), a postoperative wound 
infection, or an upper respiratory tract infection. 
 Resolved with sequelae: The event has at least one secondary outcome that may result in 
permanent disability, functional limitation, or both. Such sequelae are usually limited to 
SAEs. Examples include hip replacement resulting in foot drop (foot drop is not the intended 
outcome but is a risk of surgery), stroke resulting in paralysis, or emboli formation after a 
bacterial infection resulting in a renal infarct and loss of renal function. 
 Not resolved: At the end of the study, a nonserious event either has not changed in intensity 
or may not have recovered to baseline values, and the outcome is unknown. Examples 
include headache, low-grade fever, or nausea. 
 Unknown: The subject has withdrawn from the study prematurely or is lost to follow-up, 
and the status of the event is unknown. 
 Death 
SAEs will be followed until the event resolves (ie, when the event no longer meets any of the 
seriousness criteria), the condition stabilizes, or until the event is otherwise explained or judged 
by the Investigator to be no longer clinically significant (unless the subject is lost to follow-up or 
withdraws consent). The Investigator will ensure that follow-up information provided to the 
Sponsor includes results of any additional laboratory tests or investigations, histopathologic 
examinations, or consultations with other healthcare professionals that serve to clarify the nature 
of the event, the cause of the event, or both. New or updated information will be recorded as 
outlined in Section 8.4.1. 
8.4. 
Reporting Procedures 
8.4.1. 
Reporting Serious Adverse Events to the Sponsor 
If the Investigator determines that an event meets the protocol definition of an SAE due to any 
cause that occurs during the course of this study, regardless of relationship to study drug, he/she 
must notify the Sponsor by entering the SAE information into the eCRF within 24 hours of the 
Investigator becoming aware of the SAE. 
If EDC is not available, the Investigator must complete an SAE reporting form and email it to the 
Sponsor within 24 hours of the Investigator becoming aware of the SAE. The Investigator must 
also enter the SAE information into the eCRF as soon as possible thereafter. 
Email Address: 
htx011safety@herontx.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 


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Also, the following documents are to be forwarded: any laboratory results, diagnostic test results, 
or medical reports relevant to the SAE. 
EDC is the preferred method for notification of SAE information. In rare circumstances and in 
the absence of email capacity, notification by fax or telephone is acceptable, with a copy of the 
SAE reporting form sent by overnight mail. Initial notification via telephone does not replace the 
need for the Investigator to complete the SAE information in the eCRF within the time frames 
outlined. 
If the Investigator does not have all information regarding an SAE, he/she must not wait to 
receive additional information before notifying the Sponsor of the event. The SAE must be 
updated when additional information is received. Follow-up information received on all SAEs 
must be forwarded to the Sponsor using the same timelines as for an initial report. 
The Investigator must notify the Sponsor by reporting any unanticipated adverse device effect 
within 24 hours of the Investigator becoming aware of the effect. 
8.4.2. 
Reporting Unanticipated Problems to the Sponsor 
If the Investigator determines that an event meets the protocol definition of an unanticipated 
problem, he/she must notify the Sponsor by entering the information into the eCRF within 24 
hours of the Investigator becoming aware of the problem. 
If EDC is not available, the Investigator must complete an unanticipated problem report form 
and email it to the Sponsor within 24 hours of the Investigator becoming aware of the problem. 
The Investigator must also enter the information into the eCRF as soon as possible thereafter. 
Email Address: 
htx011safety@herontx.com 
The following information will be included with unanticipated problem reporting: 
 
Protocol identifying information: protocol title, protocol number, and Investigator’s name. 
 
A detailed description of the event, incident, experience, or outcome. 
 
An explanation of the basis for determining that the event, incident, experience, or outcome 
represents an unanticipated problem. 
It is the Investigator’s responsibility to report unanticipated problems to the Sponsor and their 
EC, as required by local regulations. 
8.4.3. 
Regulatory Reporting Requirements 
The Investigator must promptly report all SAEs and unanticipated adverse device effects to the 
Sponsor in accordance with the procedures detailed in Section 8.4.1. The Sponsor has a legal 
responsibility to notify, as appropriate, both the local regulatory authority and other regulatory 
agencies about the safety of a product under clinical investigation. Prompt notification of SAEs 
by the Investigator to the appropriate project contact for SAE receipt is essential so that serious 
suspected adverse reactions that are either unexpected or observed with increasing occurrence be 


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reported and legal obligations and ethical responsibilities regarding the safety of other subjects 
are met. 
Investigator letters are prepared according to Sponsor policy and are forwarded to the 
Investigators as necessary. An Investigator letter is prepared for any suspected adverse reaction 
that is attributable to study drug, serious, and unexpected. The purpose of the Investigator letter 
is to fulfill specific regulatory and GCP requirements regarding the product under investigation. 
The Investigator, or responsible person according to local requirements, must comply with 
requirements related to the reporting of SAEs to the EC. 
The Sponsor is responsible for informing ECs, Investigators, and regulatory authorities of 
finding that could adversely affect the safety of subjects or affect the conduct of the study. 
Events will be reported to regulatory authorities in accordance with expedited and period 
reporting requirements. 
8.4.4. 
Pregnancy Reporting 
Any subject who becomes pregnant during the study must be withdrawn from the study 
immediately. Female subjects who become pregnant within 28 days after receiving study drug 
should also notify the Investigator. The Investigator must attempt to follow the pregnancy to 
term or termination in order to report on outcome and health status of mother and child. 
The Investigator must notify the Sponsor of any pregnancy within 24 hours after the Investigator 
becomes aware of it using the SAE reporting procedures outlined in Section 8.4.1. 
8.5. 
Safety Oversight 
The internal, blinded Product Safety and Risk Management Committee will monitor safety data 
on a periodic basis throughout the study (ie, monthly unless more frequent monitoring is 
necessary due to high enrollment or safety concern), including regular review of ECG findings, 
AEs, and SAEs. ECGs and AEs will be reviewed to identify possible signs of LAST. 
The stopping criteria, enrollment suspension or study termination for safety issues, are provided 
in Section 13.5. 


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9. 
STUDY RESTRICTIONS 
9.1. 
Prohibited Medications 
Antiemetic medications may be given to treat nausea and/or vomiting, but should not be 
administered prophylactically (ie, as a routine preventative in the absence of signs or symptoms 
of nausea or vomiting). Dexamethasone also cannot to be administered prophylactically before 
surgery. 
Intraoperative administration of opioids or any other analgesics (including ketamine), local 
anesthetics, or anti-inflammatory agents except as specified by the protocol (ie, HTX-011, 
bupivacaine HCl, ropivacaine HCl, and fentanyl) is prohibited, unless needed to treat an AE that 
occurs after signing the ICF or for pretreatment prior to a needle placement. 
With the exception of the opioid rescue medications specified in Section 3.1.3, no other 
analgesic agents, including NSAIDs and acetaminophen, are permitted during the 72-hour 
postoperative observation period. After 72 hours, the analgesic regimen may be adjusted for each 
subject individually as deemed appropriate by the physician responsible for the postoperative 
care. 
9.2. 
Contraception 
Female subjects of child bearing potential with a non-surgically sterile partner must use an 
acceptable form of contraception in the event of sexual activity during the study and for 30 days 
after study drug administration. Acceptable forms of contraception include double-barrier 
contraception or an insertable, injectable, transdermal, or combination oral contraceptive 
approved by the FDA. 


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10. 
STATISTICAL CONSIDERATIONS 
10.1. General Considerations 
All efficacy and safety data will be listed by subject. Baseline is defined as the last observed 
measurement, whether scheduled or unscheduled, prior to the start of study drug administration. 
All safety and efficacy endpoints will be summarized by treatment group and/or cohort, as 
appropriate. Continuous variables will be summarized using the number of subjects with data 
(n), mean, standard deviation (SD), median, minimum, and maximum. Selected continuous 
variable summaries will also include the standard error (SE). Categorical variables will be 
summarized using frequency counts and percentages. 
Unless otherwise specified, all statistical hypothesis testing will be two-sided using α = 0.05. 
10.2. Determination of Sample Size 
The sample size of up to approximately 240 subjects in this study was selected empirically 
without formal statistical assumptions. 
10.3. Analysis Populations 
Intent-to-Treat (ITT) Population: All subjects who are randomized and do not screen fail on 
Day 0 will be included in the ITT Population. This population will be used in subject disposition 
analyses only. 
Modified ITT (mITT) Population: All subjects in the ITT Population who have at least 
1 post-treatment NRS-A pain intensity score will be included in the mITT Population. This 
population will be used as the primary analysis population for all efficacy 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. 
10.4. Statistical Analysis Methods 
10.4.1. 
Disposition and Demographics 
The number and percentage of subjects in each analysis population will be summarized. Subject 
disposition, including the number of subjects screened, randomized, dosed, completing the 
72-hour postoperative observation period, completing Day 28, and not completing Day 28 by 
reason for withdrawal will be summarized for the ITT Population. Subject demographics and 
baseline characteristics will be summarized for the mITT Population and will include age, age 
category, sex, race, ethnicity, height, weight, and BMI. 
10.4.2. 
Efficacy Analysis 
For the purposes of statistical hypothesis testing, data from subjects randomized to saline placebo 
will be pooled across cohorts into a single saline placebo treatment group, and data from subjects 


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randomized to bupivacaine HCl will be pooled across cohorts into a single bupivacaine HCl 
treatment group. Data from subjects randomized to HTX-011 will neither be pooled across dose 
levels nor pooled across methods of administration within a dose level. 
10.4.2.1. 
Primary Efficacy Analysis 
The primary analysis of mean AUC0-24 of the NRS-A pain intensity scores will be carried out on 
the mITT Population using an analysis of variance (ANOVA) model with treatment as the main 
effect. Each dose of HTX-011 will be tested against each of the pooled control arms. Results will 
be expressed as mean AUCs and SDs, least-squares mean differences and SEs with associated 
95% confidence intervals (CIs), and p-values. To account for the duration effect of opioid rescue 
medication, the windowed worst observation carried forward (wWOCF) method will be 
implemented as the primary analysis method for endpoints involving NRS pain intensity scores. 
In this method, pain intensity scores observed during the analgesic window (duration of effect) 
of any opioid rescue medication will be replaced with the worst (highest) postdose nonmissing 
NRS pain intensity score observed prior to the rescue medication window, with the following 
exception: if the NRS pain intensity score for a windowed observation is higher than the worst 
pre-window score, then it will not be replaced. Sensitivity analyses for endpoints involving NRS 
pain intensity scores will analyze the data without adjustment for the effect of opioid rescue 
medications. 
10.4.2.2. 
Secondary Efficacy Analyses 
Continuous secondary efficacy endpoints will be analyzed in a manner similar to that specified 
for the primary endpoint. 
Categorical endpoints will be analyzed using Fisher’s exact test. Results will be expressed as the 
number and percentage of subjects meeting the relevant endpoint, differences in proportions with 
95% CIs, and p-values. 
Median time in hours to first opioid rescue administration will be analyzed using Kaplan-Meier 
methods. 
10.4.2.3. 
Handling of Missing Data 
Due to the required 72-hour inpatient post-surgery observation period, the amount of missing 
data is expected to be very low. For any missing data observed, NRS pain intensity scores will be 
imputed via last observation carried forward (LOCF), in which the most recent postdose 
nonmissing value is used for a subsequent missing value. For subjects who do not have a 
postdose value prior to their first missing value, the median of the postdose values at the relevant 
timepoint from subjects with observed data in the same randomized treatment group will be 
used. Predose values will not be carried forward to postdose timepoints. Analyses that adjust for 
the effect of opioid rescue medication will perform wWOCF following LOCF (ie, perform 
LOCF first, then apply wWOCF). Other continuous efficacy endpoints with missing data will be 
handled using LOCF. In general, subjects with missing categorical data at a timepoint will be 
assumed to have not met the endpoint at that timepoint. For the analysis of time to first opioid 
rescue medication, subjects who withdraw from the study prior to completing the 72-hour 
postoperative observation period or complete the 72-hour postoperative observation period 


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without having taken rescue medication will be censored at the time of study withdrawal or 
completion of the 72-hour postoperative observation period, whichever is earlier. 
10.4.3. 
Safety Analysis 
All safety analyses will be carried out on the Safety Population. All safety data will be listed and 
summarized by treatment group. Data from subjects treated with saline placebo will be pooled 
across cohorts into a single saline placebo treatment group, and data from subjects treated with 
bupivacaine HCl will be pooled across cohorts into a single bupivacaine HCl treatment group. 
Data from subjects treated with HTX-011 will neither be pooled across dose levels nor pooled 
across methods of administration within a dose level. 
AEs will be monitored during the study and the data analyzed with respect to incidence within 
each treatment group as well as severity and potential relationship of the AEs to study drug. AEs 
that occur between the time the subject signs the ICF and the start of study drug administration 
will be considered pretreatment AEs. AEs that start during or after study drug administration, or 
AEs with an onset prior to study drug administration that worsen after study drug administration 
will be considered TEAEs. All TEAEs will be coded and tabulated by System Organ Class and 
Preferred Term. Incidence of TEAEs, SAEs, and ORAEs will be summarized and presented in 
descending order of frequency according to the highest dose of HTX-011 studied. AEs leading to 
study withdrawal, if any, will be listed separately. 
Associated laboratory parameters such as hepatic profile, renal function, and hematology values 
will be grouped and presented together in summary tables. For each laboratory test, individual 
subject values outside the standard reference range will be flagged and listed. Shift tables will be 
produced showing the frequency of shifts from Baseline to the lowest and to the highest on-study 
value in and out of the normal range as well as by visit. Laboratory parameters will also be 
summarized by visit. 
The change from Baseline to each visit for each of the vital sign variables will be summarized. 
Abnormal vital sign values will be flagged and listed. 
Wound healing assessment, time to return of motor function, and loss of sensation in the breast, 
time to return of sensory function, and blinded assessor’s satisfaction with return of sensory and 
motor function will be summarized at each timepoint or overall, as appropriate. 
10.4.4. 
Pharmacokinetic Analysis 
Plasma bupivacaine and meloxicam concentrations will be determined using validated liquid 
chromatography tandem-mass spectrometry assays. Concentrations will be calculated by 
interpolation from a calibration curve. PK parameter estimates will be calculated using 
noncompartmental analysis. 
10.5. Interim Analysis 
Up to 4 interim analyses will be performed. An internal IRC will review unblinded 
summary-level data from each cohort to make study design decisions, as outlined in 
Section 3.1.2. Each interim analysis will be performed after at least 80% of the planned number 


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of subjects have all of their pain intensity and opioid use data through the 72-hour postoperative 
assessments entered into the electronic clinical database for that cohort. The internal IRC will be 
composed of 1 Sponsor representative from the Clinical Research, Biometrics, 
Pharmacovigilance, Regulatory, and Pharmaceutical and Translational Sciences functions. The 
IRC will operate under a written, detailed IRC Charter. 


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


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12. 
REGULATORY AND ETHICAL CONSIDERATIONS 
12.1. Regulatory Authority Approval 
The Sponsor will obtain approval to conduct the study from the appropriate regulatory agency in 
accordance with any applicable country-specific regulatory requirements before any site may 
initiate the study in that country. 
12.2. Ethical Conduct of the Study 
This study will be conducted in compliance with the protocol and all applicable regulatory 
requirements in accordance with ICH/GCP and in general conformity with the most recent 
version of the Declaration of Helsinki. 
12.3. Ethics Committee Approval 
The Investigator or the Sponsor is responsible for submitting the following documents to the ECs 
for review and, if applicable, approval: study protocol, ICF(s), IB, recruitment materials, 
information about study compensation to subjects, any information for presentation to potential 
subjects by ECs. 
The Investigator is responsible for providing the Sponsor with the written EC approval prior to 
commencing the study (ie, before shipment of study drug to the site). All amendments to the 
protocol require review and approval by the EC before the changes are implemented to the study. 
All changes to the ICF will be approved by the EC; a determination will be made regarding 
whether previously consented participants need to be re-consented. If any other information 
approved by the EC for presentation to potential subjects is amended during the study, the 
Investigator is also responsible for ensuring EC review and approval. 
Study sites must adhere to all requirements stipulated by their respective ECs. This may include, 
but not be limited to, notifying the EC of serious and unexpected AEs or other local safety 
reporting requirements, submitting a final status report, or providing a synopsis of the study 
report upon study completion. 
12.4. Informed Consent Process 
Note: All references to “subject” in this section refer to the study subject or 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 a subject’s 
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 her participation in the 
study, including the nature and intended purpose of the study, possible benefits, possible risks, 
disclosures of the subject’s personal and personal health information for purposes of conducting 
the study. The ICF will include details the requirements of the participant and the fact that she is 
free to withdraw at any time without giving a reason and without prejudice to 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 her 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 


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


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13. 
STUDY ADMINISTRATION 
13.1. Clinical Monitoring 
The Sponsor (or its designee) is responsible for ensuring the proper conduct of the study. This 
includes ensuring the subjects’ rights and well-being are protected, the conduct of the study is 
within compliance of an approved protocol and GCPs, and the integrity of the data are accurate, 
complete, and verifiable from source documentation. At regular intervals during the study, the 
Sponsor’s study monitors will contact the study site via site visits, telephone calls, emails, and 
letters in order to review study progress and the eCRF completion and to address any concerns or 
questions regarding the study conduct. During monitoring visits, the following aspects of study 
conduct will be carefully reviewed: subjects’ informed consent documents, subject recruitment 
procedures, subjects’ compliance with the study procedures, source-data verification, drug 
accountability (unblinded monitor only), use of concomitant therapy by subjects, AE and SAE 
documentation and reporting, and the quality of data. 
13.2. Source Documents and Record Retention 
Each study site will maintain study documents and records as specified in ICH E6, Section 8 
(Essential Documents for the Conduct of a Clinical Trial) and as required by regulatory and 
institutional requirements. These include, but are not limited to, the following: the study 
protocol, eCRF, delegation of authority log, pharmacy dispensing records, drug accountability 
logs, AE reports, subject source data (original or certified copies), correspondence with health 
authorities and ECs, ICFs, monitoring visit logs, laboratory certification or quality control 
procedures, and laboratory reference ranges. Access to study documents and records will be 
strictly controlled (see Section 12.5). 
Study records must be retained for at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or until at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product. However, these 
documents should be retained for a longer period if required by applicable regulatory 
requirements or if agreed to in the Clinical Trial Agreement. It is the responsibility of the Sponsor 
to inform the site as to when these documents no longer need to be retained. 
13.3. Management of Protocol Amendments and Deviations 
13.3.1. 
Protocol Modification 
The protocol cannot be modified except in a formal protocol amendment by the Sponsor. 
13.3.2. 
Protocol Violations and Deviations 
The Investigator will not implement any protocol deviation without agreement by the Sponsor 
except where necessary to eliminate an immediate hazard to study subjects. 


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Protocol deviations fall into 2 categories: those with approval prior to the event (protocol 
exemptions) and those occurring during the course of the study without prior approval (protocol 
violations). If an exemption from the protocol design (eg, a missed study visit or an unmet 
inclusion or exclusion criterion) is desired for an individual subject, other than those to eliminate 
immediate hazard, the Investigator must request an exemption from the Sponsor or designee. The 
Investigator will notify the EC of exemptions and deviations, as required by EC guidelines and 
site requirements. Exemptions (with rationale) will be documented at the site and in the Sponsor 
files. For any protocol violation, the site will document the protocol violation in the subject’s 
source documents. In the event of a significant violation, the site will notify the Sponsor or 
designee. Significant violations include, but are not limited to, those that involve fraud or 
misconduct, increase the health risk to the subject, or confound interpretation of primary study 
assessments. The Sponsor is responsible for notifying the regulatory authorities, if required. 
13.4. Financial Disclosure 
Investigators are required to inform the Sponsor of all disclosable financial interests or 
arrangements (including those of their spouse and dependent children), prior to study initiation at 
the site, at study completion, and 1 year after study completion in accordance with 21 CFR 
Part 54. In addition, the Investigator or subinvestigators must promptly notify the Sponsor if 
there are any reportable changes that occur during the above described period. 
Disclosable financial interests or arrangements, or the absence thereof will be recorded on the 
Financial Disclosure for Clinical Investigators Form. 
Any Investigator(s) added as investigational staff to the FDA 1572 form must complete the 
Financial Disclosure for Clinical Investigators Form at the start of his/her participation in the 
study. The Financial Disclosure for Clinical Investigators Form for any Investigator(s) leaving 
the study prior to completion will also be obtained. 
13.5. Stopping Criteria: Suspension or Termination of Study or Investigational Site 
13.5.1. 
Suspension of Study 
Enrollment will be suspended if the Sponsor discovers the occurrence of either of the following: 
 
Any death for which a clear alternative cause (unrelated to study drug) is not readily apparent 
 
Three (3) non-fatal SAEs that are considered by the Sponsor to be possibly related to study 
drug, and that are either unexpected or for which a clear alternative cause is not readily 
apparent. 
13.5.2. 
Termination of Study or Investigational Site 
If the Sponsor, Investigator, or officials from regulatory agencies discover conditions arising 
during the study that indicate that the study should be halted or that a study site should be closed, 
this action may be taken after appropriate consultation between the Sponsor and Investigator(s). 
Reasons for terminating the study early or closing a site include, but are not limited to, the 
following: 


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 
If there is a suspension of the study and further investigation shows that any death or 
3 non-fatal SAEs are determined by the Sponsor to be related to study drug and pose an 
unacceptable risk to the study subjects, the study will be terminated. 
 
Discovery of an unexpected, significant, or unacceptable risk to the subjects. 
 
Failure of the Investigator to comply with the protocol, GCP regulations and guidelines, or 
local requirements. 
 
Insufficient adherence to protocol requirements or an unacceptably high rate of missing, 
erroneous, or improperly collected data. 
 
Data are not sufficiently complete and/or evaluable. 
 
Inadequate recruitment of subjects by the Investigator. 
 
Sponsor decision. 
If the study is terminated early by the Sponsor, written notification documenting the reason for 
study termination will be provided to the Investigator and regulatory authorities. The Investigator 
will promptly inform the EC and provide the reason(s) for study termination. 
13.6. Publication and Information Disclosure Policy 
All information provided by the Sponsor and all data and information generated by the site as 
part of the study (other than a subject’s medical records) are the sole property of Heron 
Therapeutics, Inc. 
For clinical interventional studies in patients, Heron will post study results on websites such as 
https://clinicaltrials.gov/ and https://eudract.ema.europa.eu/ in accordance with FDA and 
European Union reporting rules. Regardless of study outcome, Heron commits to submit for 
publication results of our interventional clinical studies according to the prespecified plans for 
data analysis. Wherever possible, Heron also plans to submit for publication the results of any 
nonclinical or technology studies while protecting any proprietary information. 
Any publication or presentation of the results of this study may only be made in compliance with 
the provisions outlined in the executed Clinical Trial Agreement. Heron has developed a policy 
for the publication of scientific and clinical data that follows the recommendations of the 
International Committee of Medical Journal Editors (ICMJE), the CONSORT (Consolidated 
Standards of Reporting Trials) group, and Good Publication Practice (GPP). A copy of this 
policy will be made available to the Investigator upon request. 
When the study is completed or prematurely terminated, the Sponsor or designee will ensure a 
Clinical Study Report is written in compliance with ICH E3 (Structure and Content of Clinical 
Study Reports) and submitted to the regulatory authorities, as required by the applicable 
regulatory requirement(s). Where required by applicable regulatory requirements, an Investigator 
signatory will be identified for the approval of the Clinical Study Report. The Investigator will 
be provided reasonable access to statistical tables, listings, and figures, as well as relevant 
reports, and will have the opportunity to review the complete study results. 


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14. 
REFERENCE LIST 
American Society of Anesthesiologists. (2015). "Standards for Basic Anesthetic Monitoring: 
Section 10.28.15." from http://www.asahq.org/quality-and-practice-management/standards-and-
guidelines. 
Bailey, I. S., S. E. Karran, K. Toyn, P. Brough, C. Ranaboldo and S. J. Karran (1992). 
"Community surveillance of complications after hernia surgery." BMJ 304(6825): 469-471. 
Chung, F. (1995). "Discharge criteria--a new trend." Can J Anaesth 42(11): 1056-1058. 
Fentanyl Citrate USPI (2012). Fentanyl Citrate injection. Lake Forest, IL 60045: Akorn, Inc. 
Gan, T. J., A. S. Habib, T. E. Miller, W. White and J. L. Apfelbaum (2014). "Incidence, patient 
satisfaction, and perceptions of post-surgical pain: results from a US national survey." Curr Med 
Res Opin 30(1): 149-160. 
Kehlet, H. and L. O. Andersen (2011). "Local infiltration analgesia in joint replacement: the 
evidence and recommendations for clinical practice." Acta Anaesthesiol Scand 55(7): 778-784. 
Lehmann, N., G. P. Joshi, D. Dirkmann, M. Weiss, P. Gulur, J. Peters and M. Eikermann (2010). 
"Development and longitudinal validation of the overall benefit of analgesia score: a simple 
multi-dimensional quality assessment instrument." Br J Anaesth 105(4): 511-518. 
MARCAIN SmPC (2016). MARCAIN Polyamp Steripack 0.25%. Dublin, IE: Aspen. 
MARCAINE USPI (2011). MARCAINE (Bupivacaine Hydrochloride Injection). Lake Forest, IL 
60045: Hospira, Inc. 
MOBIC SmPC (2015). MOBIC 7.5 mg tablets. Dublin, IE: Boehringer Ingelheim Limited. 
MOBIC USPI (2016). MOBIC (meloxicam) tablets, for oral use. Ridgefield, CT 06877: 
Boehringer Ingelheim Pharmaceuticals, Inc. 
Moote, C. (1992). "Efficacy of nonsteroidal anti-inflammatory drugs in the management of 
postoperative pain." Drugs 44 Suppl 5: 14-29; discussion 29-30. 
Ortiz, M. I., G. Castañeda-Hernández, J. A. Izquierdo-Vega and H. A. Ponce-Monter (2011). 
"Peripheral synergistic interaction between lidocaine and lumiracoxib on the 1% formalin test in 
rats." The Open Pain Journal 4: 8-14. 
Rothman, M., S. Vallow, C. V. Damaraju and D. J. Hewitt (2009). "Using the patient global 
assessment of the method of pain control to assess new analgesic modalities in clinical trials." 
Current Medical Research and Opinion 25(6): 1433-1443. 
Smoot, J. D., S. D. Bergese, E. Onel, H. T. Williams and W. Hedden (2012). "The efficacy and 
safety of DepoFoam bupivacaine in patients undergoing bilateral, cosmetic, submuscular 


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augmentation mammaplasty: a randomized, double-blind, active-control study." Aesthet Surg J 
32(1): 69-76. 
Vasques, F., A. U. Behr, G. Weinberg, C. Ori and G. Di Gregorio (2015). "A Review of Local 
Anesthetic Systemic Toxicity Cases Since Publication of the American Society of Regional 
Anesthesia Recommendations: To Whom It May Concern." Regional Anesthesia and Pain 
Medicine 40(6): 698-705. 
 








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Appendix D. 
Patient Global Assessment (PGA) of Pain Control 
 
Sites will ask each subject the following question: 
“Overall, please rate how well your pain has been controlled during the last 24 hours?” 
 
The response must be one of the following:  
 Poor (0) 
 Fair (1) 
 Good (2) 
 Excellent (3) 
 
 
Reference: Rothman, M., S. Vallow, C. V. Damaraju and D. J. Hewitt (2009). “Using the patient global assessment 
of the method of pain control to assess new analgesic modalities in clinical trials.” Current Medical Research and 
Opinion 25(6): 1433-1443. 
 
 


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


Signature Page for VV-CLIN-000729 v1.0
Signature Page for VV-CLIN-000729 v1.0
Approval
16-Nov-2017 01:10:19 GMT+0000

SAP_001.pdf: 
Document Type:  
Statistical Analysis Plan 
Official Title:  
A Phase 2B, Randomized, Controlled Study of HTX-011 Administered 
Via Pectoral Nerve Block in Subjects Undergoing Upper Extremity 
Surgery for Augmentation Mammoplasty 
NCT Number:  
NCT03011333 
Document Date:  
04-Jan-2018 
 


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. 
HTX-011-211 
 
A PHASE 2B, RANDOMIZED, CONTROLLED STUDY OF HTX-011 
ADMINISTERED VIA PECTORAL NERVE BLOCK IN SUBJECTS UNDERGOING 
UPPER EXTREMITY SURGERY FOR AUGMENTATION MAMMOPLASTY 
 
04 January 2018 
 
Statistical Analysis Plan 
 
Version 3.0 
 
Prepared by: 
 
Heron Therapeutics, Inc. 
4242 Campus Point Court, Suite 200 
San Diego, CA 92121  
USA 
 
 
Upon review of this document, the undersigned approves the statistical analysis plan. The 
analysis methods are acceptable, and the table, listing, and figure shell production can begin. 
 
 
 
 
 
 
Approved by: ____________________________  
 
Date:  ____________ 
 
 
 
 
 
Vice President, Biometrics 
 
 
                        Heron Therapeutics, Inc. 
 
 
 
 
 
Approved by: ____________________________  
 
Date:  ____________ 
 
 
 
 
 
 
 
                        Vice President, Clinical Research  
                        Heron Therapeutics, Inc. 
 
 
 


Heron Therapeutics, Inc. 
Statistical Analysis Plan, V 3.0
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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 .................................................................................................................10 
4.3. 
Endpoints .....................................................................................................................11 
4.3.1. 
Efficacy Endpoints .................................................................................................11 
4.3.2. 
Safety Endpoints ....................................................................................................11 
5. 
General Statistical Considerations .................................................................................12 
5.1. 
Sample Size ..................................................................................................................13 
5.2. 
Randomization, Stratification, and Blinding ...............................................................13 
5.3. 
Statistical Hypotheses and Multiple Endpoint Handling .............................................14 
5.4. 
Analysis Populations ....................................................................................................14 
5.4.1. 
Intent-to-Treat (ITT) Population ............................................................................14 
5.4.2. 
Modified ITT (mITT) 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 ...................................15 
5.5.3. 
Study Day Calculation for Reporting Purposes .....................................................15 
5.5.4. 
Visit Windows .......................................................................................................15 
5.5.5. 
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 
8.2. 
Surgery Procedure ........................................................................................................18 


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8.3. 
Study Drug ...................................................................................................................18 
9. 
Efficacy Analysis ...........................................................................................................18 
9.1. 
Primary Efficacy Endpoint ..........................................................................................19 
9.1.1. 
Primary Analysis ....................................................................................................19 
9.1.2. 
Sensitivity Analyses ...............................................................................................20 
9.2. 
Secondary Efficacy Endpoints .....................................................................................20 
9.2.1. 
Analyses .................................................................................................................20 
9.3. 
Other Efficacy Analyses ..............................................................................................25 
10. 
Safety Analysis ...............................................................................................................26 
10.1. Adverse Events ............................................................................................................27 
10.1.1. 
Incidence of Treatment Emergent Adverse Events ...............................................27 
10.1.2. 
Relationship of Adverse Events to Investigational drug ........................................28 
10.1.3. 
Severity of Adverse Event .....................................................................................28 
10.1.4. 
Serious Adverse Events .........................................................................................28 
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 .....................................................................29 
10.1.8. 
Local Anesthetic System Toxicity (LAST) related Adverse Events .....................30 
10.1.9. 
Death ......................................................................................................................30 
10.2. Clinical Laboratory Evaluations ..................................................................................31 
10.2.1. 
Hematology ............................................................................................................31 
10.2.2. 
Blood Chemistry ....................................................................................................31 
10.2.3. 
Urine Pregnancy Test and Urine Drug Screen .......................................................32 
10.3. Vital Sign Measurements .............................................................................................32 
10.4. Electrocardiogram ........................................................................................................33 
10.5. Physical Examination...................................................................................................33 
10.6. Wound Healing Assessment ........................................................................................33 
10.7. Motor Function Assessment ........................................................................................33 
10.8. Sensory Function Test..................................................................................................33 
10.9. Blinded Assessor’s Satisfaction with Return of Sensory and Motor Function ............34 
11. 
Interim Analysis .............................................................................................................34 
11.1. Interim Analysis ...........................................................................................................34 
11.2. Data Safety Monitoring Board .....................................................................................34 


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12. 
References ......................................................................................................................34 
Appendix 1. 
Imputation of Partial and Missing Dates ...................................................36 
Appendix 2. 
Document Revision History .......................................................................37 
 
 
 


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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 
IRC 
Interim Revivew Committee 
IRS 
Integrated Rank of Silverman 
ITT 
Intent-to-Treat  
IWRS 
Interactive web response system 
IV 
Intravenous(ly) 
K-M 
Kaplan-Meier 
LDH 
Lactic dehydrogenase 
LLN 
Lower limit of normal 
LOCF 
Last observation carried forward 
LSMD 
Least-squares mean difference 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified Intent-to-Treat 
MME 
Morphine milligram equivalency 
MPADSS 
Modified Postanaesthetic Discharge Scoring System 
NRI 
Non-responder imputation 
NRS 
Numeric Rating Scale 
NRS-A 
Numeric Rating Scale with activity 
NRS-R 
Numeric Rating Scale at rest 
NSAID 
Nonsteroidal anti-inflammatory drug 
OBAS 
Overall benefit of analgesia score 
ORAE 
Opioid-related adverse event 
PACU 
Post-Anesthesia Care Unit 
PcNB 
Pectoral nerve block 


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PGA 
Patient’s Global Assessment 
PK 
Pharmacokinetic(s) 
PO 
Administered orally 
PR 
Per rectum 
PRN 
As needed 
PT 
Preferred term 
q4h 
Every 4 hours 
RBC 
Red blood cell 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic blood pressure 
SD 
Standard deviation 
SDA 
Study drug administration 
SDTM 
Study Data Tabulation Model 
SDTMIG 
Study Data Tabulation Model Implementation Guide 
SE 
Standard error 
SEM 
Standard error of the mean 
SI 
Standard international 
SOC 
System Organ Class 
SPI 
Summed pain intensity 
TEAE 
Treatment-emergent adverse event 
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 


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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 the pharmacokinetic (PK) 
assessments and the Holter assessments in the study.  Planned PK analyses will be presented 
in a separate PK analysis plan and planned Holter analyses will be presented in a separate 
Holter analysis plan. 
This SAP was prepared 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: 
 To compare the efficacy and duration of analgesia following bilateral ultrasound-
guided lateral and medial pectoral nerve block with HTX-011 to bupivacaine 
hydrochloride (HCl) without epinephrine and saline placebo in subjects undergoing 
upper extremity surgery. 
The secondary objectives are: 
 To evaluate the efficacy and duration of analgesia for HTX-011 administered using 
different techniques in this study population. 
 To evaluate additional efficacy parameters in this study population. 
 To characterize the bupivacaine and meloxicam pharmacokinetic (PK) profiles of 
HTX-011 in this study population. 
 To determine the optimal administration technique of HTX-011 in this surgical 
model. 
 To further assess the safety and tolerability of HTX-011 in this study population. 
4. 
INVESTIGATIONAL PLAN 
4.1. 
Overall Study Design and Plan 
HTX-011-211 is a Phase 2B, randomized, double-blind, active- and saline placebo-
controlled, multicenter study in subjects undergoing bilateral submuscular augmentation 
mammoplasty under general anesthesia.  This study will evaluate the efficacy and safety 
profile of HTX-011 on clinical outcomes (eg, level of pain, duration of analgesia, avoidance 
of opioids, etc.) in subjects treated with a single preoperative dose of study drug administered 
by bilateral ultrasound-guided lateral and medial pectoral nerve block (PcNB) and/or 
instillation within 4 hours prior to the surgical procedure.   
A total of up to approximately 240 subjects who meet eligibility criteria will each be 
randomized into one of up to 4 sequential cohorts in the study.  Interim analyses will be 
performed on the data collected in each cohort after at least 80% of the planned subjects in 
that cohort have completed their 72-hour postoperative assessments and their pain intensity 
and opioid use data have been entered into the eCRF.  An internal Interim Review 
Committee (IRC), composed of 1 Sponsor representative from each of the Clinical Research, 
Biometrics, Pharmacovigilance, Regulatory, and Pharmaceutical and Translational Sciences 
functions will review unblinded summary-level data in order to make a determination to 
proceed with the next cohort and to select the dose of HTX-011 that will be studied in the 
next cohort.  Detailed responsibilities of the IRC will be presented in an IRC charter. 


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Cohort 1 
Approximately 24 subjects will be randomized to 1 of the following 3 treatment groups in a 
2:1:1 ratio: 
 HTX-011 60 mg (2.1 mL) via bilateral ultrasound-guided lateral and medial PcNB 
(12 subjects) 
 Bupivacaine HCl without epinephrine 0.25% (50 mg, 20 mL) via bilateral ultrasound-
guided lateral and medial PcNB (6 subjects) 
 Saline placebo (2.1 mL) via bilateral ultrasound-guided lateral and medial PcNB (6 
subjects) 
 
Cohort 2  
Cohort 2 was planned as an optional cohort. Following a review of the results from Cohort 1, 
the IRC recommended initiating enrollment in Cohort 2 and randomizing approximately 48 
subjects to 1 of the following 3 treatment groups in a 2:1:1 ratio: 
 HTX-011 (a single dose recommended by IRC of 120 mg/3.6 mg 
[bupivacaine/meloxicam doses], 4.1 mL) via bilateral ultrasound-guided lateral and 
medial PcNB (24 subjects) 
 Bupivacaine HCl without epinephrine 0.25% (50 mg, 20 mL) via bilateral ultrasound-
guided lateral and medial PcNB (12 subjects) 
 Saline placebo (volume matching HTX-011 in Cohort 2) via bilateral ultrasound-
guided lateral and medial PcNB (12 subjects) 
 
Cohort 3  
Cohort 3 was planned as an optional cohort. Following a review of the results from Cohort 2, 
the IRC recommended initiating enrollment in Cohort 3 and randomizing approximately 
48 subjects to 1 of the following 3 treatment groups in a 2:1:1 ratio: 
 HTX-011 (a single dose recommended by IRC of 240 mg/ 7.2 mg 
[bupivacaine/meloxicam doses], 8.2 mL) via bilateral ultrasound-guided lateral and 
medial PcNB (24 subjects) 
 Bupivacaine HCl without epinephrine 0.25% (50 mg, 20 mL) via bilateral ultrasound-
guided lateral and medial PcNB (12 subjects) 
 Saline placebo (volume matching HTX-011 in Cohort 3) via bilateral ultrasound-
guided lateral and medial PcNB (12 subjects) 
 
Cohort 4  
Cohort 4 was planned as an optional cohort. Following a review of the results from Cohort 3, 
the IRC recommended initiating enrollment in Cohort 4 and randomizing approximately 
120 subjects to 1 of the following 4 treatment groups in a 4:4:1:1 ratio: 


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 HTX-011 (a single dose recommended by IRC of 400 mg/12 mg 
[bupivacaine/meloxicam doses], 13.7 mL) via bilateral ultrasound-guided lateral and 
medial pectoral nerve block (48 subjects) 
 HTX-011 (a single dose recommended by IRC of 400 mg/12 mg 
[bupivacaine/meloxicam doses], 13.7 mL) via instillation into the intended space for the 
implant, with 200 mg/6 mg, 6.8 mL per side, and saline placebo (volume matching HTX-
011 in Cohort 4) via bilateral ultrasound-guided lateral and medial pectoral nerve block 
for masking (48 subjects) 
 Bupivacaine HCl without epinephrine 0.25% (50 mg, 20 mL) via bilateral ultrasound-
guided lateral and medial pectoral nerve block (12 subjects) 
 Saline placebo (volume matching HTX-011 in Cohort 4) via bilateral ultrasound-guided 
lateral and medial pectoral nerve block (12 subjects) 
It is anticipated that this trial will be performed at approximately 5 study sites in the United 
States (US). 
4.2. 
Assessments 
Efficacy assessments will include the following: 
 Pain intensity scores using the Numeric Rating Scale (NRS) with activity (NRS-A) 
 Pain intensity scores using the NRS at rest (NRS-R) 
 Use of opioid rescue medication 
 Patient’s Global Assessment (PGA) of pain control 
 Assessments of discharge readiness per the Modified Postanaesthetic Discharge 
Scoring System (MPADSS) 
 Subject’s satisfaction with postoperative pain control 
 Overall benefit of analgesia score (OBAS) 
 
Safety assessments will include the following: 
 Adverse event (AE) recording 
 Clinical safety laboratory tests (hematology and serum chemistry) 
 Physical examinations 
 Wound healing assessment 
 Vital signs collections  
 ECG  
 Continuous Holter monitoring  
 Motor function assessment  
 Sensory function assessment (cold test) 
 Blinded assessor’s satisfaction with return of sensory and motor function 
See the latest version of the study protocol for the timing of procedures and assessments. 


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4.3. 
Endpoints 
4.3.1. 
Efficacy Endpoints 
The primary efficacy endpoint is: 
 Mean area under the curve (AUC) of the NRS-A pain intensity scores through 
24 hours (AUC0-24). 
The secondary efficacy endpoints are:  
 Mean total postoperative opioid consumption (in morphine equivalents) through 24, 
48, and 72 hours. 
 Median time in hours to first opioid rescue administration through 72 hours. 
 Mean AUC of the NRS-A pain intensity scores at the following intervals: 0-6, 0-12, 
12-24, 24-48, 0-48, 48-72, and 0-72 hours. 
 Mean AUC of the NRS-R pain intensity scores at the following intervals: 0-6, 0-12, 
12-24, 0-24, 24-48, 0-48, 48-72, and 0-72 hours. 
 Mean NRS-R pain intensity scores at each assessed timepoint. 
 Mean NRS-A pain intensity scores at each assessed timepoint. 
 Integrated Rank Analysis of Silverman using the NRS-A pain intensity AUC scores 
and total opioid consumption through 24, 48, and 72 hours. 
 Proportion of subjects achieving a score of “good” or better (>1) pain control based 
on PGA at 24, 48, and 72 hours, and on Day 28. 
 Proportion of subjects who are pain free at rest (defined as an NRS-R pain intensity 
score of 0 or 1) at each assessed timepoint. 
 Proportion of subjects who are pain free with activity (defined as an NRS-A pain 
intensity score of 0 or 1) at each assessed timepoint. 
 Proportion of subjects who are opioid free through 24, 48, and 72 hours. 
 Proportion of subjects who are opioid-free from 72 hours through Day 10 and Day 
28. 
 Proportion of subjects who first achieve a MPADSS score ≥ 9 at 2, 4, 6, 8, 12, 24, 36, 
48, 60, and 72 hours. 
 Mean subject’s satisfaction with postoperative pain control at 24, 48, and 72 hours, 
and on Day 10. 
 Mean OBAS at 24, 48, and 72 hours and on Day 28. 
4.3.2. 
Safety Endpoints 
The safety endpoints are: 
 
 Incidence of treatment-emergent AEs (TEAEs), serious TEAEs (SAEs), and opioid-
related AEs (ORAEs) through Day 28. 
 Change from Baseline in clinical laboratory results. 
 Change from Baseline in vital signs at each assessed timepoint. 
 Change from Baseline in Holter data. 
 Wound healing assessment at 72 hours, and on Day 10 and Day 28. 


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 Time to return of motor function. 
 Loss of sensation in the breast at 15, 30, and 60 minutes after the start of ultrasound-
guided study drug administration. 
 Time to return of sensory function. 
 Blinded assessor’s satisfaction with return of sensory and motor function at 24, 48, 
and 72 hours and on Day 10. 
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 of the mean (SEM).  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 cohort, 
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 subjects in that treatment group within the population of interest, unless otherwise 
stated.  Non-zero percentages will be rounded to one decimal place, except 100% will be 
displayed without any decimal places.  Additional rounding rules are as follows: 
 If the original value has 0 decimal places: mean, median, and CI will have one 
decimal place and SD and SEM will have 2 decimal places. 
 If the original value has 1 decimal place: mean, median, and CI will have 2 decimal 
places and SD and SEM will have 3 decimal places. 
 If the original value has 2 or more decimal places: mean, median, CI, SD, and SEM 
will all have 3 decimal places. 
Minimum and maximum will always have the same decimal places as the original measure, 
up to a maximum of 3 decimal places.  The above rounding rules will not be applied to 
original measures displayed in listings. 
Values that are collected with “<” or “>” signs will be analyzed as the numerical value 
without the sign in tables and figures.  In listings, these data will be reported as collected 
with the sign. 
All efficacy and safety data will be collected electronically.  Datasets will be created using 
the Study Data Tabulation Model (SDTM) v. 1.3 or higher, conforming to the SDTM 


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Implementation Guide (SDTMIG) v. 3.1.3 or higher.  Datasets, tables, listings, and figures 
will be programmed using SAS® v. 9.2 or higher.  All efficacy and safety data will be listed 
via the SDTM datasets and selected efficacy and safety data will be listed via programmed 
listings. 
5.1. 
Sample Size 
The sample size of up to approximately 240 subjects in this study was selected empirically 
without formal statistical assumptions. 
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.  Once surgery is completed and the subject is transferred to the Postanesthesia Care 
Unit (PACU), the Investigator and all site staff involved in the safety and efficacy 
assessments, as well as the clinical staff at the CRO involved with study conduct and data 
collection will be blinded to treatment assignments until after database lock.  The Sponsor’s 
study team will also be blinded to the treatment assignments with the exception of the 
clinical trial materials (CTM) staff, the clinical observers, the bioanalytical staff, and an 
unblinded statistician who will perform the randomization and interim analysis data reviews, 
but will otherwise be uninvolved in the conduct of the study. 
An internal IRC consisting of 1 Sponsor representative from each of the Clinical Research, 
Biometrics, Pharmacovigilance, Regulatory, and Pharmaceutical and Translational Sciences 
functions will be unblinded to summary-level data during the interim analyses conducted 
between cohorts.  The IRC will operate under a written, detailed IRC charter. 
The randomization will be based on a blocked algorithm and will be done centrally via an 
interactive web response system (IWRS).   
A subject’s treatment group assignment will not be broken until the end of the study unless 
emergency medical treatment of that subject depends upon knowledge of the assigned 
treatment.   
The Sponsor retains the right to break a subject’s treatment code for SAEs that are 
unexpected and are suspected to be causally related to an investigational product and that 
potentially require expedited reporting to regulatory authorities. 


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5.3. 
Statistical Hypotheses and Multiple Endpoint Handling 
For the purposes of statistical hypothesis testing, data from subjects randomized to receive 
saline placebo will be pooled across cohorts into a single saline placebo treatment group, and 
data from subjects randomized to receive bupivacaine HCl will be pooled across cohorts into 
a single bupivacaine HCl treatment group.  Data from subjects randomized to receive HTX-011 
will neither be pooled across dose levels nor be pooled across methods of administration within a 
dose level. The primary comparison on the primary endpoint for each HTX-011 group will be 
against the pooled saline placebo group under the following hypotheses: 
H0: µHTX-011 = µSaline Placebo 
Ha: µHTX-011 ≠ µSaline Placebo 
Comparisons of HTX-011 against the pooled bupivacaine HCl will be considered secondary 
comparisons.  Different doses of HTX-011 will not be pooled for testing purposes. 
As this is a Phase 2b study without a prospective statistical power calculation, there will be 
no adjustments made to any hypothesis test due to multiple comparisons or multiple 
endpoints. 
5.4. 
Analysis Populations 
5.4.1. 
Intent-to-Treat (ITT) Population 
The ITT Population will consist of all subjects who are randomized and do not screen fail on 
Day 0.  This analysis population will be used in subject disposition reporting only. The 
randomized treatment assignment will be used for analysis in this population. 
5.4.2. 
Modified ITT (mITT) Population 
The mITT Population will consist of all subjects in the ITT Population who have at least 1 
post-treatment NRS-A pain intensity score.  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. 
5.4.3. 
Safety Population 
The Safety Population will consist of all subjects who receive any amount of study drug.  
This population will be used for all summaries of safety data.  The actual treatment 
assignment will be used for analysis. 
5.5. 
Other Important Considerations 
5.5.1. 
Definition of Baseline 
Baseline data are defined as the last data collected, whether scheduled or unscheduled, prior 
to the start of study drug administration.   


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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 end of surgery will be considered as Time 0 for all efficacy and safety assessments, 
except where otherwise specified. The following convention will be used to calculate study 
day for reporting purposes: 
 The study day of study drug administration is Study Day 1. 
 For measurements that are on or after the date of study drug administration:  
o Study Day = date of measurement – date of study drug administration + 1 
 For measurements that are prior to the date of study drug administration: 
o Study Day = date of measurement – date of study drug administration 
For all subjects, the day of study drug administration should be the same day as the day of 
the surgical procedure. 
5.5.4. 
Visit Windows 
Due to the short duration of the study and the primary efficacy analyses occurring during the 
3-day postoperative period of subject hospitalization, no programmatically calculated visit 
windows are defined for this study. 
5.5.5. 
Handling of Missing and Partial Data 
The amount of missing data during the 3-day postoperative primary efficacy analysis period 
is expected to be very low due to the protocol-required 3-day hospitalization of all subjects 
following surgery.  Any data that is missing 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 nonmissing values within the same 
treatment group at the relevant timepoint will be used.  Predose values will not be carried 
forward to postdose timepoints.   
For binary endpoints (those involving proportions of subjects) not involving the NRS-R or 
NRS-A, any subject with missing data at a timepoint will be considered as not meeting the 


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endpoint at that timepoint.  This is known as nonresponder imputation (NRI).  Binary 
endpoints involving the NRS-R or NRS-A (such as proportion of subjects who are pain-free) 
through 72 hours will be constructed following windowed worst observation carried forward 
(wWOCF) (see Section 9.1.1 for details). Binary endpoints involving NRS-R or NRS-A on 
Day 10 or Day 28 (such as proportion of subjects with NRS score < 4 on Day 10) will be 
constructed using NRI. 
A table displaying the number and percentage of subjects with missing NRS-A pain intensity 
scores at each nominal timepoint will be produced. 
For median time in hours to first opioid rescue administration through 72 hours, 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 mITT Population, subjects in the Safety Population, subjects 
completing the 72-hour postoperative observation period, subjects completing study 
(Day 28), subjects withdrawn from study with the primary reason for withdrawal.  Only 1 
reason for study withdrawal will be recorded for each subject.   
7. 
DEMOGRAPHICS, CHARACTERISTICS, AND MEDICAL 
HISTORY 
7.1. 
Demographics and Baseline Characteristics 
The demographics and baseline characteristics will be presented in tables using descriptive 
statistics.  The demographics consist of age, age category, sex, race, and ethnicity.  The 
baseline characteristics consist of weight, height, body mass index (BMI), nicotine status, 
and alcohol use.  A subject’s age in years is calculated using the integer part of the difference 
in number of days between the date that informed consent is signed and date of birth divided 
by 365.25, or is recorded directly on the eCRF.  The number and percentage of subjects in 


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the following age categories will be presented: 18-44, 45-54, 55-64, 65-74, 75-84, and ≥ 85 
years old. 
Demographics and baseline characteristics will be presented for the mITT Population and 
demographics only will be presented for all subjects enrolled who fail screening. 
7.2. 
Medical History 
Medical history will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA®) version 19.1.  Medical history will be summarized for the Safety Population and 
will display the number and percentage of subjects with a past and/or concomitant disease or 
past surgeries by body system.   
7.3. 
Protocol Deviations 
Deviations and violations from the protocol will be recorded.  Protocol deviations will be 
classified into, but not necessarily limited to, the following categories: 
 ICF procedures 
 Eligibility criteria 
 Prohibited concomitant medication/therapy 
 Laboratory assessment  
 Study procedure (eg, efficacy ratings, ECG, PE, etc) 
 Safety reporting 
 Randomization/blinding 
 Study drug dosing/administration 
 Visit schedule/windows 
Classification of deviations as important protocol violations will be decided on a case-by-
case basis without knowledge of the treatment assigned and before database lock.  Protocol 
deviations will be presented in a summary table by protocol deviation category and 
treatment.  Important protocol deviations will also be listed separately from all protocol 
deviations. 
8. 
TREATMENTS AND MEDICATIONS 
8.1. 
Prior and Concomitant Medications 
Prior medications are defined as medications with a stop date occurring before Study Day 1.  
Concomitant medications are defined as medications that are ongoing on Study Day 1 or with 
a start date occurring on or after Study Day 1.  Medications with start and stop dates which 
bracket Study Day 1, or for which missing start and/or stop dates make it impossible to 
determine the prior or concomitant status, will be summarized as concomitant medications. 


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All medications will be coded with the World Health Organization Drug classification 
dictionary (WHODrug). 
Prior and concomitant medications will be summarized separately by drug class and 
preferred term (PT).  At each level of summarization, a subject is counted once if that subject 
reports 1 or more medications at that level.  Drug class will correspond to the Anatomical 
Therapeutic Classification (ATC) Level 2 term. 
All prior medications and concomitant medications will be summarized for the Safety 
Population. 
8.2. 
Surgery Procedure 
The type of implant (silicone or saline), implant size per side, and the duration of surgery will 
be summarized.  Duration will be calculated as completion time minus start time, reported in 
minutes. 
8.3. 
Study Drug 
For all subjects, treatment will consist of a single preoperative dose of study drug or a 
combination of a preoperative dose of study drug plus an intraoperative dose of study drug.  
As such, extent of exposure will be reported in the CSR as the number of subjects by 
treatment received in the Safety Population.  A summary of treatment compliance will not be 
produced, as by definition it will be 100% for the Safety Population.  
9. 
EFFICACY ANALYSIS 
All efficacy analyses will be performed on the mITT Population.  Timepoints for efficacy 
analysis are relative to the end time of surgery.     Table 1 displays the planned cohorts and 
treatment groups being studied, with an assigned letter designation to each treatment group to 
facilitate statistical hypothesis testing. 
 
 
 
 
 
 


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    Table 1.  Planned Cohorts and Treatment Group Designations 
Cohort 
Group 
Treatment 
Administration 
Method 
Sample Size 
1 
A 
HTX-011 60 mg/1.8 mg (2.1 mL) 
PcNB 
12 
 
B 
Bupivacaine HCl 50 mg (20 mL) 
PcNB 
6 
 
C 
Saline placebo (2.1 mL) 
PcNB 
6 
 
 
 
 
 
2 
D 
HTX-011 120 mg/3.6 mg(4.1 mL) 
PcNB 
24 
 
E 
Bupivacaine HCl 50 mg (20 mL) 
PcNB 
12 
 
F 
Saline placebo (4.1 mL) 
PcNB 
12 
 
 
 
 
 
3 
G 
HTX-011 240 mg/7.2 mg (8.2 mL) 
PcNB 
24 
 
H 
Bupivacaine HCl 50 mg (20 mL) 
PcNB 
12 
 
J 
Saline placebo (8.2 mL) 
PcNB 
12 
 
 
 
 
 
4 
K 
HTX-011 400 mg/12 mg (13.7 mL)  
PcNB 
48 
 
L 
HTX-011 400 mg/12 mg (13.7 mL) 
instillation 
48 
 
M 
Bupivacaine HCl 50 mg (20 mL) 
PcNB 
12 
 
N 
Saline placebo (13.7 mL) 
PcNB 
12 
      Abbreviations: PcNB, pectoral nerve block. 
 
As detailed in Section 5.3, for the purposes of statistical hypothesis testing, data from 
subjects randomized to receive saline placebo (Groups C+F+J+N) will be pooled across 
cohorts into a single saline placebo treatment group, and data from subjects randomized to 
receive bupivacaine HCl (Groups B+E+H+M) will be pooled across cohorts into a single 
bupivacaine HCl treatment group.  Data from subjects randomized to receive HTX-011 will 
neither be pooled across dose levels nor be pooled across methods of administration within a 
dose level. Each of the HTX-011 treatment groups will be tested against the pooled saline 
placebo treatment group and against the pooled bupivacaine HCl treatment group.   
There will be no hypothesis testing performed against any of the individual saline placebo or 
bupivacaine HCl groups. 
9.1. 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the mean AUC of the NRS-A pain intensity scores through 
24 hours (AUC0-24). 
9.1.1. 
Primary Analysis 
During the first 24 hours following surgery, the NRS-A is measured at hours 1, 2, 4, 6, 8, 12, 
and 24.  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 AUC0-24 is thus calculated as follows: 


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𝐴𝑈𝐶0−24 = ∫𝑓(𝑡)𝑑𝑡≈∑(𝑡𝑖−𝑡𝑖−1) 𝑃𝑖−1 + 𝑃𝑖
2
24
𝑖=2
24
1
 
 
The primary endpoint of mean AUC0-24 of the NRS-A pain intensity scores will be analyzed 
using an analysis of variance (ANOVA) model with randomized treatment as the main effect.  
Each HTX-011 group as well as the pooled groups specified in Section 9 will be tested 
against each of the pooled control groups.  Results will be expressed as mean AUCs, SDs, 
and least-squares mean differences (LSMD) and standard errors (SE) with associated 95% 
CIs, and p-values.   
To adjust for the duration effect of opioid rescue medication, the windowed worst 
observation carried forward (wWOCF) method will be implemented as the primary analysis 
method for endpoints involving NRS pain intensity scores.  In this method, pain intensity 
scores observed during the analgesic window (duration of effect) of any opioid rescue 
medication will be replaced with the worst (highest) postdose 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 (ie, perform 
LOCF first, then apply wWOCF).  See      Table 2 in Section 9.2 for predefined analgesic 
windows for each opioid medication. 
The mean AUC0-24 of the NRS-A pain intensity scores using wWOCF will also be plotted 
with associated SEM in a bar chart. 
9.1.2. 
Sensitivity Analyses 
One sensitivity analysis will be performed on the primary endpoint: reproducing the primary 
analysis but without adjusting the NRS-A pain intensity scores for the use of opioid rescue 
medications (ie, without applying wWOCF). 
9.2. 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints are listed in Section 4.3.1. 
9.2.1. 
Analyses 
Secondary Endpoint: Mean total postoperative opioid consumption (in morphine 
equivalents) through 24, 48, and 72 hours 
Determination of morphine equivalents 
Use of opioid rescue medication will be summarized by preferred term.  All opiate dosages 
and formulations will have the morphine milligram equivalency (MME) calculated (Opioid 


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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) and/or intravenous 
morphine (no more than 10 mg within a 2-hour period as needed). No other analgesic agents, 
including nonsteroidal anti-inflammatory drugs (NSAIDs) and acetaminophen, are permitted 
during the 72-hour postoperative observation period. 
     Table 2 displays the MME along with the analgesic windows of selected opioid rescue 
medications for wWOCF purposes.  Protocol-allowed postoperative rescue medications are 
checked.  Medications that are not protocol-allowed will be logged as protocol violations, but 
will still be subject to MME conversion for analysis. 
     Table 2.   Analgesic Windows and 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 
Intramuscular (IM) 
4 
1.00 
 
 
MORPHINE 
Per rectum (PR) 
4 
1.00 
 
 
OXYCODONE 
IV 
4 
1.00 
 
 
OXYCODONE 
IM 
4 
1.00 
 
 
OXYCODONE 
PO 
6 
0.50 
 
 
SUFENTANIL 
PO 
2 
500.00 
 
 
TRAMADOL 
IV 
6 
0.06 
 
 
TRAMADOL 
PO 
6 
0.04 
 
 
   
Analysis method 
Opioid rescue medication use is collected from hours 0-72.  Average daily use and total use 
will be tabulated using descriptive statistics for each opiate and overall during the following 
periods: hours 0-24, hours 0-48, and hours 0-72.  Subjects who did not use a specific opioid 
rescue medication during a period of interest will have their dose set to 0 for that period. 
The Shapiro-Wilk test will be used to examine the assumption of normality.  If this test is 
statistically significant (ie, p<0.05) then the assumption of normality is violated and the total 
postoperative opioid consumption during each period of interest will be analyzed using 
Wilcoxon rank sum test. Results will be expressed as median (range) and p-values. However, 
if assumption of normality holds (ie, Shapiro-Wilk p-value ≥ 0.05), then the total 
postoperative opioid consumption during each period of interest will be analyzed using an 


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ANOVA model with randomized treatment as the main effect.  Results will be expressed as 
means, SDs, and LSMD and SE with associated 95% CI, and p-values.   
The mean total postoperative opioid consumption will also be plotted in a bar chart for each 
time period with associated SEM. 
Secondary Endpoint: Median time in hours to first opioid rescue administration 
through 72 hours 
Median time in hours to first opioid rescue administration will be plotted using Kaplan-Meier 
(K-M) curves, displaying 1-S(t).  K-M estimates of the median times will be presented along 
with their associated 95% CI in a table.  Treatment group comparisons will be summarized 
with hazard ratios and their associated 95% CI and p-values from the generalized Wilcoxon 
test.  Subjects who withdraw from the study prior to hour 72 or who complete the hour 72 
visit without having taken rescue medication will be censored at the time of study withdrawal 
or at hour 72, whichever is earlier. 
Secondary Endpoints: Mean AUC of the NRS-A pain intensity scores at the following 
intervals: 0-6, 0-12, 12-24, 24-48, 0-48, 0-72, and 48-72 hours and Mean AUC of the 
NRS-R pain intensity scores at the following intervals: 0-6, 0-12, 12-24, 0-24, 24-48, 0-
48, 48-72, and 0-72 hours 
Each of these 2 endpoints will be analyzed similarly to the methods described for the primary 
endpoint in Sections 9.1.1 and 9.1.2, with appropriate adjustments to the calculations to 
reflect the time periods of interest.  Mean AUC0-48 and mean AUC0-72 will also be plotted in a 
bar chart for NRS-A and mean AUC0-24, AUC0-48 and mean AUC0-72 will also be plotted in a 
bar chart for NRS-R. 
Secondary Endpoints: Mean NRS-A pain intensity scores at each timepoint and mean 
NRS-R pain intensity scores at each timepoint 
Mean pain intensity scores at each timepoint will be summarized with descriptive statistics.  
Mean NRS-A scores and Mean NRS-R scores at 24, 48, and 72 hours will be analyzed with 
ANOVA models with randomized treatment as the main effect.  Results will be expressed as 
means, SDs, and LSMD and SE with associated 95% CI, and p-values.  Mean pain intensity 
scores will be plotted in a line graph over time from hours 0-72, with associated SEM at each 
timepoint. 
Secondary Endpoint: Integrated Rank Analysis of Silverman using the NRS-A pain 
intensity AUC scores and total opioid consumption through 24, 48, and 72 hours 
An integrated assessment combining pain intensity scores and opioid rescue medication use 
via the use of ranks was detailed by Silverman, et al. (Silverman, O'Connor et al. 1993).  In 
this analysis, each subject is ranked for both the AUC of the NRS-A pain intensity scores and 


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total opioid rescue medication dose in MME without regard to which of the treatments being 
compared the subject was randomized.  If there are ties, then the mean of the ranks had there 
been no ties is assigned to each of the tied subjects (for example, if 3 subjects are tied for 
12th, then the mean of 12, 13 and 14 is assigned as the rank for those 3 subjects and the next 
rank starts at 15).  Then the percent difference between each subject’s 2 ranks and the overall 
mean rank is calculated, resulting in 2 percent difference ranks for each subject.  Finally the 2 
ranks are added together and analyzed.   
Let n1 and n2 be the sample sizes of the relevant treatment groups.  Then the overall mean 
rank RN is calculated as: 
𝑅𝑁= 𝑛1 + 𝑛2 + 1
2
 
and the percent difference Δi between each subject’s rank Ri and the overall mean rank is 
calculated as: 
∆𝑖= 100 (𝑅𝑖−𝑅𝑁
𝑅𝑁
) 
The integrated rank of Silverman (IRS) for each subject is then calculated as: 
𝐼𝑅𝑆𝑖= ∆𝑖(𝐴𝑈𝐶) + ∆𝑖(𝑀𝑀𝐸) 
In this analysis lower IRS are better than higher IRS.  The IRS will be rounded to the nearest 
integer before analysis. Summary statistics for the IRS0-24, IRS0-48, and IRS0-72 will be 
presented, and treatment differences will be analyzed using a Wilcoxon Rank Sum test, with 
p-values reported. 
Secondary Endpoint: Proportion of subjects achieving a score of “good” or better (>1) 
pain control based on PGA at 24, 48, and 72 hours, and on Day 28 
The PGA of pain control is a 4-point scale in which a subject rates how well her pain has 
been controlled.  The possible responses to the question are: 
 0: Poor 
 1: Fair 
 2: Good 
 3: Excellent 
The proportion of subjects answering in each category will be reported at each timepoint.  
The proportion of subjects achieving a score of “good” or better (>1) pain control based on 
PGA will be analyzed at each timepoint using Fisher’s exact test.  Descriptive statistics, 
differences in proportions, p-values, and exact 95% CI based on the score statistic (Chan and 
Zhang 1999) will be presented.    


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Secondary Endpoint: Proportion of subjects who are pain free with activity (defined as 
an NRS-A pain intensity score of 0 or 1), and proportion of subjects who are pain free 
at rest (defined as an NRS-R pain intensity score of 0 or 1) at each assessed timepoint 
Subjects with an NRS (including NRS-A or NRS-R) pain intensity score of 0 or 1 at a 
particular timepoint will be characterized as “pain-free” at that timepoint.  The proportion of 
subjects who are pain-free will tabulated with numbers and percentages.  The proportion of 
subjects who are pain-free at 24, 48, and 72 hours will be analyzed using Fisher’s exact test.  
Descriptive statistics, differences in proportions, p-values, and exact 95% CI will be 
presented, along with bar charts. 
Secondary Endpoint: Proportion of subjects who are opioid free through 24, 48, and 
72 hours 
Subjects who have a total MME opioid dose = 0 through 24 hours will be characterized as 
“opioid-free” at 24 hours, subjects who have a total MME opioid dose = 0 through 48 hours 
will be characterized as “opioid-free” at 48 hours, and subjects who have a total MME opioid 
dose = 0 through 72 hours will be characterized as “opioid-free” at 72 hours.  The proportion 
of subjects who are opioid-free at each of these 3 timepoints will be analyzed using Fisher’s 
exact test.  Descriptive statistics, differences in proportions, p-values, and exact 95% CI will 
be presented.   The proportion of subjects who are opioid free through 24, 48 and 72 hours 
will be plotted with bar charts. 
Secondary Endpoint: Proportion of subjects who are opioid-free from 72 hours through 
Day 10 and Day 28 
Subjects will be provided a diary to record if they took any opioid medication for their pain 
from 72 hours through Day 28.  Opioid-free from 72 hours through Day 10 is defined as 
answering “No” to the question “Did you take any opioid medication” on a daily basis from 
72 hours through Day 10.  Subjects who report “Yes” or have a missing report on any day 
during the period will not be considered opioid-free from 72 hours through Day 10.  Opioid-
free from 72 hours through Day 28 is defined similarly.  The proportion of subjects who are 
opioid-free during each of these 2 periods will be analyzed using Fisher’s exact test.  
Descriptive statistics, differences in proportions, p-values, and exact 95% CI will be 
presented.    
Secondary Endpoint: Proportion of subjects who first achieve an MPADSS score ≥ 9 at 
2, 4, 6, 8, 12, 24, 36, 48, 60, and 72 hours 
Discharge readiness is assessed by the MPADSS.  The proportion of subjects who first 
achieve an MPADSS score ≥ 9 at each timepoint will be analyzed cumulatively (ie, 2 hours, 
≤ 4 hours, ≤ 6 hours, etc.) using Fisher’s exact test.  Descriptive statistics, differences in 
proportions, p-values, and exact 95% CI will be presented.    


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Secondary Endpoints: Mean subject’s satisfaction with postoperative pain control at 24, 
48, and 72 hours and Day 10 
Satisfaction with postoperative pain control is collected on a scale of 1 (strongly disagree) to 
5 (strongly agree) in response to the question “are you satisfied with postoperative pain 
control?”   
Mean satisfaction at each timepoint will be summarized with descriptive statistics.   
Secondary Endpoints: Mean OBAS at 24, 48, and 72 hours and on Day 28 
Overall benefit of analgesia is collected using a 7-item, multidimensional, quality assessment 
questionnaire (Lehmann, Joshi et al. 2010) addressing pain, vomiting, itching, sweating, 
freezing, dizziness, and overall satisfaction with postoperative pain.  Each of the 7 items is 
rated on a scale of 0-4 as follows: 
 Item 1 (pain): 0 = “minimal pain”, 4 = “maximum imaginable pain” 
 Items 2-7: 0 = “not at all”, 4 = “very much” 
 
The OBAS for a subject is calculated by summing the scores in items 1-6 plus the difference 
between 4 and the score in item 7 for that subject: 
 
𝑂𝐵𝐴𝑆= (4 −𝑖𝑡𝑒𝑚7) + ∑𝑖𝑡𝑒𝑚𝑖
6
𝑖=1
 
Therefore the range of possible scores goes from 0 (answering 0 to the first 6 questions and 4 
to question 7) to 28 (answering 4 to the first 6 questions and 0 to question 7).  Question 7 is 
scored inversely because it is the only question where higher scores represent better 
outcomes. 
Mean OBAS at each timepoint will be summarized with descriptive statistics. 
9.3. 
Other Efficacy Analyses 
Analyses will be carried out on the pain intensity scores to evaluate the following: 
 Acute moderate and severe pain with activity: 
o The proportion of subjects with an NRS-A pain intensity score ≥ 4 at any 
timepoint through 24, 48, and 72 hours 
o The proportion of subjects with an NRS-A pain intensity score ≥ 7 at any 
timepoint through 24, 48, and 72 hours 
 
 Acute moderate and severe pain at rest: 
o The proportion of subjects with an NRS-R pain intensity score ≥ 4 at any 
timepoint through 24, 48, and 72 hours 


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o The proportion of subjects with an NRS-R pain intensity score ≥ 7 at any 
timepoint through 24, 48, and 72 hours 
 
 Persistent moderate and severe pain with activity: 
o The proportion of subjects with an NRS-A pain intensity score ≥ 4 at Day 10 
o The proportion of subjects with an NRS-A pain intensity score ≥ 4 at Day 28 
o The proportion of subjects with an NRS-A pain intensity score ≥ 7 at Day 10 
o The proportion of subjects with an NRS-A pain intensity score ≥ 7 at Day 28 
 
 Persistent moderate and severe pain at rest: 
o The proportion of subjects with an NRS-R pain intensity score ≥ 4 at Day 10 
o The proportion of subjects with an NRS-R pain intensity score ≥ 4 at Day 28 
o The proportion of subjects with an NRS-R pain intensity score ≥ 7 at Day 10 
o The proportion of subjects with an NRS-R pain intensity score ≥ 7 at Day 28 
 
 Maintenance of mild or no pain with activity: 
o The proportion of subjects with an NRS-A pain intensity score < 4 at hour 72 
who also are < 4 at Day 10 
o The proportion of subjects with an NRS-A pain intensity score < 4 at hour 72 
who are also < 4 at Day 28 
o The proportion of subjects with an NRS-A pain intensity score < 4 at hour 72 
and at Day 10 
o The proportion of subjects with an NRS-A pain intensity score < 4 at hour 72 
and at Day 28 
 
 Maintenance of mild or no pain at rest: 
o The proportion of subjects with an NRS-R pain intensity score < 4 at hour 72 
who also are < 4 at Day 10 
o The proportion of subjects with an NRS-R pain intensity score < 4 at hour 72 
who are also < 4 at Day 28 
o The proportion of subjects with an NRS-R pain intensity score < 4 at hour 72 
and at Day 10 
o The proportion of subjects with an NRS-R pain intensity score < 4 at hour 72 
and at Day 28 
 
Pain parameters through 72 hours will be constructed using wWOCF.  Pain parameters on 
Day 10 or Day 28 will be constructed using NRI.  
Each of the above proportions will be analyzed using Fisher’s exact test.  Descriptive 
statistics, differences in proportions, p-values, and exact 95% CI will be presented.  
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 


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safety data will be performed except in the case of partial AE and concomitant medication 
onset dates (Appendix 1). Baseline for safety analysis is defined as the last data collected, 
whether scheduled or unscheduled, prior to the start of study drug administration.   
10.1. 
Adverse Events 
An AE is defined as any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related.  A TEAE is any AE which occurs any time 
during or after study drug administration, or any AE with an onset prior to study drug 
administration that worsens during or after study drug administration.  An AE may be any 
unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a study drug, whether or not considered 
causally associated with the use of the study drug. Any abnormal laboratory value, vital sign 
result, or ECG finding deemed clinically significant by the Investigator, regardless of causal 
relationship, must be reported as an AE.  
For an event to be a TEAE, it must meet one of the following conditions: 
 Begins on Study Day 1, during or after administration of study drug 
 Begins after Study Day 1 
 Begins before Study Day 1 and worsens in severity during or after the Study Day 1 
administration of study drug 
AEs with unknown onset dates or unknown end dates will be counted as TEAEs unless the 
event resolves before Study Day 1.   
AEs will be coded using MedDRA version 19.1.  Only TEAEs will be presented in AE 
tables, according to the System Organ Class (SOC), and PT.  Any AEs that occur prior to 
Study Day 1 will be considered pretreatment AEs and will appear in the AE listing but not in 
TEAE tables. 
10.1.1. 
Incidence of Treatment Emergent Adverse Events 
The incidence of TEAEs table will include only 1 occurrence of a PT per subject.  If a 
subject reports the same PT multiple times, then that PT will only be incremented by 1 since 
subject counts will be presented.  As with the PT, if a subject reports multiple TEAEs within 
the same SOC, then that SOC will only be incremented by 1 since subject counts will be 
presented.  For tables showing incidence by SOC and PT, SOCs will be sorted by the 
internationally agreed order and PTs will be sorted within SOC in descending order of 
incidence in the HTX-011 total column.  For tables showing incidence by PT only, the PTs 
will be sorted in descending order of incidence in the HTX-011 total column.   
An overall summary of TEAEs will be presented, and will include the following: 
 Number of TEAEs 


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 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.   
10.1.2. 
Relationship of Adverse Events to Investigational drug 
Incidence of possibly related TEAEs to study drug will be presented in a table by SOC and 
PT.  The potential relationships are “Unlikely Related” and “Possibly Related”. TEAEs that 
are missing relationship will be presented in the summary table as “Possibly Related” but 
will be presented in the data listing with a missing relationship.    
10.1.3. 
Severity of Adverse Event 
Incidence of severe TEAEs will be presented in a table by SOC and PT.  TEAEs that are 
missing severity will be presented in summary tables as “severe” but will be presented in the 
data listing with a missing severity. 
10.1.4. 
Serious Adverse Events 
The seriousness of a TEAE should be assessed by the Investigator independently from the 
severity of the TEAE.  A SAE is an AE occurrence that results in death, is life-threatening, 
requires inpatient hospitalization or prolongation of existing inpatient hospitalization, results 
in persistent or significant disability/incapacity, or is a congenital abnormality/birth defect. 
Important medical events that may not be immediately life-threatening or result in death, or 
require hospitalization may be considered SAEs when, based upon medical judgment, they 
may jeopardize the subject or may require intervention to prevent one of the outcomes listed 
above. 
Incidence of treatment-emergent SAEs will be presented in a table by SOC and PT.  
Incidence of possibly related SAEs will also be presented by PT.  The incidence of SAE 
tables will include only 1 occurrence of a PT per subject.  If a subject reports the same SAE 
multiple times, then that PT will only be incremented by 1 since subject counts will be 
presented.  As with the PT, if a subject reports multiple SAEs within the same SOC, then that 
SOC will only be incremented by 1 since subject counts will be presented.  SAEs will also be 
listed separately. 


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10.1.5. 
Adverse Events Leading to Study Withdrawal 
All TEAEs reported with “Withdrawal from Study” checked on the eCRF will be presented 
in a listing. 
10.1.6. 
Opioid-related Adverse Events 
Incidence of TEAEs that are potentially opioid-related, regardless of whether a subject 
actually received an opioid medication, will be presented by PT.  Prespecified PTs that may 
be opioid-related include the following: 
 Nausea 
 Vomiting 
 Constipation 
 Pruritus 
 Somnolence 
 Respiratory depression 
 Urinary retention 
 
Incidence of ORAEs will be presented separately as follows: 
 
 Incidence of ORAEs through Day 28 
 Incidence of ORAEs through 72 hours 
 Incidence of ORAEs through Day 28 in the subset of subjects who received at least 1 
opioid rescue medication through 72 hours 
 Incidence of ORAEs through 72 hours in the subset of subjects who received at least 
1 opioid rescue medication through 72 hours 
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 as below. 
 
 Blister    
 Blood blister 
 Cellulitis 
 Erythema 
 Impaired healing 
 Incision site cellulitis 
 Incision site complication  
 Incision site infection       
 Incision site erythema       
 Incision site haemorrhage  
 Incision site vesicles         


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 Infection       
 Medical device site cellulitis        
 Post procedural cellulitis        
 Postoperative wound complication  
 Postoperative wound infection  
 Purulent discharge  
 Wound complication  
 Wound dehiscence 
 Wound infection 
 
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 PT. Local 
inflammatory TEAEs will also be listed separately. 
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 as below. 
 
 Arrhythmia 
 Bradycardia 
 Cardiac arrest 
 Dizziness 
 Dysguesia 
 Hypotension 
 Muscle twitching 
 Paresthesia oral 
 Respiratory arrest 
 Seizure 
 Tinnitus 
 Tremor 
 Visual impairment 
 
Incidence of LAST-related TEAEs will be presented in a table by 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. 


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10.2. 
Clinical Laboratory Evaluations 
Laboratory assessments will be performed by a central laboratory (hematology and serum 
chemistry) or locally (pregnancy test and drug screen).  All summaries of central laboratory 
data will be based on the standard international (SI) units provided by the central lab.  
Associated laboratory parameters such as hepatic profile, renal function, and hematology 
values will be grouped and presented together. 
Summary tables for hematology and chemistry including actual values and change from 
Baseline values will be presented for clinical laboratory tests with numeric values.  These 
tables will include each visit (Baseline, hour 24 [hematology only], hour 72), highest 
postdose value, lowest postdose value, and last postdose value. 
Laboratory data will also be summarized using shift tables where appropriate.  Each subject’s 
hematology and serum chemistry values will be flagged as “low”, “normal”, or “high” 
relative to the normal ranges of the central laboratory.  
Laboratory data collected at unscheduled visits will be included in listings and will contribute 
to tables of shifts from Baseline and in tables showing changes from Baseline to highest 
value, lowest value, and last value.  Unscheduled laboratory results will not be windowed for 
the purposes of assigning a nominal visit. 
Listings of laboratory values will include flags for values outside the central laboratory 
normal ranges that indicate how far out of the normal range an abnormal value is.  For 
example, a value that is ≥ 3 times the upper limit of normal (ULN) but below 4 times the 
upper limit of normal will have a “3H” flag.  Flag multipliers will show values that are 1, 2, 
3, 4, 5, and 10 times relative to the ULN if high.  Values that are below the lower limit of 
normal (LLN) will be flagged simply with “L”.   
Listings of abnormal values for hematology and chemistry will be presented separately in 
addition to listings of all laboratory values.  
10.2.1. 
Hematology 
The following laboratory tests will be included in hematology summary tables: hematocrit, 
hemoglobin, platelet count, red blood cell (RBC) count, and total and differential white blood 
cell (WBC) count (basophils, eosinophils, lymphocytes, monocytes, and neutrophils). 
10.2.2. 
Blood Chemistry 
The following laboratory tests will be included in the blood chemistry summary tables: 
alanine aminotransferase (ALT), albumin, alkaline phosphatase (ALP), aspartate 
aminotransferase (AST), bicarbonate, blood urea nitrogen (BUN), calcium, chloride, 
creatinine, direct bilirubin, gamma-glutamyltransferase (GGT), glucose, lactate 


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dehydrogenase (LDH), magnesium, phosphorus, potassium, sodium, total bilirubin, total 
protein, and uric acid. 
Associated laboratory parameters such as hepatic profile (ALT, albumin, ALP, AST, direct 
bilirubin, GGT, total bilirubin), electrolytes (bicarbonate, calcium, chloride, magnesium, 
phosphorus, potassium, sodium), renal profile (BUN, creatinine), and other (glucose, LDH, 
total protein, uric acid) will be sorted/grouped together in table and listing presentations.   
Evaluation of drug-induced serious hepatotoxicity (eDISH) scatterplots of the highest 
postdose ALT vs. total bilirubin observed at the same draw as the high ALT value, and of the 
highest postdose AST vs. total bilirubin observed at the same draw as the high AST value, 
will be produced. 
The incidence of subjects with abnormalities in Liver Function Tests (ALT, AST) will be 
summarized at each visit for each treatment group for the following categories:  
 > 1 x ULN  
 ≥ 2 x ULN 
 ≥ 3 x ULN 
 ≥ 4 x ULN 
 ≥ 5 x ULN  
10.2.3. 
Urine Pregnancy Test and Urine Drug Screen 
Urine pregnancy test results (women of child-bearing potential) and urine drug screen results 
will be listed. 
10.3. 
Vital Sign Measurements 
Vital signs including systolic blood pressure (SBP), diastolic blood pressure (DBP), heart 
rate/pulse (HR), and respiration rate will be collected at screening, on Day 0 before study 
drug administration, and at 24, 48, and 72 hours.   
Summary tables including actual values and changes from Baseline will be presented for 
vital signs.   
The number and percentage of subjects with clinically relevant abnormalities will be 
presented using data from any postdose visit (including unscheduled visits). The criteria for 
clinically relevant abnormalities are shown in   Table 3.  
 
 
 


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  Table 3.  Clinically Relevant Vital Signs Abnormalities 
Vital Sign 
Low 
High 
HR 
≤50 bpm and  ≥15 bpm decrease from 
Baseline 
≥120 bpm and  ≥15 bpm increase from 
Baseline 
SBP 
≤90 mmHg and  ≥20 mmHg decrease from 
Baseline 
≥160 mmHg and  ≥20 mmHg increase from 
Baseline 
DBP 
≤50 mmHg and  ≥15 mmHg decrease from 
Baseline 
≥100 mmHg and  ≥15 mmHg increase from 
Baseline 
  Abbreviations: bpm, beats per minute; DBP, diastolic blood pressure; HR, heart rate; SBP, systolic blood pressure. 
10.4. 
Electrocardiogram 
12-lead ECG (triplicate) is performed at screening.  Screening ECG results will be listed 
only, and will include each of the 3 triplicate ECGs as well as the mean values from the 
triplicate assessments. 
10.5. 
Physical Examination 
Physical examination is performed at Screening, 72 hours, and early termination.  Physical 
examination results will be listed only. 
10.6. 
Wound Healing Assessment 
Wound healing assessment according to the Southampton Wound Scoring System (Bailey, 
Karran et al. 1992) is performed at 72 hours, and on Days 10 and 28.  A summary of wound 
healing assessment results will be produced, showing the number and percentage of subjects 
at each visit by grade with subgrade breakdown.  Wound healing assessment results will also 
be listed. 
10.7. 
Motor Function Assessment 
Motor function assessment is performed at Screening, at 6, 12, 24, 48, and 72 hours, and on 
Day 10.  The proportion of subjects able to perform a successful motor function assessment 
(ie, with the elbows at the side and against the body, raise hands in front of abdomen, clasp 
hands together, and hold that position for at least 5 seconds) will be summarized at each 
timepoint.  Overall time to first successful motor function assessment will be summarized. 
Subjects who withdraw from the study prior to hour 72 or who complete the hour 72 visit 
without performing a successful motor function assessment will be censored at the time of 
study withdrawal or at hour 72, whichever is earlier. 
10.8. 
Sensory Function Test 
The proportion of subjects with loss of sensation in the breast on the side of the dominate 
hand at 15, 30, and 60 minutes after the start of study drug administration will be 
summarized.  The median time to loss of sensation in the same breast will be presented.  


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Following the surgical procedure, the sensory function test is performed at 6, 12, 24, 48, and 
72 hours, and on Day 10.  The proportion of subjects with a response of “yes” at each 
timepoint will be summarized.  The median time to return of sensory function (the first 
“yes”) will also be presented.   
10.9. 
Blinded Assessor’s Satisfaction with Return of Sensory and Motor 
Function 
Satisfaction with return of sensory and motor function is collected on a scale of 1 (strongly 
disagree) to 5 (strongly agree) in response to the question “are you satisfied with return of 
sensory and motor function?”   
Mean satisfaction at each timepoint will be summarized with descriptive statistics.   
11. 
INTERIM ANALYSIS 
11.1. 
Interim Analysis 
Up to 4 interim analyses will be performed.  An internal IRC composed of 1 Sponsor 
representative from each of the Clinical Research, Biometrics, Pharmacovigilance, 
Regulatory, and Pharmaceutical and Translational Sciences functions will review unblinded 
summary-level data from each cohort in order to make a determination to proceed with the 
next cohort and to select the dose(s) of HTX-011 that will be studied in the next cohort.  
Each interim analysis will be performed after at least 80% of the planned subjects have had 
their pain intensity and opioid use data through the 72-hour postoperative assessments 
entered into the eCRF for that cohort.  Detailed responsibilities of the IRC will be presented 
in an IRC charter.   
No adjustments to the type-1 error rate will be made in the efficacy hypothesis testing as a 
result of these interim analyses. 
11.2. 
Data Safety Monitoring Board 
An independent Data Safety Monitoring Board (DSMB) will not be involved with the 
conduct of this study.  The Sponsor will review blinded tables and listings of accumulating 
data approximately bi-weekly to check enrollment, adherence to follow-up schedule, and 
ongoing safety results.   
12. 
REFERENCES 
Bailey, I. S., S. E. Karran, K. Toyn, P. Brough, C. Ranaboldo and S. J. Karran (1992). 
"Community surveillance of complications after hernia surgery." BMJ 304(6825): 469-471. 


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Chan, I. S. and Z. Zhang (1999). "Test-based exact confidence intervals for the difference of 
two binomial proportions." Biometrics 55(4): 1202-1209. 
Lehmann, N., G. P. Joshi, D. Dirkmann, M. Weiss, P. Gulur, J. Peters and M. Eikermann 
(2010). "Development and longitudinal validation of the overall benefit of analgesia score: a 
simple multi-dimensional quality assessment instrument." Br J Anaesth 105(4): 511-518. 
Silverman, D. G., T. Z. O'Connor and S. J. Brull (1993). "Integrated assessment of pain 
scores and rescue morphine use during studies of analgesic efficacy." Anesth Analg 77(1): 
168-170. 
 


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APPENDIX 1. IMPUTATION OF PARTIAL AND MISSING DATES 
Incomplete Dates of Adverse Event start 
All AE onset dates must be entered on the eCRF as complete dates.  In the rare case that all 
or part of an AE onset date is missing but an AE resolution date is present and after study 
drug administration then the AE onset date will be imputed as follows: 
 
Year of onset 
Month of onset 
Day of onset 
Onset date to be imputed as 
Missing 
Missing 
Missing 
Date of SDA 
year = year of SDA 
Missing 
Nonmissing 
Set month to month of SDA 
year = year of SDA 
Missing 
Missing 
Set month and day to those of SDA 
year < year of SDA 
Missing 
Nonmissing 
set month to December 
year < year of SDA 
Missing 
Missing 
set month and day to December 31 
year > year of SDA 
Missing 
Nonmissing 
set month to January 
year > year of SDA 
Missing 
Missing 
set month and day to January 1 
year = year of SDA 
Month = month of first dose 
Missing 
Set day as day of 1st dose 
year = year of SDA 
Month < month of first dose 
Missing 
Set day as last day of onset month 
year = year of SDA 
Month > month of first dose 
Missing 
Set day as first day of onset month 
year < year of SDA 
Nonmissing 
Missing 
Set day as last day of onset month 
year > year of SDA 
Nonmissing 
Missing 
Set day as first day of onset month 
SDA = study drug administration. 
 
If AE resolution date is present and prior to study drug administration, 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. 
 


Heron Therapeutics, Inc. 
Statistical Analysis Plan, V 3.0
Protocol HTX-011-211 
04 January 2018
 
Confidential                                  
 
 
 
 
37 
 
APPENDIX 2. DOCUMENT REVISION HISTORY 
Version 
Date 
Notes/Revisions 
1.0 
23 DEC 2016 
Initial version, based on protocol version 2 (16 DEC 2016) 
2.0 
08 FEB 2017 
Second version, based on protocol version 3 (2 February 2017).  Revised 
endpoint list to match new protocol version.  Minor clarifications to the age 
ranges in demographics table, and to some of the secondary endpoint and 
safety analyses. 
3.0 
04 JAN 2018 
Third version, based on protocol version 6 (15 November 2017).   
 
Revised endpoint list to match new protocol version and updated 
corresponding secondary endpoint analysis 
 
Revised sections 5.5.3 and 10.1 to update study day algorithm (ie, 
remove study day 0 to compliant with CDISC standard).    
 
Modified section 9.3 to align with planned analyses in studies 
209,301 and 302 
 
Used wWOCF as the primary method to analyze primary endpoint. 
The LOCF method was changed to be sensitivity analysis. 
 
Used Shapiro-Wilk test to determine normality before choosing 
ANOVA or Wilcoxon rank sum test to analyze mean total opioid 
consumption. 
 
Added custom lists of preferred terms for analysis of Inflammatory 
and LAST symptoms 
 
 
 


Signature Page for VV-CLIN-000797 v1.0
Signature Page for VV-CLIN-000797 v1.0
Approval
04-Jan-2018 18:56:49 GMT+0000
Approval
05-Jan-2018 21:29:19 GMT+0000