Clinical trial NCT03718039
Conditions: Postoperative Pain
Keywords: bunion bunionectomy bunion surgery postoperative pain
Sponsor: Heron Therapeutics
Start date: 2018-10-24; Completion date: 2019-03-11
Enrollment: 78 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
This is a Phase 2, open-label, multi-cohort study to evaluate the analgesic efficacy, safety, and pharmacokinetics (PK) of a single, individualized dose of HTX-011 administered into the surgical site as a monotherapy or with other medications to enhance analgesia in subjects undergoing unilateral simple bunionectomy.

Detailed description:

Arms: arm 1: HTX-011 (bupivacaine/meloxicam), up to but not to exceed 60 mg/1.8 mg, via instillation. arm 2: HTX-011 (bupivacaine/meloxicam), up to but not to exceed 60 mg/1.8 mg, via instillation; Aprepitant, three single doses of aprepitant will be administered orally. arm 3: HTX-011 (bupivacaine/meloxicam), up to but not to exceed 60 mg/1.8 mg, via instillation and a scheduled multimodal analgesic (MMA) regimen.
Interventions: intervention 1: HTX-011 intervention 2: Luer Lock applicator intervention 3: Vial access device intervention 4: aprepitant
Intervention descriptions: intervention 1: HTX-011 (bupivacaine/meloxicam), up to but not to exceed 60 mg/1.8 mg, via instillation. intervention 2: Applicator for instillation. intervention 3: Device for withdrawal of drug product. intervention 4: Aprepitant, three single doses of aprepitant will be administered orally.

Protocol documents:
Prot_000.pdf: 
Document Type:  
Study Protocol 
Official Title:  
A Phase 2 Open-Label Study of HTX-011 via Individualized Dosing 
Administration for Postoperative Analgesia Following Unilateral 
Simple Bunionectomy 
NCT Number:  
NCT03718039 
Document Date:  
14-Jan-2019 
 


 
Confidentiality Statement 
This document contains confidential information of Heron Therapeutics, Inc. 
Do not copy or distribute without prior written permission of the Sponsor. 
Any unauthorized use, reproduction, publication, or dissemination is strictly prohibited. 
 
 
CLINICAL STUDY PROTOCOL: HTX-011-218 
 
Protocol Title: 
A Phase 2 Open-Label Study of HTX-011 via Individualized Dosing 
Administration for Postoperative Analgesia Following Unilateral 
Simple Bunionectomy 
Brief Title: 
Phase 2 Bunionectomy HTX-011 Administration Study 
Investigational 
Products: 
HTX-011 (bupivacaine and meloxicam) extended-release solution  
Aprepitant oral capsules 
Phase of Development: 
2 
Sponsor: 
Heron Therapeutics, Inc. 
4242 Campus Point Court, Suite 200 
San Diego, CA 92121 
1-858-251-4400 
Medical Monitors: 
 
 
 
 
Medical Project 
Leader: 
  
Vice President, Clinical Research 
 
 
Protocol Version: 
Version 4 
14 January 2019 
 
Version 3 
12 December 2018 
 
Version 2 
27 November 2018 
 
Version 1 
27 September 2018 


Protocol No: HTX-011-218 Version 4 
Heron Therapeutics, Inc. 
Phase 2 Bunionectomy HTX-011 Administration Study 
Confidential 
2 
INVESTIGATOR AGREEMENT 
CLINICAL STUDY PROTOCOL: HTX-011-218 
TITLE: A Phase 2 Open-Label Study of HTX-011 via Individualized Dosing for 
Postoperative Analgesia Following Unilateral Simple Bunionectomy 
I have read the protocol and agree that it contains all necessary details for carrying out this study. 
I am qualified by education, experience, and training to conduct this clinical research study. 
I will conduct the study as outlined herein. 
I will provide copies of the protocol, Investigator’s Brochure, and all other information on the 
investigational products 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 products 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-011-218 Version 4 
Heron Therapeutics, Inc. 
Phase 2 Bunionectomy HTX-011 Administration Study 
Confidential 
3 
PROTOCOL SYNOPSIS 
Sponsor: Heron Therapeutics, Inc. 
Protocol Number: HTX-011-218 
Name of Investigational Products: 
HTX-011 (bupivacaine and meloxicam) 
extended-release solution  
Aprepitant capsules (Cohorts 2 and 4 only) 
Protocol Title:  
A Phase 2 Open-Label Study of HTX-011 via 
Individualized Dosing Administration for Postoperative 
Analgesia Following Unilateral Simple Bunionectomy 
Name of Active Ingredients: 
bupivacaine and meloxicam 
aprepitant (Cohorts 2 and 4 only) 
Phase of Development: 2 
Study Objectives: 
Primary Objectives: 
 To assess the efficacy and duration of analgesia, following a single individualized dose of 
HTX-011, during the first 72 hours after unilateral simple bunionectomy (Cohort 1). 
 To assess the analgesic efficacy following a 3-day regimen of oral aprepitant and a single 
individualized dose of HTX-011 during the first 72 hours after unilateral simple bunionectomy 
(Cohort 2). 
 To assess the analgesic efficacy following a single individualized dose of HTX-011 as part of a 
multimodal analgesic regimen during the first 72 hours after unilateral simple bunionectomy 
(Cohort 3). 
 To assess the analgesic efficacy following a 3-day regimen of oral aprepitant and a single 
individualized dose of HTX-011 as part of a multimodal analgesic regimen during the first 72 hours 
after unilateral simple bunionectomy (optional Cohort 4). 
Secondary Objectives: 
 To assess the effect of study treatment on opioid load during the first 72 hours following surgery in 
this study population.  
 To assess the proportion of subjects who are opioid-free after receiving HTX-011 as part of a 
multimodal analgesic regimen during the first 72 hours in this study population (Cohort 3 and 
optional Cohort 4). 
 To assess the proportion of subjects who are opioid-free after receiving HTX-011 as part of a 
multimodal analgesic regimen during the first 72 hours with or without aprepitant and who remain 
opioid-free through Day 10 and Day 28 (Cohort 3 and optional Cohort 4). 
 To assess the safety and tolerability of study treatment in this study population. 
 To confirm the pharmacokinetic (PK) parameters of bupivacaine and meloxicam for a single 
individualized dose of HTX-011 in this study population. 
 To analyze the PK parameters of aprepitant in the presence of HTX-011 in this study population 
(Cohort 2 and optional Cohort 4). 
Methodology:  
This is a Phase 2, open-label, multi-cohort study to evaluate the analgesic efficacy, safety, and PK of a 
single, individualized dose of HTX-011 administered into the surgical site as a monotherapy or with other 
medications to enhance analgesia in subjects undergoing unilateral simple bunionectomy. The study will 
include up to 4 cohorts, which will be conducted sequentially. Subjects in all cohorts will receive 




Protocol No: HTX-011-218 Version 4 
Heron Therapeutics, Inc. 
Phase 2 Bunionectomy HTX-011 Administration Study 
Confidential 
5 
bandage clean, dry, and intact until the Day 7 visit. In addition, the subject should be provided with a cast 
guard to assist with keeping the bandage dry and instructed to contact the site if the bandage gets wet.  
Subjects in Cohorts 3 and 4 (whether or not they were discharged with an opioid prescription) will receive 
a diary at discharge, which they will complete each day to record whether they take an opioid medication 
between 72 hours and Day 28.  
All subjects will return to the study site on Days 7 and 28 to complete follow-up assessments. In addition, 
subjects will return for a Safety Follow-Up Visit on Day 42. 
Postoperative Analgesic Medications:  
Rescue Medication During Inpatient 72-Hour Postoperative Period  
Subjects should only receive rescue medication upon request for pain control, as needed, during the 
72-hour postoperative observation period. Rescue medication should not be given for pain prophylaxis, 
but only for treating postoperative pain. Prior to the administration of the first dose of rescue medication, 
if the subject has not already had at least 1 postoperative pain score assessed, then a Numeric Rating 
Scale (NRS) score at rest (NRS-R) followed by an NRS score with activity (NRS-A) must be obtained. 
Cohorts 1 and 2: Postoperative rescue medication will consist of oral immediate-release oxycodone (no 
more than 10 mg within a 4-hour period as needed), IV morphine (no more than 10 mg within a 2-hour 
period as needed), and/or oral acetaminophen (no more than 1 gram [1000 mg] in a 6-hour window). For 
subjects administered any acetaminophen-containing product, the total combined daily dose must not 
exceed 4 grams (4000 mg). Combination products containing an opioid and non-opioid are not allowed. 
No other analgesic agents, including nonsteroidal anti-inflammatory drugs (NSAIDs), are permitted 
during the 72-hour postoperative observation period.  
Cohorts 3 and 4: Postoperative rescue medication will consist of oral immediate-release oxycodone (no 
more than 10 mg within a 4-hour period as needed) and/or IV morphine (no more than 10 mg within a 
2-hour period as needed). Combination products containing an opioid and non-opioid are not allowed. 
With the exception of oral ibuprofen and oral acetaminophen, no other analgesic agents, including 
NSAIDs, are permitted during the 72-hour postoperative observation period. 
Subjects who are not medically ready for discharge at 72 hours may receive the same rescue medication 
as above to treat postoperative pain until discharge.  
Postoperative Analgesia After Discharge 
Cohorts 1 and 2: For subjects who are medically ready for discharge at 72 hours, oral acetaminophen (no 
more than 1000 mg every 6 hours as needed) should be recommended for postoperative pain. If a subject 
received 10 mg or more of oxycodone in the 12 hours prior to discharge, the subject should be provided 
with a prescription for immediate-release oxycodone (up to 10 mg orally [PO] q4h as needed). 
Cohorts 3 and 4: Upon discharge, subjects will be instructed to manage pain with the following regimen: 
 600 mg oral ibuprofen every 6 hours as needed (PRN) as first-line therapy (before acetaminophen). 
 1g oral acetaminophen every 6 hours PRN as second-line therapy (ie, if ibuprofen has been 
administered but the subject is still in pain). 
If a subject received 10 mg or more of oxycodone in the 12 hours prior to discharge, the subject should be 
provided with a prescription for immediate-release oxycodone (up to 10 mg PO q4h as needed). 
Pharmacists should be instructed that substitutions with any other opioid-containing product are not 
permitted, including combination opioid/non-opioid products. Sites must record if a subject is discharged 
with an opioid prescription (yes or no) for Cohorts 3 and 4. 
Number of Planned Subjects: Up to approximately 90 subjects will be enrolled and dosed: 30 subjects 
in Cohort 1, 15 subjects in Cohort 2, 30 subjects in Cohort 3, and 15 subjects in optional Cohort 4. 
Study Sites: Up to 2 sites. 


Protocol No: HTX-011-218 Version 4 
Heron Therapeutics, Inc. 
Phase 2 Bunionectomy HTX-011 Administration Study 
Confidential 
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Study Population: 
Inclusion Criteria 
Each subject must meet all of the following criteria to be enrolled in this study: 
1. Is able to provide written informed consent, adhere to the study visit schedule, and complete all 
study assessments. 
2. Is male or female, and ≥18 years of age at screening. 
3. Is scheduled to undergo a primary unilateral, distal, first metatarsal bunionectomy with osteotomy 
and internal fixation under regional anesthesia. 
4. Has an American Society of Anesthesiologists Physical Status of I, II, or III. 
5. Female subjects are eligible only if all of the following apply: 
a. Not pregnant (female subjects of child-bearing potential must have a negative urine 
pregnancy test at screening and on Day 1 before surgery). 
b. Not lactating. 
c. Not planning to become pregnant during the study. 
d. For Cohorts 1 and 3, is surgically sterile; or is at least 2 years post-menopausal; or is in a 
monogamous relationship with a partner who is surgically sterile; or is practicing abstinence 
or agrees to use double-barrier contraception in the event of sexual activity; or is using an 
insertable, injectable, transdermal, or combination oral contraceptive approved by applicable 
regulatory authorities for greater than 2 months prior to screening and commits to the use of 
an acceptable form of birth control for the duration of the study and for 30 days after study 
drug administration. Note: women in only a same-sex relationship do not need to meet this 
criterion. 
e. For Cohorts 2 and 4, is surgically sterile; or is at least 2 years post-menopausal; or is in a 
monogamous relationship with a partner who is surgically sterile; or is practicing abstinence 
or agrees to use double-barrier contraception or a non-hormonal intra-uterine device (eg, 
copper) in the event of sexual activity for greater than 2 months prior to screening, for the 
duration of the study and for 30 days after last study drug administration. Note: Women in 
only a same-sex relationship do not need to meet this criterion. Hormonal contraceptives are 
not an acceptable form of birth control since the efficacy of hormonal contraceptives may be 
reduced with aprepitant. 
Exclusion Criteria 
A subject who meets any of the following criteria will be excluded from the study: 
1. Has had a contralateral foot bunionectomy in the past 3 months prior to the scheduled surgery. 
2. Has a planned concurrent surgical procedure (eg, bilateral bunionectomy or collateral procedures 
on the surgical foot). 
3. Has a pre-existing concurrent acute or chronic painful physical/restrictive condition expected to 
require analgesic treatment in the postoperative period for pain that is not strictly related to the 
bunionectomy and which may confound the postoperative assessments. 
4. Has a contraindication or a known or suspected history of hypersensitivity or clinically significant 
idiosyncratic reaction to bupivacaine (or other local anesthetics), meloxicam (or other NSAIDs), 
oxycodone, morphine, acetaminophen, aprepitant (Cohorts 2 and 4 only), or ibuprofen (Cohorts 3 
and 4 only). 
5. Has known or suspected daily use of opioids for 7 or more consecutive days within the previous 
6 months prior to the scheduled surgery. 
6. Has taken any NSAIDs (including meloxicam) within at least 10 days prior to the scheduled 


Protocol No: HTX-011-218 Version 4 
Heron Therapeutics, Inc. 
Phase 2 Bunionectomy HTX-011 Administration Study 
Confidential 
7 
surgery with the exception of subjects on low-dose (≤100 mg) daily acetylsalicylic acid for cardio 
protection. 
7. Has taken long-acting opioids within 3 days prior to the scheduled surgery. 
8. Has taken any opioids within 24 hours prior to the scheduled surgery. 
9. Has been administered bupivacaine within 5 days prior to the scheduled surgery.  
10. For Cohorts 2 and 4 only, has been administered aprepitant or another NK1 receptor antagonist 
such as rolapitant, netupitant, or fosaprepitant within 5 days prior to the scheduled surgery. 
11. Has been administered any local anesthetic within 72 hours prior to the scheduled surgery, other 
than for pretreatment prior to IV needle placement, to treat an AE that occurs after signing the 
ICF, or to decrease venous irritation (eg, caused by propofol, in which case no more than a single 
administration of lidocaine 1% plain 20 mg IV may be administered). 
12. Has initiated treatment with any of the following medications within 1 month prior to study drug 
administration or is taking any of these medications to control pain: selective serotonin reuptake 
inhibitors (SSRIs), selective norepinephrine reuptake inhibitors (SNRIs), gabapentin, pregabalin, 
or cyclooxygenase-2 (COX-2) inhibitors. (Note: If a subject is taking one of these medications for 
a reason other than pain control, the subject must be on a stable scheduled dose [ie, not “as 
needed”] for at least 1 month prior to study drug administration.) Anxiolytics prior to surgery are 
permitted, if necessary.  
13. Has been administered systemic steroids within 5 half-lives or 10 days prior to administration of 
study drug (whichever is longer).  
14. Has a medical condition such that, in the opinion of the Investigator, participating in the study 
would pose a health risk to the subject or confound the postoperative assessments. Conditions 
may include, but are not limited to, any of the following: 
a. History of clinically significant cardiac abnormality such as myocardial infarction within 
6 months prior to signing the ICF, New York Heart Association class III or IV, or clinically 
significant abnormalities in cardiac function or on electrocardiogram (ECG; including but not 
limited to a PR interval >200 msec, a QT corrected by Fridericia’s formula [QTcF] 
>480 msec, or 3rd degree heart block). 
b. History of coronary artery bypass graft surgery within 12 months prior to signing the ICF.  
c. History of severe liver function impairment as defined by Child-Pugh Class C, having an 
aspartate aminotransferase >3 × the upper limit of normal (ULN), or having an alanine 
aminotransferase >3 × ULN. 
d. History of severe kidney function impairment as defined by creatinine clearance 
(Cockcroft-Gault) <30 mL/min, being on dialysis, and/or having a serum creatinine 
>2 × ULN. 
e. History of known or suspected coagulopathy or uncontrolled anticoagulation (platelet count 
<100,000/μL, hemoglobin <12 g/dL, or hematocrit <35%). 
f. Loss of sensation in extremities or significant peripheral neuropathy. 
15. 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). 
16. Has uncontrolled anxiety, psychiatric, or neurological disorder that, in the opinion of the 
Investigator, might interfere with study assessments. 
17. For Cohorts 2 and 4 only, is receiving pimozide, a strong or moderate CYP3A4 inhibitor (eg, 
diltiazem, ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir, 
nelfinavir), or a strong CYP3A4 inducer (eg, rifampin, carbamazepine, phenytoin). 


Protocol No: HTX-011-218 Version 4 
Heron Therapeutics, Inc. 
Phase 2 Bunionectomy HTX-011 Administration Study 
Confidential 
8 
18. 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. 
19. Has a known or suspected history of drug abuse, a positive urine drug screen at the screening visit 
or on the day of surgery prior to surgery, or a recent history of alcohol abuse (ie, within 10 years). 
Note: Subjects with a positive drug screen who are taking an allowed, prescribed medication that 
is known to result in a positive drug test (eg, amphetamine and dextroamphetamine for attention-
deficit/hyperactivity disorder, benzodiazepine for anxiety disorder) may be eligible for 
participation in the study with Medical Monitor approval. Subjects taking medical or recreational 
marijuana are not allowed to participate in the study. 
20. Previously participated in an HTX-011 study.  
21. 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. 
22. Has undergone 3 or more surgeries within 12 months prior to signing the ICF, other than for 
diagnostic procedures (eg, colonoscopy). 
23. Has a body mass index (BMI) >39 kg/m2. 
Investigational Products, Doses, and Modes of Administration: 
HTX-011 (All cohorts) 
HTX-011 is a novel, extended-release, fixed-dose combination product that contains bupivacaine and 
low-dose meloxicam. Bupivacaine is an amide-type local anesthetic and meloxicam is a nonsteroidal anti-
inflammatory drug (NSAID). HTX-011 is a solution that is formulated in a proprietary tri(ethylene 
glycol)-based poly(orthoester) polymer (TEG-POE), termed Biochronomer®. HTX-011 will be supplied 
by the Sponsor as a sterile, viscous liquid in 20 mL clear glass vials. 
A single dose of no more than 2.1 mL HTX-011 [up to 60 mg/1.8 mg (bupivacaine/meloxicam doses)] 
will be applied without a needle into the surgical site using a Luer lock applicator to coat the tissues 
within the surgical site that could result in pain generation. Application of HTX-011 should follow final 
irrigation and suction and prior to suturing. A sufficient amount should be used to coat the tissues, 
ensuring there is not an excess that could be expressed from the site during closure. When using 
monofilament sutures, 3 or more knots are recommended because contact with HTX-011 may cause a 
single knot to loosen or untie. HTX-011 should be applied only to the tissue layers below the skin incision 
and not directly onto the skin. The syringe and Luer lock applicator will also be supplied by the Sponsor. 
After preparing the syringe and before administration, the amount of HTX-011 withdrawn into the 
syringe (to the nearest tenth of 1 mL) and the weight of the syringe (to the nearest gram) will be recorded 
in the eCRF. After administering HTX-011, the amount of HTX-011 remaining in the syringe and the 
weight of the syringe will also be recorded in the eCRF. 
Aprepitant (Cohorts 2 and 4) 
Aprepitant is a substance P neurokinin-1 (NK-1) receptor antagonist. Aprepitant was initially approved by 
the US FDA in 2003 for the prevention of acute and delayed chemotherapy-induced nausea and vomiting 
(CINV) and in 2006 for postoperative nausea and vomiting (PONV). Its use has also been investigated for 
the management of pain. Aprepitant capsules will be supplied by the Sponsor as a pack containing one 
125 mg capsule and two 80 mg capsules. 
Subjects in Cohorts 2 and 4 will take 3 single oral doses of aprepitant: approximately 3 hours presurgery 
on Day 1 (125 mg) and at approximately 24 hours (Day 2) and approximately 48 hours (Day 3) after the 
presurgery dose (80 mg at each of the 2 timepoints). 
Required Concomitant Medications  
Study sites will supply other required concomitant medications (eg, ibuprofen and acetaminophen for 


Protocol No: HTX-011-218 Version 4 
Heron Therapeutics, Inc. 
Phase 2 Bunionectomy HTX-011 Administration Study 
Confidential 
9 
Cohorts 3 and 4) as well as rescue medications during the 72-hour postoperative period (all cohorts, as 
needed).  
Reference Therapy, Dose, and Mode of Administration: 
None. 
Duration of Treatment: 
All subjects will receive a single dose of HTX-011. Subjects in Cohorts 2 and 4 will also receive 3 single 
doses of aprepitant. Subjects in Cohort 3 and 4 will also receive scheduled multimodal analgesia through 
72 hours. The total duration of study participation for each subject (from Screening through the Safety 
Follow-Up on Day 42) will be up to 77 days. The overall duration of the study is anticipated to be 
approximately 7 months. 
Criteria for Evaluation: 
Efficacy, safety, and PK assessments will be performed. For Cohorts 1 and 3, the start of HTX-011 
administration will be considered as Time 0 for all efficacy, safety, and PK timepoints. For Cohorts 2 and 
4, the start of aprepitant administration will be considered Time 0 for aprepitant alone safety and PK 
assessments. The start of HTX-011 administration will be considered as Time 0 for all efficacy, safety, 
and PK assessments for HTX-011 with aprepitant. 
Efficacy Assessments: 
 Pain intensity scores using NRS-R and NRS-A at 1, 2, 4, 8, 12, 24, 36, 48, 60, 72 hours, and on 
Day 7 and Day 28. 
 
NRS-R: Subjects should be seated/recumbent with the surgically attended leg elevated or lying 
supine. Measurements should be obtained after the subject is in the resting position for at least 
5 minutes. 
 
NRS-A: Subjects should be seated with the plantar surface of the ball of the surgically 
attended foot touching the floor (no weight-bearing). 
 Date, time of administration, and amount of all opioid rescue medication taken through 72 hours. 
 Subject daily diary to record whether any opioids were taken from 72 hours through Day 28 
(Cohorts 3 and 4 only). 
Safety Assessments: 
 AEs from the time the subject signs the ICF through the Safety Follow-Up on Day 42. 
 Clinical safety laboratory tests (hematology and serum chemistry) at the Screening Visit and at 
72 hours. 
 Physical examination at Screening Visit that also includes height, weight, and BMI calculation. 
 Wound healing assessment on Day 7, Day 28, and at the Safety Follow-Up on Day 42. 
 Vital signs (resting heart rate, blood pressure, respiration rate, and body temperature) at the 
Screening Visit, on Day 1 before surgery, and post-treatment at 30, 60, and 90 minutes and at 2, 4, 
8, 12, 18, 24, 36, 48, 60, and 72 hours. 
 ECG at the Screening Visit. 
PK Assessments: 
A presurgery blood sample for bupivacaine and meloxicam PK analysis will be collected from subjects in 
Cohort 3. Presurgery blood samples for bupivacaine, meloxicam, and aprepitant PK analysis will be 
collected from subjects in Cohorts 2 and 4 at approximately 2, 2.5, and 3 hours following the presurgery 
dose of aprepitant 125 mg. Blood samples for bupivacaine and meloxicam PK analysis (all subjects) and 
for aprepitant PK analysis (Cohorts 2 and 4 only) will be collected at 0.5, 1, 2, 4, 8, 12, 18, 24, 36, 48, 


Protocol No: HTX-011-218 Version 4 
Heron Therapeutics, Inc. 
Phase 2 Bunionectomy HTX-011 Administration Study 
Confidential 
10 
60, and 72 hours following the start of HTX-011 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: 
 Area under the curve (AUC) of the Numeric Rating Scale of pain intensity scores with activity 
(NRS-A) through 72 hours (AUC0-72). 
Secondary Efficacy Endpoints: 
 Total postoperative opioid consumption (in morphine equivalents) through 72 hours. 
 Proportion of subjects who are opioid-free through 72 hours.  
 Proportion of subjects who are opioid-free through 72 hours who remain opioid-free through 
Day 10 and Day 28 (Cohorts 3 and 4 only). 
 AUC0-72 of the NRS-R pain intensity scores. 
Safety Endpoints 
 Incidence of treatment-emergent AEs (TEAEs), serious TEAEs (SAEs), and opioid-related AEs 
(ORAEs) through the Safety Follow-Up on Day 42. 
 Change from baseline in clinical laboratory results. 
 Change from baseline in vital signs. 
 Wound healing assessment on Day 7 and Day 28, and at the Safety Follow-Up on Day 42. 
PK Endpoints 
 The area under the plasma concentration-time curve from time zero to time t of the last measured 
concentration above the limit of quantification (AUC0-last) (for bupivacaine and meloxicam only). 
 The area under the plasma concentration-time curve from zero to infinity (AUC0-inf) (for bupivacaine 
and meloxicam only). 
 The maximum plasma concentration (Cmax). 
 Apparent total body clearance over bioavailability (Cl/F). 
 Apparent total volume of distribution over bioavailability (VZ/F). 
 The time to reach maximum plasma concentration (Tmax). 
 The terminal elimination rate constant (λZ) with the respective half-life (t½). 
Statistical Methods: 
Efficacy Analyses 
All efficacy data will be summarized by cohort. AUCs of the NRS pain intensity scores will be adjusted 
for opioid use via windowed worst observation carried forward (wWOCF) method. 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 prewindow score, then it will not be replaced. 
Sensitivity analyses for endpoints involving NRS pain intensity scores will summarize the data without 
adjustment for the effect of opioid rescue medications. 
Handling of Missing Data 
Due to the required 72-hour inpatient postoperative observation period, the amount of missing data is 
expected to be very low. For any missing data observed through 72 hours in subjects who complete the 
72-hour postoperative observation period, NRS pain intensity scores will be imputed via last observation 
carried forward (LOCF), in which the most recent post-dose value is used for a subsequent missing value. 


Protocol No: HTX-011-218 Version 4 
Heron Therapeutics, Inc. 
Phase 2 Bunionectomy HTX-011 Administration Study 
Confidential 
11 
For subjects who do not have a post-dose value prior to their first missing value, the median of the post-
dose values at the relevant timepoint from subjects with observed data in the same treatment group will be 
used. Pre-dose values will not be carried forward to post-dose timepoints. In subjects who withdraw from 
the study prior to 72 hours, missing NRS pain intensity scores through 72 hours that were to be collected 
following withdrawal will be imputed via WOCF, in which the worst (highest) NRS pain intensity score 
observed prior to withdrawal will be used for post-withdrawal values through 72 hours. Analyses that 
adjust for the effect of opioid rescue medication will perform wWOCF following LOCF/WOCF (ie, 
perform LOCF/WOCF first, then apply wWOCF). The number and percentage of missing NRS pain 
intensity scores will be summarized. 
Pharmacokinetic Analysis: 
The PK parameters for bupivacaine and meloxicam (all subjects) and for aprepitant (Cohorts 2 and 4) will 
be calculated using noncompartmental analysis. 
Safety Analyses 
All safety data will be listed and summarized by cohort. 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. Associated laboratory parameters such as hepatic profile, 
renal function, and hematology values will be grouped and presented together in summary tables. 
Individual subject values will be listed and values outside of the standard reference range will be flagged. 
Changes in vital sign parameters will be summarized. Wound healing assessment results will be 
summarized. 
Determination of Sample Size 
The sample size was selected empirically without formal statistical assumptions. 




Protocol No: HTX-011-218 Version 4 
Heron Therapeutics, Inc. 
Phase 2 Bunionectomy HTX-011 Administration Study 
Confidential 
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Abbreviations: D or d, day; ECG, electrocardiogram; ET, Early Termination; F/up, follow-up; h, hour; min, minutes; NRS-A, Numeric Rating Scale with activity; NRS-R, 
Numeric Rating Scale at rest; OR, operating room; PK, pharmacokinetic; Preop, preoperative assessments; WOCBP, women of childbearing potential. 
* The start of HTX-011 administration will be considered as Time 0 for all efficacy, safety, and PK assessments for HTX-011 with or without aprepitant. For Cohorts 2 and 4, the 
start of aprepitant administration will be considered Time 0 for aprepitant alone safety and PK assessments. For assessments at timepoints when the subject is asleep, an attempt 
should be made to wake the subject. If there is no response, the assessments at these timepoints may be recorded as “Not Done.” Assessments that can be done without waking 
the subject (eg, blood collection for PK) should be completed. When PK and Numeric Rating Scale (NRS) pain intensity assessments coincide, the NRS pain intensity 
assessments should be conducted before the blood draw. See Section 6 for more information on study procedures and assessments. 
a Subjects who withdraw from the study will be asked to complete Early Termination procedures based on the timing of withdrawal (ie, prior to 72 hours, prior to the Day 28 Visit, 
or after the Day 28 Visit and prior to the Safety Follow-Up Visit on Day 42). 
b The urine drug screen and urine pregnancy test should be performed first. Results should be confirmed negative prior to performing any additional assessments and prior to 
initiation of surgery. A subject who fails the drug test may be rescreened at the discretion of the Investigator. Subjects with a positive drug screen who are taking an allowed, 
prescribed medication that is known to result in a positive drug test (eg, amphetamine and dextroamphetamine for attention-deficit/hyperactivity disorder, benzodiazepine for 
anxiety disorder) may be eligible for participation in the study. Subjects taking medical and recreational marijuana are not allowed to participate in the study. 
c Includes height, weight, and body mass index calculation. 
d Only if subject withdraws prior to 72 hours. 
e Subjects in Cohorts 2 and 4 will be administered 3 single doses of aprepitant orally: approximately 3 hours presurgery on Day 1 (125 mg) and at approximately 24 hours (Day 2) 
and approximately 48 hours (Day 3) after the presurgery dose (80 mg at each of the 2 timepoints). 
f The length of the surgical incision should be recorded. 
g Postoperatively and upon discharge, subjects in Cohort 3 and 4 will be administered the following scheduled analgesic regimen: 600 mg oral ibuprofen every 6 hours as needed 
(PRN) as first-line therapy before acetaminophen, and 1g oral acetaminophen ibuprofen every 6 hours PRN as second-line therapy through Day 28. 
h NRS-R should be assessed while the subject is seated/recumbent with the surgically attended leg elevated or lying supine. Measurements should be obtained after the subject is 
in the resting position for at least 5 minutes. NRS-R should be completed prior to the NRS-A. 
i If a subject requires rescue medication before the 1-hour pain intensity assessments, then an unscheduled NRS-R pain score followed by an NRS-A pain score must be obtained 
before administering the first dose of rescue medication. These do not replace the 1-hour NRS-R and NRS-A assessments.  
j Only if subject withdraws prior to Day 28. 
k The prescribed activity for NRS-A is sitting with the plantar surface of the ball of the surgically attended foot touching the floor (no weight-bearing). NRS-R should be 
completed prior to the NRS-A. 
l Sites must record if a subject is discharged with an opioid prescription (yes or no) in Cohorts 3 and 4. 
m A presurgery blood sample for bupivacaine and meloxicam PK analysis will be collected from subjects in Cohort 3. Presurgery blood samples for bupivacaine, meloxicam, and 
aprepitant PK analysis will be collected from subjects in Cohorts 2 and 4 at approximately 2, 2.5, and 3 hours following the presurgery dose of aprepitant 125 mg.  
n Subjects in Cohorts 3 and 4 will complete a daily diary from 72 hours through Day 28 to record if they take any opioid medication. Subject diary results will be reviewed at the 
Day 7 and Day 28 Visits. If a subject recorded “yes” for taking an opioid, sites must record the medication on concomitant medication electronic Case Report Form (eCRF). 
o At the Screening Visit, ensure subject is not taking any prohibited medications. Record all medications taken from the time the subject signs the Informed Consent Form (ICF) 
through the Safety Follow-Up on Day 42. 
p Adverse events will be collected from the time the subject signs the ICF through the Safety Follow-Up Visit on Day 42. 
 


Protocol No: HTX-011-218 Version 4 
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Phase 2 Bunionectomy HTX-011 Administration Study 
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TABLE OF CONTENTS 
INVESTIGATOR AGREEMENT...................................................................................................2 
PROTOCOL SYNOPSIS ................................................................................................................3 
SCHEDULE OF EVENTS ............................................................................................................12 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ..................................................19 
1. 
INTRODUCTION ......................................................................................................21 
1.1. 
Background Information and Study Rationale ...........................................................21 
1.2. 
Rationale for Study Design, Doses, and Control Groups ...........................................22 
1.3. 
Potential Risks and Benefits .......................................................................................24 
1.3.1. 
HTX-011 .....................................................................................................................25 
1.3.2. 
Aprepitant ...................................................................................................................28 
2. 
STUDY OBJECTIVES ..............................................................................................29 
2.1. 
Primary Objectives .....................................................................................................29 
2.2. 
Secondary Objectives .................................................................................................29 
3. 
INVESTIGATIONAL PLAN AND ENDPOINTS ....................................................30 
3.1. 
Description of the Study Design .................................................................................30 
3.1.1. 
Overall Study Design ..................................................................................................30 
3.1.1.1. 
Study Cohorts .............................................................................................................30 
3.1.2. 
Postoperative Observation Period and Follow-Up .....................................................32 
3.1.3. 
Postoperative Analgesic Medications .........................................................................32 
3.1.3.1. 
Rescue Medication During Inpatient 72-Hour Postoperative Period .........................32 
3.1.3.2. 
Postoperative Analgesia After Discharge ...................................................................33 
3.1.4. 
Pharmacokinetic Assessments ....................................................................................33 
3.1.5. 
Efficacy and Safety Assessments ...............................................................................33 
3.2. 
Study Endpoints ..........................................................................................................34 
3.2.1. 
Efficacy Endpoints ......................................................................................................34 
3.2.1.1. 
Primary Efficacy Endpoint .........................................................................................34 
3.2.1.2. 
Secondary Efficacy Endpoints ....................................................................................34 
3.2.2. 
Safety Endpoints .........................................................................................................34 
3.2.3. 
Pharmacokinetic Endpoints ........................................................................................34 
3.3. 
Study Duration ............................................................................................................34 
4. 
STUDY ENROLLMENT AND WITHDRAWAL ....................................................36 


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4.1. 
Study Population .........................................................................................................36 
4.1.1. 
Inclusion Criteria ........................................................................................................36 
4.1.2. 
Exclusion Criteria .......................................................................................................36 
4.2. 
Method of Assigning Subjects to Treatment Groups .................................................38 
4.2.1. 
Procedures for Handling Subjects Who Do Not Meet the Study Eligibility 
Criteria ........................................................................................................................39 
4.3. 
Subject Withdrawal and Replacement ........................................................................39 
4.3.1. 
Subject Withdrawal ....................................................................................................39 
4.3.2. 
Subject Replacement ..................................................................................................39 
5. 
STUDY TREATMENT ..............................................................................................40 
5.1. 
Description of Investigational Products ......................................................................40 
5.2. 
Manufacturing, Packaging, and Labeling ...................................................................40 
5.3. 
Storage ........................................................................................................................40 
5.4. 
Preparation ..................................................................................................................40 
5.5. 
Study Drug Administration.........................................................................................41 
5.6. 
Study Drug Compliance .............................................................................................41 
5.7. 
Study Drug Accountability .........................................................................................41 
6. 
STUDY PROCEDURES AND ASSESSMENTS......................................................42 
6.1. 
Medical History and Demographics ...........................................................................42 
6.1.1. 
Medical History ..........................................................................................................42 
6.1.2. 
Demographics .............................................................................................................42 
6.2. 
Prior and Concomitant Therapy ..................................................................................42 
6.2.1. 
Allowed Concomitant Medications ............................................................................42 
6.2.2. 
Prohibited Medications ...............................................................................................43 
6.2.2.1. 
Medications Prohibited Prior to Surgery ....................................................................43 
6.2.2.2. 
Medications Prohibited During Surgery .....................................................................43 
6.2.2.3. 
Medications Prohibited From Time 0 Through 72 Hours ..........................................43 
6.3. 
Efficacy Assessments .................................................................................................43 
6.3.1. 
Pain Intensity Assessment ..........................................................................................43 
6.3.2. 
Use of Opioid Medications .........................................................................................44 
6.3.2.1. 
Opioid Rescue Medication Through 72 Hours ...........................................................44 
6.3.2.2. 
Subject Daily Diary of Opioid Use From 72 Hours Through Day 28 (Cohorts 
3 and 4 Only) ..............................................................................................................44 


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6.4. 
Safety Assessments .....................................................................................................44 
6.4.1. 
Adverse Events ...........................................................................................................44 
6.4.2. 
Physical Examinations ................................................................................................45 
6.4.3. 
Vital Signs ..................................................................................................................45 
6.4.4. 
12-Lead Electrocardiograms .......................................................................................45 
6.4.5. 
Wound Healing Assessment .......................................................................................45 
6.4.6. 
Clinical Laboratory Tests ...........................................................................................45 
6.5. 
Pharmacokinetic Assessments ....................................................................................46 
7. 
TIMING OF PROCEDURES AND ASSESSMENTS ..............................................47 
7.1. 
Screening Period .........................................................................................................47 
7.2. 
Treatment and Postoperative Observation Period ......................................................48 
7.2.1. 
Day of Surgery (Day 1) ..............................................................................................48 
7.2.1.1. 
Prior to Surgery ...........................................................................................................48 
7.2.1.2. 
Surgery and HTX-011 Administration .......................................................................49 
7.2.2. 
Postoperative Assessment Period (Up to 72 Hours) ...................................................49 
7.2.3. 
End of the Postoperative Assessment Period ..............................................................50 
7.3. 
Follow-Up Period .......................................................................................................51 
7.3.1.1. 
Day 7 Visit (+3 Days) .................................................................................................51 
7.3.1.2. 
Day 28 Visit (±4 Days) ...............................................................................................51 
7.3.1.3. 
Safety Follow-Up (Day 42 ±7 Days) ..........................................................................51 
7.4. 
Early Termination Visit ..............................................................................................51 
7.4.1. 
Withdrawal Prior to the Day 28 Visit .........................................................................52 
7.4.2. 
Withdrawal After the Day 28 Visit and Prior to the Safety Follow-Up on 
Day 42 .........................................................................................................................52 
7.5. 
Unscheduled Visits and Assessments .........................................................................52 
8. 
SAFETY MONITORING AND REPORTING .........................................................53 
8.1. 
Definition of Safety Parameters..................................................................................53 
8.1.1. 
Definition of an Adverse Event ..................................................................................53 
8.1.2. 
Definition of a Serious Adverse Event .......................................................................54 
8.1.3. 
Definition of a Suspected Adverse Reaction ..............................................................55 
8.1.4. 
Definition of a Serious Suspected Adverse Reaction .................................................55 
8.1.5. 
Definition of Unanticipated Problems ........................................................................55 
8.2. 
Classification of Adverse Events ................................................................................55 


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8.2.1. 
Severity of Adverse Events ........................................................................................55 
8.2.2. 
Relationship to Study Drug ........................................................................................56 
8.3. 
Time Period and Frequency for Event Assessment and Follow Up ...........................56 
8.3.1. 
Adverse Event and Serious Adverse Event Monitoring .............................................56 
8.3.2. 
Follow-Up of Events ...................................................................................................57 
8.4. 
Reporting Procedures ..................................................................................................57 
8.4.1. 
Reporting Serious Adverse Events to the Sponsor .....................................................57 
8.4.2. 
Reporting Unanticipated Problems to the Sponsor .....................................................58 
8.4.3. 
Regulatory Reporting Requirements ..........................................................................59 
8.4.4. 
Pregnancy Reporting ..................................................................................................59 
8.5. 
Safety Oversight .........................................................................................................59 
9. 
OTHER STUDY RESTRICTIONS ...........................................................................60 
9.1. 
Contraception ..............................................................................................................60 
10. 
STATISTICAL CONSIDERATIONS .......................................................................61 
10.1. 
General Considerations ...............................................................................................61 
10.2. 
Determination of Sample Size ....................................................................................61 
10.3. 
Analysis Populations ..................................................................................................61 
10.4. 
Statistical Analysis Methods.......................................................................................61 
10.4.1. 
Disposition and Demographics ...................................................................................61 
10.4.2. 
Efficacy Analysis ........................................................................................................61 
10.4.2.1. 
Handling of Missing Data ...........................................................................................61 
10.4.3. 
Safety Analysis ...........................................................................................................62 
10.4.4. 
Pharmacokinetic Analysis ..........................................................................................62 
10.5. 
Interim Analysis ..........................................................................................................62 
11. 
QUALITY ASSURANCE AND QUALITY CONTROL .........................................63 
12. 
REGULATORY AND ETHICAL CONSIDERATIONS ..........................................64 
12.1. 
Regulatory Authority Approval ..................................................................................64 
12.2. 
Ethical Conduct of the Study ......................................................................................64 
12.3. 
Ethics Committee Approval .......................................................................................64 
12.4. 
Informed Consent Process ..........................................................................................64 
12.5. 
Confidentiality ............................................................................................................65 
13. 
STUDY ADMINISTRATION ...................................................................................67 
13.1. 
Clinical Monitoring ....................................................................................................67 


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13.2. 
Source Documents and Record Retention ..................................................................67 
13.3. 
Management of Protocol Amendments and Deviations .............................................67 
13.3.1. 
Protocol Modification .................................................................................................67 
13.3.2. 
Protocol Violations and Deviations ............................................................................67 
13.4. 
Financial Disclosure ...................................................................................................68 
13.5. 
Stopping Criteria: Suspension or Termination of Study or Investigational 
Site ..............................................................................................................................68 
13.5.1. 
Suspension of Study ...................................................................................................68 
13.5.2. 
Termination of Study or Investigational Site ..............................................................68 
13.6. 
Publication and Information Disclosure Policy ..........................................................69 
14. 
REFERENCE LIST ....................................................................................................70 
APPENDIX A. AMERICAN SOCIETY OF ANESTHESIOLOGISTS PHYSICAL 
STATUS CLASSIFICATION SYSTEM ...................................................................74 
APPENDIX B. BMI CALCULATION ......................................................................................75 
APPENDIX C. PAIN INTENSITY ASSESSMENTS USING THE NUMERIC 
RATING SCALE (NRS) ............................................................................................76 
APPENDIX D. WOUND HEALING ASSESSMENT ...............................................................77 
APPENDIX E. INSTRUCTIONS FOR POSTOPERATIVE PAIN MANAGEMENT 
FOR SUBJECTS MEDICALLY READY FOR DISCHARGE ................................78 
 
LIST OF TABLES 
Table 1: 
Overview of Treatment by Study Cohort ...................................................................30 
Table 2: 
Clinical Laboratory Tests ...........................................................................................46 
 


Protocol No: HTX-011-218 Version 4 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
AE 
Adverse event 
AUC 
Area under the curve  
BMI 
Body mass index 
CFR 
Code of Federal Regulations 
CHMP 
Committee for Medicinal Products for Human Use 
CINV 
Chemotherapy induced nausea and vomiting 
Cmax 
Maximum observed plasma concentration 
CONSORT 
Consolidated Standards of Reporting Trials 
COX-2 
Cyclooxygenase-2 
CV 
Cardiovascular  
EC 
Ethics Committee  
ECG 
Electrocardiogram  
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GPP 
Good Publication Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human immunodeficiency virus 
h 
Hour(s) 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
ICMJE 
International Committee of Medical Journal Editors 
IEC 
Independent Ethics Committee 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat  
IV 
Intravenous(ly)  
LAST 
Local Anesthetic Systemic Toxicity 


Protocol No: HTX-011-218 Version 4 
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Phase 2 Bunionectomy HTX-011 Administration Study 
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LOCF 
Last observation carried forward 
min 
Minute 
NK1 
Neurokinin-1 
NRS 
Numeric Rating Scale 
NRS-A 
NRS scores with activity  
NRS-R 
NRS scores at rest  
NSAID 
Nonsteroidal anti-inflammatory drug 
ORAE 
Opioid-related adverse event 
PACU 
Postanesthesia care unit 
PK 
Pharmacokinetic(s) 
PO 
By mouth, orally 
PONV 
Postoperative nausea and vomiting 
PRN 
As needed 
QTcF 
QT correction Fridercia’s formula 
REB 
Research Ethics Board 
SAE 
Serious adverse event 
SAR 
Serious adverse reaction 
SD 
Standard deviation 
SE 
Standard error 
SNRI 
Selective norepinephrine reuptake inhibitor 
SOP 
Standard operating procedure 
SSRI 
Selective serotonin reuptake inhibitor 
TEAE 
Treatment-emergent adverse event 
TEG-POE 
Tri(ethylene glycol) poly(orthoester) 
Tmax 
Time to maximum plasma concentration 
ULN 
Upper limit of normal 
US 
United States 
WOCF 
Worst observation carried forward 
wWOCF 
Windowed worst observation carried forward 


Protocol No: HTX-011-218 Version 4 
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Phase 2 Bunionectomy HTX-011 Administration Study 
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1. 
INTRODUCTION 
1.1. 
Background Information and Study Rationale 
Up to 70% of patients have moderate to severe pain after surgery, and the most severe pain 
occurs within the first 72 hours (Lynch 1997; Svensson 2000; Apfelbaum 2003; Gan 2014; 
Misiolek 2014; Singla 2014; Meissner 2015). Administering a local anesthetic (eg, bupivacaine, 
ropivacaine, or levobupivacaine) is a relatively simple and safe means of providing postoperative 
pain relief. A major limitation of current local anesthetics is their short duration of effect (6 to 
12 hours following surgery) (Kehlet 2011). Consequently, many patients are given opioids for 
pain management. The requirement for opioids postoperatively is a serious manifestation of 
ineffective pain relief. Exposure to opioids can lead to opioid-related adverse events (ORAEs) 
resulting in worse patient outcomes and increased hospital costs (Coley 2002; Wheeler 2002; 
Stephens 2003; Cashman 2004; Shirakami 2005; Jarzyna 2011; Ramachandran 2011; Chan 
2013; Kessler 2013; Oderda 2013; Lee 2015; Lee 2016). Furthermore, transition from acute 
opioid use to chronic use can occur quickly. A recent review of a random sample of records from 
patients who had at least 1 opioid prescription between 2006 and 2015 showed that the 
probability of chronic opioid use begins to increase after the third day supplied and rises rapidly 
thereafter (Shah 2017). The United States (US) is facing a national opioid crisis that has led to a 
public health epidemic with multiple national and state responses. In 2015, 2 million Americans 
had a substance use disorder involving prescription pain relievers, and over 20,000 accidental 
overdose deaths were related to prescription pain relievers (Bose 2016; Rudd 2016). Reduced 
exposure to opioids and better pain management is associated with improved patient outcomes 
and reduced risk for the development of persistent pain and consequent opioid abuse (Barnett 
2017). Therefore, there is a medical need for clinical alternatives to prescription opioids to 
manage ambulatory nonmalignant pain. The development of an extended-release local anesthetic 
applicable for a broad range of surgeries that could significantly reduce both pain and opioid use 
after surgery and can be easily administered with a favorable safety profile would address an 
important public health need. 
Heron Therapeutics, Inc. (Heron) is developing HTX-011 for application into the surgical site to 
reduce postoperative pain for up to 72 hours and the need for opioid analgesics. HTX-011 is a 
novel, extended-release (also referred to as prolonged-release), fixed-dose combination product 
that contains bupivacaine and low-dose meloxicam. Bupivacaine is the disease-active ingredient 
and meloxicam enhances the effectiveness of bupivacaine. HTX-011 is a solution that is 
formulated in a proprietary tri(ethylene glycol)-based poly(orthoester) polymer (TEG-POE), 
termed Biochronomer®. HTX-011 is administered as a single dose that is applied into the 
surgical site to coat the affected tissues that could result in pain generation. Unlike other local 
anesthetics, HTX-011 is not injected; it is applied without a needle using a syringe with an 
applicator attached. After administration, the polymer enables extended release of bupivacaine 
and meloxicam simultaneously for approximately 3 days. 
Both bupivacaine and meloxicam are approved in the US, Europe, and other regions, and have a 
long history of clinical use. Bupivacaine is an amide-type local anesthetic and meloxicam is a 
nonsteroidal anti-inflammatory drug (NSAID). Inclusion of low-dose meloxicam in HTX-011 
reduces local inflammation caused by surgery and normalizes the local pH. This is believed to 


Protocol No: HTX-011-218 Version 4 
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Phase 2 Bunionectomy HTX-011 Administration Study 
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result in enhanced penetration of bupivacaine into the nerves, thereby potentiating its analgesic 
effect. Bupivacaine is commercially available as a solution for injection and is approved for 
surgical anesthesia and for acute pain management (nerve block) in adults and children 
(MARCAINE, SENSORCAINE®, and VIVACAINETM). Meloxicam is available as an oral 
tablet that is approved for the relief of signs and symptoms of osteoarthritis, relief of signs and 
symptoms of rheumatoid arthritis and relief of the signs and symptoms of pauciarticular or 
polyarticular course Juvenile Rheumatoid Arthritis in patients who weigh ≥60 kg. 
This Phase 2 open-label study will evaluate the analgesic efficacy, safety, and pharmacokinetics 
(PK) of a single, individualized dose of HTX-011 administered into the surgical site as a 
monotherapy or with other medications to enhance analgesia in subjects undergoing a primary 
unilateral bunionectomy. The study will include up to 4 cohorts. 
Cohort 1 will evaluate HTX-011 as a monotherapy. Cohort 2 will evaluate HTX-011 and a 3-day 
regimen of aprepitant. Aprepitant is approved in the US and many other countries in the world 
for chemotherapy induced nausea and vomiting (CINV) and postoperative nausea and vomiting 
(PONV). In the US, it is commercially available as oral capsules, an oral solution, and an 
injectable emulsion for intravenous (IV) use. Aprepitant exerts its effects by blocking substance 
P activity on the neurokinin-1 (NK1) receptor. Substance P is involved in a vast array of 
processes other than emesis including pain, anxiety, depression, and inflammation (Patel 2003). 
The use of aprepitant as an adjuvant to existing analgesics has shown some promising results 
(Kakuta 2011; Moon 2014).  
Cohort 3 will evaluate HTX-011 as part of a multimodal analgesic regimen of ibuprofen and 
acetaminophen. The American Pain Society guidelines recommend the use of multimodal 
analgesia for the treatment of postoperative pain (Kehlet 1993; Kehlet 2006; Krenzel 2009; 
Garimella 2013; Chou 2016). Multimodal analgesia is defined as the use of a variety of analgesic 
medication and techniques that target different mechanisms of action in the peripheral and/or 
central nervous system. These medications and techniques can also be combined with 
nonpharmacological interventions and may have additive or synergistic effects and more 
effective pain relief compared with single modality interventions. The goal of this approach is to 
provide improved pain control while reducing or eliminating the need for opioids. 
An optional Cohort 4 will evaluate HTX-011 as part of a multimodal analgesic regimen of 
ibuprofen and acetaminophen and with a 3-day regimen of aprepitant. 
1.2. 
Rationale for Study Design, Doses, and Control Groups 
This study in subjects undergoing a simple unilateral bunionectomy is designed to evaluate the 
safety and effectiveness of HTX-011 using an individualized dose, as tested in the completed 
Human Factor Validation Study for HTX-011, rather than a fixed dose. Bunionectomy is a bony 
surgical model that has shown good assay sensitivity for approximately 72 hours after the 
surgical insult (Singla 2014), which allows for analysis of acute analgesia over an extended 
period of time. 
The study includes 4 cohorts. In each cohort, a single dose of HTX-011 will be evaluated in this 
study of no more than 2.1 mL (up to 60 mg/1.8 mg [bupivacaine/meloxicam doses]) 
administered via instillation (ie, application into the surgical site). Subjects in Cohort 2 and 
optional Cohort 4 will also receive 3 single doses of aprepitant orally: approximately 3 hours 


Protocol No: HTX-011-218 Version 4 
Heron Therapeutics, Inc. 
Phase 2 Bunionectomy HTX-011 Administration Study 
Confidential 
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presurgery on Day 1 (125 mg) and at approximately 24 hours (Day 2) and 48 hours (Day 3) after 
the presurgery dose (80 mg at each timepoint). Subjects in Cohort 3 and optional Cohort 4 will 
receive a scheduled postoperative multimodal analgesic regimen consisting of ibuprofen and 
acetaminophen. 
In a previous Phase 2, dose finding study in bunionectomy (Study 208) that evaluated doses 
ranging from 30 mg/0.9 mg to 200 mg/6 mg administered via different local administration 
techniques (injection, injection using a Mayo block, instillation), the 30 mg/0.9 mg dose 
administered via injection was determined to be the minimally effective dose; however, 
60 mg/1.8 mg administered via instillation was selected for Phase 3 based on superior 
postoperative analgesia through 72 hours with a favorable safety profile. The incidence of local 
inflammatory treatment-emergent adverse events (TEAEs) appeared to be dose dependent with a 
higher incidence for HTX-011 120 mg/3.6 mg, and 200 mg/6 mg doses compared with 
bupivacaine HCl. 
In Phase 3, HTX-011 60 mg/1.8 mg provided superior, sustained pain relief and less need for 
opioids, with fewer subjects experiencing severe pain, more subjects who were opioid-free, and 
fewer subjects who experienced ORAEs over 72 hours compared with bupivacaine HCl 
(standard of care) and saline placebo. The overall safety profile of HTX-011 was similar to the 
well-established safety profile of bupivacaine HCl. The proportion of subjects with any wound 
healing symptom was similar across all treatment groups; however, there was a small increase in 
the incidence of local inflammatory TEAEs in the HTX-011 group. 
In both Phase 2 (Study 208) and Phase 3 (Study 301) studies, the full dose of HTX-011 of 
60 mg/1.8 mg (2.1 mL) was required to be administered into the surgical site. Surgeons 
performing the surgeries noted that HTX-011 drug product was expressed from the surgical site 
at closure in some subjects. Despite some product being expressed from the surgical site with the 
HTX-011 60 mg/1.8 mg dose given by instillation, efficacy was demonstrated in both Phase 2 
and Phase 3. Since the excess volume of HTX-011 expressed from the surgical site cannot 
contribute to efficacy and may cause some of the local irritation observed in patients, the volume 
of HTX-011 should be individualized up to 60 mg/1.8 mg (ie, no more than 2.1 mL) for each 
subject undergoing bunionectomy using a sufficient amount to coat the tissues without 
expressing excess from the surgical site during closure. This individualized approach to dosing 
was tested in a completed Human Factors Validation Study for HTX-011 and is also consistent 
with the planned package insert instructions for use of HTX-011 once commercially available. 
Aprepitant is often used in the surgical setting to prevent PONV. Single oral doses of 40 mg and 
125 mg of aprepitant were studied in 2 large Phase 3 multicenter, randomized, double-blind 
controlled trials in patients undergoing open abdominal surgery to support registration for PONV 
(Diemunsch 2007; Gan 2007). In these studies the 40 mg dose was more effective at preventing 
PONV and is the approved dose; however, the 125 mg dose that was administered to a total of 
525 patients across the 2 studies was well-tolerated with a similar safety profile to the 40 mg 
dose. The most commonly reported AEs across the studies were consistent and typical of 
surgical patients and included bradycardia, pyrexia, constipation, headache, pruritus, and nausea. 
The nociception system uses numerous transmitter substances in parallel and its sensitivity is 
adjusted in response to tissue injury; therefore, the use of an NK1 receptor antagonist as an 
adjuvant to existing analgesics could provide more promising results (Hill 2000).The initial 
clinical studies investigating NK1 receptor antagonists for pain management performed in 


Protocol No: HTX-011-218 Version 4 
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Phase 2 Bunionectomy HTX-011 Administration Study 
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subjects undergoing molar extraction were encouraging, but subsequent studies in peripheral 
neuropathy, osteoarthritis, and migraine were less promising (Rupniak 1999). Two recent studies 
of aprepitant in PONV in subjects undergoing laparoscopic gynaecologic surgery evaluated pain 
intensity and analgesic use at single doses of 40 mg and 80 mg. In a double-blind, randomized 
clinical study, IV fentanyl administration using patient-controlled analgesia was significantly 
lower 24 hours after surgery in subjects who received a single oral 40 mg dose of aprepitant than 
in subjects who received a single IV dose of palonosetron, although there was no significant 
difference in pain intensity (Moon 2014). These results were similar to that of an earlier study in 
which the rescue analgesic requirement was lower for subjects who received a single oral 80 mg 
dose of aprepitant preoperatively compared with a no treatment control despite no effect on pain 
intensity (Kakuta 2011). 
The approved dose regimen of oral aprepitant for CINV prevention is a 3-day regimen with 
125 mg given on Day 1, followed by 80 mg on Days 2 and 3 (EMEND Oral USPI May 2017). 
Due to the inconsistent effects on pain reduction in prior studies that utilized a single dose of 
aprepitant at doses of 40 mg and 80 mg, this study will include the approved 3-day dosing 
regimen to examine the potential added benefit of aprepitant in the reduction in pain and use of 
opioids observed with HTX-011 alone. 
Acetaminophen and ibuprofen (an NSAID) were selected for the scheduled multimodal regimen 
in this study using doses consistent with the prescribing information for each medication. Both 
are commonly used analgesics with a long history of use and relatively few side effects. These 
pain medications are frequently given as part of multimodal therapy for pain management 
following foot and ankle surgery (Halaszynski 2016; Kohring 2017), and a review of the 
literature showed that combining acetaminophen with NSAIDs reduced acute postoperative pain 
better than either medication alone (Ong 2010). 
No control group is included in this study because the efficacy and safety of HTX-011 in 
bunionectomy was demonstrated in the prior Phase 2 and Phase 3 studies, Study 208 and Study 
301, respectively. Local inflammatory TEAEs and wound healing assessments will be evaluated 
using the same methods as in Study 301. The main efficacy endpoints for this study are the same 
as included in Study 301 to permit cross-study comparisons. The primary endpoint is mean area 
under the curve (AUC) of the Numeric Rating Scale of pain intensity scores with activity 
(NRS-A) through 72 hours (AUC0-72) for HTX-011. It was selected based on FDA and 
Committee for Medicinal Products for Human Use (CHMP) guidance as well as regulatory 
precedent. Draft FDA Guidance for Industry on Analgesic Indications: Developing Drug and 
Biological Products (February 2014) states that “pain intensity is the fundamental measure that 
defines the efficacy of an analgesic drug.” 
1.3. 
Potential Risks and Benefits 
For more information on HTX-011, refer to the Investigator’s Brochure (IB). For more 
information on the active ingredients, bupivacaine and meloxicam, refer to the US prescribing 
information for MARCAINE and MOBIC, respectively. For information on aprepitant, refer to 
the US prescribing information for aprepitant capsules. The Investigator should also refer to the 
respective US prescribing information for information on risks associated with the required 
concomitant medications or rescue medications. 


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1.3.1. 
HTX-011 
As of July 2018, a total of 1077 subjects had received a single dose of the intended commercial 
formulation of HTX-011 in 8 clinical studies. The numbers of subjects exposed to HTX-011 by 
study phase include 10 in one Phase 1 study, 430 in three Phase 2a studies, 317 in two Phase 2b 
studies, and 320 in two Phase 3 studies. 
The potential risks and benefits of the intended commercial formulation of HTX-011 are 
described for all clinical studies, including the 2 studies in which subjects underwent 
bunionectomy (Study 208 and Study 301). 
Safety 
In the Phase 1 study in healthy volunteers (Study 102) and the Phase 2a studies in bunionectomy 
(Study 208), herniorrhaphy (Study 202), and abdominoplasty (Study 203), study drug was 
administered via subcutaneous injection (Study 102) or via local administration into the surgical 
site (injection, instillation, a combination of injection and instillation, or injection using a Mayo 
block) at doses ranging from 30 mg/0.9 mg to 600 mg/18 mg (bupivacaine/meloxicam doses). In 
Study 102, treatment with HTX-011 400 mg/12 mg was safe and well tolerated. All TEAEs were 
mild, and the most frequently reported TEAE was injection site bruising in 8 of 10 subjects. No 
serious adverse events (SAEs) were reported. In the Phase 2a studies, results showed that 
treatment with HTX-011 was generally well tolerated. The most common TEAEs were nausea, 
constipation, headache, and dizziness. The majority of TEAEs were mild or moderate in severity 
and resolved without sequelae. In subjects who received the intended commercial formulation of 
HTX-011, the incidence of SAEs was low: 2 subjects in Study 202, 1 subject in Study 203, and 
1 subject in Study 208. The SAEs in Studies 203 and 208 were considered related to study drug 
and were, therefore categorized as, serious adverse reactions (SARs). 
Safety data from subjects who received HTX-011 via instillation into the surgical site in the two 
Phase 2b studies in total knee arthroplasty (TKA; Study 209) and augmentation mammoplasty 
(Study 211), and from the two Phase 3 studies in bunionectomy (Study 301) and herniorrhaphy 
(Study 302) were integrated for analysis. Results from these studies revealed that the safety 
profile of a single dose of HTX-011 was similar to the well-established safety profile of 
bupivacaine HCl, but without the risk of injection-related high plasma concentrations and 
resulting toxicities. Specifically, the incidences of any TEAE and of any study drug-related 
TEAE were similar for the total HTX-011 group (60 mg/1.8 mg to 400 mg/12 mg doses 
combined) compared with active and placebo controls (ie, the total bupivacaine HCl group 
[50 mg to 125 mg doses combined] and the saline placebo group, respectively), and there were 
no dose-dependent trends in the individual HTX-011 dose groups. The most common TEAEs 
were nausea, constipation, dizziness, vomiting, and headache. The incidences were generally 
similar for HTX-011 compared with the controls, and there was no apparent dose-dependent 
trend in the HTX-011 dose groups. The majority of TEAEs were mild or moderate in severity. 
The incidence of severe TEAEs was low and similar across all treatment groups, as well as the 
individual HTX-011 dose groups. The incidences of SAEs were low (1.8% to 2.2%) for the 
integrated treatment groups, with the highest incidences reported in the HTX-011 400 mg/12 mg 
(3.7%) and bupivacaine HCl 125 mg group (4.6%). No deaths were reported for subjects who 
received HTX-011. 


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The incidences of ORAEs were similar for the total HTX-011 and control groups (50.5% to 
55.5%), and there was no apparent dose-dependent trend in the HTX-011 dose groups. However, 
the incidences were higher for HTX-011 200 mg/6 mg and 400 mg/12 mg and bupivacaine 
HCl 125 mg. All except for 5 subjects administered these doses received at least 1 opioid rescue 
medication during the 72-hour postoperative period. 
There were no clinically meaningful differences in laboratory results, vital sign measurements, 
physical examination findings, or electrocardiogram (ECG) findings. 
There was no evidence of Local Anesthetic System Toxicity (LAST) based on a review of 
potential LAST-related TEAEs, vital signs, ECGs, and bupivacaine plasma concentrations. The 
incidence of local inflammatory TEAEs was similar for the total HTX-011 group and 
comparators; however, the incidences were higher for the HTX-011 60 mg/1.8 mg and 
bupivacaine HCl 50 mg groups, which were the doses used in the Phase 3 bunionectomy study 
(Study 301). Finally, there were no clinically meaningful differences among treatment groups in 
assessments of wound healing or bone healing (Study 301). 
Serious Adverse Reactions 
As of 30 May 2018, a total of 3 SARs (SAEs considered related to study drug by the Investigator 
and/or the Sponsor) have been reported in 3 subjects who received the intended commercial 
formulation of HTX-011. One SAR of severe impaired healing was reported in a subject who 
received HTX-011 200 mg/6 mg via injection using a Mayo block in the bunionectomy study 
(Study 208), 1 SAR of mild wound dehiscence was reported in a subject who received HTX-011 
300 mg/9 mg via combination (injection and instillation) administration technique in the 
abdominoplasty study (Study 203), and 1 SAR of moderate post procedural cellulitis was 
reported in a subject who received HTX-011 400 mg/12 mg instillation + 50 mg ropivacaine in 
the TKA study (Study 209). All 3 SARs resolved; the 1 SAR of impaired healing resolved with 
sequelae. 
Efficacy 
A precedent Phase 2a formulation-, dose-, and administration technique-finding study was 
conducted in bunionectomy (Study 208). The study evaluated 4 HTX-011 doses (30 mg/0.9 mg, 
60 mg/1.8 mg, 120 mg/3.6 mg, and 200 mg/6 mg) administered into the surgical site via different 
administration techniques (injection, injection using a Mayo block, or instillation [with or 
without a Luer lock applicator]). All subjects also received a 1% lidocaine Mayo block just prior 
to the start of surgery for intraoperative pain control. HTX-011 60 mg/1.8 mg (the Phase 3 dose) 
administered via instillation significantly reduced the mean area under the curve from Time 0 
through 72 hours (AUC0-72) of Numeric Rating Scale (NRS) pain intensity scores compared with 
saline placebo and bupivacaine HCl controls (p=0.0128 and p=0.0083, respectively) and 
significantly reduced the mean total opioid consumption through 72 hours compared with both 
controls (p=0.0392 and p=0.0267, respectively). In addition, a higher proportion of HTX-011-
treated subjects were opioid-free for 72 hours compared with both controls (17.6% vs 5.6% and 
10.0%, respectively), but the differences were not statistically significant. 
In the adequate and well-controlled Cohort 2 of the Phase 2b TKA study (Study 209), a bony 
surgical model, HTX-011 400 mg/12 mg administered with or without low-dose ropivacaine 
significantly reduced pain over 48 and 72 hours compared with saline placebo. In addition, 
HTX-011 + low-dose ropivacaine significantly reduced pain over 48 and 72 hours compared 


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with bupivacaine HCl. Furthermore, fewer subjects in the HTX-011 alone group and 
significantly fewer subjects in the HTX-011 + low-dose ropivacaine group experienced severe 
pain (NRS of pain intensity score at rest [NRS-R] score ≥7) at any timepoint through 72 hours 
compared with saline placebo and bupivacaine HCl. Finally, total opioid consumption was lower 
for HTX-011 and significantly lower for HTX-011 + low dose ropivacaine compared with saline 
placebo and bupivacaine HCl over 48 and 72 hours. 
Efficacy was also demonstrated in the 2 adequate and well-controlled Phase 3 studies in subjects 
undergoing bunionectomy (Study 301) and herniorrhaphy (Study 302). HTX-011 provided 
superior, sustained pain relief, reduced opioid intake, and increased the proportion of subjects 
who were opioid-free over the first 72 hours following study drug administration compared with 
both bupivacaine HCl and saline placebo in the bony and soft tissue surgical models of 
postoperative pain. These results are consistent with those from 2 precedent Phase 2a studies 
(Studies 208 and 202). The proportion of subjects who experienced severe pain (NRS-A score 
≥7) at any timepoint during the 72-hour postoperative period was also significantly lower in the 
HTX-011 groups compared with the saline placebo and bupivacaine HCl groups in both studies. 
This was consistent with the observed reduction in total opioid consumption and increase in the 
proportions of opioid-free subjects. Finally, across the 2 studies, >91% of the subjects who 
received HTX-011 and were opioid-free during the 72-hour postoperative period remained 
opioid-free through Day 7, and >82% remained opioid free through Day 28. 
The primary and key secondary efficacy endpoints in all 3 adequate and well-controlled studies 
were achieved for HTX-011. 
Risks 
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 2015). Close attention should be given to conditions that 
may represent reported toxicities associated with bupivacaine including, but not limited to, 
perioral tingling, metallic taste, visual and auditory disturbances, muscle twitching, seizure, 
acidosis, shortness of breath, bradycardia (heart rate <50 beats per minute with symptoms), 
hypotension (systolic blood pressure <90 mmHg or symptomatic decrease from baseline), low 
oxygen saturation, and cardiac arrest. 
Potential risks for meloxicam include CV adverse reactions, gastrointestinal bleeding, and liver 
tests elevations (MOBIC Tablets USPI 2016). NSAIDs may cause an increased risk of serious 
CV thrombotic events, myocardial infarction, and stroke, which can be fatal, and this risk may 
increase with duration of use. Patients with known CV disease or risk factors for CV disease may 
be at greater risk. NSAIDs may also cause an increased risk of serious gastrointestinal adverse 
events (AEs) including inflammation, bleeding, ulceration, and perforation of the esophagus, 
stomach or intestines, which can be fatal. Elderly patients are at greater risk for serious 
gastrointestinal events. Borderline elevations of 1 or more liver tests may occur in patients taking 
NSAIDs, including meloxicam, which may worsen. It is unclear how applicable these potential 
risks are for meloxicam when given as single dose via application into the surgical site (a novel 
administration method for meloxicam) for postoperative pain as part of a fixed-ratio combination 


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(eg, HTX-011). Any subject in this study with symptoms and/or signs suggesting liver 
dysfunction, or in whom an abnormal liver function test has occurred, should be evaluated for 
evidence of the development of a more severe hepatic reaction. 
Use of HTX-011 in subjects with hypersensitivity to bupivacaine, meloxicam, or any of the 
components of HTX-011 is contraindicated. 
1.3.2. 
Aprepitant 
Potential benefits of aprepitant for postoperative pain based on the published literature are 
described in Section 1.2. 
Potential risks for aprepitant include clinically significant CYP3A4 drug interactions, a decrease 
in International Normalized Ratio (INR) with concomitant warfarin, risk of reduced efficacy of 
hormonal contraceptives, and hypersensitivity including anaphylactic reactions have been 
reported (EMEND Oral USPI May 2017). Aprepitant is contraindicated in patients with 
hypersensitivity to aprepitant or any component of the capsules and in patients taking pimozide 
due to inhibition of CYP3A4 by aprepitant that could result in elevated plasma concentrations 
potentially causing serious or life-threatening reactions, such as QT prolongation (a known 
adverse reaction of pimozide). INR must be monitored in patients on chronic warfarin therapy for 
2 weeks following initiation of the 3-day regimen of aprepitant. Upon coadministration with 
aprepitant, the efficacy of hormonal contraceptives may be reduced during administration of and 
for 30 days following the last dose of aprepitant; therefore, effective alternative or back-up 
methods of contraception during treatment with aprepitant and for 1 month following the last dose 
of aprepitant is required. Although very rare, Stevens-Johnson syndrome has been reported in a 
patient receiving the aprepitant regimen with cancer chemotherapy (EMEND Oral USPI May 
2017). The most common adverse reactions reported for aprepitant given as a 3-day regimen 
(125 mg on day 1 and 80 mg on days 2 and 3) in patients receiving emetogenic chemotherapy 
included fatigue, diarrhea, asthenia, dyspepsia, abdominal pain, hiccups, white blood cell count 
decreased, dehydration, and alanine aminotransferase increased (EMEND Oral USPI May 2017). 


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2. 
STUDY OBJECTIVES 
2.1. 
Primary Objectives 
The primary objectives are as follows: 
 To assess the efficacy and duration of analgesia, following a single individualized 
dose of HTX-011, during the first 72 hours after unilateral simple bunionectomy. 
 To assess the analgesic efficacy following a 3-day regimen of oral aprepitant and a 
single individualized dose of HTX-011 during the first 72 hours after unilateral 
simple bunionectomy (Cohort 2). 
 To assess the analgesic efficacy following a single individualized dose of HTX-011 
as part of a multimodal analgesic regimen during the first 72 hours after unilateral 
simple bunionectomy (Cohort 3). 
 To assess the analgesic efficacy following a 3-day regimen of oral aprepitant and a 
single individualized dose of HTX-011 as part of a multimodal analgesic regimen 
during the first 72 hours after unilateral simple bunionectomy (optional Cohort 4). 
2.2. 
Secondary Objectives 
The secondary objectives are as follows: 
 To assess the effect of study treatment on opioid load during the first 72 hours 
following surgery in this study population. 
 To assess the proportion of subjects who are opioid-free after receiving HTX-011 as 
part of a multimodal analgesic regimen during the first 72 hours in this study 
population (Cohort 3 and optional Cohort 4). 
 To assess the proportion of subjects who are opioid-free after receiving HTX-011 as 
part of a multimodal analgesic regimen during the first 72 hours with or without 
aprepitant and who remain opioid-free through Day 10 and Day 28 (Cohort 3 and 
optional Cohort 4). 
 To assess the safety and tolerability of study treatment in this study population. 
 To confirm the PK parameters of bupivacaine and meloxicam for a single 
individualized dose of HTX-011 in this study population. 
 To analyze the PK parameters of aprepitant in the presence of HTX-011 in this study 
population (Cohort 2 and optional Cohort 4). 




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intraoperatively via application into the surgical site, as described in Section 5.5. The exact 
amount of HTX-011 instilled will be determined by the Investigator at the time of surgery. 
Following surgery and immediate postoperative recovery, all subjects will be transferred to the 
postanesthesia care unit (PACU).  
3.1.1.1.2. Cohort 2 
Approximately 15 subjects will be enrolled in Cohort 2. Subjects will receive a single oral dose 
of aprepitant 125 mg approximately 3 hours prior to the start of surgery. Near the completion of 
surgery and after irrigation and suction have been completed, a single individualized dose of 
HTX-011 of no more than 2.1 mL HTX-011 [up to 60 mg/1.8 mg (bupivacaine/meloxicam 
doses)] will be given intraoperatively via application into the surgical site, as described in 
Section 5.5. The exact amount of HTX-011 instilled will be determined by the Investigator at the 
time of surgery. 
Following surgery and immediate postoperative recovery, all subjects will be transferred to the 
PACU. Subjects will be administered a single oral dose of aprepitant 80 mg at approximately 24 
hours (Day 2) and at approximately 48 hours (Day 3) after the presurgery dose of aprepitant.  
3.1.1.1.3. Cohort 3 
Approximately 30 subjects will be enrolled in Cohort 3. Near the completion of surgery and after 
irrigation and suction have been completed, a single dose of HTX-011 will be given 
intraoperatively via application into the surgical site. The dose is individualized for each subject, 
up to a maximum of 2.1 mL [up to 60 mg/1.8 mg (bupivacaine/meloxicam doses)]. The exact 
amount of HTX-011 instilled will be determined by the Investigator at the time of surgery. 
Following surgery and immediate postoperative recovery, all subjects will be transferred to the 
PACU. Subjects will receive a scheduled postoperative analgesic regimen as follows: start with 
600 mg oral ibuprofen once they are able to tolerate oral intake in the PACU, then 3 hours after 
the ibuprofen dose administer the first postoperative dose of 1 g oral acetaminophen, then 
alternate these 2 medications so a dose is delivered every 3 hours. (In other words, 3 hours after 
their first 600 mg oral ibuprofen dose, subjects will receive a 1 g oral acetaminophen dose, then 
after 3 more hours another 600 mg oral ibuprofen dose, and so on until the 72-hour postoperative 
period is complete.) These medications will be administered on a round-the-clock, scheduled 
basis through the 72-hour postoperative period. 
3.1.1.1.4. Cohort 4 (Optional) 
At the Sponsor’s discretion upon completion of Cohort 3, Cohort 4 may be initiated. If initiated, 
approximately 15 subjects will be enrolled in Cohort 4. Subjects will receive a single oral dose of 
aprepitant 125 mg approximately 3 hours prior to the start of surgery. Near the completion of 
surgery and after irrigation and suction have been completed, a single dose of HTX-011 will be 
given intraoperatively via application into the surgical site. The dose is individualized for each 
subject, up to a maximum of 2.1 mL [up to 60 mg/1.8 mg (bupivacaine/meloxicam doses)]. The 
exact amount of HTX-011 instilled will be determined by the Investigator at the time of surgery. 
Following surgery and immediate postoperative recovery, all subjects will be transferred to the 
PACU. Subjects will receive a scheduled postoperative analgesic regimen as follows: start with 


Protocol No: HTX-011-218 Version 4 
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600 mg oral ibuprofen once they are able to tolerate oral intake in the PACU, then 3 hours after 
the ibuprofen dose administer the first postoperative dose of 1 g oral acetaminophen, then 
alternate these 2 medications so a dose is delivered every 3 hours. (In other words, 3 hours after 
their first 600 mg oral ibuprofen dose, subjects will receive a 1 g oral acetaminophen dose, then 
after 3 more hours another 600 mg oral ibuprofen dose, and so on until the 72-hour postoperative 
period is complete.) In addition, subjects will be administered a single oral dose of aprepitant 
80 mg at approximately 24 hours (Day 2) and at approximately 48 hours (Day 3) after the 
presurgery dose of aprepitant. 
3.1.2. 
Postoperative Observation Period and Follow-Up 
All subjects will remain in the hospital/research facility for a minimum of 72 hours after the start 
of study drug administration to undergo postoperative assessments. After the 72-hour 
assessments have been completed, subjects may be discharged. Subjects should be instructed at 
the time of discharge to leave the bandage clean, dry, and intact until the Day 7 visit. In addition, 
the subject should be provided with a cast guard to assist with keeping the bandage dry and 
instructed to contact the site if the bandage gets wet.  
Subjects in Cohorts 3 and 4 (whether or not they were discharged with an opioid prescription) 
will receive a diary at discharge, which they will complete each day to record whether they take 
an opioid medication between 72 hours and Day 28.  
All subjects will return to the study site on Days 7 and 28 to complete follow-up assessments. In 
addition, subjects will return for a Safety Follow-Up Visit on Day 42. 
3.1.3. 
Postoperative Analgesic Medications 
3.1.3.1. 
Rescue Medication During Inpatient 72-Hour Postoperative Period 
Subjects should only receive rescue medication upon request for pain control, as needed, during 
the 72-hour postoperative observation period. Rescue medication should not be given for pain 
prophylaxis, but only for treating postoperative pain. Prior to the administration of the first dose 
of rescue medication, if the subject has not already had at least 1 postoperative pain score 
assessed, then a Numeric Rating Scale (NRS) score at rest (NRS-R) followed by a Numeric 
Rating Scale score with activity (NRS-A) pain score must be obtained. 
Cohorts 1 and 2: Postoperative rescue medication will consist of oral immediate-release 
oxycodone (no more than 10 mg within a 4-hour period as needed), IV morphine (no more than 
10 mg within a 2-hour period as needed), and/or oral acetaminophen (no more than 1 gram 
[1000 mg] in a 6-hour window). For subjects administered any acetaminophen-containing 
product, the total combined daily dose must not exceed 4 grams (4000 mg) as severe liver 
damage may occur. Combination products containing an opioid and non-opioid are not allowed. 
No other analgesic agents, including NSAIDs, are permitted during the 72-hour postoperative 
observation period. 
Cohorts 3 and 4: Postoperative rescue medication will consist of oral immediate-release 
oxycodone (no more than 10 mg within a 4-hour period as needed) and/or IV morphine (no more 
than 10 mg within a 2-hour period as needed). Combination products containing an opioid and 
non-opioid are not allowed. With the exception of oral ibuprofen and oral acetaminophen, no 


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other analgesic agents, including NSAIDs, are permitted during the 72-hour postoperative 
observation period. 
Subjects who are not medically ready for discharge at 72 hours may receive the same rescue 
medication as above to treat postoperative pain until discharge. 
3.1.3.2. 
Postoperative Analgesia After Discharge 
Cohorts 1 and 2: For subjects who are medically ready for discharge at 72 hours, oral 
acetaminophen (no more than 1000 mg every 6 hours as needed) should be recommended for 
postoperative pain. If a subject received 10 mg or more of oxycodone in the 12 hours prior to 
discharge, the subject should be provided with a prescription for immediate-release oxycodone 
(up to 10 mg orally [PO] q4h as needed).  
Cohorts 3 and 4: Upon discharge, subjects will be instructed to manage pain with the following 
regimen: 
 600 mg oral ibuprofen every 6 hours as needed (PRN) as first-line therapy (before 
acetaminophen). 
 1g oral acetaminophen every 6 hours PRN as second-line therapy (ie, if ibuprofen has 
been administered but the subject is still in pain). 
If a subject received 10 mg or more of oxycodone in the 12 hours prior to discharge, the subject 
should be provided with a prescription for immediate-release oxycodone (up to 10 mg PO q4h as 
needed). Pharmacists should be instructed that substitutions with any other opioid-containing 
product are not permitted, including combination opioid/non-opioid products. Sites must record 
if a subject is discharged with an opioid prescription (yes or no) in Cohorts 3 and 4.  
See Appendix E for instructions on postoperative pain management for subjects medically ready 
for discharge. 
3.1.4. 
Pharmacokinetic Assessments 
PK assessments will include the collection of blood samples for bupivacaine, meloxicam, and 
aprepitant PK analysis. 
3.1.5. 
Efficacy and Safety Assessments 
Efficacy assessments will include pain intensity scores using NRS-R and NRS-A, and use of 
opioid medication. 
Safety assessments will include AE recording, physical examinations, vital signs, hematology 
and serum chemistry, and wound healing assessments. 
See Section 6 for more information on the study procedures and assessments. For the timing of 
procedures and assessments, see Section 7 and the Schedule of Events table. 


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3.2. 
Study Endpoints 
3.2.1. 
Efficacy Endpoints 
3.2.1.1. 
Primary Efficacy Endpoint 
 Area under the curve (AUC) of the Numeric Rating Scale of pain intensity scores 
with activity (NRS-A) through 72 hours (AUC0-72). 
3.2.1.2. 
Secondary Efficacy Endpoints 
 Total postoperative opioid consumption (in morphine equivalents) through 72 hours. 
 Proportion of subjects who are opioid-free through 72 hours. 
 AUC0-72 of the NRS-R pain intensity scores. 
 Proportion of subjects who are opioid-free through 72 hours who remain opioid-free 
through Day 10 and Day 28 (Cohorts 3 and 4 only). 
3.2.2. 
Safety Endpoints 
 Incidence of TEAEs, SAEs, and ORAEs through the Safety Follow-Up on Day 42. 
 Change from baseline in clinical laboratory results. 
 Change from baseline in vital signs. 
 Wound healing assessment at 72 hours, on Day 7 and Day 28, and at the Safety 
Follow-Up on Day 42. 
3.2.3. 
Pharmacokinetic Endpoints 
 The area under the plasma concentration-time curve from time zero to time t of the 
last measured concentration above the limit of quantification (AUC0-last) (for 
bupivacaine and meloxicam only). 
 The area under the plasma concentration-time curve from zero to infinity (AUC0-inf) 
(for bupivacaine and meloxicam only). 
 The maximum plasma concentration (Cmax). 
 Apparent total body clearance over bioavailability (Cl/F). 
 Apparent total volume of distribution over bioavailability (VZ/F). 
 The time to reach maximum plasma concentration (Tmax). 
 The terminal elimination rate constant (λZ) with the respective half-life (t½). 
3.3. 
Study Duration 
The overall duration of the study is anticipated to be approximately 7 months. The total duration 
of study participation for each subject (from Screening through the Safety Follow-Up on Day 42) 
will be up to 77 days. 


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For regulatory reporting purposes, the end of the study is defined as the date of the last subject’s 
last assessment (scheduled or unscheduled). 


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4. 
STUDY ENROLLMENT AND WITHDRAWAL 
4.1. 
Study Population 
Approximately 90 subjects will be enrolled in this study at up to approximately 2 study sites. 
4.1.1. 
Inclusion Criteria 
Each subject must meet all of the following criteria to be enrolled in this study: 
1. Is able to provide written informed consent, adhere to the study visit schedule, and 
complete all study assessments. 
2. Is male or female, and ≥18 years of age at screening. 
3. Is scheduled to undergo a primary unilateral, distal, first metatarsal bunionectomy with 
osteotomy and internal fixation under regional anesthesia. 
4. Has an American Society of Anesthesiologists Physical Status of I, II, or III. 
5. Female subjects are eligible only if all of the following apply: 
a. Not pregnant (female subjects of child-bearing potential must have a negative urine 
pregnancy test at screening and on Day 1 before surgery). 
b. Not lactating. 
c. Not planning to become pregnant during the study. 
d. For Cohorts 1 and 3, is surgically sterile; or is at least 2 years post-menopausal; or is 
in a monogamous relationship with a partner who is surgically sterile; or is practicing 
abstinence or agrees to use double-barrier contraception in the event of sexual 
activity; or is using an insertable, injectable, transdermal, or combination oral 
contraceptive approved by applicable regulatory authorities for greater than 2 months 
prior to screening and commits to the use of an acceptable form of birth control for 
the duration of the study and for 30 days after study drug administration. Note: 
women in only a same-sex relationship do not need to meet this criterion. 
e. For Cohorts 2 and 4, is surgically sterile; or is at least 2 years post-menopausal; or is 
in a monogamous relationship with a partner who is surgically sterile; or is practicing 
abstinence or agrees to use double-barrier contraception or a non-hormonal intra-
uterine device (eg, copper) in the event of sexual activity for greater than 2 months 
prior to screening, for the duration of the study and for 30 days after last study drug 
administration. Notes: Women in only a same-sex relationship do not need to meet 
this criterion. Hormonal contraceptives are not an acceptable form of birth control 
since the efficacy of hormonal contraceptives may be reduced with aprepitant. 
4.1.2. 
Exclusion Criteria 
A subject who meets any of the following criteria will be excluded from the study: 
1. Has had a contralateral foot bunionectomy in the past 3 months. 
2. Has a planned concurrent surgical procedure (eg, bilateral bunionectomy or collateral 
procedures on the surgical foot). 


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3. Has a pre-existing concurrent acute or chronic painful physical/restrictive condition 
expected to require analgesic treatment in the postoperative period for pain that is not 
strictly related to the bunionectomy and which may confound the postoperative 
assessments. 
4. Has a contraindication or a known or suspected history of hypersensitivity or clinically 
significant idiosyncratic reaction to bupivacaine (or other local anesthetics), meloxicam 
(or other NSAIDs), oxycodone, morphine, acetaminophen, aprepitant (Cohorts 2 and 4 
only), or ibuprofen (Cohorts 3 and 4 only). 
5. Has known or suspected daily use of opioids for 7 or more consecutive days within the 
previous 6 months. 
6. Has taken any NSAIDs (including meloxicam) within at least 10 days prior to the 
scheduled surgery with the exception of subjects on low dose (≤100 mg) daily 
acetylsalicylic acid for cardioprotection. 
7. Has taken long-acting opioids within 3 days prior to the scheduled surgery. 
8. Has taken any opioids within 24 hours prior to the scheduled surgery. 
9. Has been administered bupivacaine within 5 days prior to the scheduled surgery. 
10. For Cohorts 2 and 4 only, has been administered aprepitant or another NK1 receptor 
antagonist such as rolapitant, netupitant, or fosaprepitant within 5 days prior to the 
scheduled surgery. 
11. Has been administered any local anesthetic within 72 hours prior to the scheduled 
surgery, other than for pretreatment prior to a needle placement, to treat an AE that 
occurs after signing the ICF, or to decrease venous irritation (eg, caused by propofol, in 
which case no more than a single administration of lidocaine 1% plain 20 mg IV may be 
administered). 
12. Has initiated treatment with any of the following medications within 1 month prior to 
study drug administration or is taking any of these medications to control pain: selective 
serotonin reuptake inhibitors (SSRIs), selective norepinephrine reuptake inhibitors 
(SNRIs), gabapentin, pregabalin, or cyclooxygenase-2 (COX-2) inhibitors. (Note: If a 
subject is taking one of these medications for a reason other than pain control, the subject 
must be on a stable scheduled dose [ie, not “as needed”] for at least 1 month prior to 
study drug administration.) Anxiolytics prior to surgery are permitted, if necessary. 
13. Has been administered systemic steroids within 5 half-lives or 10 days prior to 
administration of study drug (whichever is longer). 
14. Has a medical condition such that, in the opinion of the Investigator, participating in the 
study would pose a health risk to the subject or confound the postoperative assessments. 
Conditions may include, but are not limited to, any of the following: 
a. History of clinically significant cardiac abnormality such as myocardial infarction 
within 6 months prior to signing the ICF, New York Heart Association class III or IV, 
or clinically significant abnormalities in cardiac function or on ECG (including but 
not limited to a PR interval >200 msec, a QT corrected by Fridericia’s formula 
[QTcF] >480 msec, or 3rd degree heart block). 


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b. History of coronary artery bypass graft surgery within 12 months prior to signing the 
ICF. 
c. History of severe liver function impairment as defined by Child-Pugh Class C, having 
an aspartate aminotransferase >3 × the upper limit of normal (ULN), or having an 
alanine aminotransferase >3 × ULN. 
d. History of severe kidney function impairment as defined by creatinine clearance 
(Cockcroft-Gault) <30 mL/min, being on dialysis, and/or having a serum creatinine 
>2 × ULN. 
e. History of known or suspected coagulopathy or uncontrolled anticoagulation (platelet 
count <100,000/μL, hemoglobin <12 g/dL, or hematocrit <35%). 
f. Loss of sensation in extremities or significant peripheral neuropathy. 
15. 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). 
16. Has uncontrolled anxiety, psychiatric, or neurological disorder that, in the opinion of the 
Investigator, might interfere with study assessments. 
17. For Cohorts 2 and 4 only, is receiving pimozide, a strong or moderate CYP3A4 inhibitor 
(eg, diltiazem, ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, 
ritonavir, nelfinavir), or a strong CYP3A4 inducer (eg, rifampin, carbamazepine, 
phenytoin). 
18. Had a malignancy in the last year, with the exception of nonmetastatic basal cell or 
squamous cell carcinoma of the skin or localized carcinoma in situ of the cervix. 
19. Has a known or suspected history of drug abuse, a positive urine drug screen on the day 
of surgery, or a recent history of alcohol abuse (ie, within 10 years). Note: Subjects with 
a positive drug screen who are taking an allowed, prescribed medication that is known to 
result in a positive drug test (eg, amphetamine and dextroamphetamine for 
attention-deficit/hyperactivity disorder, benzodiazepine for anxiety disorder) may be 
eligible for participation in the study. Subjects taking medical or recreational marijuana 
are not allowed to participate in the study. 
20. Previously participated in an HTX-011 study. 
21. 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. 
22. Has undergone 3 or more surgeries within 12 months prior to signing the ICF, other than 
for diagnostic procedures (eg, colonoscopy). 
23. Has a body mass index (BMI) >39 kg/m2. 
4.2. 
Method of Assigning Subjects to Treatment Groups 
The study is not randomized. All eligible subjects will be enrolled into 1 of 4 cohorts. Cohorts 1 
through 4 will be conducted sequentially. 


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4.2.1. 
Procedures for Handling Subjects Who Do Not Meet the Study Eligibility 
Criteria 
Subjects who fail to meet the eligibility criteria should not, under any circumstances, receive 
study drug: HTX-011 (all subjects) or aprepitant (Cohorts 2 and 4). 
Subjects who meet the Screening eligibility criteria, but who do not meet the eligibility criteria 
on Day 1 will be withdrawn from the study without receiving study drug. In the event a subject 
does not meet the eligibility criteria, but receives study drug, HTX-011 (all subjects) or 
aprepitant (Cohorts 2 and 4), 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. 
Subject Withdrawal and Replacement 
4.3.1. 
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. 
 Withdrawal by subject. 
 Death. 
 Lost to follow up. 
 Pregnancy. 
 Investigator’s decision. 
 Sponsor’s decision. 
 Failure to meet eligibility criteria at Day 1. 
The date and the primary reason for early withdrawal will be recorded on the electronic case 
report form (eCRF). At the time of withdrawal from the study, every attempt should be made to 
complete the Early Termination Visit assessments (see Section 7.4). 
4.3.2. 
Subject Replacement 
Subjects who withdraw from study will not be replaced. To account for withdrawal of subjects 
who are ineligible at Day 1, enrollment will continue until at least 30 subjects have been dosed in 
Cohort 1, 15 subjects in Cohort 2, 30 subjects in Cohort 3, and 15 subjects in optional Cohort 4. 


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5. 
STUDY TREATMENT 
Study drug is defined as HTX-011 (investigational product) and aprepitant capsules 
(investigational use of a marketed product). HTX-011 and aprepitant capsules will be supplied 
by the Sponsor. 
Study sites will supply other required concomitant medications (eg, ibuprofen and 
acetaminophen for Cohorts 3 and 4) as well as rescue medications during the 72-hour 
postoperative period (all cohorts, as needed [Section 3.1.3.1]). 
5.1. 
Description of Investigational Products 
HTX-011 is a slightly yellow, viscous, solution. HTX-011 will be supplied in 20 mL clear glass 
vials. The vials serve only as a closed container for the drug product. For administration of study 
drug, the formulation in the vials will be aseptically transferred to sterile syringes. 
Aprepitant capsules for oral administration contain either 80 mg or 125 mg of aprepitant and the 
following inactive ingredients: sucrose, microcrystalline cellulose, hydroxypropyl cellulose and 
sodium lauryl sulfate. The capsule shell excipients are gelatin, titanium dioxide, and may contain 
sodium lauryl sulfate and silicon dioxide. The 125-mg capsule also contains red ferric oxide and 
yellow ferric oxide. 
5.2. 
Manufacturing, Packaging, and Labeling 
HTX-011 will be manufactured according to Good Manufacturing Practices. 
HTX-011 will be packaged and labeled by the Sponsor or designee and will be packed and 
dispatched to comply with shipping and storage conditions. Study drug labeling will comply with 
all applicable national and local laws and regulations. 
Aprepitant capsules will be provided as a commercial pack containing one 125 mg capsule and 
two 80 mg capsules and labeled for investigational use in compliance with all applicable national 
and local laws and regulations. 
5.3. 
Storage 
At the study site, HTX-011 should be stored at a controlled room temperature of 20 to 25°C 
(with excursions permitted from 15 to 30°C). The room should be locked with restricted access. 
A temperature log must be maintained to monitor the room’s temperature. 
Aprepitant capsules should be stored according to the US prescribing information. 
5.4. 
Preparation 
Study drug will be prepared at the study site. HTX-011 will be prepared in a group of syringes 
without a needle. Refer to the Instructions for Use (IFU) and the Pharmacy Manual for details on 
HTX-011 preparation. Refer to the US prescribing information for aprepitant capsules. 


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5.5. 
Study Drug Administration 
HTX-011 will be given via application into the surgical wound prior to wound closure, after final 
irrigation and suction of each layer are complete. Refer to the IFU for details on HTX-011 
administration. 
HTX-011 will be administered via instillation (ie, application into the surgical site) using a 
syringe and a Luer lock applicator supplied by the Sponsor. A single dose of no more than 
2.1 mL HTX-011 [up to 60 mg/1.8 mg (bupivacaine/meloxicam doses)] will be applied without a 
needle into the surgical site using a Luer lock applicator to coat the tissues within the surgical 
site that could result in pain generation. Application of HTX-011 should follow final irrigation 
and suction prior to suturing. A sufficient amount should be used to coat the tissues, ensuring 
there is not an excess that could be expressed from the site during closure. HTX-011 should be 
applied only to the tissue layers below the skin incision and not directly onto the skin. 
Thereafter, skin closure will commence to complete the surgical procedure (ie, there should be 
no betadine wash until after skin closure at the end of the case). When using monofilament 
sutures, 3 or more knots are recommended as contact with HTX-011 may cause a single knot to 
loosen or untie. 
In Cohorts 2 and 4 only, subjects should be administered 3 single oral doses of aprepitant: 
approximately 3 hours presurgery on Day 1 (125 mg) and at approximately 24 hours (Day 2) and 
48 hours (Day 3) after the presurgery dose (80 mg at each timepoint). 
5.6. 
Study Drug Compliance 
Because HTX-011 is being administered as a component of the surgical procedure, a lack of 
treatment compliance is not expected. Aprepitant capsules are being administered when the 
subjects are inpatient; therefore, a lack of treatment compliance is also not expected for 
aprepitant. 
For HTX-011, after preparing the syringe and before administration, the amount of HTX-011 
withdrawn into the syringe (to the nearest tenth of 1 mL) and the weight of the syringe (to the 
nearest tenth of a gram) will be recorded in the CRF. After administering HTX-011, the amount 
remaining in the syringe and the weight of the syringe will also be recorded in the eCRF. 
5.7. 
Study Drug Accountability 
The study drugs provided for this study (HTX-011 and aprepitant capsules) will be used only as 
directed in the study protocol. In accordance with Good Clinical Practice (GCP), Investigators 
are required to maintain accurate and up-to-date records of all study drug to permit 
reconciliation. The Investigator or designee must maintain adequate records of distribution, 
including the date received, number and units received, lot numbers, dispensing, and return or 
destruction of all study drug (ie, accountability or dispensing logs). 
All study drug records must be readily available for inspection by the site’s clinical monitor 
and/or auditor. No study drug can be returned to the Sponsor or designee or disposed of at the 
study site until the 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. Additional information about the timing of assessments is provided in Section 7 
and the Schedule of Events table. 
6.1. 
Medical History and Demographics 
6.1.1. 
Medical History 
A complete medical history will be obtained to ensure subjects qualify for the study. Medical 
history will be obtained through subject interview. A review of the subject’s medical records 
from their primary care physician is recommended. Data collected will include medical and 
surgical history. 
6.1.2. 
Demographics 
Demographic information collected will include age, sex, race, and ethnicity. 
6.2. 
Prior and Concomitant Therapy 
All medications taken by subjects between signing the ICF and the Safety Follow-Up Visit on 
Day 42 will be recorded in the subject’s eCRF. The dosing regimen of “prn” should not be 
recorded on the eCRF for medications taken during the 72-hour postoperative period. 
During the 72-hour postoperative period, the name, dose, and route, as well as the start date and 
time, of concomitant medications must be recorded. Medications include prescription and 
over-the-counter medications (including herbal products and vitamins). For subjects entering on 
a stable dose of permitted medication, any change in dose should also be recorded. Note: All 
medications received during this period must have a start time recorded, except for IV fluids and 
oxygen during surgery, which do not need to be recorded unless being used to treat an AE. 
After the 72-hour period until the Safety Follow-Up on Day 42, at least the start date of each 
concomitant medication should be recorded and stop date if the medication was discontinued 
prior to Day 42. 
6.2.1. 
Allowed Concomitant Medications 
All treatments that the Investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the Investigator’s in keeping with the standard of medical care. 
In Cohorts 1 and 3, 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). In Cohorts 2 and 4, granisetron, palonosetron, or 
ondansetron are permitted to treat nausea and/or vomiting following surgery, but should not be 
administered prophylactically. Another NK1 receptor antagonist such as rolapitant (VARUBI®), 
netupitant (AKYNZEO®), or fosaprepitant (EMEND® IV) should not be given. 
During surgery, the use of IV fentanyl up to 4 μg/kg is permitted for intraoperative pain control. 
As the prescribing information for fentanyl citrate (Fentanyl Citrate USPI 2012) specifies that for 


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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. 
See Section 3.1.3 for information on rescue medications permitted. 
See Appendix E for information on postoperative pain management for subjects who are 
medically ready for discharge. 
6.2.2. 
Prohibited Medications 
6.2.2.1. 
Medications Prohibited Prior to Surgery 
Refer to exclusion criteria 5 through 9, 11, 12, and 19 (all subjects) and exclusion criteria 10 and 
16 (Cohorts 2 and 4 only) for medications that are prohibited prior to the scheduled surgery 
(Section 4.1.2). Of note, for exclusion criterion 13, oral, parenteral, and topical steroids are 
considered systemic steroids, but inhaled and ophthalmic steroids are not considered systemic 
steroids. 
6.2.2.2. 
Medications Prohibited During Surgery 
Epidural or spinal anesthesia is not permitted. 
Intraoperative administration of opioids or any other analgesics (including ketamine), local 
anesthetics, or anti-inflammatory agents except as specified by the protocol (ie, HTX-011, and 
fentanyl) is prohibited, unless needed to treat an AE that occurs after signing the ICF, for 
pretreatment prior to a needle placement, or to decrease venous irritation (eg, caused by 
propofol, in which case no more than a single administration of lidocaine 1% plain 20 mg IV 
may be administered). 
6.2.2.3. 
Medications Prohibited From Time 0 Through 72 Hours 
With the exception of study treatment specified in Section 3.1.1.1 and rescue medications 
specified in Section 3.1.3, no other analgesic agents, including NSAIDs, are permitted during the 
72-hour postoperative observation period. 
Refer to exclusion criterion 16 (Cohorts 2 and 4 only) for medications that are prohibited during 
the study with aprepitant (Section 4.1.2). 
In Cohorts 1 and 3, subjects should not receive an antiemetic prophylactically. In Cohorts 2 and 
4, subjects should not receive an antiemetic prophylactically or another NK1 receptor antagonist 
as an antiemetic to treat nausea and/or vomiting (Section 6.2.1). 
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. 


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Pain intensity scores will be assessed using an 11-point NRS (0–10) where 0 represents “no 
pain” and 10 represents “worst pain imaginable” (Breivik 2008). NRS scores will be recorded 
first at rest (NRS-R) and then with activity (NRS-A). 
For NRS-R assessments, subjects should be seated/recumbent with the surgically attended leg 
elevated or lying supine. Measurements should be obtained after the subject is in the resting 
position for at least 5 minutes. 
For NRS-A assessments, subjects should be seated with the plantar surface of the ball of the 
surgically attended foot touching the floor (no weight-bearing; see photo below). 
If a subject withdraws from the study before 72 hours, NRS-R and NRS-A pain intensity scores 
will be recorded at the time of withdrawal. See Appendix C. 
6.3.2. 
Use of Opioid Medications 
6.3.2.1. 
Opioid Rescue Medication Through 72 Hours 
The name, dose, and route as well as the date and time of administration of any opioid rescue 
medication must be recorded in the subject’s eCRF from Time 0 through 72 hours. For more 
information on opioid rescue medications permitted, see Section 3.1.3. 
6.3.2.2. 
Subject Daily Diary of Opioid Use From 72 Hours Through Day 28 (Cohorts 3 
and 4 Only) 
At discharge, subjects in Cohorts 3 and 4 will be provided a daily diary to record if they take any 
opioid medication from 72 hours through the Day 28 Visit (yes or no). If a subject records “yes” 
for taking an opioid, sites must record the medication on concomitant medication eCRF. 
6.4. 
Safety Assessments 
6.4.1. 
Adverse Events 
All AEs regardless of causality or seriousness will be recorded from the time the subject signs 
the ICF through the Safety Follow-Up on Day 42. Additional safety information is provided in 
Section 8. Clinically significant post-treatment findings for laboratory results, vital signs, should 


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be recorded as AEs. Abnormal physical examination findings and wound healing abnormalities 
should also be recorded as AEs. 
6.4.2. 
Physical Examinations 
Scheduled physical examinations will include an evaluation of the following: head, eyes, ears, 
nose, and throat as well as CV, respiratory, gastrointestinal, neurological, dermatological, and 
musculoskeletal systems. 
Baseline height and weight measurements, and calculation of BMI (see Appendix B) will be 
conducted. 
Unscheduled physical examinations may also be performed (the extent of which is to be 
determined by the Investigator) at any time during the study if indicated by a change in the 
subject’s medical history or condition. 
6.4.3. 
Vital Signs 
Vital signs will include systolic and diastolic blood pressure, resting heart rate, respiration rate, 
and body temperature. Subjects should be in a supine position or semi-supine position (eg, sitting 
in a recliner chair) for at least 5 minutes before taking vital signs. 
6.4.4. 
12-Lead Electrocardiograms 
Screening ECGs will be obtained for all subjects. Standard digital 12-lead ECGs will be 
performed in triplicate. Subjects should be in the supine position or semi-supine position (eg, 
sitting in a recliner chair) for at least 5 minutes before each initial ECG recording. The mean of 
the 3 ECGs will be used as the baseline result. 
6.4.5. 
Wound Healing Assessment 
A wound healing assessment questionnaire is provided (see Appendix D). 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. Any abnormality of wound healing should be followed to resolution. 
6.4.6. 
Clinical Laboratory Tests 
Blood and urine samples will be collected for diagnostic screening tests and for safety laboratory 
tests (hematology and serum chemistry). A list of clinical laboratory tests and parameters is 
provided in Table 2. Urine samples will be tested by local laboratories. Blood samples will be 
tested by a central laboratory. 
Laboratory results will be reviewed by the Investigator. Any laboratory values outside of the 
normal reference range will be evaluated for clinical significance. 
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. Information on study procedures and assessments is provided in 
Section 6. 
Unless there is a safety concern, every effort should be made to avoid protocol deviations. For 
pain assessments at timepoints when the subject is asleep, an attempt should be made to wake the 
subject. If there is no response, the assessments at these timepoints may be recorded as “Not 
Done.” Assessments that can be done without waking the subject (eg, blood collection for PK) 
should be completed. Additional visits and/or assessments are permitted if clinically indicated in 
the opinion of the Investigator. 
When the following assessments are scheduled at the same timepoint, it is recommended that 
they be performed in this order: 
 NRS-R pain intensity assessment (subjects should be seated/recumbent with the 
surgically attended leg elevated or lying supine; measurements should be obtained 
after the subject is in the resting position for at least 5 minutes). 
 Vital signs. 
 12-lead ECG (Screening only). 
 NRS-A pain intensity assessment (subjects should be seated with the plantar surface 
of the ball of the surgically attended foot touching the floor [no weight bearing]). 
 Blood sample collection. 
 Physical examination. 
 Wound healing assessment. 
7.1. 
Screening Period 
After providing written informed consent, potential study subjects will undergo Screening 
procedures to confirm eligibility to participate in the study. Screening procedures must be 
performed within 28 days prior to surgery. The Investigator must evaluate the subject’s medical 
history and the results of all Screening assessments to determine study eligibility. 
Screening procedures and assessments will include the following: 
 Urine drug screen. 
 Urine pregnancy test (female subjects of child-bearing potential only). 
 Medical history. 
 Demographic recording. 
 Physical examination (including weight, height, and BMI calculation). 
 Vital signs measurements. 
 12-lead ECG (in triplicate). 


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 Blood sample collection for the hematology and serum chemistry. 
 Subject training for pain intensity assessments. 
 AE recording (from the time the subject signs the ICF). 
 Prior and concomitant medication recording (from the time the subject signs the ICF). 
The urine drug screen and urine pregnancy test should be performed first, and the results should 
be confirmed as negative prior to performing any additional assessments. A subject who fails the 
drug test may be rescreened at the discretion of the Investigator. Subjects with a positive drug 
screen who are taking an allowed, prescribed medication that is known to result in a positive 
drug test (eg, amphetamine and dextroamphetamine for attention-deficit/hyperactivity disorder, 
benzodiazepine for anxiety disorder) may be eligible for participation in the study. Any other 
screening laboratory test result that does not meet the eligibility criteria may not be repeated 
without the Sponsor’s approval. 
7.2. 
Treatment and Postoperative Observation Period 
7.2.1. 
Day of Surgery (Day 1) 
7.2.1.1. 
Prior to Surgery 
On Day 1, subjects will be reassessed for study eligibility. This includes a urine drug screen test 
(all subjects) and urine pregnancy test (female subjects of child-bearing potential only). Results 
should be confirmed as negative prior to performing any additional assessments. 
Subjects who continue to meet the eligibility criteria can continue on study and will be admitted 
to the surgical unit. The following additional study procedures and assessments will be 
performed prior to receiving any study drug and before surgery: 
 Blood sample collection for bupivacaine and meloxicam PK (Cohort 3). 
 Vital signs measurements. 
 Subject training for pain intensity assessments (refresher training). 
 AE recording. 
 Prior and concomitant medication assessment. 
Subjects in Cohorts 2 and 4 only will receive a single oral dose of aprepitant 125 mg 
approximately 3 hours prior to the start of surgery and have the following study procedures and 
assessments prior to surgery: 
 Blood sample collection for bupivacaine, meloxicam, and aprepitant PK: 2 hours 
(±15 min), 2.5 hours (±15 min), and 3 hours (±15 min) post aprepitant study drug 
administration. 
 AE recording: (Note: the start date and time of all AEs during this timeframe must 
be recorded). 
Note: The start of aprepitant administration will be considered as Time 0 for aprepitant 
alone safety and PK assessments. 


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7.2.1.2. 
Surgery and HTX-011 Administration 
Subjects will undergo a unilateral simple bunionectomy under regional anesthesia (no more than 
20 mL of 1% lidocaine without epinephrine administered as a Mayo block; epidural or spinal 
anesthesia is not permitted). Sites should follow intraoperative safety monitoring in accordance 
with ASA Standards for Basic Anesthetic Monitoring (American Society of Anesthesiologists 
2015), which is consistent with the European Board of Anesthesiology (EBA) recommendations 
for minimal monitoring during Anesthesia and Recovery (for review in 2018) (EBA UEMS 
2016). The start and stop time of surgery and additional surgical details (including the length of 
the surgical incision) should be recorded in the eCRF. 
Subjects will be administered HTX-011 unless they experience a clinically significant event 
during surgery (eg, excessive bleeding, hemodynamic instability) that would render the subject 
medically unstable or complicate their postoperative course. Study drug will be administered via 
application into the surgical site at the end of the surgical procedure, but prior to wound closure. 
Complete details on the study drug administration technique are provided in Section 5.5. 
The start and stop times of study drug dosing will be recorded in the eCRF. Details of 
administration will be recorded on a worksheet, which will be used in the dictation of the 
surgical notes and will become part of the source document. Note: The start of HTX-011 
administration will be considered as Time 0 for all efficacy, safety, and PK assessments for 
HTX-011 with and without aprepitant. Placement of the last suture will be considered the end 
of surgery. 
Concomitant medications used during surgery will be recorded (note that IV fluids and oxygen 
are not required to be recorded unless being used to treat an AE). AEs will also be recorded. 
After immediate postoperative recovery, subjects will be transferred to the PACU. 
7.2.2. 
Postoperative Assessment Period (Up to 72 Hours) 
Subjects in Cohorts 2 and 4 will receive single doses of aprepitant 80 mg at approximately 
24 hours (Day 2) and approximately 48 hours (Day 3) after the presurgery aprepitant dose. 
Subjects in Cohorts 3 and 4 will be started on a scheduled multimodal analgesic regimen once 
they are able to tolerate oral intake in the PACU. The regimen will consist of 600 mg oral 
ibuprofen alternating with 1 g oral acetaminophen every 6 hours and will be administered as 
follows: 3 hours after the first 600 mg oral ibuprofen dose, subjects will receive a 1 g oral 
acetaminophen dose, then after 3 more hours another 600 mg oral ibuprofen dose, and so on until 
the 72-hour postoperative period is complete. These medications will be administered on a 
round-the-clock, scheduled basis through the 72-hour postoperative period. 
Subjects will remain in the hospital/research facility for 72 hours after HTX-011 administration. 
Study procedures and assessments that will be performed are listed below. 
All postoperative timepoints are referenced to the start of HTX-011 administration. Actual times 
will be recorded for all events, and any deviation outside the specified ranges must be clearly 
documented in the subject’s study records. 
 NRS-R and NRS-A pain intensity assessments: at 1 hour (±5 min), 2 and 4 hours 
(±15 min), 8 and 12 hours (±30 min), 24 hours (±1 h), 36 and 48 hours (±2 h), 60 and 
72 hours (±4 h). 


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 Note: NRS-R should be collected prior to the NRS-A. If a subject requires 
rescue medication before the 1-hour pain intensity assessments, then an 
unscheduled NRS-R pain score followed by an NRS-A pain score must be 
obtained before administering the first dose of rescue medication. These do not 
replace the 1-hour NRS-R and NRS-A assessments. 
 Vital signs measurements: 30 minutes (±5 min), 60 minutes (±5 min), 90 minutes 
(±10 min), 2 hours (±15 min), 4 hours (±15 min), 8 hours (±30 min), 12 hours 
(±30 min), 18 hours (±30 min), 24 hours (±1 h), 36 hours (±2 h), 48 hours (±2 h), 
60 hours (±4 h), and 72 hours (±4 h). 
 Blood sample for hematology and serum chemistry tests: 72 hours (±4 h; 
hematology and serum chemistry). 
 Blood sample collection for PK: 30 minutes (±5 min), 1 hour (±5 min), 2 hours (±15 
min), 4 hours (±15 min), 8 hours (±30 min), 12 hours  
(±30 min), 18 hours (±30 min), 24 hours (±1 h), 36 hours (±2 h), 48 hours (±2 h), 
60 hours (±4 h), and 72 hours (±4 h) post HTX-011 administration. 
 AE recording: (Note: the start date and time of all AEs during this timeframe must 
be recorded). 
 Concomitant medication recording: (Note: the start date and time of all 
concomitant medications during this timeframe must be recorded). 
 Use of pain medication (rescue and scheduled) recording: Any time between 
HTX-011 administration and 72 hours (Note: the start date and time of all 
medications during this timeframe must be recorded). 
7.2.3. 
End of the Postoperative Assessment Period 
After the 72-hour assessments have been completed, the subject may be discharged if medically 
ready. The time of discharge will be recorded. If a subject is not ready to be discharged due to an 
AE, it should be recorded on the AE eCRF as per Section 8.3.1. If a subject is ready for 
discharge but is not discharged for any reason other than AE, the reason should be recorded on 
the eCRF. 
Subjects who are not medically ready for discharge at 72 hours may receive the same rescue 
medication as outlined in Section 3.1.3.1 to treat postoperative pain until discharge. 
Postoperative analgesia after discharge is outlined in Section 3.1.3.2. In Cohorts 3 and 4, sites 
must record if a subject is discharged with an opioid prescription (yes or no). 
Subject should be instructed at the time of discharge to leave the bandage clean, dry, and intact 
until the Day 7 visit. In addition, the subject should be provided with a cast guard to keep the 
bandage dry and instructed to contact the site if the bandage gets wet. 
All subjects in Cohort 3 and 4 will be given a diary at discharge to complete daily and record 
whether they take any opioid medication from 72 hours through Day 28.  


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7.3. 
Follow-Up Period 
7.3.1.1. 
Day 7 Visit (+3 Days) 
All subjects will return to the study site and will have the following procedures and assessments: 
 NRS-R pain intensity assessment. (NRS-R should be collected prior to the NRS-A.) 
 NRS-A pain intensity assessment. 
 Wound healing assessment. 
 New dry dressing applied. Instruct subjects that they may remove bandage after 
Day 21. 
 Review subject diary results (Cohorts 3 and 4). If a subject recorded “yes” for taking 
an opioid, sites must record the medication on concomitant medication eCRF. 
 AE recording. 
 Concomitant medication recording. 
7.3.1.2. 
Day 28 Visit (±4 Days) 
All subjects will return to the study site and will have the following procedures and assessments: 
 NRS-R pain intensity assessment. (NRS-R should be collected prior to the NRS-A.) 
 NRS-A pain intensity assessment. 
 Wound healing assessment. 
 Review subject diary results (Cohorts 3 and 4). If a subject recorded “yes” for taking 
an opioid, sites must record the medication on concomitant medication eCRF. 
 AE recording. 
 Concomitant medication recording. 
7.3.1.3. 
Safety Follow-Up (Day 42 ±7 Days) 
All subjects will return to the study site and will have the following procedures and assessments: 
 Wound healing assessment. 
 Review and record subject diary results in the eCRF (if after the 72-hour discharge 
but before Day 28). If a subject recorded “yes” for taking an opioid, sites must record 
the medication on concomitant medication eCRF. 
 AE recording. 
 Concomitant medication recording. 
7.4. 
Early Termination Visit 
Subjects who withdraw from the study before their Day 28 Visit will be asked to complete Early 
Termination procedures, which will include the items listed in Section 7.4.1. Subjects who 


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withdraw from the study after the Day 28 Visit but prior to the Safety Follow-Up on Day 42 will 
be asked to complete Early Termination procedures, which will include the items listed in 
Section 7.4.2. 
7.4.1. 
Withdrawal Prior to the Day 28 Visit 
 NRS-R pain intensity assessment. (NRS-R should be collected prior to the NRS-A.) 
 NRS-A pain intensity assessment. 
 Vital signs (if withdrew prior to 72 hours). 
 Blood sample collection for hematology and serum chemistry (if withdrew prior to 
72 hours). 
 Wound healing assessment. 
 AE recording. 
 Concomitant medication recording. 
7.4.2. 
Withdrawal After the Day 28 Visit and Prior to the Safety Follow-Up on Day 42 
 AE recording. 
 Concomitant medication recording. 
 Wound healing assessment. 
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 hematology and chemistry. 


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8. 
SAFETY MONITORING AND REPORTING 
Investigators are responsible for the detection and documentation of AEs, SAEs, suspected 
adverse reactions, serious suspected adverse reactions, unanticipated adverse device effects, 
unanticipated problems, or pregnancies as detailed in this protocol. 
Investigators must review the HTX-011 IB and aprepitant capsules US prescribing information 
so as to be aware of the safety-related events, which may be anticipated with their 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 or 
vital sign result deemed clinically significant by the Investigator, regardless of causal 
relationship, must be reported as an AE. Clinically significant wound healing abnormalities 
should also be recorded as AEs. When appropriate, a clinical diagnosis, rather than the changes 
in laboratory analyte or other assessment, should be recorded (eg, anemia rather than low 
hemoglobin value). 
Examples of AEs include the following: 
 Significant or unexpected worsening or exacerbation of the condition or indication 
under study. 
 Exacerbation of a chronic or intermittent pre-existing condition, including either an 
increase in frequency or intensity of the condition (eg, abnormal physical examination 
finding). 
 Signs, symptoms, or clinical sequelae of a suspected interaction. 
 Signs, symptoms, or clinical sequelae of a suspected overdose of the study drug or a 
concurrent medication (overdose per se should not be reported as an AE or SAE, 
unless non-serious or serious sequelae occur). 
 The following clinically significant abnormal laboratory results: 
 Any laboratory abnormality suggestive of a new disease/organ toxicity or a 
worsening of a pre-existing condition. 
 Any laboratory abnormality that required the subject to have investigational 
product interrupted or discontinued. 
 Any laboratory abnormality that required the subject to receive specific treatment 
for the lab abnormality. 


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


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occurrence of an AE, or hospitalization or an emergency room visit that lasts less than 24 hours 
that does not meet the criteria of an important medical or a life-threatening event. 
According to 21 CFR 812.3(s), an unanticipated adverse device effect means any serious adverse 
effect on health or safety or any life-threatening problem or death caused by, or associated with, 
a device, if that effect, problem, or death was not previously identified in nature, severity, or 
degree of incidence in the investigational plan or application (including a supplementary plan or 
application), or any other unanticipated serious problem associated with a device that relates to 
the rights, safety, or welfare of subjects. 
8.1.3. 
Definition of a Suspected Adverse Reaction 
A suspected adverse reaction is defined as any AE for which there is a reasonable possibility that 
the AE was caused by the study drug. 
8.1.4. 
Definition of a Serious Suspected Adverse Reaction 
A serious suspected adverse reaction is any suspected adverse reaction that is determined to be 
serious, based on the outcomes of a SAE described in Section 8.1.2. 
8.1.5. 
Definition of Unanticipated Problems 
Unanticipated problems are incidents, experiences, or outcomes that meet all of the following 
criteria: 
 Unexpected in terms of nature, severity, or frequency given (a) the research 
procedures that are described in the protocol-related documents, such as the research 
protocol and informed consent document approved by the Ethics Committee (EC; 
includes Institutional Review Boards [IRBs], Independent Ethics Committees [IECs], 
and Research Ethics Boards [REBs]) and (b) the characteristics of the participant 
population being studied. 
 Related or possibly related to participation in the research (“possibly related” means 
there is a reasonable possibility that the incident, experience, or outcome may have 
been caused by the procedures involved in the research). 
 Suggest that the research places subjects or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized. 
An unanticipated adverse device effect is defined in Section 8.1.2. 
8.2. 
Classification of Adverse Events 
8.2.1. 
Severity of Adverse Events 
The Investigator will assess the severity of each AE based on his/her clinical judgment using one 
of the following categories: 
 Mild: Event is easily tolerated by the subject, causes minimal discomfort, and does 
not interfere with everyday activities. 


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 Moderate: Event results in a low level of inconvenience or concern with the 
therapeutic measures. Moderate events may cause some interference with 
functioning. 
 Severe: Event interrupts a participant’s usual daily activity and may require systemic 
drug therapy or other treatment. Severe events are usually potentially life-threatening 
or incapacitating. 
8.2.2. 
Relationship to Study Drug 
The Investigator will assess the relationship of each AE to study drug based on his/her clinical 
judgment. The Investigator’s assessment of an AE’s relationship to study drug is part of the 
documentation process, but it is not a factor in determining what is or is not reported in the study. 
If there is any doubt as to whether a clinical observation is an AE, the event should be reported. 
All AEs must have their relationship to study agent assessed. In a clinical trial, the study drug 
must always be suspect. The Sponsor’s assessment of relationship may differ from the 
Investigator’s assessment. 
Relationship to study drug will be assessed according to the following guidelines: 
 Possibly related: The AE is known to occur with the study drug, there is a reasonable 
possibility that the study drug caused the AE, or there is a temporal relationship 
between the study drug and event. Reasonable possibility means that there is evidence 
to suggest a causal relationship between the study drug and the AE. 
 Unlikely related: There is not a reasonable possibility that the administration of the 
study drug caused the event, there is no temporal relationship between the study drug 
and event onset, or an alternate etiology has been established. 
Even in situations in which minimal information is available for initially reporting an SAE, it is 
important that the Investigator always make an assessment of causality for every event before 
entering the information into the eCRF or completing the SAE reporting form, in the event 
electronic data capture (EDC) is not available. The causality assessment is one of the criteria 
used when determining regulatory reporting requirements. The Investigator may change his or 
her opinion of causality in light of follow-up information and amend the SAE information 
accordingly in the eCRF or the SAE reporting form, as applicable. 
8.3. 
Time Period and Frequency for Event Assessment and Follow Up 
8.3.1. 
Adverse Event and Serious Adverse Event Monitoring 
All AEs regardless of causality or seriousness will be recorded from the time the subject signs 
the ICF through the Safety Follow-Up on Day 42. Note: the AE start time, as well as the date, 
must be recorded during the 72-hour postoperative period. After this period, only the start and 
stop dates must be recorded. 
For subjects who received study drug, if an Investigator becomes aware of an SAE that occurs 
after the subject’s study participation and the Investigator considers the event to be possibly 
related to the study drug, the Investigator needs to report the SAE to the Sponsor as described in 
Section 8.4.1. 


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8.3.2. 
Follow-Up of Events 
After the occurrence of an AE or SAE, the Investigator is required to follow each subject 
proactively and provide further information on the subject’s condition. All AEs and SAEs 
documented at a previous visit or contact and designated as ongoing will be reviewed at 
subsequent visits or contacts. 
Non-serious 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: 
 Recovered/Resolved: The event resolved or the subject recovered without sequelae. 
An event (either serious or non-serious) occurred and had an endpoint, and the subject 
experienced no restrictions. Examples include stent placement for coronary artery 
disease (a device implanted is not a sequela), an appendectomy (a scar is not a 
sequela), a postoperative wound infection, or an upper respiratory tract infection. 
 Recovered/Resolved with sequelae: The event has at least one secondary outcome 
that may result in permanent disability, functional limitation, or both. Such sequelae 
are usually limited to SAEs. Examples include hip replacement resulting in foot drop 
(foot drop is not the intended outcome but is a risk of surgery), stroke resulting in 
paralysis, or emboli formation after a bacterial infection resulting in a renal infarct 
and loss of renal function. 
 Recovering/Resolving: The event is improving. 
 Not recovered/resolved: At the end of the study, a nonserious event either has not 
changed in intensity or may not have recovered to baseline values, and the outcome is 
unknown. Examples include headache, low-grade fever, or nausea. 
 Unknown: The subject has withdrawn from the study prematurely or is lost to 
follow-up, and the status of the event is unknown. 
 Fatal 
SAEs will be followed until the event resolves (ie, when the event no longer meets any of the 
seriousness criteria), the condition stabilizes, or until the event is otherwise explained or judged 
by the Investigator to be no longer clinically significant (unless the subject is lost to follow-up or 
withdraws consent). The Investigator will ensure that follow-up information provided to the 
Sponsor includes results of any additional laboratory tests or investigations, histopathologic 
examinations, or consultations with other healthcare professionals that serve to clarify the nature 
of the event, the cause of the event, or both. New or updated information will be recorded as 
outlined in Section 8.4.1. 
8.4. 
Reporting Procedures 
8.4.1. 
Reporting Serious Adverse Events to the Sponsor 
If the Investigator determines that an event meets the protocol definition of an SAE due to any 
cause that occurs during the course of this study, regardless of relationship to study drug, he/she 


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


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It is the Investigator’s responsibility to report unanticipated problems to the Sponsor and their 
EC, as required by local regulations. 
8.4.3. 
Regulatory Reporting Requirements 
The Investigator must promptly report all SAEs and unanticipated adverse device effects to the 
Sponsor in accordance with the procedures detailed in Section 8.4.1. The Sponsor has a legal 
responsibility to notify, as appropriate, both the local regulatory authority and other regulatory 
agencies about the safety of a product under clinical investigation. Prompt notification of SAEs 
by the Investigator to the appropriate project contact for SAE receipt is essential so that serious 
suspected adverse reactions that are either unexpected or observed with increasing occurrence be 
reported and legal obligations and ethical responsibilities regarding the safety of other subjects 
are met. 
Investigator letters are prepared according to Sponsor policy and are forwarded to the 
Investigators as necessary. An Investigator letter is prepared for any suspected adverse reaction 
that is attributable to study drug, serious, and unexpected. The purpose of the Investigator letter 
is to fulfill specific regulatory and GCP requirements regarding the product under investigation. 
The Investigator, or responsible person according to local requirements, must comply with 
requirements related to the reporting of SAEs to the EC. 
The Sponsor is responsible for informing ECs, Investigators, and regulatory authorities of 
finding that could adversely affect the safety of subjects or affect the conduct of the study. 
Events will be reported to regulatory authorities in accordance with expedited and period 
reporting requirements. 
8.4.4. 
Pregnancy Reporting 
Pregnancy is not considered to be an adverse event; however, any subject who becomes pregnant 
during the study must be withdrawn from the study immediately. Female subjects who become 
pregnant within 28 days after receiving study drug should also notify the Investigator. The 
Investigator must attempt to follow the pregnancy to term or termination in order to report on 
outcome and health status of mother and child. 
The Investigator must notify the Sponsor of any pregnancy by completing a Pregnancy Form and 
emailing it to the Sponsor within 24 hours after the Investigator becomes aware of the 
pregnancy. 
Email Address: 
Heron_PV@ubc.com 
8.5. 
Safety Oversight 
The internal, 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 AEs, wound healing 
assessments, and SAEs. 
The stopping criteria, enrollment suspension or study termination for safety issues, are provided 
in Section 13.5. 


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9. 
OTHER STUDY RESTRICTIONS 
9.1. 
Contraception 
Female subjects of child-bearing potential must use an acceptable form of contraception in the 
event of sexual activity during the study and for 30 days after study drug administration. Note: 
This does not apply to women in only a same-sex relationship or women in a monogamous 
relationship with a surgically sterile partner. 
For Cohorts 1 and 3, acceptable forms of contraception include double-barrier contraception or 
an insertable, injectable, transdermal, or combination oral contraceptive approved by applicable 
regulatory authorities. 
For Cohorts 2 and 4, hormonal contraceptives are not an acceptable form of birth control since 
the efficacy of hormonal contraceptives may be reduced with aprepitant. Therefore, female 
subjects in Cohorts 2 and 4 must agree to use double-barrier contraception or a non-hormonal 
intra-uterine device (eg, copper) in the event of sexual activity for greater than 2 months prior to 
screening, for the duration of the study and for 30 days after last study drug administration. 


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10. 
STATISTICAL CONSIDERATIONS 
10.1. 
General Considerations 
All efficacy and safety data will be listed by subject. Unless otherwise specified, Baseline is 
defined as the last observed measurement, whether scheduled or unscheduled, prior to study drug 
administration. All safety and efficacy endpoints will be summarized by treatment group. 
Continuous variables will be summarized using the number of subjects with data (n), mean, SD, 
median, minimum, and maximum. Selected continuous variable summaries will also include the 
SE. Categorical variables will be summarized using frequency counts and percentages. 
10.2. 
Determination of Sample Size 
The sample size in this study was selected empirically without a formal statistical assumption. 
10.3. 
Analysis Populations 
Intent-to-Treat (ITT) Population: All subjects who receive HTX-011 will be included in the ITT 
Population. This population will be used as the analysis population for all efficacy and safety 
endpoints. 
10.4. 
Statistical Analysis Methods 
10.4.1. 
Disposition and Demographics 
Subject disposition, including the number of subjects screened, dosed, completing the 72-hour 
postoperative observation period, completing Day 28, completing the Safety Follow-up Visit on 
Day 42, and not completing the Safety Follow-up Visit on Day 42 by reason for withdrawal will 
be summarized by cohort. Subject demographics and baseline characteristics will also be 
summarized and will include age, age category, sex, race, ethnicity, height, weight, and BMI. 
10.4.2. 
Efficacy Analysis 
All efficacy data will be summarized by cohort. AUCs of the NRS pain intensity scores will be 
adjusted for opioid use via windowed worst observation carried forward (wWOCF) method. 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 
prewindow score, then it will not be replaced. Sensitivity analyses for endpoints involving NRS 
pain intensity scores will summarize the data without adjustment for the effect of opioid rescue 
medications. 
10.4.2.1. Handling of Missing Data 
Due to the required 72-hour inpatient postoperative observation period, the amount of missing 
data is expected to be very low. For any missing data observed through 72 hours in subjects who 
complete the 72-hour postoperative observation period, NRS pain intensity scores will be 


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imputed via last observation carried forward (LOCF), in which the most recent post-dose value is 
used for a subsequent missing value. For subjects who do not have a post-dose value prior to 
their first missing value, the median of the post-dose values at the relevant timepoint from 
subjects with observed data in the same treatment group will be used. Pre-dose values will not be 
carried forward to post-dose timepoints. In subjects who withdraw from the study prior to 
72 hours, missing NRS pain intensity scores through 72 hours that were to be collected following 
withdrawal will be imputed via worst observation carried forward (WOCF), in which the worst 
(highest) NRS pain intensity score observed prior to withdrawal will be used for post-withdrawal 
values through 72 hours. Analyses that adjust for the effect of opioid rescue medication will 
perform windowed worst observation carried forward (wWOCF) following LOCF/WOCF (ie, 
perform LOCF/WOCF first, then apply wWOCF). The number and percentage of missing NRS 
pain intensity scores will be summarized. 
10.4.3. 
Safety Analysis 
All safety data will be listed and summarized by cohort. 
AEs that occur between the time the subject signs the ICF and the start of study drug (HTX-011 
for Cohorts 1 and 3 or aprepitant for Cohorts 2 and 4) administration will be considered 
pretreatment AEs. AEs that start during or after study drug administration, or AEs with an onset 
prior to study drug administration that worsen after study drug administration will be considered 
TEAEs. All TEAEs will be coded and tabulated by System Organ Class and Preferred Term. 
Incidence of TEAEs and SAEs will be summarized and presented in descending order of 
frequency. AEs leading to study withdrawal, if any, will be listed separately. 
Associated laboratory parameters such as hepatic profile, renal function, and hematology values 
will be grouped and presented together in summary tables. For each laboratory test, individual 
subject values will be listed and values outside of the standard reference range will be flagged. 
Shift tables will be produced showing the frequency of shifts from Baseline to the lowest and to 
the highest on-study value in and out of the normal range as well as by visit. Laboratory 
parameters will also be summarized by visit. 
The change from Baseline to each visit for each of the vital sign variables will be summarized. 
Abnormal vital sign values will be flagged and listed. 
Wound healing assessment results will be summarized at each timepoint. 
10.4.4. 
Pharmacokinetic Analysis 
Plasma bupivacaine, meloxicam, and aprepitant 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 
No formal interim analyses are planned; however, preliminary analyses of data by cohort may be 
conducted to plan future studies or for regulatory reporting purposes. 


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


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


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


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


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


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documented at the site and in the Sponsor files. In the event of an Important Protocol Deviation, 
the site will notify the Sponsor or designee. The Sponsor is responsible for notifying the 
regulatory authorities of any protocol deviations, 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 sub-investigators 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: 
 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. 


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


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14. 
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Wkly Rep 66(10): 265-269. 
Shirakami, G., Y. Teratani, T. Namba, H. Hirakata, M. Tazuke-Nishimura and K. Fukuda 
(2005). "Delayed discharge and acceptability of ambulatory surgery in adult outpatients 
receiving general anesthesia." Journal of Anesthesia 19(2): 93-101. 
Singla, N. K., P. J. Desjardins and P. D. Chang (2014). "A comparison of the clinical and 
experimental characteristics of four acute surgical pain models: Dental extraction, bunionectomy, 
joint replacement, and soft tissue surgery." PAIN 155(3): 441-456. 
Stephens, J., B. Laskin, C. Pashos, B. Pena and J. Wong (2003). "The burden of acute 
postoperative pain and the potential role of the COX-2-specific inhibitors." Rheumatology 
42(90003): 40-52. 
Svensson, I., B. Sjöström and H. Haljamäe (2000). "Assessment of Pain Experiences after 
Elective Surgery." Journal of Pain and Symptom Management 20(3): 193-201. 
Wheeler, M., G. M. Oderda, M. A. Ashburn and A. G. Lipman (2002). "Adverse events 
associated with postoperative opioid analgesia: A systematic review." The Journal of Pain 3(3): 
159-180. 
 




Protocol No: HTX-011-218 Version 4 
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APPENDIX B. BMI CALCULATION 
Body Mass Index = Weight in kilograms / (height in meters)2 
Meters = inches × 0.0254 
Kilograms = pounds × 0.45 
 
Example: 
For a man who weighs 165 pounds and is 71 inches tall: 
165 lbs. × 0.45 = 74.25 kg 
71 in. × 0.0254 = 1.8 m 
74.25 / (1.8 × 1.8) = 22.92 kg/m2 
 


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APPENDIX C. PAIN INTENSITY ASSESSMENTS USING THE 
NUMERIC RATING SCALE (NRS) 
 
The following question will be answered by the subject for all NRS with activity (NRS-A) and 
NRS at rest (NRS-R) pain intensity assessments: 
 
“On a scale of 0–10, please rate your pain by marking an ‘X’ in the appropriate box that 
best describes your pain NOW.” 
 
The response must be one of the following: 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No Pain 
 
 
 
 
 
 
 
 
 
Worst Pain 
Imaginable 
 
Reference: Breivik, H., P. C. Borchgrevink, S. M. Allen, L. A. Rosseland, L. Romundstad, E. K. Hals, G. Kvarstein 
and A. Stubhaug (2008). “Assessment of pain.” Br J Anaesth 101(1): 17-24. 


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


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Phase 2 Bunionectomy HTX-011 Administration Study 
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APPENDIX E. INSTRUCTIONS FOR POSTOPERATIVE PAIN 
MANAGEMENT FOR SUBJECTS MEDICALLY READY 
FOR DISCHARGE  
Cohorts 1 and 2 
The following text should be read by the Investigator or designee to subjects in Cohorts 1 and 2 
at the time of discharge: 
You have completed the initial part of the study which required you to stay at the facility. You 
are now being discharged to go home. You will come back here again for check-up visits on 
Day 7 (approximately 1 week from now), Day 28 (approximately 3½ weeks from now), and for a 
Safety Follow-Up on Day 42 (approximately 5½ weeks from now). 
While you are at home, if you experience any pain from your operation, please take up to 
2 over-the-counter extra-strength (500 mg) acetaminophen tablets (eg, Tylenol) every 6 hours as 
needed. Do not take more than 8 tablets (4000 mg) in a 24-hour period. If this does not control 
your pain, please call <<insert name and contact information>> so that we can talk about 
providing you with a prescription for something stronger, if needed. 
Do not take other acetaminophen-containing products that are available over the counter 
without first checking with your doctor. As an example, cold medicine over the counter may 
contain acetaminophen and may result in exceeding the daily dose limit of acetaminophen and 
can cause liver damage. 
NOTE: If a subject required 10 mg or more of oxycodone in the 12 hours prior to discharge, the 
subject should be provided with a prescription for oxycodone up to 10 mg PO q4h, #15, as 
needed. Pharmacists should be instructed that substitutions for any other opioid-containing 
product are not permitted.  
 
Cohorts 3 and 4 
The following text should be read by the Investigator or designee to subjects in Cohorts 3 and 4 
at the time of discharge: 
You have completed the initial part of the study, which required you to stay at the facility. You 
are now being discharged to go home. You will come back here again for check-up visits on 
Day 7 (approximately 1 week from now), Day 28 (approximately 3½ weeks from now), and for a 
Safety Follow-Up on Day 42 (approximately 5½ weeks from now). 
While you are at home, please take 3 over-the-counter (200 mg) ibuprofen tablets (eg, Advil or 
Motrin) every 6 hours for pain, as needed. If you are still in pain, you can take 2 over-the-
counter extra-strength (500 mg) acetaminophen tablets (eg, Tylenol) every 6 hours as needed. 
Do not take more than 8 acetaminophen tablets (4000 mg) in a 24-hour period. If this does not 
control your pain, please call <<insert name and contact information>> so that we can talk 
about providing you with a prescription for a different pain medicine, if needed. 


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Phase 2 Bunionectomy HTX-011 Administration Study 
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Do not take other acetaminophen-containing products that are available over the counter 
without first checking with your doctor. As an example, cold medicine over the counter may 
contain acetaminophen and may result in exceeding the daily dose limit of acetaminophen and 
can cause liver damage. 
NOTE: If a subject required 10 mg or more of oxycodone in the 12 hours prior to discharge, the 
subject should be provided with a prescription for oxycodone up to 10 mg PO q4h #15, as 
needed. Pharmacists should be instructed that substitutions for any other opioid-containing 
product are not permitted. Sites must record if a subject is discharged with an opioid prescription 
(yes or no). 
 


Signature Page for VV-CLIN-003792 v1.0
Signature Page for VV-CLIN-003792 v1.0
Approval
15-Jan-2019 00:46:57 GMT+0000

SAP_001.pdf: 
Document Type:  
Statistical Analysis Plan 
Official Title:  
A Phase 2 Open-Label Study of HTX-011 via Individualized Dosing 
Administration for Postoperative Analgesia Following Unilateral 
Simple Bunionectomy 
NCT Number:  
NCT03718039 
Document Date:  
04-Jan-2019 
 


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. 
 
STATISTICAL ANALYSIS PLAN 
 
HTX-011-218 
A Phase 2 Open-Label Study of HTX-011 via Individualized Dosing Administration for 
Postoperative Analgesia Following Unilateral Simple Bunionectomy 
 
Prepared by: 
 
Heron Therapeutics, Inc. 
4242 Campus Point Court, Suite 200 
San Diego, CA 92121  
USA 
 
 
Version 2:  04 January 2019 
 
 
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:   
 
 
 
Director of Biostatistics 
Heron Therapeutics, Inc. 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
  
Approved by: 
 
 
 
Date:   
 
 
 
Vice President, Clinical Research 
Heron Therapeutics, Inc. 
 
 
  
 
 
 


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Statistical Analysis Plan, V2
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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 ...............................................................................................................7 
4. 
INVESTIGATIONAL PLAN .......................................................................................8 
4.1. 
Overall Study Design and Plan .....................................................................................8 
4.1.1. 
Cohort 1 ........................................................................................................................9 
4.1.2. 
Cohort 2 ........................................................................................................................9 
4.1.3. 
Cohort 3 ........................................................................................................................9 
4.1.4. 
Cohort 4 (Optional) .......................................................................................................9 
4.2. 
Assessments ................................................................................................................10 
4.3. 
Endpoints ....................................................................................................................10 
4.3.1. 
Efficacy Endpoints ......................................................................................................10 
4.3.2. 
Safety Endpoints .........................................................................................................11 
5. 
GENERAL STATISTICAL CONSIDERATIONS ....................................................11 
5.1. 
Sample Size ................................................................................................................12 
5.2. 
Randomization, Stratification, and Blinding ..............................................................12 
5.3. 
Analysis Populations ..................................................................................................12 
5.3.1. 
Safety Population ........................................................................................................12 
5.4. 
Other Important Considerations .................................................................................12 
5.4.1. 
Calculation of HTX-011 Dose Received ....................................................................12 
5.4.2. 
Compliance of Aprepitant ...........................................................................................12 
5.4.3. 
Definition of Baseline .................................................................................................13 
5.4.4. 
Calculation of Change and Percent Change from Baseline ........................................13 
5.4.5. 
Study Day Calculation for Reporting Purposes ..........................................................13 
5.4.6. 
Start date/time of Study Drug Administration (Time 0) .............................................13 
5.4.7. 
72-Hour Postoperative Observation Period ................................................................13 
5.4.8. 
Visit Windows ............................................................................................................14 
5.4.9. 
Handling of Missing and Partial Data ........................................................................14 
6. 
SUBJECT DISPOSITION ..........................................................................................14 


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7. 
DEMOGRAPHICS, CHARACTERISTICS, AND MEDICAL 
HISTORY ...................................................................................................................15 
7.1. 
Demographics and Baseline Characteristics ...............................................................15 
7.2. 
Medical History ..........................................................................................................15 
7.3. 
Protocol Deviations ....................................................................................................15 
8. 
TREATMENTS AND MEDICATIONS ....................................................................15 
8.1. 
Prior and Concomitant Medications ...........................................................................15 
8.2. 
Rescue Medication ......................................................................................................16 
8.3. 
Surgery Procedure ......................................................................................................16 
8.4. 
Study Drug ..................................................................................................................16 
9. 
EFFICACY ANALYSIS ............................................................................................17 
9.1. 
Primary Efficacy Endpoint .........................................................................................17 
9.1.1. 
Primary Analysis ........................................................................................................17 
9.1.2. 
Sensitivity Analyses ....................................................................................................18 
9.2. 
Secondary Efficacy Endpoints ....................................................................................18 
10. 
SAFETY ANALYSIS ................................................................................................20 
10.1. 
Adverse Events ...........................................................................................................20 
10.1.1. 
Incidence of Treatment Emergent Adverse Events ....................................................21 
10.1.2. 
Relationship of Adverse Events to Investigational Drug ...........................................22 
10.1.3. 
Severity of Adverse Event ..........................................................................................22 
10.1.4. 
Serious Adverse Events ..............................................................................................22 
10.1.5. 
Adverse Events Leading to Study Withdrawal ...........................................................22 
10.1.6. 
Opioid-related Adverse Events ...................................................................................22 
10.1.7. 
Local Inflammatory Adverse Events ..........................................................................23 
10.1.8. 
Potential Local Anesthetic Systemic Toxicity (LAST) related Adverse 
Events .........................................................................................................................23 
10.1.9. 
Death ...........................................................................................................................24 
10.2. 
Clinical Laboratory Evaluations .................................................................................24 
10.3. 
Hematology .................................................................................................................24 
10.3.1. 
Blood Chemistry .........................................................................................................24 
10.3.2. 
Urine Pregnancy Test and Urine Drug Screen ...........................................................25 
10.4. 
Vital Sign Measurements ............................................................................................25 
10.5. 
Electrocardiogram .......................................................................................................26 


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10.6. 
Physical Examination .................................................................................................26 
10.7. 
Wound Healing Assessment .......................................................................................26 
11. 
INTERIM ANALYSIS ...............................................................................................27 
11.1. 
Interim Analysis ..........................................................................................................27 
11.2. 
Data Safety Monitoring Board ....................................................................................27 
APPENDIX 1.  IMPUTATION OF PARTIAL AND MISSING DATES ..................................28 
APPENDIX 2.  DOCUMENT REVISION HISTORY ...............................................................29 
 
LIST OF TABLES 
Table 1. 
Planned Treatment Group ...........................................................................................17 
Table 2.     Analgesic Windows and IV Morphine Milligram Equivalents for Opioid 
Rescue Medications in Preferred Terms .....................................................................19 
Table 3. 
Local Inflammatory Adverse Events by Preferred Term ...........................................23 
Table 4.  
Potential LAST-Related Adverse Events by Preferred Term .....................................23 
Table 5.   
Clinically Relevant Vital Signs Abnormalities ...........................................................26 
 
 


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List of Abbreviations 
Abbreviation 
Term 
AE 
Adverse event  
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
ATC 
Anatomic Therapeutic Classification 
AUC 
Area under the curve 
bpm 
Beats per minute 
BMI 
Body mass index 
BUN 
Blood urea nitrogen 
CRO 
Contract research organization 
CSR 
Clinical Study Report 
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 
IV 
Intravenous(ly) 
LAST 
Local Anesthetic Systemic Toxicity 
LOCF 
Last observation carried forward 
MCV 
Mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MME 
Morphine milligram equivalent 
NRS 
Numeric Rating Scale 
NRS-A 
Numeric Rating Scale with activity 
NRS-R 
Numeric Rating Scale at rest 
NSAID 
Nonsteroidal anti-inflammatory drug 
ORAE 
Opioid-related adverse event 
PK 
Pharmacokinetic(s) 


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Abbreviation 
Term 
PT 
Preferred term 
RBC 
Red blood cell 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic blood pressure 
SD 
Standard deviation 
SDA 
Study drug administration 
SDTM 
Study Data Tabulation Model 
SDTMIG 
Study Data Tabulation Model Implementation Guide 
SE 
Standard error 
SI 
Standard international 
SOC 
System Organ Class 
TEAE 
Treatment-emergent adverse event 
ULN 
Upper limit of normal 
WBC 
White blood cell 
WHODDE 
World Health Organization Drug Dictionary Enhanced 
wWOCF 
Windowed worst observation carried forward 




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 To assess the analgesic efficacy following a 3-day regimen of oral aprepitant and 
a single individualized dose of HTX-011 during the first 72 hours after unilateral 
simple bunionectomy (Cohort 2). 
 To assess the analgesic efficacy following a single individualized dose of HTX-
011 as part of a multimodal analgesic regimen during the first 72 hours after 
unilateral simple bunionectomy (Cohort 3). 
 To assess the analgesic efficacy following a 3-day regimen of oral aprepitant and 
a single individualized dose of HTX-011 as part of a multimodal analgesic 
regimen during the first 72 hours after unilateral simple bunionectomy (optional 
Cohort 4). 
The secondary objectives are as follows: 
 To assess the effect of study treatment on opioid load during the first 72 hours 
following surgery in this study population. 
  To assess the proportion of subjects who are opioid-free after receiving HTX-011 
as part of a multimodal analgesic regimen during the first 72 hours in this study 
population (Cohort 3 and optional Cohort 4). 
 To assess the proportion of subjects who are opioid-free after receiving HTX-011 
as part of a multimodal analgesic regimen during the first 72 hours with or 
without aprepitant and who remain opioid-free through Day 10 and Day 28 
(Cohort 3 and optional Cohort 4). 
 To assess the safety and tolerability of study treatment in this study population. 
 To confirm the pharmacokinetic (PK) parameters of bupivacaine and meloxicam 
for a single individualized dose of HTX 011 in this study population. 
 To analyze the PK parameters of aprepitant in the presence of HTX-011 in this 
study population (Cohort 2 and optional Cohort 4). 
4. 
INVESTIGATIONAL PLAN 
4.1. 
Overall Study Design and Plan 
This is a Phase 2 open-label, multi-cohort study to evaluate the analgesic efficacy, safety, and 
PK of a single, individualized dose of HTX-011 administered into the surgical site as a 
monotherapy or with other medications to enhance analgesia in subjects undergoing 
unilateral simple bunionectomy. The study will include up to 4 cohorts, which will be 
conducted sequentially. Subjects in all cohorts will receive HTX-011. Cohort 2 will also 
include administration of oral aprepitant on Days 1 through 3. Cohort 3 and optional Cohort 
4 will include a scheduled multimodal analgesic regimen during the 72-hour postoperative 
period. Optional Cohort 4 will also include oral aprepitant on Days 1 through 3. 


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4.1.1. 
Cohort 1 
Approximately 30 subjects will be enrolled in Cohort 1. Near the completion of surgery and 
after irrigation and suction have been completed, a single individualized dose of HTX-011 of 
no more than 2.1 mL HTX-011 [up to 60 mg/1.8 mg (bupivacaine/meloxicam doses)] will be 
given intraoperatively via application into the surgical site. The exact amount of HTX-011 
instilled will be determined by the Investigator at the time of surgery. Following surgery and 
immediate postoperative recovery, all subjects will be transferred to the post anesthesia care 
unit (PACU). 
4.1.2. 
Cohort 2 
Approximately 15 subjects will be enrolled in Cohort 2. Subjects will receive a single oral 
dose of aprepitant 125 mg approximately 3 hours prior to the start of surgery. Near the 
completion of surgery and after irrigation and suction have been completed, a single 
individualized dose of HTX-011 of no more than 2.1 mL HTX-011 [up to 60 mg/1.8 mg 
(bupivacaine/meloxicam doses)] will be given intraoperatively via application into the 
surgical site. The exact amount of HTX-011 instilled will be determined by the Investigator 
at the time of surgery. 
Following surgery and immediate postoperative recovery, all subjects will be transferred to 
the PACU. Subjects will be administered a single oral dose of aprepitant 80 mg at 
approximately 24 hours (Day 2) and at approximately 48 hours (Day 3) after the presurgery 
dose of aprepitant. 
4.1.3. 
Cohort 3 
Approximately 15 subjects will be enrolled in Cohort 3. Near the completion of surgery and 
after irrigation and suction have been completed, a single dose of HTX-011 will be given 
intraoperatively via application into the surgical site. The dose is individualized for each 
subject, up to a maximum of 2.1 mL [up to 60 mg/1.8 mg (bupivacaine/meloxicam doses)]. 
The exact amount of HTX-011 instilled will be determined by the Investigator at the time of 
surgery. 
Following surgery and immediate postoperative recovery, all subjects will be transferred to 
the PACU. Subjects will receive a scheduled postoperative analgesic regimen as follows: 
start with 600 mg oral ibuprofen once they are able to tolerate oral intake in the PACU, then 
3 hours after the ibuprofen dose administer the first postoperative dose of 1 g oral 
acetaminophen, then alternate these 2 medications so a dose is delivered every 3 hours. (In 
other words, 3 hours after their first 600 mg oral ibuprofen dose, subjects will receive a 1 g 
oral acetaminophen dose, then after 3 more hours another 600 mg oral ibuprofen dose, and so 
on until the 72-hour postoperative period is complete.) These medications will be 
administered on a round-the-clock, scheduled basis through the 72-hour postoperative period. 
4.1.4. 
Cohort 4 (Optional) 
At the Sponsor’s discretion upon completion of Cohort 3, Cohort 4 may be initiated. If 
initiated, approximately 15 subjects will be enrolled in Cohort 4. Subjects will receive a 
single oral dose of aprepitant 125 mg approximately 3 hours prior to the start of surgery. 
Near the completion of surgery and after irrigation and suction have been completed, a single 


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04 January 2019
 
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dose of HTX-011 will be given intraoperatively via application into the surgical site. The 
dose is individualized for each subject, up to a maximum of 2.1 mL [up to 60 mg/1.8 mg 
(bupivacaine/meloxicam doses)]. The exact amount of HTX-011 instilled will be determined 
by the Investigator at the time of surgery. 
Following surgery and immediate postoperative recovery, all subjects will be transferred to 
the PACU. Subjects will receive a scheduled postoperative analgesic regimen as follows: 
start with 600 mg oral ibuprofen once they are able to tolerate oral intake in the PACU, then 
3 hours after the ibuprofen dose administer the first postoperative dose of 1 g oral 
acetaminophen, then alternate these 2 medications so a dose is delivered every 3 hours. (In 
other words, 3 hours after their first 600 mg oral ibuprofen dose, subjects will receive a 1 g 
oral acetaminophen dose, then after 3 more hours another 600 mg oral ibuprofen dose, and so 
on until the 72-hour postoperative period is complete.) In addition, subjects will be 
administered a single oral dose of aprepitant 80 mg at approximately 24 hours (Day 2) and at 
approximately 48 hours (Day 3) after the presurgery dose of aprepitant. 
4.2. 
Assessments 
Efficacy assessments will include the following: 
 Pain intensity scores using the NRS with activity (NRS-A) and using the NRS at 
rest (NRS-R). 
 Use of opioid rescue medication. 
Safety assessments will include the following: 
 Adverse event (AE) recording. 
 Concomitant medication recording. 
 Clinical safety laboratory tests (hematology and serum chemistry). 
 12-lead electrocardiogram (ECG) at screening only. 
 Physical examination at screening only. 
 Wound healing assessment. 
 Vital signs collections. 
4.3. 
Endpoints 
4.3.1. 
Efficacy Endpoints 
The primary efficacy endpoint is the following: 
 Mean area under the curve (AUC) of the NRS-A pain intensity scores through 
72 hours (AUC0-72). 
 
The secondary efficacy endpoints are the following:  
 Total postoperative opioid consumption (in morphine equivalents) through 
72 hours. 


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 Proportion of subjects who are opioid-free through 72 hours. 
 Mean AUC0-72 of the NRS-R pain intensity scores. 
 Proportion of subjects who are opioid-free through 72 hours who remain opioid-
free through Day 10 and Day 28 (Cohorts 3 and 4 only). 
4.3.2. 
Safety Endpoints 
The safety endpoints are the following: 
 Incidence of treatment-emergent AEs (TEAEs), serious TEAEs (SAEs), and 
opioid-related AEs (ORAEs) through the Safety Follow-Up on Day 42. 
 Change from baseline in clinical laboratory results. 
 Change from baseline in vital signs. 
 Wound healing assessment on Day 7 and Day 28, and the Safety Follow-Up on 
Day 42. 
5. 
GENERAL STATISTICAL CONSIDERATIONS 
No statistical hypothesis testing will be performed. Continuous data will be presented using 
descriptive statistics: number of subjects (n), mean, standard deviation (SD), median, 
minimum and maximum. Descriptive statistics on efficacy measures will also include the 
standard error (SE). Categorical data will be summarized by the number and percent of 
subjects. Data will be displayed in all listings sorted by treatment group, subject number and 
visit/study day. When count data are presented, the percent will be suppressed when the 
count is zero in order to draw attention to the non-zero counts. A row denoted “Missing” will 
be included in count tabulations where necessary to account for dropouts and missing values. 
The denominator for all percentages will be the number of subjects in that treatment group 
within the population of interest, unless otherwise stated. Non-zero percentages will be 
rounded to 1 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 
1 decimal place and SD and SE 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 SE will have 3 decimal places. 
 If the original value has 2 or more decimal places: mean, median, CI, SD, and SE 
will all have 3 decimal places. 
Minimum and maximum will always have the same decimal places as the original measure, 
up to a maximum of 3 decimal places. The above rounding rules will not be applied to 
original measures displayed in listings. 
Values that are collected with “<” or “>” signs will be analyzed as the numerical value 
without the sign in tables and figures. In listings, these data will be reported as collected with 
the sign. 


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All efficacy and safety data will be collected electronically. Datasets will be created using the 
Study Data Tabulation Model (SDTM) v. 1.4 or higher, conforming to the SDTM 
Implementation Guide (SDTMIG) v. 3.2 or higher. Datasets, tables, listings, and figures will 
be programmed using SAS® v. 9.4 or higher. All efficacy and safety data will be listed via 
the SDTM datasets and selected efficacy and safety data will be listed via programmed 
listings. 
All summary tables and figures will be presented by cohort. Data listings will include the 
cohort variable. 
5.1. 
Sample Size 
The sample size in this study was selected empirically without a formal statistical 
assumption. 
5.2. 
Randomization, Stratification, and Blinding 
This is an open-label study.   
5.3. 
Analysis Populations 
5.3.1. 
Safety Population 
The Safety Population will consist of all subjects who receive study drug. This population 
will be used for all summaries of efficacy and safety data. 
5.4. 
Other Important Considerations 
5.4.1. 
Calculation of HTX-011 Dose Received 
After preparing the syringe and before administration, the weight of the syringe (to the 
nearest gram) containing HTX-011 will be recorded in the eCRF. After administering HTX-
011, the weight of the syringe (to the nearest gram) will also be recorded in the eCRF. The 
calculation of the dose of study drug received is calculated as follows: 
D = Wb – Wa – 0.3, where: 
 Wb is the weight of the syringe in gram before study drug administration. 
 Wa is the weight of syringe in gram after study drug administration. 
Bupivacaine/meloxicam doses are calculated as follows: 
Bupivacaine dose (mg) = D *25 mg 
Meloxicam dose (mg) = D *0.75 mg 
5.4.2. 
Compliance of Aprepitant 
For subjects in Cohorts 2 and 4, number and percentage of subjects for each dose of 
aprepitant received will be summarized. 


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5.4.3. 
Definition of Baseline 
Baseline data are defined as the last observed measurement collected, whether scheduled or 
unscheduled, prior to the start of study drug administration.   
5.4.4. 
Calculation of Change and Percent Change from Baseline 
Change from Baseline to any timepoint t (Ct) is calculated as follows: 
 
Ct = Mt – MB, where: 
 Mt is the measurement of interest at timepoint t. 
 MB is the measurement of interest at Baseline. 
Percent change from Baseline to any timepoint (Pt) is calculated as follows: 
 
Pt = 100*(Ct/MB) 
5.4.5. 
Study Day Calculation for Reporting Purposes 
The following convention will be used to calculate study day for reporting purposes: 
 The study day of study drug administration is Study Day 1. 
 For measurements that are on or after the date of study drug administration:  
 Study Day = date of measurement – date of study drug administration + 1. 
 For measurements that are prior to the date of study drug administration: 
 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. 
5.4.6. 
Start date/time of Study Drug Administration (Time 0) 
The start date/time of study drug administration is defined as the date and time of the start of 
HTX-011 instillation. The start date/time of study drug administration will be Time 0 for all 
efficacy and safety assessments.  
For Cohorts 2 and 4, first dose of aprepitant study drug administration start time will be used 
to determine treatment emergent AE status. Otherwise, T0 is defined as HTX-011 study drug 
administration time.  
5.4.7. 
72-Hour Postoperative Observation Period 
The 72-hour postoperative observation period will be defined as the period of time from the 
start date/time of HTX-011 to the date/time of NRS-A pain intensity score assessment at the 
nominal 72-hour postoperative timepoint.  
Subjects who have a reported NRS-A pain intensity score at the nominal 72-hour 
postoperative timepoint will be considered as completing the 72-hour postoperative 
observation period. 


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5.4.8. 
Visit Windows 
Due to the short duration of the study and the primary efficacy analyses occurring during the 
72-hour postoperative period of subject hospitalization, no programmatically calculated visit 
windows are defined for this study. 
5.4.9. 
Handling of Missing and Partial Data 
The amount of missing data during the primary efficacy analysis period is expected to be 
very low due to the protocol-required 72-hour hospitalization of all subjects following 
surgery.   
For any data that is missing through 72 hours in subjects who complete the 72-hour 
postoperative observation period, the NRS pain intensity scores will be imputed via last 
observation carried forward (LOCF), in which the most recent postdose nonmissing value is 
used for a subsequent missing value. If there is no postdose value available prior to the first 
missing value, then the median of values from subjects with observed values within the same 
treatment group at the relevant timepoint will be used. Predose values will not be carried 
forward to postdose timepoints.  
In subjects who withdraw from the study prior to 72 hours, missing NRS pain intensity 
scores through 72 hours that were to be collected following withdrawal will be imputed via 
worst observation carried forward (WOCF), in which the worst (highest) NRS pain intensity 
score observed prior to withdrawal will be used for post-withdrawal values through 72 hours. 
Any missing NRS pain intensity scores prior to the point of withdrawal will be imputed via 
LOCF. 
A table displaying the number and percentage of subjects with missing NRS-A pain intensity 
scores at each nominal timepoint will be produced. 
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 in the Safety Population, 
subjects completing the 72-hour postoperative observation period, subjects completing 
Day 28, subjects completing the Safety Follow-up on Day 42, and subjects not completing 
the Safety Follow-up on Day 42 by reason for withdrawal. Only 1 reason for study 
withdrawal will be recorded for each subject.   


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7. 
DEMOGRAPHICS, CHARACTERISTICS, AND MEDICAL 
HISTORY 
7.1. 
Demographics and Baseline Characteristics 
Demographics and baseline characteristics will be presented in tables using descriptive 
statistics. Demographics consist of age, age category, sex, race, and ethnicity. Baseline 
characteristics consist of weight, height, and body mass index (BMI). A subject’s age in 
years is recorded directly on the eCRF. The number and percentage of subjects in the 
following age categories will be presented: 18-44, 45-54, 55-64, 65-74, 75-84, and ≥ 85. 
7.2. 
Medical History 
Medical history will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA®) version 19.1. Medical history will be summarized for the Safety Population and 
will display the number and percentage of subjects with a past and/or concomitant disease or 
past surgeries by System Organ Class (SOC) and preferred term (PT).  
7.3. 
Protocol Deviations 
Deviations and violations from the protocol will be recorded. Protocol deviations will be 
classified into, but not necessarily limited to, the following categories: 
 ICF procedures. 
 Eligibility criteria. 
 Prohibited concomitant medication/therapy. 
 Laboratory assessment. 
 Study procedure (eg, efficacy ratings). 
 Safety reporting. 
 Study drug dosing/administration 
 Visit schedule/windows 
 
Protocol deviations will be presented in a summary table by protocol deviation category.   
8. 
TREATMENTS AND MEDICATIONS 
8.1. 
Prior and Concomitant Medications 
Prior medications are defined as medications with a stop date occurring before Day 1. 
Concomitant medications are defined as medications that are ongoing on Day 1 or with a 
start date occurring on or after Day 1. Medications with start and stop dates which bracket 
Day 1, or for which missing start and/or stop dates make it impossible to determine the prior 
or concomitant status, will be summarized as concomitant medications. 


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All medications will be coded with the World Health Organization Drug Dictionary 
Enhanced (WHODDE), September 1, 2016. 
Prior and concomitant medications will be summarized separately by drug class and PT. At 
each level of summarization, a subject is counted once if that subject reports 1 or more 
medications at that level. Drug class will correspond to the Anatomical Therapeutic 
Classification (ATC) Level 2 term. 
All prior and concomitant medications will be summarized for the Safety Population.   
8.2. 
Rescue Medication 
The following steps will be implemented to identify rescue medication in the study: 
1. Select concomitant medications that are coded as an opioid analgesic (for all cohorts) 
or acetaminophen/paracetamol (Cohorts 1 and 2 only). 
2. Identify rescue medications from Step 1 in which the start date/time of medication is 
within the 72-hour postoperative observation period (see Section 5.4.7 for details). 
Opioid rescue medication in intravenous (IV) morphine milligram equivalent (MME) dose 
(see Section 9.2 for details) and non-opioid rescue medication dose (Cohorts 1 and 2 only) 
will be summarized for 0-24 hours, 0-48 hours, and 0-72 hours. In addition, proportions of 
subjects who received no rescue medication, who received opioid rescue medication only, 
who received non-opioid rescue medication only, and who received both opioid and non-
opioid rescue medication will be summarized through 72 hours for Cohorts 1 and 2 only.  
8.3. 
Surgery Procedure 
The foot subject to the surgical procedure (left or right), length of incision in centimeters, and 
the duration of surgery will be summarized.  Duration will be calculated as completion time 
minus start time, reported in minutes.  
8.4. 
Study Drug 
For all subjects, treatment will consist of a single dose of HTX-011.  Cohorts 2 and 4 will 
also include administration of oral aprepitant on Days 1 through 3. Cohorts 3 and 4 will also 
receive scheduled postoperative analgesic of acetaminophen and ibuprofen during the 72-
hour postoperative period. . Because a single individualized dose of HTX-011 will be given 
to all subjects, the actual dose received will be calculated (see Section 5.4.1 for details). 
A summary of HTX-011 dose will be produced to include mean, standard deviation, median, 
minimum and maximum descriptive statistics for both bupivacaine and meloxicam doses, 
and categorical dose in bupivacaine (20-30 mg, >30-40 mg, >40-50 mg, >50-60 mg) will be 
summarized.    
A summary of treatment compliance will be produced for aprepitant in Cohorts 2 and 4. 
For subjects in Cohorts 3 and 4, average daily use and total use of protocol-specified 
postoperative analgesic medications will also be summarized using descriptive statistics for 
each analgesic (ibuprofen or acetaminophen) for hours 0-24, 0-48, and 0-72. 


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9. 
EFFICACY ANALYSIS 
All efficacy summaries will be performed on the Safety Population and summarized by 
cohort. 
Table 1 displays the planned treatment group being studied. 
Table 1. 
Planned Treatment Group 
Cohort 
Treatment 
Planned 
Sample 
Size 
Cohort 1 
HTX-011, up to but not to exceed 60 mg/1.8 mg (bupivacaine/meloxicam 
doses), 2.1 mL, via instillation into the surgical site 
30 
Cohort 2 
3 single oral doses of aprepitant and HTX-011, up to but not to exceed 60 
mg/1.8 mg (bupivacaine/meloxicam doses), 2.1 mL, via instillation into the 
surgical site 
15 
Cohort 3 
HTX-011, up to but not to exceed 60 mg/1.8 mg (bupivacaine/meloxicam 
doses), 2.1 mL, via instillation into the surgical site; in addition to 
scheduled postoperative analgesic regimen 
15 
Cohort 4 
(Optional) 
3 single oral doses of aprepitant and HTX 011, up to but not to exceed 60 
mg/1.8 mg (bupivacaine/meloxicam doses), 2.1 mL, via instillation into the 
surgical site; in addition to scheduled postoperative analgesic regimen 
15 
All efficacy analyses will consist of reporting summary statistics in tables and figures. 
9.1. 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the mean AUC of the NRS-A pain intensity scores through 
72 hours (AUC0-72). 
9.1.1. 
Primary Analysis 
During the first 72 hours following surgery, the NRS-A is measured at hours 1, 2, 4, 8, 12, 
24, 36, 48, 60, and 72. Using the trapezoidal rule and letting Pt = the NRS-A pain intensity 
score at time t, then:  
ሺݐെݐିଵሻܲ௧షభ൅ܲ௧
2
 
 
is the trapezoidal area between times t and t-1. The AUC0-72 is thus calculated as follows: 
 
ܣܷܥ଴ି଻ଶൌන݂ሺݐሻ݀ݐൎ෍ሺݐ௜െݐ௜ିଵሻܲ௜ିଵ൅ܲ௜
2
଻ଶ
௜ୀଶ
଻ଶ
ଵ
 
 
To adjust for the duration effect of opioid rescue medication, the windowed WOCF 
(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 


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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 prewindow score, then it will not be 
replaced. wWOCF will be performed following LOCF/WOCF (ie, perform LOCF/WOCF 
first, then apply wWOCF). See Table 2 in Section 9.2 for predefined analgesic windows for 
each opioid medication.  
The mean AUC0-72 of the NRS-A pain intensity scores using wWOCF will also be plotted 
with associated SEs in a bar chart.   
The AUC0-12, AUC0-24, AUC24-48, AUC0-48, AUC24-72, and AUC48-72 of the NRS-A pain 
intensity scores will be summarized similarly as for the AUC0-72 of the NRS-A pain intensity 
scores, with appropriate adjustments to the calculations to reflect the time periods of interest. 
Mean AUC0-24, and mean AUC0-48 of NRS-A will also be plotted with associated SEs in a bar 
chart. 
In addition, the mean NRS-A pain intensity scores will be summarized at each assessed 
timepoint through Day 28. Mean NRS-A pain intensity scores will also be plotted in a line 
graph over time through 72 hours, with associated SEs at each timepoint. 
9.1.2. 
Sensitivity Analyses 
The following sensitivity analysis will be performed on the primary endpoint: AUC0-72 will 
be summarized using descriptive statistics 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: 
 Total postoperative opioid consumption (in morphine equivalents) through 72 hours. 
 Proportion of subjects who are opioid-free through 72 hours. 
 Proportion of subjects who are opioid-free through 72 hours who remain opioid-
free through Day 10 and Day 28 (Cohorts 3 and 4 only). 
 Mean AUC0-72 of the NRS-R pain intensity scores. 
Total postoperative opioid consumption (in morphine equivalents) through 72 hours 
Determination of morphine equivalents 
Use of rescue medications will be summarized by preferred term. All opioid dosages and 
formulations will have the IV MME calculated (Opioid Morphine Equivalent Conversion 
Factors, Centers for Disease Control and Prevention, Atlanta, GA, May 2014).  
Protocol-allowed postoperative rescue medications consist of oral (PO) immediate-release 
oxycodone (no more than 10 mg within a 4-hour period as needed), intravenous (IV) 
morphine (no more than 10 mg within a 2-hour period as needed), and/or oral acetaminophen 
(no more than 1 gram [1000 mg] in a 6-hour window) for cohorts 1 and 2. Oral 
acetaminophen and ibuprofen are not considered as rescue medication for Cohorts 3 and 4 


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rather than scheduled postoperative analgesic regimen. For subjects administered any 
acetaminophen-containing product, the total combined daily dose must not exceed 4 grams 
(4000 mg). Combination products containing an opioid and non-opioid are not allowed. No 
other analgesic agents, including nonsteroidal anti-inflammatory drugs (NSAIDs), IV 
acetaminophen, or combination products of opioids and NSAIDs, are permitted during the 
72-hour postoperative observation period.  
Table 2 displays the IV MME along with the analgesic windows of selected opioid rescue 
medications for wWOCF purposes. Protocol-allowed postoperative opioid rescue 
medications are checked. Opioid medications that are not protocol-allowed will be logged as 
protocol deviations, but will still be subject to IV MME conversion for analysis. 
Table 2.    
Analgesic Windows and IV Morphine Milligram Equivalents for Opioid 
Rescue Medications in Preferred Terms 
Medication 
Route 
Window 
(hr) 
IV MME Factor 
Protocol Allowed 
CODEINE 
PO 
6 
0.05 
 
 
HYDROMORPHONE 
HYDROCHLORIDE 
PO 
4 
1.33 
 
 
HYDROMORPHONE 
HYDROCHLORIDE 
IV 
4 
6.67 
 
 
FENTANYL 
IV 
1 
50.00 
 
 
HYDROCODONE 
PO 
6 
0.40 
 
 
MORPHINE 
IV 
4 
1.00 
 
 
MORPHINE 
PO 
4 
0.33 
 
 
MORPHINE 
IM 
4 
1.00 
 
 
MORPHINE 
PR 
4 
1.00 
 
 
OXYCODONE 
IV 
4 
1.00 
 
 
OXYCODONE 
IM 
4 
1.00 
 
 
OXYCODONE 
PO 
6 
0.50 
 
 
PETHIDINE 
IV 
4 
0.13 
 
 
TRAMADOL 
IV 
6 
0.06 
 
 
TRAMADOL 
PO 
6 
0.04 
 
 
Abbreviations: hr, hour; IM, intramuscular; IV, intravenous; MME, morphine milligram equivalent; PO, by 
mouth (orally); PR, per rectum. 
 
Analysis method 
Rescue medication use is collected from hours 0-72. Average daily use and total use will be 
tabulated using descriptive statistics for each opioid, for overall opioids, and for 
acetaminophen (for cohorts 1 and 2) during the following periods: hours 0-24, hours 24-48, 


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hours 0-48, hours 48-72, and hours 0-72. Subjects who did not use a specific rescue 
medication during a period of interest will have their dose set to 0 for that period.  
The mean total postoperative opioid consumption will also be plotted in a bar chart for hours 
0-24, hours 0-48 and hours 0-72 with associated SEs. 
Proportion of subjects who are opioid-free through 72 hours 
Subjects who have a total MME postoperative opioid dose = 0 through 72 hours will be 
characterized as “opioid-free” through 72 hours. The proportion of subjects who are 
opioid-free through 72 hours will be summarized. 
In addition, the proportion of subjects who are opioid-free through 24 hours and through 
48 hours will be summarized.  
Proportion of subjects who are opioid-free through 72 hours who remain opioid-frree 
through Day 10 and Day 28 (Cohorts 3 and 4 only) 
Using the number of subjects receiving no opioid rescue medication from 0-72 hours as the 
denominator, the proportion of these subjects receiving no opioid rescue medication through 
Day 10 and through Day 28 will be summarized. The opioid use through Day 10 and Day 28 
will come from the subject diary. 
Subjects will be provided a diary to record if they took any opioid medication 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. 
Mean AUC0-72 of the NRS-R pain intensity scores 
AUC0-72 of the NRS-R pain intensity scores will be summarized similarly to the methods 
described for the primary endpoint in Sections 9.1.1 and 9.1.2. AUC0-12, AUC0-24, AUC24-48, 
AUC0-48, AUC24-72, and AUC48-72 of the NRS-R pain intensity scores will also be 
summarized. 
10. 
SAFETY ANALYSIS 
All analyses of safety data will be conducted using the Safety Population. No imputation of 
missing safety data will be performed except in the case of partial AE and concomitant 
medication onset dates (Appendix 1). 
10.1. 
Adverse Events 
An AE is defined as any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related. A TEAE is any AE which occurs any time 
during or after study drug administration (for cohorts 1 and 3, use HTX-011 administration 
start time and for cohorts 2 and 4, use the first dose of aprepitant administration start time), 
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 


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


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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 
The incidence of possibly related TEAEs will be presented in a table by SOC and PT. TEAEs 
that are missing relationship will be considered “Possibly Related” for the purpose of this 
incidence table but will be presented in the data listing with a missing relationship.   
10.1.3. 
Severity of Adverse Event 
The incidence of severe TEAEs will be presented in a table by SOC and PT. TEAEs that are 
missing severity will be considered “severe” for the purpose of this incidence table but will 
be presented in the data listing with a missing severity.  
10.1.4. 
Serious Adverse Events 
The seriousness of a TEAE should be assessed by the Investigator independently from the 
severity of the TEAE. An 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. 
SAEs will be presented in a listing. 
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 
 Pruritus generalised 
 Somnolence 
 Respiratory depression 
 Urinary retention 


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Incidence of ORAEs will be presented separately as follows: 
 Incidence of ORAEs.  
 Incidence of ORAEs through the 72-hour postoperative observation period. 
10.1.7. 
Local Inflammatory Adverse Events 
To enable a broad and comprehensive analysis of TEAEs potentially related to adverse 
effects on wound healing, local inflammatory TEAEs will be reviewed by searching the 
clinical database using a custom list of PTs created by Heron (Table 3). 
Table 3. 
Local Inflammatory Adverse Events by Preferred Term 
 
Blister 
 
Blood blister 
 
Cellulitis 
 
Erythemaa 
 
Impaired healing 
 
Incision site cellulitis 
 
Incision site 
complication 
 
Incision site erythema 
 
Incision site haemorrhage 
 
Incision site infection 
 
Incision site oedema 
 
Incision site rash 
 
Incision site swelling 
 
Incision site vesicles 
 
Infection 
 
Postoperative wound 
complication 
 
Postoperative wound 
infection 
 
Post procedural cellulitis 
 
Purulent discharge 
 
Wound complication  
 
Wound dehiscence 
 
Wound infection 
 
Wound secretion 
a The Preferred Term of erythema was included in addition to incision site erythema for the most 
comprehensive review. 
 
Incidence of local inflammatory TEAEs will be presented in a table by SOC and PT.  
10.1.8. 
Potential Local Anesthetic Systemic Toxicity (LAST) related Adverse Events 
The symptoms that are potentially related to LAST will be reviewed by searching the clinical 
database using a custom list of PTs created by Heron (Table 4). 
Table 4.  
Potential LAST-Related Adverse Events by Preferred Term 
 
Arrhythmia (any preferred term 
with the string of “Arrhythmia”) 
 
Bradycardia (any preferred term 
with the string of “Bradycardia”) 
 
Cardiac arrest 
 
Dizziness 
 
Dysgeusia 
 
Hypotension 
 
Muscle twitching 
 
Paraesthesia 
 
Paraesthesia oral 
 
Respiratory arrest 
 
Seizure 
 
Tinnitus 
 
Tremor 
 
Vision blurred 
 
Visual impairment 
 
Incidence of potential LAST-related TEAEs will be presented in a table by SOC and PT.  


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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 (AE 
preferred term), and relationship of death to study drug. 
10.2. 
Clinical Laboratory Evaluations 
Laboratory assessments will be performed by a central laboratory (hematology and serum 
chemistry) or locally (pregnancy test and drug screen). All summaries of central laboratory 
data will be based on the standard international (SI) units provided by the central lab. 
Associated laboratory parameters such as hepatic profile, renal function, and hematology 
values will be grouped and presented together. 
Summary tables for hematology and chemistry including actual values and change from 
Baseline values will be presented for clinical laboratory tests with numeric values. These 
tables will include each visit (Baseline and 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.  
10.3. 
Hematology 
The following laboratory tests will be included in hematology summary tables: hematocrit, 
hemoglobin, mean corpuscular volume (MCV), platelet count, red blood cell (RBC) count, 
and total and differential white blood cell (WBC) count (basophils, eosinophils, lymphocytes, 
monocytes, and neutrophils). 
10.3.1. 
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 clinically relevant abnormalities in liver function tests will be 
summarized at each visit for the following categories. Subjects with clinical relevant 
abnormalities in Liver Function Tests will be presented in data listing as well. 
 ALT or AST: 
o > 1 × ULN  
o ≥ 2 × ULN 
o ≥ 3 × ULN 
o ≥ 4 × ULN 
o ≥ 5 × ULN  
 Total bilirubin ≥ 2 × ULN 
 ALP: 
o ≥ 1.5 × ULN 
o ≥ 2 × ULN 
 ALT ≥ 3 × ULN and AST ≥ 3 × ULN 
 ALT ≥ 3 x ULN and total bilirubin ≥ 2 × ULN 
 AST ≥ 3 x ULN and total bilirubin ≥ 2 × ULN 
 Potential Hy’s Law: (ALT or AST ≥ 3 × ULN) and ALP < 2 × ULN and total 
bilirubin ≥ 2 × ULN 
10.3.2. 
Urine Pregnancy Test and Urine Drug Screen 
Urine pregnancy test results (women of childbearing potential) and urine drug screen results 
will be listed. 
10.4. 
Vital Sign Measurements 
Vital signs including systolic blood pressure (SBP), diastolic blood pressure (DBP), heart 
rate/pulse (HR), body temperature, and respiration rate will be collected at screening, on Day 


Heron Therapeutics, Inc. 
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1 before surgery, and post-treatment at 30 minutes and at 1, 1.5, 2, 4, 8, 12, 18, 24, 36, 48, 
60, and 72 hours.  
Summary tables including actual values and changes from Baseline will be presented for 
vital signs.   
The number and percentage of subjects with clinically relevant abnormalities will be 
presented using data from any postdose visit (including unscheduled visits). Subjects with 
clinical relevant abnormalities in vital signs will be presented in data listing as well. The 
criteria for clinically relevant abnormalities are shown in Table 5.  
Table 5.   
Clinically Relevant Vital Signs Abnormalities 
Vital Sign 
Low 
High 
HR 
≤50 bpm and  ≥15 bpm decrease from 
Baseline 
≥120 bpm and  ≥15 bpm increase from Baseline 
SBP 
≤90 mmHg and  ≥20 mmHg decrease from 
Baseline 
≥160 mmHg and  ≥20 mmHg increase from 
Baseline 
DBP 
≤50 mmHg and  ≥15 mmHg decrease from 
Baseline 
≥100 mmHg and  ≥15 mmHg increase from 
Baseline 
Abbreviations: bpm, beats per minute; DBP, diastolic blood pressure; HR, heart rate; SBP, systolic blood 
pressure. 
 
10.5. 
Electrocardiogram 
 
12-lead ECG (triplicate) is performed at screening only. ECG data will be listed only. 
10.6. 
Physical Examination 
Physical examination is performed at screening only. Physical examination data will be listed 
only. 
10.7. 
Wound Healing Assessment 
Surgical wound healing will be assessed using a wound healing assessment questionnaire on 
Day 7, Day 28 and the Safety Follow-Up on Day 42. A summary of wound healing 
assessment results will be produced, showing the number and percentage of subjects with 
abnormal wound healing symptoms at each visit and final assessment. Any symptoms 
present overall at each visit (Day 7, Day 28, Safety Follow-Up on Day 42 and the final 
assessment) will also be summarized.  
Wound healing data collected at unscheduled visits will be included in listings and will 
contribute to the final assessment summary. Unscheduled wound healing results will not be 
windowed for the purposes of assigning a nominal visit. 


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11. 
INTERIM ANALYSIS 
11.1. 
Interim Analysis 
No formal interim analyses are planned; however, preliminary analyses of data by cohort 
may be conducted to plan future studies or for regulatory reporting purposes. 
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 tables and listings of accumulating data 
approximately monthly to check enrollment, adherence to follow-up schedule, and ongoing 
safety results.   
 
 
 


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04 January 2019
 
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APPENDIX 1. IMPUTATION OF PARTIAL AND MISSING DATES 
Incomplete Dates of Adverse Event start 
All AE onset dates must be entered on the eCRF as complete dates. In the rare case that all or 
part of an AE onset date is missing but an AE resolution date is present and after study drug 
administration then the AE onset date will be imputed as follows: 
 
Year of onset 
Month of onset 
Day of onset 
Onset date to be imputed as 
Missing 
Missing 
Missing 
Date of SDA 
year = year of SDA 
Missing 
Nonmissing 
Date of SDA 
year = year of SDA 
Missing 
Missing 
Set month and day to those of SDA 
year < year of SDA 
Missing 
Nonmissing 
set month to December 
year < year of SDA 
Missing 
Missing 
set month and day to December 31 
year > year of SDA 
Missing 
Nonmissing 
set month to January 
year > year of SDA 
Missing 
Missing 
set month and day to January 1 
year = year of SDA 
Month = month of SDA 
Missing 
Set day as day of SDA 
year = year of SDA 
Month < month of SDA 
Missing 
Set day as last day of onset month 
year = year of SDA 
Month > month of SDA 
Missing 
Set day as first day of onset month 
year < year of SDA 
Nonmissing 
Missing 
Set day as last day of onset month 
year > year of SDA 
Nonmissing 
Missing 
Set day as first day of onset month 
SDA = study drug administration. 
 
If AE resolution date is present and prior to study drug administration, no need to impute 
incomplete AE start date, as the AE is not treatment emergent and the event should be in the 
medical history. 
Concomitant Medications 
 If year and month are present and day is missing then set day to first day of month 
for start date, and set day to last day of month for end date. 
 If year and day are present and month is missing then set month to January for 
start date, and set month to December for end date. 
 If year is present and month and day are missing then set month and day to 
January 1 for start date, and set month and day to December 31 for end date. 
 Completely missing dates will not be imputed. 
If start date is completely missing and end date is not prior to study drug administration, then 
the medication will be classified as concomitant; if the end date is missing, then the 
medication will be classified as ongoing. Medications for which the start and end dates are 
completely missing will be classified as concomitant. 
 


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APPENDIX 2. DOCUMENT REVISION HISTORY 
Version 
Date 
Notes/Revisions 
1 
05 October 2018 
Initial version, based on protocol version 1 (27 September 2018) 
2 
04 January 2019 
2nd version, based on protocol version 3 (12 December 2018)