Conditions: Postoperative Pain
Keywords: inguinal hernia hernia hernia surgery postoperative pain herniorrhaphy
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 63
Healthy volunteers: no

Brief summary:
This is a Phase 2, open-label study in subjects undergoing unilateral open inguinal herniorrhaphy.

Detailed description:

Arms:
arm 1: HTX-011 (bupivacaine/meloxicam), 300 mg/9 mg via instillation; non-opioid multimodal analgesic (MMA) regimen. arm 2: HTX-011 (bupivacaine/meloxicam), 300 mg/9 mg via instillation; non-opioid multimodal analgesic (MMA) regimen and IV ketorolac.

Interventions: intervention 1: HTX-011 intervention 2: Luer lock applicator intervention 3: Vial access device intervention 4: Ibuprofen intervention 5: Acetaminophen intervention 6: Ketorolac
Intervention descriptions: intervention 1: HTX-011 (bupivacaine/meloxicam), 300 mg/ 9 mg via instillation. intervention 2: Applicator for instillation. intervention 3: Device for withdrawal of drug product. intervention 4: Ibuprofen, 600 mg. intervention 5: Acetaminophen, 1 g. intervention 6: Intraoperative IV ketorolac.

Protocol document:
Prot_000.pdf: 
Document Type:  
Study Protocol 
Official Title:  
A Phase 2, Open-Label Study of HTX-011 in a Multimodal Analgesic 
Regimen for Decreased Opioid Use Following Unilateral Open Inguinal 
Herniorrhaphy 
NCT Number:  
NCT03695367 
Document Date:  
31-Aug-2018 
 


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-011-215 
 
Protocol Title: 
A Phase 2, Open-Label Study of HTX-011 in a Multimodal 
Analgesic Regimen for Decreased Opioid Use Following 
Unilateral Open Inguinal Herniorrhaphy 
Brief Title: 
Phase 2 Herniorrhaphy Study for Opioid Elimination 
Investigational Products: 
HTX-011 (bupivacaine and meloxicam) extended-release 
solution  
Phase of Development: 
2 
Sponsor: 
Heron Therapeutics, Inc. 
4242 Campus Point Court, Suite 200 
San Diego, CA 92121 
1-858-251-4400 
Medical Monitor: 
 
 
 
Medical Project Leader: 
  
Vice President, Clinical Research  
 
 
Protocol Version Date: 
31 August 2018 
 


Protocol No: HTX-011-215 (Version 1) 
 
Heron Therapeutics, Inc. 
Phase 2 Herniorrhaphy Study for Opioid Elimination 
Confidential 
2 
SPONSOR SIGNATURE 
 
Protocol Number:  
 
HTX-011-215 
 
Protocol Title:  
A Phase 2, Open-Label Study of HTX-011 in a Multimodal Analgesic 
Regimen for Decreased Opioid Use Following Unilateral Open Inguinal 
Herniorrhaphy 
 
This protocol Version 1 has been reviewed and approved by the Sponsor. 
 
 
The electronic signature is appended. 
 
VP Clinical Research 
Heron Therapeutics, Inc. 
 


Protocol No: HTX-011-215 (Version 1) 
 
Heron Therapeutics, Inc. 
Phase 2 Herniorrhaphy Study for Opioid Elimination 
Confidential 
3 
INVESTIGATOR AGREEMENT 
 
CLINICAL STUDY PROTOCOL: HTX-011-215 
TITLE: A Phase 2, Open-Label Study of HTX-011 in a Multimodal Analgesic Regimen 
for Decreased Opioid Use Following Unilateral Open Inguinal Herniorrhaphy 
I have read the protocol and agree that it contains all necessary details for carrying out this study. 
I am qualified by education, experience, and training to conduct this clinical research study. 
I will conduct the study as outlined herein. 
I will provide copies of the protocol, Investigator’s Brochure, and all other information on the 
investigational product that were furnished to me by the Sponsor to all physicians and other 
study personnel responsible to me who participate in this study and will discuss this material 
with them to ensure that they are fully informed regarding the investigational product and the 
conduct of the study. 
I agree to keep records on all subject information (ie, medical records, case report forms, and 
informed consent statements), study drug shipment and return forms, and all other information 
collected during the study in accordance with local and national Good Clinical Practice (GCP) 
guidelines. 
 
 
Principal Investigator: 
Address: 
Signature: 
Date: 
 
 


Protocol No: HTX-011-215 (Version 1) 
 
Heron Therapeutics, Inc. 
Phase 2 Herniorrhaphy Study for Opioid Elimination 
Confidential 
4 
PROTOCOL SYNOPSIS 
Sponsor: Heron Therapeutics, Inc.  
Protocol Number: HTX-011-215 
Name of Investigational Product: 
HTX-011 (bupivacaine and meloxicam) 
extended-release solution 
Protocol Title:  
A Phase 2, Open-Label Study of HTX-011 in a 
Multimodal Analgesic Regimen for Decreased Opioid 
Use Following Unilateral Open Inguinal Herniorrhaphy 
Name of Active Ingredients: 
bupivacaine and meloxicam 
Phase of Development: 2 
Study Objectives:   
Primary Objective: 
 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 following unilateral open inguinal 
herniorrhaphy with mesh. 
Secondary Objectives: 
 To assess the total opioid use following HTX-011 as part of a multimodal analgesic regimen 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 that remain opioid-free through Day 10 and 
Day 28.  
 To assess the relationship between opioid use and severe pain. 
Methodology:  
This is a Phase 2, open-label study in subjects undergoing unilateral open inguinal herniorrhaphy.  
Cohort 1 
Cohort 1 will be composed of approximately 30 subjects. Subjects will be screened within 21 days prior 
to surgery. Subjects who meet the Screening eligibility criteria will be allowed to participate in the study.  
On the day of surgery (Day 1), subjects who continue to meet the eligibility criteria will undergo inguinal 
herniorrhaphy with mesh under general anesthesia. Spinal, epidural, or regional anesthesia are not 
allowed. Preoperative nonsteroidal anti-inflammatory drugs (NSAIDs) are not allowed. Approximately 
2 hours prior to the start of induction of general anesthesia, subjects are to receive 1 g oral 
acetaminophen. However, if the start of general anesthesia is delayed by more than 4 hours, the subject 
must not be enrolled unless the surgery is rescheduled for a later day (if this puts the subject out of the 
screening window, screening assessments may be re-performed). All subjects will then receive a 
scheduled postoperative analgesic regimen as follows: start with 600 mg oral ibuprofen once they are able 
to tolerate oral intake in the postoperative care unit, 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, they 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. 
Optional Cohort 2 
At the Sponsor’s discretion upon completion of Cohort 1, Optional Cohort 2 may be initiated. If 
conducted, Optional Cohort 2 will be composed of approximately 30 subjects. The same required 
preoperative, intraoperative, and scheduled postoperative pain medication regimen as in Cohort 1 would 


Protocol No: HTX-011-215 (Version 1) 
 
Heron Therapeutics, Inc. 
Phase 2 Herniorrhaphy Study for Opioid Elimination 
Confidential 
5 
Sponsor: Heron Therapeutics, Inc.  
Protocol Number: HTX-011-215 
Name of Investigational Product: 
HTX-011 (bupivacaine and meloxicam) 
extended-release solution 
Protocol Title:  
A Phase 2, Open-Label Study of HTX-011 in a 
Multimodal Analgesic Regimen for Decreased Opioid 
Use Following Unilateral Open Inguinal Herniorrhaphy 
Name of Active Ingredients: 
bupivacaine and meloxicam 
Phase of Development: 2 
be required with the intra-operative addition prior to wound closure of 1 dose of intravenous (IV) 
ketorolac as follows: 
 For subjects aged ≥65 years, serum creatinine >1.5, and/or weight <50 kg: 15 mg. 
 For subjects aged <65years and/or weight ≥50 kg: 30 mg. 
Optional Cohort 3 
At the Sponsor’s discretion upon completion of Optional Cohort 2, Optional Cohort 3 may be initiated. If 
conducted, Optional Cohort 3 will be composed of approximately 30 subjects. The specific multimodal 
analgesic regimen in Optional Cohort 3 will be determined by the Sponsor and included in a protocol 
amendment. 
Inpatient Scheduled Analgesic Regimen (Preoperative, Intraoperative, and Through 72 hours 
Postoperative) – All Cohorts 
Approximately 2 hours prior to the start of induction of general anesthesia, subjects are to receive 1 g oral 
acetaminophen.  
During surgery, the use of IV fentanyl up to 3 μg/kg will be permitted for intraoperative pain control. 
Just prior to the end of the surgery, all subjects will receive an additional 50 μg IV fentanyl to decrease 
the inherent variability of intraoperative pain control on immediate postoperative pain. As an example, 
the maximum total amount of fentanyl used during surgery for a 70 kg subject should not exceed 260 μg 
(3 μg/kg × 70 kg = 210 μg for intraoperative pain control + 50 μg at the end of the case = 260 μg total).  
Administration of other opioids or any other analgesics (eg, ketamine, pregabalin), local anesthetics, or 
anti-inflammatory agents (except as specified by the protocol) is prohibited, unless needed to treat an 
adverse event (AE) that occurs after signing the informed consent form (ICF), for pretreatment prior to a 
needle placement, or to decrease venous irritation (eg, caused by propofol, in which case no more than a 
single administration of lidocaine 1% 20 mg IV may be administered).  
Near the completion of surgery and after final irrigation and suction of each layer have been completed, a 
single dose of HTX-011 will be given intraoperatively via instillation into the surgical site.  
In Optional Cohort 2, subjects will also receive IV ketorolac intraoperatively prior to wound closure. 
Following surgery and immediate postoperative recovery, subjects will be transferred to the post-
anesthesia care unit (PACU). Subjects will remain in the hospital/research facility for a minimum of 
72 hours after administration of HTX-011. During the 72-hour inpatient period, subjects’ pain will be 
assessed via pain Numeric Rating Scale at rest (NRS-R).  
During the 72-hour postoperative period, 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 
postoperative care unit, 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, they 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 are given on a round-the-clock, scheduled basis 
through the 72-hour postoperative period. 


Protocol No: HTX-011-215 (Version 1) 
 
Heron Therapeutics, Inc. 
Phase 2 Herniorrhaphy Study for Opioid Elimination 
Confidential 
6 
Sponsor: Heron Therapeutics, Inc.  
Protocol Number: HTX-011-215 
Name of Investigational Product: 
HTX-011 (bupivacaine and meloxicam) 
extended-release solution 
Protocol Title:  
A Phase 2, Open-Label Study of HTX-011 in a 
Multimodal Analgesic Regimen for Decreased Opioid 
Use Following Unilateral Open Inguinal Herniorrhaphy 
Name of Active Ingredients: 
bupivacaine and meloxicam 
Phase of Development: 2 
Inpatient Postoperative Opioid Rescue Medications 
During the 72-hour postoperative period, subjects should only receive opioid rescue medication upon 
request for pain control, as needed. Rescue medication should not be given for pain prophylaxis, but only 
for treating postoperative pain. Each administration of opioid rescue medication will be recorded.  
Prior to the administration of the first dose of opioid rescue medication, if the subject has not already had 
at least 1 postoperative pain score assessed, then an NRS-R score must be obtained.  
Postoperative rescue medication will consist of oral (PO) immediate-release oxycodone (no more than 
10 mg within a 4-hour period as needed) or IV morphine (no more than 10 mg within a 2-hour period as 
needed). Administration of other opioids or any other analgesics (eg, ketamine, pregabalin), local 
anesthetics, or anti-inflammatory agents (except as specified by the protocol) is prohibited, unless needed 
to treat an AE that occurs after signing the ICF, for pretreatment prior to a needle placement, or to 
decrease venous irritation (eg, caused by propofol, in which case no more than a single administration of 
lidocaine 1% 20 mg IV may be administered). Combination opioid/non-opioid products (eg, Percocet) are 
not allowed. 
After the 72-hour inpatient period has been completed, subjects may be discharged. Subjects who are not 
medically ready for discharge at 72 hours may receive the same scheduled and rescue medications to treat 
postoperative pain until discharge.  
Discharge/Postoperative Analgesic Regimen (following the 72-hour postoperative period to Day 28) 
Upon discharge, subjects will be instructed to manage pain with the following regimen: 
 
600 mg oral ibuprofen every 6 hours 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 has not received any opioids during the 72-hour postoperative period, they should not receive 
an opioid prescription on discharge. 
If a subject has received any opioids in the 12 hours prior to discharge, the subject should be provided 
with a paper prescription for oxycodone (up to 5 mg PO q4h, #15, as needed). Pharmacists should be 
instructed that substitutions with any other opioid-containing product are not permitted, including 
combination opioid/non-opioid products.  
All subjects (whether or not they were discharged with an opioid prescription) will complete a daily diary 
to record whether they take an opioid medication between 72 hours and Day 28.  
Subjects will return to the study site on Days 10 and 28 to complete follow-up assessments.  
Number of Planned Subjects: Up to approximately 90 subjects may be enrolled in the study. 
Approximately 30 subjects will be dosed in Cohort 1; up to 2 additional optional cohorts of 
approximately 30 subjects each may also be dosed.  
Study Sites: Up to 5 sites in the United States (US) 


Protocol No: HTX-011-215 (Version 1) 
 
Heron Therapeutics, Inc. 
Phase 2 Herniorrhaphy Study for Opioid Elimination 
Confidential 
7 
Sponsor: Heron Therapeutics, Inc.  
Protocol Number: HTX-011-215 
Name of Investigational Product: 
HTX-011 (bupivacaine and meloxicam) 
extended-release solution 
Protocol Title:  
A Phase 2, Open-Label Study of HTX-011 in a 
Multimodal Analgesic Regimen for Decreased Opioid 
Use Following Unilateral Open Inguinal Herniorrhaphy 
Name of Active Ingredients: 
bupivacaine and meloxicam 
Phase of Development: 2 
Study Population: 
Inclusion Criteria: 
Each subject must meet all the following criteria to be enrolled in this study: 
1. Is able to provide written informed consent. 
2. Is able to adhere to the study visit schedule and complete all study assessments.  
3. Is male or female, and ≥18 years of age at screening.  
4. Is scheduled to undergo a unilateral open inguinal herniorrhaphy with mesh under general 
anesthesia.  
5. Has an American Society of Anesthesiologists Physical Status of I, II, or III.  
6. Female subjects are eligible only if all the following apply: 
a. Not pregnant (female subjects of childbearing potential must have a negative urine pregnancy test 
at screening and on Day 1 before surgery).  
b. Not lactating.  
c. Not planning to become pregnant during the study.  
d. Is surgically sterile (eg, has had a bilateral tubal ligation); or is at least 2 years postmenopausal; or 
is in a monogamous relationship with a partner who is surgically sterile; or is practicing 
abstinence or agrees to use double-barrier contraception in the event of sexual activity; or is using 
an insertable, injectable, transdermal, or combination oral contraceptive approved by applicable 
regulatory authorities for greater than 2 months prior to screening and commits to the use of an 
acceptable form of birth control for the duration of the study and for 30 days after study drug 
administration. Note: women in only a same-sex relationship do not need to meet this criterion.  
Exclusion Criteria 
A subject who meets any of the following criteria will be excluded from the study: 
1. Had any prior inguinal hernia repair except as a child (less than 6 years of age).  
2. Has a planned concurrent surgical procedure (eg, bilateral herniorrhaphy).  
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 
herniorrhaphy 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, ibuprofen, and for 
Optional Cohort 2 ketorolac (or other NSAIDs), oxycodone, morphine, acetaminophen, 
pregabalin, or fentanyl. Subjects in all cohorts must not have any contraindications to any of the 
protocol-specified drugs (bupivacaine, meloxicam, fentanyl, ibuprofen, acetaminophen, 
morphine, or oxycodone). Subjects in Optional Cohort 2 must also not have any contraindications 
to ketorolac. 
5. Has known or suspected daily use of opioids for 7 or more consecutive days within the previous 
6 months.  


Protocol No: HTX-011-215 (Version 1) 
 
Heron Therapeutics, Inc. 
Phase 2 Herniorrhaphy Study for Opioid Elimination 
Confidential 
8 
Sponsor: Heron Therapeutics, Inc.  
Protocol Number: HTX-011-215 
Name of Investigational Product: 
HTX-011 (bupivacaine and meloxicam) 
extended-release solution 
Protocol Title:  
A Phase 2, Open-Label Study of HTX-011 in a 
Multimodal Analgesic Regimen for Decreased Opioid 
Use Following Unilateral Open Inguinal Herniorrhaphy 
Name of Active Ingredients: 
bupivacaine and meloxicam 
Phase of Development: 2 
6. Has taken any NSAIDs (including meloxicam, ibuprofen or, for Optional Cohort 2 ketorolac) 
within 10 days prior to the scheduled surgery with the exception of subjects on low-dose (≤100 
mg) daily acetylsalicylic acid for cardioprotection.  
7. Has taken long-acting opioids within 3 days prior to the scheduled surgery.  
8. Has taken any opioids within 24 hours prior to the scheduled surgery.  
9. Has been administered bupivacaine within 5 days prior to the scheduled surgery.  
10. Has been administered any local anesthetic within 72 hours prior to the scheduled surgery, other 
than for pretreatment prior to a needle placement, to treat an AE that occurs after signing the ICF, 
or to decrease venous irritation (eg, caused by propofol, in which case no more than a single 
administration of lidocaine 1% 20 mg IV may be administered).  
11. Has initiated treatment with any of the following medications within 1 month prior to study drug 
administration or is taking any of these medications to control pain: selective serotonin reuptake 
inhibitors (SSRIs), selective norepinephrine reuptake inhibitors (SNRIs), gabapentin, pregabalin, 
or cyclooxygenase-2 (COX-2) inhibitors. (Note: If a subject is taking one of these medications for 
a reason other than pain control, the subject must be on a stable scheduled dose [ie, not “as 
needed”] for at least 1 month prior to study drug administration.) Anxiolytics prior to surgery are 
permitted, if necessary.  
12. Has been administered systemic steroids within 5 half-lives or 10 days prior to administration of 
study drug (whichever is longer). Note that for purposes of this exclusion criterion, inhaled, 
ophthalmic, and over-the-counter steroids are not considered systemic.  
13. Has a medical condition such that, in the opinion of the Investigator, participating in the study 
would pose a health risk to the subject or confound the postoperative assessments. Conditions 
may include, but are not limited to, any of the following: 
a. History of asthma or urticarial/ allergic-type reactions after taking aspirin or NSAIDs.  
b. History of clinically significant cardiac abnormality such as myocardial infarction within 
6 months prior to signing the ICF, New York Heart Association class III or IV, or clinically 
significant abnormalities of electrocardiogram (ECG) or cardiac function.  
c. History of coronary artery bypass graft surgery within 12 months prior to signing the ICF.  
d. 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.  
e. 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.  
f. History of known or suspected coagulopathy or uncontrolled anticoagulation (PLT count 
<100,000/μL; hemoglobin <12 g/dL; or hematocrit <35%).  
g. Loss of sensation in extremities or significant peripheral neuropathy.  
14. As per subject history and/or medical records, has active infection or is currently undergoing 


Protocol No: HTX-011-215 (Version 1) 
 
Heron Therapeutics, Inc. 
Phase 2 Herniorrhaphy Study for Opioid Elimination 
Confidential 
9 
Sponsor: Heron Therapeutics, Inc.  
Protocol Number: HTX-011-215 
Name of Investigational Product: 
HTX-011 (bupivacaine and meloxicam) 
extended-release solution 
Protocol Title:  
A Phase 2, Open-Label Study of HTX-011 in a 
Multimodal Analgesic Regimen for Decreased Opioid 
Use Following Unilateral Open Inguinal Herniorrhaphy 
Name of Active Ingredients: 
bupivacaine and meloxicam 
Phase of Development: 2 
treatment for Hepatitis B, Hepatitis C, or human immunodeficiency virus (HIV).  
15. Has uncontrolled anxiety, psychiatric, or neurological disorder that, in the opinion of the 
Investigator, might interfere with study assessments.  
16. Had a malignancy in the last year, with the exception of nonmetastatic basal cell or squamous cell 
carcinoma of the skin or localized carcinoma in situ of the cervix.  
17. Has a known or suspected history of drug abuse, a positive drug screen on the day of surgery, or a 
recent history of alcohol abuse. Note: Subjects with a positive drug screen who are taking an 
allowed, prescribed medication that is known to result in a positive drug test (eg, amphetamine 
and dextroamphetamine for attention-deficit/hyperactivity disorder, benzodiazepine for anxiety 
disorder) may be eligible for participation in the study at the discretion of the Sponsor. Subjects 
taking any marijuana (medical or recreational) are not allowed to participate in the study.  
18. Previously participated in an HTX-011 study.  
19. Received an investigational product or device in a clinical trial within 30 days or within 
5 elimination half-lives (whichever is longer) prior to surgery, or is planning to take part in 
another clinical trial while participating in this study.  
20. Has undergone 3 or more surgeries within 12 months prior to signing the ICF, other than for 
diagnostic procedures (eg, colonoscopy).  
21. Has a body mass index (BMI) >39 kg/m2.  
Investigational Product, Dose, and Mode of Administration: 
HTX-011 is 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.  
A single dose of HTX-011 300 mg/9 mg (bupivacaine/meloxicam doses) will be administered via 
instillation into the surgical site. HTX-011 will be prepared in syringes without a needle using a Luer lock 
applicator, also supplied by the Sponsor. Following irrigation and suction of each fascial layer, study drug 
will be administered evenly so that all tissues receive adequate coverage at both the level below and the 
level above the fascia.  
Required Concomitant Medications 
Other mandatory medications in this study include oral acetaminophen preoperatively, IV fentanyl 
intraoperatively, and both oral ibuprofen and oral acetaminophen postoperatively. Additionally, all 
subjects in Optional Cohort 2 will receive IV ketorolac intraoperatively. 
Reference Therapy, Dose, and Mode of Administration: 
Not applicable 


Protocol No: HTX-011-215 (Version 1) 
 
Heron Therapeutics, Inc. 
Phase 2 Herniorrhaphy Study for Opioid Elimination 
Confidential 
10 
Sponsor: Heron Therapeutics, Inc.  
Protocol Number: HTX-011-215 
Name of Investigational Product: 
HTX-011 (bupivacaine and meloxicam) 
extended-release solution 
Protocol Title:  
A Phase 2, Open-Label Study of HTX-011 in a 
Multimodal Analgesic Regimen for Decreased Opioid 
Use Following Unilateral Open Inguinal Herniorrhaphy 
Name of Active Ingredients: 
bupivacaine and meloxicam 
Phase of Development: 2 
Duration of Treatment:   
The overall duration of the study is anticipated to be approximately 8 months. The total duration of study 
participation for each subject (from Screening through the Day 28 follow-up visit) will be up to 53 days.  
Criteria for Evaluation: 
The start of HTX-011 administration will be considered as Time 0 for all assessment timepoints.  
Efficacy Assessments: 
 Date, time of administration, amount and type 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. 
 Pain intensity scores using NRS-R at 1, 2, 4, 8, 12, 24, 36, 48, 60, 72 hours, and on Day 10.  
o NRS-R: Subjects should be recumbent or lying supine. Measurements should be obtained after 
the subject is in the resting position for at least 5 minutes.  
Safety Assessments: 
 AEs from the time the subject signs the ICF through Day 28. 
 Clinical safety laboratory tests (hematology and serum chemistry) at the Screening Visit, at 24 hours 
(hematology only), at 72 hours, and on Day 10. 
 Physical examination at Screening Visit and 72 hours; the Screening Visit will also include height, 
weight, and BMI calculation. 
 Wound healing assessment at 72 hours and on Day 10 and Day 28. 
 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 60 minutes , 90 minutes, 2, 4, 8, 12, 24, 36, 48, 
60, and 72 hours. 


Protocol No: HTX-011-215 (Version 1) 
 
Heron Therapeutics, Inc. 
Phase 2 Herniorrhaphy Study for Opioid Elimination 
Confidential 
11 
Sponsor: Heron Therapeutics, Inc.  
Protocol Number: HTX-011-215 
Name of Investigational Product: 
HTX-011 (bupivacaine and meloxicam) 
extended-release solution 
Protocol Title:  
A Phase 2, Open-Label Study of HTX-011 in a 
Multimodal Analgesic Regimen for Decreased Opioid 
Use Following Unilateral Open Inguinal Herniorrhaphy 
Name of Active Ingredients: 
bupivacaine and meloxicam 
Phase of Development: 2 
Study Endpoints: 
Primary Efficacy Endpoint: 
 
Proportion of subjects receiving no opioid rescue from 0-72 hours. 
Secondary Efficacy Endpoints 
 
Total postoperative opioid consumption (in IV morphine milligram equivalents [IV MME]) 
through 72 hours. 
 
Proportion of subjects receiving no opioid rescue over the following time intervals: 0-to 4 hours, 
24 to 48 hours, 0 - 48 hours, 24 - 72 hours, 48 - 72 hours. 
 
Proportion of subjects receiving no opioid rescue from 0 - 72 hours who receive no opioid rescue 
through Day 10, and through Day 28. 
 
Proportion of subjects in severe pain (NRS >7) at any point in the first 72 hours postoperatively.  
Safety Endpoints 
 
Incidence of treatment-emergent AEs (TEAEs), serious TEAEs (SAEs), and opioid-related AEs 
(ORAEs) through Day 28. 
 
Change from baseline in clinical laboratory results. 
 
Change from baseline in ECG data. 
 
Change from baseline in vital signs. 
 
Wound healing assessment at 72 hours and on Day 10 and Day 28. 
 


Protocol No: HTX-011-215 (Version 1) 
 
Heron Therapeutics, Inc. 
Phase 2 Herniorrhaphy Study for Opioid Elimination 
Confidential 
12 
Sponsor: Heron Therapeutics, Inc.  
Protocol Number: HTX-011-215 
Name of Investigational Product: 
HTX-011 (bupivacaine and meloxicam) 
extended-release solution 
Protocol Title:  
A Phase 2, Open-Label Study of HTX-011 in a 
Multimodal Analgesic Regimen for Decreased Opioid 
Use Following Unilateral Open Inguinal Herniorrhaphy 
Name of Active Ingredients: 
bupivacaine and meloxicam 
Phase of Development: 2 
Statistical Methods 
All efficacy data will be summarized by treatment group. No statistical hypothesis testing will be 
performed. For opioid rescue summaries, the proportion of subjects receiving no opioid rescue will be 
summarized as subjects with a total IV MME dose = 0 over the relevant timeframe.  
Handling of Missing NRS 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 postdose value is 
used for a subsequent missing value. For subjects who do not have a postdose value prior to their 
first missing value, the median of the postdose values at the relevant timepoint from subjects 
with observed data in the same treatment group will be used. Predose values will not be carried 
forward to postdose timepoints. In subjects who withdraw from the study prior to 72 hours, 
missing NRS pain intensity scores through 72 hours that were to be collected following 
withdrawal will be imputed via 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. 
Safety Analyses 
All safety data will be listed and summarized by treatment group; no statistical hypothesis testing will be 
performed. All TEAEs will be coded and tabulated by System Organ Class and Preferred Term. Incidence 
of TEAEs, SAEs, and ORAEs will be summarized. Associated laboratory parameters such as hepatic 
profile, renal function, and hematology values will be grouped and presented together in summary tables. 
Individual subject values will be listed and values outside of the standard reference range will be flagged. 
Changes in vital sign parameters and ECG results will be summarized. Wound healing assessment results 
will be summarized. 
Determination of Sample Size 
The sample size in this study was selected empirically without a formal statistical assumption. 




Protocol No: HTX-011-215 (Version 1) 
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Abbreviations: ECG, electrocardiogram; ET, Early Termination; h, hour; min, minutes; NRS-R, Numeric Rating Scale at rest; OR, operating room; PGA, Patient 
Global Assessment; Preop, preoperative assessments; WOCBP, women of childbearing potential; D10, Day 10; D28, Day 28. 
Note: The start of study drug administration will be considered as Time 0 (T0). 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 should be completed. Section 6.0 provides information on study procedures and assessments. 
a Subjects who withdraw from the study before their Day 28 Visit will be asked to complete Early Termination procedures.  
b 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 any marijuana (medical or 
recreational) are not allowed to participate in the study.  
c Includes height, weight, and body mass index calculation.  
d Only if the subject withdraws prior to 72 hours.  
e If early neurologic and cardiac signs and symptoms of LAST are observed, unscheduled vital sign measurements, 12-lead ECG, and blood sample collection 
for measurement of bupivacaine plasma concentration must be performed.  
f Hematology only.  
g The length of the surgical incision should be recorded.  
h NRS-R should be assessed while the subject is recumbent or lying supine. Measurements should be obtained after the subject is in the resting position for at 
least 5 minutes.  
i If a subject requires rescue medication before the 1-hour pain intensity assessments, then an unscheduled NRS-R pain score must be obtained before 
administering the first dose of rescue medication. This does not replace the 1-hour NRS-R assessment.  
j Subjects will complete a daily diary from 72 hours through Day 28 to record if they take any opioid medication. Subject diary results will be reviewed at the 
Day 28 Visit. 
k Only if the subject withdraws after 72 hours. 
l 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 Day 28.  
m Postoperatively and upon discharge, subjects manage pain with the following regimen: 600 mg oral ibuprofen every 6 hours PRN as first-line therapy before 
acetaminophen, and 1g oral acetaminophen ibuprofen every 6 hours PRN as second-line therapy. 
n Adverse events will be collected from the time the subject signs the ICF through Day 28. 
o Cohort 2 only: IV ketorolac intra-operatively per subject age, weight, and creatinine. 


Protocol No: HTX-011-215 (Version 1) 
 
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Phase 2 Herniorrhaphy Study for Opioid Elimination 
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TABLE OF CONTENTS 
SPONSOR SIGNATURE ................................................................................................................2 
INVESTIGATOR AGREEMENT...................................................................................................3 
PROTOCOL SYNOPSIS ................................................................................................................4 
SCHEDULE OF EVENTS ............................................................................................................13 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ..................................................20 
1. 
INTRODUCTION ......................................................................................................22 
1.1. 
Background Information and Study Rationale ...........................................................22 
1.2. 
Rationale for Study Design, Doses, and Control Groups ...........................................23 
1.3. 
Potential Risks and Benefits .......................................................................................24 
2. 
STUDY OBJECTIVES ..............................................................................................27 
2.1. 
Primary Objective .......................................................................................................27 
2.2. 
Secondary Objectives .................................................................................................27 
3. 
INVESTIGATIONAL PLAN AND ENDPOINTS ....................................................28 
3.1. 
Description of the Study Design .................................................................................28 
3.1.1. 
Overall Study Design ..................................................................................................28 
3.1.2. 
Treatment Groups .......................................................................................................28 
3.1.3. 
Inpatient Scheduled Analgesic Regimen (Preoperative, Intraoperative, and 
Through 72 hours Postoperative) – All Cohorts .........................................................29 
3.2. 
Study Endpoints ..........................................................................................................30 
3.2.1. 
Efficacy Endpoints ......................................................................................................30 
3.2.1.1. 
Primary Efficacy Endpoint .........................................................................................30 
3.2.1.2. 
Secondary Efficacy Endpoints ....................................................................................31 
3.2.2. 
Safety Endpoints .........................................................................................................31 
3.3. 
Study Duration ............................................................................................................31 
4. 
STUDY ENROLLMENT AND WITHDRAWAL ....................................................31 
4.1. 
Study Population .........................................................................................................31 
4.1.1. 
Inclusion Criteria ........................................................................................................31 
4.1.2. 
Exclusion Criteria .......................................................................................................32 
4.2. 
Method of Enrolling Subjects .....................................................................................34 
4.2.1. 
Procedures for Handling Enrolled Subjects Who Do Not Meet the Study 
Eligibility Criteria .......................................................................................................34 
4.3. 
Blinding ......................................................................................................................34 


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4.4. 
Subject Withdrawal and Replacement ........................................................................34 
4.4.1. 
Subject Withdrawal ....................................................................................................34 
4.4.2. 
Subject Replacement ..................................................................................................35 
5. 
STUDY TREATMENT ..............................................................................................35 
5.1. 
Description of Investigational Product .......................................................................35 
5.2. 
Manufacturing, Packaging, and Labeling ...................................................................35 
5.3. 
Storage ........................................................................................................................35 
5.4. 
Preparation ..................................................................................................................36 
5.5. 
Study Drug Administration.........................................................................................36 
5.5.1. 
Instillation of HTX-011 ..............................................................................................36 
5.6. 
Study Drug Compliance .............................................................................................36 
5.7. 
Study Drug Accountability .........................................................................................36 
6. 
STUDY PROCEDURES AND ASSESSMENTS......................................................37 
6.1. 
Medical History and Demographics ...........................................................................37 
6.1.1. 
Medical History ..........................................................................................................37 
6.1.2. 
Demographics .............................................................................................................37 
6.2. 
Prior and Concomitant Therapy ..................................................................................37 
6.2.1. 
Required Concomitant Medications ...........................................................................37 
6.2.2. 
Allowed Concomitant Medications ............................................................................38 
6.2.3. 
Prohibited Medications ...............................................................................................40 
6.2.3.1. 
Medications Prohibited Prior to Surgery ....................................................................40 
6.2.3.2. 
Medications Prohibited During Surgery .....................................................................40 
6.2.3.3. 
Medications Prohibited From Time 0 Through 72 Hours ..........................................40 
6.3. 
Efficacy Assessments .................................................................................................40 
6.3.1. 
Use of Opioid Medications .........................................................................................40 
6.3.1.1. 
Opioid Rescue Medication Through 72 Hours ...........................................................40 
6.3.1.2. 
Subject Daily Diary of Opioid Use From 72 Hours Through Day 28 ........................40 
6.3.2. 
Pain Intensity Assessment ..........................................................................................41 
6.4. 
Safety Assessments .....................................................................................................41 
6.4.1. 
Adverse Events ...........................................................................................................41 
6.4.2. 
Physical Examinations ................................................................................................41 
6.4.3. 
Vital Signs ..................................................................................................................41 
6.4.4. 
12-Lead Electrocardiograms .......................................................................................41 


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6.4.5. 
Wound Healing Assessment .......................................................................................41 
6.4.6. 
Clinical Laboratory Tests ...........................................................................................42 
7. 
TIMING OF PROCEDURES AND ASSESSMENTS ...............................................43 
7.1. 
Screening Period .........................................................................................................44 
7.2. 
Treatment and Postoperative Observation Period ......................................................45 
7.2.1. 
Day of Surgery (Day 1) ..............................................................................................45 
7.2.1.2. 
Surgery and Study Drug Administration ....................................................................45 
7.2.2. 
Postoperative Assessment Period (Up to 72 Hours) ...................................................46 
7.2.3. 
End of the Postoperative Assessment Period ..............................................................46 
7.3. 
Follow-Up Period .......................................................................................................47 
7.3.1. 
Day 10 Visit (±3 Days) ...............................................................................................47 
7.3.2. 
Day 28 Visit (±4 Days) ...............................................................................................47 
7.4. 
Early Termination Visit ..............................................................................................47 
7.5. 
Unscheduled Visits and Assessments .........................................................................48 
8. 
SAFETY MONITORING AND REPORTING .........................................................48 
8.1. 
Definition of Safety Parameters ..................................................................................48 
8.1.1. 
Definition of an Adverse Event ..................................................................................48 
8.1.2. 
Definition of a Serious Adverse Event .......................................................................49 
8.1.3. 
Definition of a Suspected Adverse Reaction ..............................................................50 
8.1.4. 
Definition of a Serious Suspected Adverse Reaction .................................................50 
8.1.5. 
Definition of Unanticipated Problems ........................................................................50 
8.2. 
Classification of Adverse Events ................................................................................51 
8.2.1. 
Severity of Adverse Events ........................................................................................51 
8.2.2. 
Relationship to Study Drug ........................................................................................51 
8.3. 
Time Period and Frequency for Event Assessment and Follow Up ...........................52 
8.3.1. 
Adverse Event and Serious Adverse Event Monitoring .............................................52 
8.3.2. 
Follow-Up of Events ...................................................................................................52 
8.4. 
Reporting Procedures ..................................................................................................53 
8.4.1. 
Reporting Serious Adverse Events to the Sponsor .....................................................53 
8.4.2. 
Reporting Unanticipated Problems to the Sponsor .....................................................54 
8.4.3. 
Regulatory Reporting Requirements ..........................................................................54 
8.4.4. 
Pregnancy Reporting ..................................................................................................55 
8.5. 
Safety Oversight .........................................................................................................55 


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9. 
OTHER STUDY RESTRICTIONS ...........................................................................55 
9.1. 
Contraception ..............................................................................................................55 
10. 
STATISTICAL CONSIDERATIONS .......................................................................55 
10.1. 
General Considerations ...............................................................................................55 
10.2. 
Determination of Sample Size ....................................................................................56 
10.3. 
Analysis Populations ..................................................................................................56 
10.4. 
Statistical Analysis Methods .......................................................................................56 
10.4.1. 
Disposition and Demographics ...................................................................................56 
10.4.2. 
Efficacy Analysis ........................................................................................................56 
10.4.2.1. 
Handling of Missing Data ...........................................................................................56 
10.4.3. 
Safety Analysis ...........................................................................................................57 
10.5. 
Interim Analysis ..........................................................................................................57 
11. 
QUALITY ASSURANCE AND QUALITY CONTROL .........................................57 
12. 
REGULATORY AND ETHICAL CONSIDERATIONS ..........................................58 
12.1. 
Regulatory Authority Approval ..................................................................................58 
12.2. 
Ethical Conduct of the Study ......................................................................................58 
12.3. 
Ethics Committee Approval .......................................................................................58 
12.4. 
Informed Consent Process ..........................................................................................58 
12.5. 
Confidentiality ............................................................................................................59 
13. 
STUDY ADMINISTRATION ...................................................................................60 
13.1. 
Clinical Monitoring ....................................................................................................60 
13.2. 
Source Documents and Record Retention ..................................................................60 
13.3. 
Management of Protocol Amendments and Deviations .............................................60 
13.3.1. 
Protocol Modification .................................................................................................60 
13.3.2. 
Protocol Deviations ....................................................................................................61 
13.4. 
Financial Disclosure ...................................................................................................61 
13.5. 
Stopping Criteria: Suspension or Termination of Study or Investigational Site .........61 
13.5.1. 
Suspension of Study ...................................................................................................61 
13.5.2. 
Termination of Study or Investigational Site ..............................................................61 
13.6. 
Publication and Information Disclosure Policy ..........................................................62 
14. 
REFERENCE LIST ....................................................................................................63 
APPENDIX A. AMERICAN SOCIETY OF ANESTHESIOLOGISTS PHYSICAL 
STATUS CLASSIFICATION SYSTEM ...................................................................66 


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APPENDIX B. BMI CALCULATION ......................................................................................67 
APPENDIX C. PAIN INTENSITY ASSESSMENTS USING THE NUMERIC 
RATING SCALE (NRS) ...................................................................................68 
APPENDIX D. WOUND HEALING ASSESSMENT – SOUTHAMPTON WOUND 
SCORING SYSTEM .........................................................................................69 
APPENDIX E. INSTRUCTIONS FOR POSTOPERATIVE PAIN MANAGEMENT 
FOR SUBJECTS MEDICALLY READY FOR DISCHARGE ........................70 
 
LIST OF TABLES 
Table 1: 
Clinical Laboratory Tests ...........................................................................................43 
 
 
 


Protocol No: HTX-011-215 (Version 1) 
 
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Phase 2 Herniorrhaphy Study for Opioid Elimination 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Definition 
AE 
Adverse event 
AUC 
Area under the curve 
BMI 
Body mass index 
CFR 
Code of Federal Regulations 
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 
HIV 
Human immunodeficiency virus 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
IV 
Intravenous(ly) 
IV MME 
IV morphine milligram equivalents 
LOCF 
Last observation carried forward  
NRS 
Numeric Rating Scale 
NRS-R 
NRS scores at rest 
NSAID 
Nonsteroidal anti-inflammatory drug  
ORAE 
Opioid-related adverse event 
PACU 
Postanesthesia care unit 
PK 
Pharmacokinetic 
PO 
Oral 
SAE 
Serious adverse event 
TEAE 
Treatment-emergent adverse event 


Protocol No: HTX-011-215 (Version 1) 
 
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Abbreviation 
Definition 
TKA 
Total knee arthroplasty 
ULN 
Upper limit of normal 
US 
United States 
WOCF 
Worst observation carried forward 
wWOCF 
Windowed worst observation carried forward 
 


Protocol No: HTX-011-215 (Version 1) 
 
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1. 
INTRODUCTION 
1.1. 
Background Information and Study Rationale 
Up to 70% of patients have moderate to severe pain after surgery, and the most severe pain 
occurs within the first 72 hours (Lynch 1997; Svensson 2000; Apfelbaum 2003; Gan 2014; 
Misiolek 2014; Singla 2014; Meissner 2015). Administering a local anesthetic (eg, bupivacaine, 
ropivacaine, or levobupivacaine) is a relatively simple and safe means of providing postoperative 
pain relief. A major limitation of current local anesthetics is their duration of effect is only 6 to 
12 hours (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). Patients can quickly transition from acute opioid use to chronic use. 
A 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 and rises rapidly thereafter (Shah 2017). Reduced exposure to opioids and better 
pain management is associated with improved patient outcomes as well as reduced risk for the 
development of persistent pain and consequent opioid abuse (Barnett 2017). These facts 
highlight the medical need for safer and more effective clinical alternatives to prescription 
opioids for management of 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 a Luer lock 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 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 


Protocol No: HTX-011-215 (Version 1) 
 
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Phase 2 Herniorrhaphy Study for Opioid Elimination 
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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 is designed to evaluate the safety and analgesic efficacy of 
HTX-011 administered via instillation into the surgical site of subjects who are undergoing 
unilateral open inguinal herniorrhaphy. 
1.2. 
Rationale for Study Design, Doses, and Control Groups 
This study is designed to evaluate the effectiveness of HTX-011 to reduce the need for 
postoperative opioid pain relief in subjects who have undergone herniorrhaphy (primary 
Cohort 1). Herniorrhaphy is a well-accepted soft tissue model for acute postoperative pain. 
Herniorrhaphy produces generally reliable and persistent pain symptoms after surgery, which 
allows for analysis of acute analgesia over an extended period.  
In Optional Cohort 2, the study will evaluate HTX-011 via instillation into the surgical site with 
the intraoperative addition (prior to wound closure) of 1 dose of intravenous (IV) ketorolac as 
follows:  
 For subjects aged ≥65 years, Creatinine > 1.5, and/or weight < 50 kg: 15 mg. 
 For subjects aged < 65 years and/or weight ≥50 kg: 30 mg. 
Optional Cohort 3 will be decided upon based upon results of the earlier cohorts.  
One dose level of HTX-011 will be evaluated in this study, 300 mg/9 mg 
(bupivacaine/meloxicam doses) administered via instillation. The dose and administration 
technique were selected based on a previous Phase 2 dose-finding study in herniorrhaphy 
(Study 202). In Study 202, HTX-011 doses ranging from 200 mg/6 mg to 400 mg/12 mg via 
different local administration techniques (injection, instillation, or a combination of the 
2 techniques) were evaluated. All doses were determined to be effective at producing 
postoperative analgesia through 72 hours. Additional study results are provided in Section 1.3. 
Based on these findings, 300 mg/9 mg administered via instillation was selected for this Phase 2 
study.  
The primary endpoint for this study, the proportion of subjects receiving no opioid rescue from 
0-72 hours post operation, is consistent with the goal of this study to assess whether use of 
HTX-011 to control pain can eliminate or reduce the need for opioid pain killers. The timepoint 
of 72 hours selected for this study is considered clinically relevant for patients as literature shows 
that the most severe postoperative pain occurs within the first 72 hours after surgery (Lynch 
1997; Svensson 2000; Apfelbaum 2003; Gan 2014; Misiolek 2014; Singla 2014; Meissner 2015). 
The numeric rating scale (NRS) was selected as an appropriate measurement because activity is 
known to be a more sensitive measure of pain control (Breivik 2008), and the prescribed activity 
reflects a simple daily activity for patients (sitting up from a resting position). All subjects will 
have a prespecified scheduled non-opioid pain medication routine, and will be able to receive 
opioid rescue for inadequately controlled pain.  
The mean area under the curve (AUC) of the Numeric Rating Scale of pain intensity scores 
through 72 hours (AUC0-72) was selected based on the United States (US) Food and Drug 


Protocol No: HTX-011-215 (Version 1) 
 
Heron Therapeutics, Inc. 
Phase 2 Herniorrhaphy Study for Opioid Elimination 
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Administration (FDA) and Committee for Medicinal Products for Human Use (CHMP) 
guidances as well as regulatory precedent. Draft FDA Guidance for Industry on Analgesic 
Indications: Developing Drug and Biological Products (February 2014) states that “pain intensity 
is the fundamental measure that defines the efficacy of an analgesic drug.” In addition, the FDA 
agreed to a primary endpoint of AUC of the NRS pain intensity scores over the first 24-hour 
period in a bony model (bunionectomy) for EXPAREL® (EXPAREL USPI 2018). 
Given the concern for misuse and abuse of opioids, a reduction in opioid load and an increase in 
the number of subjects who are opioid-free are clinically meaningful endpoints and are in 
alignment with the February 2014 FDA Draft Guidance for Industry on Analgesic Indications: 
Developing Drug and Biological Products. Opioid sparing endpoints were also included in 
recently approved labels for EXPAREL, OFIRMEV®, and CALDOLOR®, and NAROPIN®. 
1.3. 
Potential Risks and Benefits 
As of June 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 
herniorrhaphy (Study 202 and Study 302). 
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 treatment 
emergent adverse events (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 


Protocol No: HTX-011-215 (Version 1) 
 
Heron Therapeutics, Inc. 
Phase 2 Herniorrhaphy Study for Opioid Elimination 
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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. 
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 2 subjects administered these doses received at least 1 opioid rescue 
medication.  
There were no clinically meaningful differences in laboratory results, vital sign measurements, 
physical examination findings, or electrocardiogram (ECG) findings.  
There was no evidence of 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 and Study 209). 
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 
In the Phase 2a study in herniorrhaphy (Study 202), HTX 011 doses ranging from 200 mg/6 mg 
to 400 mg/12 mg via different local administration techniques (injection, instillation, or a 
combination of the 2 techniques) were evaluated. All doses were determined to be effective at 
producing postoperative analgesia through 72 hours. The HTX-011 300 mg/9 mg dose given by 
local administration via instillation was noted to have similar efficacy to the highest dose tested, 


Protocol No: HTX-011-215 (Version 1) 
 
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Phase 2 Herniorrhaphy Study for Opioid Elimination 
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400 mg/12 mg, while demonstrating a good safety profile and improved PK profile (ie, lower 
systemic exposure). The proportion of subjects who did not require an opioid (ie, were opioid 
free through 72 hours) was significantly higher in the HTX-011 300 mg/9 mg dose group 
compared with saline placebo (50.0% vs 7.2%; p = 0.0001) and compared with bupivacaine 
HCl (50.0% vs 12.5%; p = 0.0108) groups.  
The primary and key secondary efficacy endpoints in all 3 adequate and well-controlled studies 
were achieved for HTX-011.  
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 
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 10, and >82% remained opioid free through Day 28. 
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 (≤90% for ≥1 minute), 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 


Protocol No: HTX-011-215 (Version 1) 
 
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Phase 2 Herniorrhaphy Study for Opioid Elimination 
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27 
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 local administration (a novel 
administration method for meloxicam) for postoperative pain as part of a fixed-ratio combination 
(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.  
Prior HTX-011 clinical study protocols did not include scheduled preoperative NSAIDs, such as 
ketorolac. 
For more information on HTX-011, refer to the Investigator’s Brochure (IB). For more 
information on the active pharmaceutical ingredients , bupivacaine and meloxicam, refer to the 
local product labels. Literature reports that intraoperative ketorolac is used in conjunction with 
postoperative NSAIDs (Kelley 2013; Dalury 2016). The Investigator should also refer to the 
respective package inserts for information on risks associated with the required concomitant 
medications (oral acetaminophen, IV fentanyl, oral ibuprofen, and in Optional Cohort 2 ketorolac) 
as well as midazolam, general anesthetics, anti-emetics, antibiotics, other opioids and any other 
approved medications likely to be administered while a subject participates in this study.  
2. 
STUDY OBJECTIVES 
2.1. 
Primary Objective 
Primary Objective: 
 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 following unilateral 
open inguinal herniorrhaphy with mesh. 
2.2. 
Secondary Objectives 
Secondary Objectives: 
 To assess the total opioid use following HTX-011 as part of a multimodal analgesic 
regimen 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 that remain 
opioid-free through Day 10 and Day 28.  
 To assess the relationship between opioid use and severe pain. 


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3. 
INVESTIGATIONAL PLAN AND ENDPOINTS 
3.1. 
Description of the Study Design 
3.1.1. 
Overall Study Design 
This is a Phase 2, open-label study in subjects undergoing unilateral open inguinal 
herniorrhaphy. 
3.1.2. 
Treatment Groups 
Cohort 1 
Cohort 1 will be composed of approximately 30 subjects. Subjects will be screened within 
21 days prior to surgery. Subjects who meet the Screening eligibility criteria will be allowed to 
participate in the study.  
On the day of surgery (Day 1), subjects who continue to meet the eligibility criteria will undergo 
inguinal herniorrhaphy with mesh under general anesthesia. Spinal, epidural, or regional 
anesthesia is not allowed. Preoperative NSAIDs are not allowed. Approximately 2 hours prior to 
the start of induction of general anesthesia, subjects are to receive 1 g oral acetaminophen. 
However, if the start of general anesthesia is delayed by more than 4 hours, the subject must not 
be enrolled unless the surgery is rescheduled for a later day (if this puts the subject out of the 
screening window, screening assessments may be re-performed). All subjects will then receive a 
scheduled postoperative analgesic regimen as follows: start with 600 mg oral ibuprofen once 
they are able to tolerate oral intake in the postoperative care unit, then 3 hours after the ibuprofen 
dose administer the first postoperative dose of 1 g oral acetaminophen, then alternate these 
2medications so a dose is delivered every 3 hours. In other words, 3 hours after their first 600 mg 
oral ibuprofen dose, they 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. 
Optional Cohort 2 
At the Sponsor’s discretion upon completion of Cohort 1, Optional Cohort 2 may be initiated. If 
conducted, Optional Cohort 2 will be composed of approximately 30 subjects. Optional Cohort 2 
would consist of the same required preoperative, intraoperative, and scheduled pain medication 
regimen as in Cohort 1 would be required with the intra-operative addition prior to wound 
closure of 1 dose of IV ketorolac as follows: 
 For subjects aged ≥65 years, Serum Creatinine >1.5, and/or weight <50 kg: 15 mg. 
 For subjects aged <65 years and/or weight ≥50 kg: 30 mg. 
Optional Cohort 3 
At the Sponsor’s discretion upon completion of Optional Cohort 2, Optional Cohort 3 may be 
initiated. If conducted, Optional Cohort 3 will be composed of approximately 30 subjects. The 
specific multimodal analgesic regimen in Optional Cohort 3 will be determined by the Sponsor 
and included in a protocol amendment. 


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3.1.3. 
Inpatient Scheduled Analgesic Regimen (Preoperative, Intraoperative, and 
Through 72 hours Postoperative) – All Cohorts 
Preoperative 
Approximately 2 hours prior to the start of induction of general anesthesia, subjects are to 
receive 1 g oral (PO) acetaminophen. 
Intraoperative 
During surgery, the use of IV fentanyl up to 3 μg/kg will be permitted for intraoperative pain 
control. Just prior to the end of the surgery, all subjects will receive an additional 50 μg IV 
fentanyl in order to decrease the inherent variability of intraoperative pain control on immediate 
postoperative pain. As an example, the maximum total amount of fentanyl used during surgery 
for a 70 kg subject should not exceed 260 μg (3 μg/kg × 70 kg = 210 μg for intraoperative pain 
control + 50 μg at the end of the case = 260 μg total).  
Administration of other opioids or any other analgesics (eg, ketamine, pregabalin), local 
anesthetics, or anti-inflammatory agents (except as specified by the protocol) is prohibited, 
unless needed to treat an AE that occurs after signing the informed consent form (ICF), for 
pretreatment prior to a needle placement, or to decrease venous irritation (eg, caused by 
propofol, in which case no more than a single administration of lidocaine 1% 20 mg IV may be 
administered).  
Near the completion of surgery and after final irrigation and suction of each layer have been 
completed, a single dose of HTX-011 will be given intraoperatively via instillation into the 
surgical site.  
In Optional Cohort 2, subjects will also receive IV ketorolac intraoperatively prior to wound 
closure. 
Postoperative 
Following surgery and immediate postoperative recovery, subjects will be transferred to the 
postanesthesia care unit (PACU). Subjects will remain in the hospital/research facility for a 
minimum of 72 hours after administration of HTX-011. During the 72-hour inpatient period, 
subjects’ pain will be assessed via pain NRS-R.  
During the 72-hour postoperative period, subjects will receive a scheduled analgesic regimen as 
follows: start with 600 mg oral ibuprofen once they are able to tolerate oral intake in the 
postoperative care unit, 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, they 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 are given on a round-
the-clock, scheduled basis through the 72-hour postoperative period.  
Inpatient Postoperative Opioid Rescue Medications 
During the 72-hour postoperative period, subjects should only receive opioid rescue medication 
upon request for pain control, as needed. Rescue medication should not be given for pain 
prophylaxis, but only for treating postoperative pain. Each administration of opioid rescue 
medication will be recorded.  


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Prior to the administration of the first dose of opioid rescue medication, if the subject has not 
already had at least 1 postoperative pain score assessed, then an NRS-R score must be obtained.  
Postoperative rescue medication will consist of PO immediate-release oxycodone (no more than 
10 mg within a 4-hour period as needed) or IV morphine (no more than 10 mg within a 2-hour 
period as needed). Administration of other opioids or any other analgesics (eg, ketamine, 
pregabalin), local anesthetics, or anti-inflammatory agents (except as specified by the protocol) is 
prohibited, unless needed to treat an AE that occurs after signing the ICF, for pretreatment prior 
to a needle placement, or to decrease venous irritation (eg, caused by propofol, in which case no 
more than a single administration of lidocaine 1% 20 mg IV may be administered). Combination 
opioid/non-opioid products (eg, Percocet) are not allowed. 
After the 72-hour inpatient period has been completed, subjects may be discharged. Subjects 
who are not medically ready for discharge at 72 hours may receive the same scheduled and 
rescue medications to treat postoperative pain until discharge.  
Discharge/ Postoperative Analgesic Regimen (following the 72-hour postoperative period to 
Day 28) 
Upon discharge, subjects will be instructed to manage pain with the following regimen: 
 600 mg oral ibuprofen every 6 hours PRN as first-line therapy (before 
acetaminophen). 
 1g oral acetaminophen every 6 hours PRN as second-line therapy (ie, if ibuprofen has 
been tried but the subject is still in pain). 
See Appendix E  for instructions on postoperative pain management for subjects medically ready 
for discharge. 
If a subject has not received any opioids during the 72-hour postoperative period, they should not 
receive an opioid prescription on discharge. If a subject has received any opioids in the 12 hours 
prior to discharge, the subject should be provided with a paper prescription for oxycodone (up to 
5 mg PO q4h, #15, as needed). Pharmacists should be instructed that substitutions with any other 
opioid-containing product are not permitted, and combination opioid/non-opioid products are not 
allowed. All subjects (whether or not they were discharged with an opioid prescription) will 
complete a daily diary to record whether they take an opioid medication between 72 hours and 
Day 28 and, if yes, reason for taking (relative to surgery or other).  
Subjects will return to the study site on Days 10 and 28 to complete follow up assessments per 
the Schedule of Events.  
See Section 6 for more information on the study procedures and assessments. For the timing of 
procedures and assessments, see Section 7 and the Schedule of Events table. 
3.2. 
Study Endpoints 
3.2.1. 
Efficacy Endpoints 
3.2.1.1. 
Primary Efficacy Endpoint 
 Proportion of subjects receiving no opioid rescue from 0-72 hours. 


Protocol No: HTX-011-215 (Version 1) 
 
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3.2.1.2. 
Secondary Efficacy Endpoints  
 Total postoperative opioid consumption (in IV morphine milligram equivalents 
[IV MME]) through 72 hours. 
 Proportion of subjects receiving no opioid rescue over the following time intervals: 
0-24 hours, 24-48 hours, 0-48 hours, 24-72 hours, 48-72 hours. 
 Proportion of subjects receiving no opioid rescue from 0-72 hours who receive no 
opioid rescue through Day 10, and through Day 28. 
 Proportion of subjects in severe pain (NRS >7) at any point in the first 72 hours 
postoperatively. 
3.2.2. 
Safety Endpoints 
 Incidence of TEAEs, SAEs, and ORAEs through Day 28.  
 Change from baseline in clinical laboratory results.  
 Change from baseline in ECG data.  
 Change from baseline in vital signs.  
 Wound healing assessment at 72 hours and on Day 10 and 28.  
3.3. 
Study Duration 
The overall duration of the study is anticipated to be approximately 8 months. The total duration 
of study participation for each subject (from Screening through the Day 28 follow-up visit) will 
be up to 53 days.  
For regulatory reporting purposes, the end of the study is defined as the date of the last subject’s 
last assessment (scheduled or unscheduled). 
4. 
STUDY ENROLLMENT AND WITHDRAWAL 
4.1. 
Study Population 
Up to approximately 90 subjects may be enrolled in the study. 
Approximately 30 subjects will be dosed in Cohort 1 of this study at up to 5 study sites in the 
US. An additional 30 subjects may be dosed in the additional optional cohorts using the same 
study sites.  
4.1.1. 
Inclusion Criteria 
Each subject must meet all the following criteria to be enrolled in this study: 
1. Is able to provide written informed consent. 
2. Is able to adhere to the study visit schedule and complete all study assessments. 
3. Is male or female, and ≥18 years of age at screening. 


Protocol No: HTX-011-215 (Version 1) 
 
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4. Is scheduled to undergo a unilateral open inguinal herniorrhaphy with mesh under general 
anesthesia. 
5. Has an American Society of Anesthesiologists Physical Status of I, II, or III. 
6. Female subjects are eligible only if all the following apply: 
a. Not pregnant (female subjects of childbearing potential must have a negative urine 
pregnancy test at screening and on Day 1 before surgery). 
b. Not lactating. 
c. Not planning to become pregnant during the study. 
d. Is surgically sterile (eg, has had a bilateral tubal ligation); or is at least 2 years 
postmenopausal; or is in a monogamous relationship with a partner who is surgically 
sterile; or is practicing abstinence or agrees to use double barrier contraception in the 
event of sexual activity; or is using an insertable, injectable, transdermal, or 
combination oral contraceptive approved by applicable regulatory authorities for 
greater than 2 months prior to screening and commits to the use of an acceptable form 
of birth control for the duration of the study and for 30 days after study drug 
administration. Note: women in only a same-sex relationship do not need to meet this 
criterion. 
4.1.2. 
Exclusion Criteria 
A subject who meets any of the following criteria will be excluded from the study: 
1. Had any prior inguinal hernia repair except as a child (less than 6 years of age). 
2. Has a planned concurrent surgical procedure (eg, bilateral herniorrhaphy). 
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 herniorrhaphy 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, 
ibuprofen, and for Optional Cohort 2 ketorolac (or other NSAIDs), oxycodone, morphine, 
acetaminophen, pregabalin, or fentanyl. Subjects in all cohorts must not have any 
contraindications to any of the protocol-specified drugs (bupivacaine, meloxicam, 
fentanyl, ibuprofen, acetaminophen, morphine, or oxycodone). Subjects in Optional 
Cohort 2 must also not have any contraindications to ketorolac. 
5. Has known or suspected daily use of opioids for 7 or more consecutive days within the 
previous 6 months. 
6. Has taken NSAIDs (including meloxicam, ibuprofen or, for Optional Cohort 2, ketorolac) 
within 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. 


Protocol No: HTX-011-215 (Version 1) 
 
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10. Has been administered any local anesthetic within 72 hours prior to the scheduled 
surgery, other than for pretreatment prior to a needle placement, to treat an AE that 
occurs after signing the ICF, or to decrease venous irritation (eg, caused by propofol, in 
which case no more than a single administration of lidocaine 1% 20 mg IV may be 
administered).  
11. Has initiated treatment with any of the following medications within 1 month prior to 
study drug administration or is taking any of these medications to control pain: selective 
serotonin reuptake inhibitors (SSRIs), selective norepinephrine reuptake inhibitors 
(SNRIs), gabapentin, pregabalin, or cyclooxygenase-2 (COX-2) inhibitors. (Note: If a 
subject is taking one of these medications for a reason other than pain control, the subject 
must be on a stable scheduled dose [ie, not “as needed”] for at least 1 month prior to 
study drug administration.) Anxiolytics prior to surgery are permitted, if necessary. 
12. Has been administered systemic steroids within 5 half-lives or 10 days prior to 
administration of study drug (whichever is longer). Note that for purposes of this 
exclusion criterion, inhaled, ophthalmic, and over-the-counter steroids are not considered 
systemic. 
13. Has a medical condition such that, in the opinion of the Investigator, participating in the 
study would pose a health risk to the subject or confound the postoperative assessments. 
Conditions may include, but are not limited to, any of the following: 
a. History of asthma or urticarial/ allergic-type reactions after taking aspirin or NSAIDs. 
b. History of clinically significant cardiac abnormality such as myocardial infarction 
within 6 months prior to signing the ICF, New York Heart Association class III or IV, 
or clinically significant abnormalities of ECG or cardiac function. 
c. History of coronary artery bypass graft surgery within 12 months prior to signing the 
ICF. 
d. 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. 
e. 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. 
f. History of known or suspected coagulopathy or uncontrolled anticoagulation (PLT 
count <100,000/μL; hemoglobin <12 g/dL; or hematocrit <35%). 
g. Loss of sensation in extremities or significant peripheral neuropathy. 
14. As per subject history and/or medical records, has active infection or is currently 
undergoing treatment for Hepatitis B, Hepatitis C, or human immunodeficiency virus 
(HIV). 
15. Has uncontrolled anxiety, psychiatric, or neurological disorder that, in the opinion of the 
Investigator, might interfere with study assessments. 
16. Had a malignancy in the last year, with the exception of nonmetastatic basal cell or 
squamous cell carcinoma of the skin or localized carcinoma in situ of the cervix. 
17. Has a known or suspected history of drug abuse, a positive drug screen on the day of 
surgery, or a recent history of alcohol abuse. Note: Subjects with a positive drug screen 


Protocol No: HTX-011-215 (Version 1) 
 
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Phase 2 Herniorrhaphy Study for Opioid Elimination 
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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 at the discretion of the Sponsor. Subjects taking any marijuana (medical or 
recreational) are not allowed to participate in the study. 
18. Previously participated in an HTX-011 study. 
19. Received an investigational product or device in a clinical trial within 30 days or within 5 
elimination half-lives (whichever is longer) prior to surgery or is planning to take part in 
another clinical trial while participating in this study. 
20. Has undergone 3 or more surgeries within 12 months prior to signing the ICF, other than 
for diagnostic procedures (eg, colonoscopy). 
21. Has a body mass index (BMI) >39 kg/m2. (Appendix B provides information about how 
to determine BMI.) 
4.2. 
Method of Enrolling Subjects  
Subjects who meet the screening eligibility criteria will be enrolled across the study sites into the 
sequential cohorts. No slotting of subjects per site will be implemented.  
4.2.1. 
Procedures for Handling Enrolled Subjects Who Do Not Meet the Study 
Eligibility Criteria 
Subjects who fail to meet the eligibility criteria should not, under any circumstances, receive 
study drug. 
Subjects who meet the Screening eligibility criteria but who do not meet the eligibility criteria on 
Day 1 will be withdrawn from the study without receiving study drug. In the event a subject does 
not meet the eligibility criteria, but is enrolled and receives study drug, the Investigator should 
inform the Sponsor immediately. The Sponsor’s Medical Monitor and the Investigator will 
discuss whether to allow the subject to continue in the study. 
4.3. 
Blinding 
This is an open label study.  
4.4. 
Subject Withdrawal and Replacement 
4.4.1. 
Subject Withdrawal 
Subjects are free to withdraw from the study at any time without prejudice to further treatment. 
A subject may also be withdrawn from the study by the Investigator or the Sponsor at any time if 
either determines that it is not in the subject’s best interest to continue participation. 
Possible reasons for early withdrawal include the following: 
 Adverse event. 
 Withdrawal by subject.  


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 Death. 
 Lost to follow up. 
 Pregnancy. 
 Investigator’s decision. 
 Sponsor’s decision. 
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 ). 
4.4.2. 
Subject Replacement 
Enrolled subjects who withdraw from study will not be replaced. To account for withdrawal of 
subjects who are ineligible at Day 1 or are otherwise enrolled but not dosed, enrollment will 
continue until at least 30 subjects have been enrolled and dosed in each cohort. 
5. 
STUDY TREATMENT 
All subjects will receive a single dose of HTX-011 300 mg/9 mg (bupivacaine/meloxicam doses) 
administered via instillation into the surgical site while undergoing a herniorrhaphy. Study drug 
is defined as HTX-011 (investigational product). 
HTX-011 will be supplied by the Sponsor. Other required medications and rescue medications 
will be supplied by the sites (eg, fentanyl, ketorolac, ibuprofen, acetaminophen, oxycodone, 
morphine); HTX-011 is the only medication considered “study drug.” 
5.1. 
Description of Investigational Product 
HTX-011 is a slightly yellow, viscous, solution. HTX-011 is 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 as described in study 
Pharmacy Manual. 
5.2. 
Manufacturing, Packaging, and Labeling 
HTX-011 will be manufactured according to Good Manufacturing Practices. 
Study drug will be packaged and labeled by the Sponsor or designee and will be packed and 
dispatched to comply with shipping and storage conditions. Study drug labeling will comply with 
all applicable national and local laws and regulations. 
5.3. 
Storage 
At the study site, HTX-011 should be stored at a controlled room temperature of 20 to 25°C 
(with excursions permitted from 15 to 30°C) and protected from light. A temperature log must be 
maintained to monitor the room’s temperature. Temperature monitoring includes min/max temp 
over each 24-hour period. 


Protocol No: HTX-011-215 (Version 1) 
 
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The storage location should be locked with restricted access.  
Acetaminophen, ibuprofen, and (for Optional Cohort 2) ketorolac will be stored as per the 
prescribing information. 
5.4. 
Preparation 
Study drug will be prepared at the study site. HTX-011 will be prepared in a group of syringes 
with a Luer lock applicator attached. Refer to the Pharmacy Manual for details on study drug 
preparation. 
5.5. 
Study Drug Administration 
HTX-011 will be given via instillation into the surgical site after irrigation and suction of each 
layer are complete and prior to suturing. 
5.5.1. 
Instillation of HTX-011  
HTX-011 will be administered via instillation using a Luer lock applicator supplied by the 
Sponsor. Following irrigation and suction of each fascial layer, the Luer lock applicator should 
be used to instill HTX-011 evenly to the tissues within the surgical site that could result in pain 
generation. After the hernia repair is complete, but prior to surgical site closure, apply HTX-011 
at both the level below and the level above the fascia. Note that the shallow subdermal layer is to 
be avoided, and that all study drug within the syringe should be utilized (ie, there should be no 
residual study drug left). Thereafter, skin closure will commence to complete the surgical 
procedure (ie, there should be no betadine wash until after skin closure at the end of the case). 
5.6. 
Study Drug Compliance 
All study drug must be administered in accordance with the treatment assignment. Because study 
drug is being administered as a component of the surgical procedure, a lack of treatment 
compliance is not expected. 
5.7. 
Study Drug Accountability 
The study drugs provided for this study will be used only as directed in the study protocol. In 
accordance with Good Clinical Practice (GCP), Investigators are required to maintain accurate 
and up-to-date records of all study drug to permit reconciliation. The Investigator or designee 
must maintain adequate records of distribution, including the date received, number and units 
received, lot numbers, dispensing, and return or destruction of all study drug (ie, accountability 
or dispensing logs). 
All study drug records must be readily available for inspection by the site’s 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. See Section 7 and the Schedule of Events table. 
6.1. 
Medical History and Demographics 
6.1.1. 
Medical History 
A complete medical history will be obtained before enrollment 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, where acceptable 
by local authorities. 
6.2. 
Prior and Concomitant Therapy 
All medications taken by subjects between signing the ICF and Day 28 will be recorded in the 
subject’s eCRF if enrolled.   
During the 72-hour postoperative period, the name, dose, and route, as well as the start date and 
time, of concomitant medications must be recorded. Medications include prescription or 
over-the-counter medications (including herbal products and vitamins). For subjects entering on 
a stable dose of permitted medication, any change in dose should also be recorded. Note: All 
medications received during this period must have a start time recorded except for IV fluids and 
oxygen used during surgery, which do not need to be recorded unless being used to treat an AE. 
After the 72-hour period until the Day 28 Visit, at least the start date of each concomitant 
medication should be recorded. 
6.2.1. 
Required Concomitant Medications 
Other mandatory medications in this study include oral acetaminophen preoperatively, IV 
fentanyl intraoperatively, and both oral ibuprofen and oral acetaminophen postoperatively. 
If performed, all subjects in Optional Cohort 2 will receive IV ketorolac intraoperatively in 
addition to the regimen specified in Cohort 1. The other mandatory medications for Optional 
Cohort 3 will be defined in a protocol amendment following the results of Cohort 1 and 
Optional Cohort 2.  
Cohort 1 
Preoperative Medication:  
Approximately 2 hours prior to the start of induction of general anesthesia, subjects are to 
receive 1 g oral acetaminophen. 
Intraoperative medication: All subjects will receive 50 µg IV fentanyl just prior to the end of the 
surgery. 


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Postoperative medication: During the 72-hour postoperative period, subjects will receive a 
scheduled analgesic regimen as follows: start with 600 mg oral ibuprofen once they are able to 
tolerate oral intake in the postoperative care unit, 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, they 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 are given on a round-the-clock, scheduled basis through the 
72-hour postoperative period. 
Optional Cohort 2 
Preoperative Medication:  
Approximately 2 hours prior to the start of induction of general anesthesia, subjects are to 
receive 1 g oral acetaminophen. 
Intraoperative medication:  
All subjects will receive 50 µg IV fentanyl just prior to the end of the surgery. In addition, one 
dose of IV ketorolac will be given intraoperatively prior to wound closure as follows: 
 For subjects aged ≥65 years, serum creatinine >1.5 and/or weight <50 kg: 15 mg. 
 For subjects aged <65years and/or weight ≥50 kg: 30 mg. 
Postoperative medication:   
During the 72-hour postoperative period, subjects will receive a scheduled analgesic regimen as 
follows: start with 600 mg oral ibuprofen once they are able to tolerate oral intake in the 
postoperative care unit, 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, they 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 are given on a round-
the-clock, scheduled basis through the 72-hour postoperative period. 
Optional Cohort 3 
The required preoperative, intraoperative, and postoperative medications are to be confirmed by 
protocol amendment. 
6.2.2. 
Allowed Concomitant Medications 
All treatments that the Investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the Investigator in keeping with the standard of medical care. 
Antiemetic medications may be given to treat nausea and/or vomiting, but should not be 
administered prophylactically (ie, as a routine preventative in the absence of signs or symptoms 
of nausea or vomiting). 
During surgery, the use of IV fentanyl up to 3 μg/kg is permitted for intraoperative pain control. 
As an example, the maximum total amount of fentanyl used during surgery for a 70 kg subject 
should not exceed 260 μg (3 μg/kg × 70 kg = 210 μg for intraoperative pain control + 50 μg at 


Protocol No: HTX-011-215 (Version 1) 
 
Heron Therapeutics, Inc. 
Phase 2 Herniorrhaphy Study for Opioid Elimination 
Confidential 
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the end of the case = 260 μg total). As the prescribing information for fentanyl citrate (Fentanyl 
Citrate USPI 2012) specifies that for intraoperative use a “moderate dose” of 2 to 20 μg/kg IV is 
necessary in order to allow the anesthesiologist to respond to any signal that the surgical stress is 
increasing or anesthesia lightening, this dose was chosen to be in the lowermost portion of that 
range and therefore not interfere with assessment of postoperative opioid load. As clinically 
appropriate, the minimum possible fentanyl dose should be used. 
Inpatient Postoperative Opioid Rescue Medications 
During the 72-hour postoperative period, subjects should only receive opioid rescue medication 
upon request for pain control, as needed. Rescue medication should not be given for pain 
prophylaxis, but only for treating postoperative pain. Each administration of opioid rescue 
medication will be recorded.  
Prior to the administration of the first dose of opioid rescue medication, if the subject has not 
already had at least 1 postoperative pain score assessed, then an NRS-R score must be obtained.  
Postoperative rescue medication will consist of PO immediate-release oxycodone (no more than 
10 mg within a 4-hour period as needed) or IV morphine (no more than 10 mg within a 2-hour 
period as needed). Administration of other opioids or any other analgesics (eg, ketamine, 
pregabalin), local anesthetics, or anti-inflammatory agents (except as specified by the protocol) is 
prohibited, unless needed to treat an AE that occurs after signing the ICF, for pretreatment prior 
to a needle placement, or to decrease venous irritation (eg, caused by propofol, in which case no 
more than a single administration of lidocaine 1% 20 mg IV may be administered). Combination 
opioid/non-opioid products (eg, Percocet) are not allowed. 
Discharge/ Postoperative Analgesic Regimen (following the 72-hour postoperative period to 
Day 28) 
Upon discharge, subjects will be instructed to manage pain with the following regimen: 
 600 mg oral ibuprofen every 6 hours PRN as first-line therapy (before acetaminophen). 
 1 g 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 has not received any opioids during the 72-hour postoperative period, they should not 
receive an opioid prescription on discharge. 
If a subject has received any opioids in the 12 hours prior to discharge, the subject should be 
provided with a paper prescription for oxycodone (up to 5 mg PO q4h, #15, as needed). 
Pharmacists should be instructed that substitutions with any other opioid-containing product are 
not permitted, including combination opioid/non-opioid products.  
All subjects (whether or not they were discharged with an opioid prescription) will complete a 
daily diary to record whether they take an opioid medication between 72 hours and Day 28 and, 
if yes, reason for taking (relative to surgery or other). 
Appendix E  provides information on postoperative pain management for subjects who are 
medically ready for discharge. 


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6.2.3. 
Prohibited Medications 
6.2.3.1. 
Medications Prohibited Prior to Surgery 
Refer to exclusion criteria 5 through 12 and 17 for medications that are prohibited prior to the 
scheduled surgery (Section 4.1.2). The Investigator should refer to the respective package inserts 
for information on risks associated with fentanyl, midazolam, acetaminophen, general 
anesthetics, anti-emetics, antibiotics, other opioids and any other approved medications likely to 
be administered while a subject participates in this study; medications for any specific subject 
that would be prohibited based on their package inserts are also prohibited from use in this study.  
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). 
6.2.3.2. 
Medications Prohibited During Surgery 
Spinal, epidural, or regional 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% 20 mg IV may be administered). 
Antiemetic medications should not be administered prophylactically, ie, as a routine preventative 
in the absence of signs or symptoms of nausea or vomiting. 
6.2.3.3. 
Medications Prohibited From Time 0 Through 72 Hours 
With the exception of rescue medications specified in Section 3.1.3, no other analgesic agents, 
including NSAIDs, are permitted during the 72-hour postoperative observation period. 
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). 
6.3. 
Efficacy Assessments 
6.3.1. 
Use of Opioid Medications 
6.3.1.1. 
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. Information 
on the procedure for postoperative opioid rescue, as well as the opioid rescue medications that 
are permitted, is provided in Section 3.1.3.  
6.3.1.2. 
Subject Daily Diary of Opioid Use From 72 Hours Through Day 28 
Subjects will be provided a daily diary to record if they take any opioid medication from 
72 hours through Day 28 (±4 days) (yes or no). 


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6.3.2. 
Pain Intensity Assessment 
Subjects will be asked to evaluate their current pain level at scheduled timepoints after surgery. 
Subjects will receive training by the site on how to provide pain intensity assessments. 
Pain intensity scores will be assessed using an 11-point NRS-R (0–10) where 0 represents “no 
pain” and 10 represents “worst pain imaginable” (Breivik 2008).  
For the assessment, subjects should be recumbent or lying supine. Measurements should be 
obtained after the subject is in the resting position for at least 5 minutes. 
If a subject withdraws from the study before 72 hours, an NRS-R pain intensity score will be 
recorded at the time of withdrawal. See Appendix C. 
6.4. 
Safety Assessments 
6.4.1. 
Adverse Events 
All AEs regardless of causality or seriousness will be recorded from the time the subject signs 
the ICF through Day 28. Section 8 provides details on safety monitoring and recording. 
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 (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 (includes sitting in a recliner 
chair) for at least 5 minutes before taking vital signs. Clinically significant post-treatment vital 
sign results should be recorded as AEs. 
6.4.4. 
12-Lead Electrocardiograms 
Screening and post-treatment ECGs will be obtained for all subjects locally. Standard digital 12-
lead ECGs will be performed in triplicate by local ECG machines. Subjects should be in the 
supine position (includes sitting in a recliner chair) for at least 5 minutes before each initial ECG 
recording. The local ECG tracings will be reviewed by the investigator for safety. 
6.4.5. 
Wound Healing Assessment 
Surgical wound healing will be evaluated by the Investigator or other medically qualified clinical 
site personnel; every attempt should be made by the site to use the same assessor for individual 


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subject assessments. The findings will be graded according to the Southampton Wound Scoring 
System (Bailey 1992); Appendix E. 
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). See Table 1 for a list of clinical laboratory tests and 
parameters. Urine samples will be tested by local laboratories. Blood samples will be tested by a 
central laboratory. 
Laboratory results will be reviewed by the Investigator. Any laboratory values outside of the 
normal reference range will be evaluated for clinical significance. Clinically significant findings 
after study drug administration will be recorded as AEs. 
Refer to the Laboratory Manual for detailed instructions on sample collection, processing, and 
shipping procedures. 


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Table 1: 
Clinical Laboratory Tests 
Diagnostic Screening Tests (Local Laboratories): 
Urine 
Pregnancy test: Human chorionic gonadotropin test (female subjects of child-bearing potential only) 
Drug screen: Amphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine, opiates/opioids, phencyclidine, 
propoxyphene, and methadone 
Safety Laboratory Tests (Central Laboratory): 
Hematology 
Serum Chemistry 
Hematocrit 
Alanine aminotransferase 
Hemoglobin 
Albumin 
Red blood cell count 
Alkaline phosphatase 
Mean Corpuscular Volume  
White blood cell count (with automated differential) 
Platelet count 
Aspartate aminotransferase 
Bicarbonate 
Blood urea nitrogen 
 
Calcium 
 
Chloride 
 
Creatinine 
 
Direct bilirubin 
 
Gamma-glutamyltransferase 
 
Glucose 
 
Lactate dehydrogenase 
 
Magnesium 
 
Phosphorus 
 
Potassium 
 
Sodium 
 
Total bilirubin 
 
Total protein 
 
Uric acid 
7. 
TIMING OF PROCEDURES AND ASSESSMENTS 
This section lists the study procedures and assessments that will be performed at scheduled 
timepoints during the study. See Section 6 for information on study procedures and assessments. 
Unless there is a safety concern, every effort should be made to avoid protocol deviations. For 
pain assessments at timepoints when the subject is asleep, an attempt should be made to wake the 
subject. If there is no response, the assessments at these timepoints may be recorded as “Not 
Done.” Assessments that can be done without waking the subject (eg, blood collection for PK) 


Protocol No: HTX-011-215 (Version 1) 
 
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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 (except at screening): 
 NRS-R pain intensity assessment (subjects should be recumbent 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. 
 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 21 days prior to surgery. The Investigator must evaluate the subject’s medical 
history and the results of all Screening assessments to determine study eligibility before the 
subject is enrolled. 
Screening procedures and assessments will include the following: 
 Urine drug screen. 
 Urine pregnancy test (female subjects of childbearing potential only). 
 Medical history. 
 Demographic recording. 
 Physical examination (including weight, height, and BMI calculation). 
 Vital signs measurements. 
 12-lead ECG (in triplicate). 
 Blood sample collection for the hematology and serum chemistry. 
 Subject training for pain intensity assessments. 
 AE recording (from the time the subject signs the ICF). 
 Prior 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 once 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 


Protocol No: HTX-011-215 (Version 1) 
 
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Phase 2 Herniorrhaphy Study for Opioid Elimination 
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disorder, benzodiazepine for anxiety disorder) may be eligible for participation in the study. Any 
other screening laboratory test result that does not meet the eligibility criteria may not be 
repeated without the Sponsor's approval. 
All subjects who meet the screening eligibility criteria will be enrolled.  
7.2. 
Treatment and Postoperative Observation Period 
7.2.1. 
Day of Surgery (Day 1) 
7.2.1.1.1. Prior to Surgery 
On Day 1, subjects will be reassessed for study eligibility. This includes a urine drug screen test 
(all subjects) and a urine pregnancy test (female subjects of childbearing potential only). Results 
should be confirmed as negative prior to performing any additional assessments. 
Subjects who continue to meet the eligibility criteria will be admitted to the surgical unit. The 
following additional study procedures and assessments will be performed before surgery: 
 Vital signs measurements. 
 Subject training for pain intensity assessments (refresher training). 
 AE recording. 
 Prior medication assessment. 
7.2.1.2. 
Surgery and Study Drug Administration 
Subjects will undergo an inguinal herniorrhaphy under general anesthesia. Epidural spinal, or 
regional anesthesia is not permitted. Sites should follow intraoperative safety monitoring in 
accordance with American Society of Anesthesiologists (ASA) Standards for Basic Anesthetic 
Monitoring (American Society of Anesthesiologists 2015), which is consistent with the European 
Board of Anaesthesiology recommendations for minimal monitoring during Anaesthesia and 
Recovery (for review in 2018) (EBA UEMS 2016). The start and stop time of surgery and 
additional surgical details (including the length of the surgical incision) should be recorded in the 
eCRF. 
Subjects will be administered study drug unless they experience a clinically significant event 
during surgery (eg, excessive bleeding, hemodynamic instability) that would render the subject 
medically unstable or complicate their postoperative course. Study drug will be administered via 
instillation into the surgical site at the end of the surgical procedure, but prior to wound closure. 
See Section 5.5 for further details on the study drug administration technique. 
The start and stop times of study drug dosing will be recorded in the eCRF. Details of 
administration will be recorded on a worksheet, which will be used in the dictation of the 
surgical notes and will become part of the source document. Note: The start of study drug 
administration will be considered as Time 0 for all efficacy and safety assessments. 
Placement of the last suture will be considered the end of surgery. 


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Prior and concomitant medications used during surgery will be recorded (note that IV fluids and 
oxygen are not required to be recorded unless being used to treat an AE). AEs will also be 
recorded. 
After immediate postoperative recovery, subjects will be transferred to the PACU. 
7.2.2. 
Postoperative Assessment Period (Up to 72 Hours) 
Subjects will remain in the hospital/research facility for 72 hours after study drug administration. 
Study procedures and assessments that will be performed are listed. 
All timepoints are referenced to the start of study drug administration. Actual times will be 
recorded for all events, and any deviation outside the specified ranges must be clearly 
documented in the subject’s study records. 
 NRS-R pain intensity assessments: at 60 minutes (±5 min), 120 minutes and 4 hours 
(±15 min), 8 and 12 hours (±30 min), 24 hours (±1 h); 36 and 48 hours (±2 h), 60 and 
72 hours (±4 h). 
 Note: If a subject requires rescue medication before the 1-hour pain intensity 
assessments, then an unscheduled NRS-R pain score must be obtained before 
administering the first dose of rescue medication. This does not replace the 1-hour 
NRS-R assessment. 
 Vital signs measurements: 60 minutes (±5 min), 90 minutes(±15 min), 4 hours 
(±15 min), 8 hours (±30 min), 12 hours (±30 min), 24 hours (±1 h), 36 hours (±2 h), 
48 hours (±2 h), 60 hours (±4 h), and 72 hours (±4 h). 
 12-lead ECG (in triplicate): 4 hours (±15 min), 24 hours (±1 h), 48 hours (±2 h), and 
72 hours (±4 h). 
 Physical examination: 72 hours (±4 h; height and weight not required). 
 Blood sample for hematology and serum chemistry tests: 24 hours (±1 h; 
hematology only) and 72 hours (±4 h; hematology and serum chemistry). 
 Wound healing assessment: 72 hours (±4 h). 
 AE recording: (Note: the start date and time of all AEs during this timeframe must 
be recorded). 
 Concomitant medication recording: (Note: the start date and time of all concomitant 
medications during this timeframe must be recorded). 
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 for all enrolled subjects as 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 for all enrolled subjects. 
Subjects who are not medically ready for discharge at 72 hours may receive the same rescue 
medication as outlined in Section 3.1.3  to treat postoperative pain until discharge. 


Protocol No: HTX-011-215 (Version 1) 
 
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For subjects who are medically ready for discharge at 72 hours, oral ibuprofen (no more than 
600 mg every 6 hours as needed) and 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 any opioids in the 12 hours prior to discharge, the subject should be provided with a 
prescription for oxycodone (up to 10 mg PO q4h as needed, #15, no substitutions). See 
Appendix E for instructions on postoperative pain management for subjects medically ready for 
discharge. 
All subjects will be given a diary to complete daily and record whether they take any opioid 
medication from 72 hours through Day 28. This applies to all subjects. 
7.3. 
Follow-Up Period 
7.3.1. 
Day 10 Visit (±3 Days) 
All subjects will return to the study site and will have the following procedures and assessments: 
 NRS-R pain intensity assessment. 
 Wound healing assessment. 
 Blood sample collection for the hematology and serum chemistry. 
 Review subject diary results. 
 AE recording. 
 Concomitant medication recording. 
7.3.2. 
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. 
 Wound healing assessment. 
 Review subject diary results. 
 AE recording. 
 Concomitant medication recording 
7.4. 
Early Termination Visit 
Subjects who withdraw from the study before their Day 28 Visit will be asked to complete Early 
Termination procedures, which will include the following: 
 NRS-R pain intensity assessment. 
 Vital signs (if withdrew prior to 72 hours). 
 Blood sample collection for hematology and serum chemistry (if withdrew prior to 
72 hours). 
 12-lead ECG (triplicate) (if withdrew prior to 72 hours). 


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 Physical examination (if withdrew prior to 72 hours [height and weight not required]) 
 Wound healing assessment 
 Review and record subject diary results in the eCRF (if after the 72-hour discharge 
but before Day 28) 
 AE recording 
 Concomitant medication recording 
7.5. 
Unscheduled Visits and Assessments 
Unscheduled visits and assessments should be performed if clinically indicated in the opinion of 
the Investigator. Except when urgent clinical evaluation is necessary, it is expected that the 
Investigator will have the subject return for an unscheduled visit rather than directing the subject 
to a hospital emergency room. The following procedures and assessments are examples of what 
may be performed at an unscheduled visit, depending on the clinical situation: 
 Vital signs. 
 Physical examination. 
 ECG. 
 Wound healing assessment. 
 AE recording. 
 Concomitant medication recording. 
8. 
SAFETY MONITORING AND REPORTING 
Investigators are responsible for the detection and documentation of events that meet the 
definition of an AE, SAE, suspected adverse reaction, serious suspected adverse reaction, 
unanticipated adverse device effect, or unanticipated problem, as provided in this protocol. 
Investigators must review the HTX-011 IB to be aware of the safety-related events, which may 
be anticipated with its use. Investigators will also be versed in the latest standard of care 
guidelines. 
8.1. 
Definition of Safety Parameters 
8.1.1. 
Definition of an Adverse Event 
An AE is defined as any untoward medical occurrence associated with the use of a drug in 
humans, whether 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 considered 
causally associated with the use of the study drug. Any abnormal physical examination findings, 
laboratory value, vital sign result, ECG finding, or wound healing assessment finding deemed 
clinically significant by the Investigator, regardless of causal relationship, must be reported as an 


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AE. A clinical diagnosis, rather than the changes in laboratory analyte or other assessment, 
should be recorded (eg, anemia rather than low hemoglobin value). 
Examples of AEs include the following: 
 Significant or unexpected worsening or exacerbation of the condition or indication 
under study. 
 Exacerbation of a chronic or intermittent pre-existing condition, including either an 
increase in frequency or intensity of the condition (eg, abnormal physical examination 
finding). 
 Signs, symptoms, or clinical sequelae of a suspected interaction. 
 Signs, symptoms, or clinical sequelae of a suspected overdose of the study drug or a 
concurrent medication (overdose per se should not be reported as an AE or SAE, 
unless nonserious or serious sequelae occur). 
 The following abnormal laboratory results: 
 Any laboratory abnormality suggestive of a new disease/organ toxicity or a 
worsening of a pre-existing condition. 
 Any laboratory abnormality that required the subject to have investigational 
product interrupted or discontinued. 
 Any laboratory abnormality that required the subject to receive specific treatment 
for the lab abnormality. 
 Any laboratory abnormality that required additional monitoring and follow-up 
visits. 
 Any laboratory abnormality requiring further diagnostic investigation. 
The following examples are not considered AEs: 
 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 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: 


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 Death. 
 A life-threatening AE (ie, presented an immediate risk of death from the event as it 
occurred. This criterion is not intended to include an AE that, had it occurred in a 
more severe form, might have caused death.) 
 Inpatient hospitalization or prolongation of existing hospitalization. 
 A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions. 
 A congenital anomaly/birth defect. 
 Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the patient or subject and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition. 
Examples of such medical events include allergic bronchospasm requiring intensive treatment in 
an emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse. 
The following events do not meet the definition of an SAE: hospitalization for elective treatment 
of a pre-existing condition that does not worsen from baseline, hospitalizations for a standard 
procedure for study drug administration and routine monitoring of the studied indication not 
associated with any deterioration in condition, social or convenience admission to a hospital, 
prolongation of a hospitalization for social or convenience reasons not associated with the 
occurrence of an AE, or hospitalization or an emergency room visit that lasts less than 24 hours 
that does not meet the criteria of an important medical or a life-threatening event. 
According to 21 Code of Federal Regulations (CFR) 812.3(s), an unanticipated adverse device 
effect means any serious adverse effect on health or safety or any life-threatening problem or 
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 the following 
criteria: 


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


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 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 for enrolled subjects or completing the SAE reporting 
form, in the event electronic data capture (EDC) is not available. The causality assessment is one 
of the criteria used when determining regulatory reporting requirements. The Investigator may 
change his or her opinion of causality in light of follow-up information and amend the SAE 
information accordingly in the eCRF or the SAE reporting form, as applicable. 
8.3. 
Time Period and Frequency for Event Assessment and Follow Up 
8.3.1. 
Adverse Event and Serious Adverse Event Monitoring 
All AEs regardless of causality or seriousness will be recorded from the time the subject signs 
the ICF through Day 28. Note: the AE start time, as well as the date, must be recorded during the 
72-hour postoperative period. 
For subjects who received study drug, if an Investigator becomes aware of an SAE that occurs in 
a subject more than 28 days after study drug administration and the Investigator considers the 
event to be possibly related to the study drug, the Investigator needs to report the SAE to the 
Sponsor as described in Section 8.4.1. 
8.3.2. 
Follow-Up of Events 
After the occurrence of an AE or SAE, the Investigator is required to follow each subject 
proactively and provide further information on the subject’s condition. All AEs and SAEs 
documented at a previous visit or contact and designated as ongoing will be reviewed at 
subsequent visits or contacts. 
Nonserious AEs will be followed after the last scheduled study visit until the event resolves, the 
condition stabilizes, or until the event is otherwise explained or judged by the Investigator to be 
no longer clinically significant (unless the subject is lost to follow-up or withdraws consent). 
The Investigator will assess the outcome of each AE using the following categories: 
 Recovered/Resolved: The event resolved, or the subject recovered without sequelae. 
An event (either serious or nonserious) occurred and had an endpoint, and the subject 
experienced no restrictions. Examples include stent placement for coronary artery 
disease (a device implanted is not a sequela), an appendectomy (a scar is not a 
sequela), a postoperative wound infection, or an upper respiratory tract infection. 
 Recovered/Resolved with sequelae: The event has at least one secondary outcome 
that may result in permanent disability, functional limitation, or both. Such sequelae 
are usually limited to SAEs. Examples include hip replacement resulting in foot drop 
(foot drop is not the intended outcome but is a risk of surgery), stroke resulting in 
paralysis, or emboli formation after a bacterial infection resulting in a renal infarct 
and loss of renal function. 


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 Not recovered/Not resolved: At the end of the study, a nonserious event either has 
not changed in intensity or may not have recovered to baseline values, and the 
outcome is unknown. Examples include headache, low-grade fever, or nausea. 
 Unknown: The subject has withdrawn from the study prematurely or is lost to follow-
up, and the status of the event is unknown. 
 Fatal. 
SAEs will be followed until the event resolves (ie, when the event no longer meets any of the 
seriousness criteria), the condition stabilizes, or 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 this study, regardless of relationship to study drug, he/she must notify 
the Sponsor by entering the SAE information into the eCRF within 24 hours of the Investigator 
becoming aware of the SAE. 
If EDC is not available, the Investigator must complete an SAE reporting form and email it to the 
Sponsor within 24 hours of the Investigator becoming aware of the SAE. The Investigator 
must also enter the SAE information into the eCRF as soon as possible thereafter. 
Email Address: 
Heron_PV@ubc.com 
In the initial email, the Investigator must provide to the Sponsor the following eCRF pages, 
completed to the greatest extent possible: 
 AE record. 
 Medical history. 
 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 


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updated when additional information is received. Follow-up information received on all SAEs 
must be forwarded to the Sponsor using the same timelines as for an initial report. 
The Investigator must notify the Sponsor by reporting any unanticipated adverse device effect 
within 24 hours of the Investigator becoming aware of the effect. 
8.4.2. 
Reporting Unanticipated Problems to the Sponsor 
If the Investigator determines that an event meets the protocol definition of an unanticipated 
problem, he/she must notify the Sponsor by completing an Unanticipated Problem Form and 
emailing it to the Sponsor within 24 hours of the Investigator becoming aware of the 
problem. 
Email Address: 
Heron_PV@ubc.com 
The following information will be included with unanticipated problem reporting: 
 Protocol identifying information: protocol title, protocol number, and Investigator’s 
name. 
 A detailed description of the event, incident, experience, or outcome. 
 An explanation of the basis for determining that the event, incident, experience, or 
outcome represents an unanticipated problem. 
It is the Investigator’s responsibility to report 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 
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8.4.4. 
Pregnancy Reporting 
Pregnancy is not considered an AE; however, any subject who becomes pregnant during the 
study must be withdrawn from the study immediately. Female subjects who become pregnant 
within 28 days after receiving study drug should also notify the Investigator. The Investigator 
must attempt to follow the pregnancy to term or termination 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 ECG findings, AEs, and 
SAEs. 
The stopping criteria, enrollment suspension or study termination for safety issues, are provided 
in Section 13.5. 
9. 
OTHER STUDY RESTRICTIONS 
9.1. 
Contraception 
Female subjects of childbearing potential must use an acceptable form of contraception in the 
event of sexual activity during the study and for 30 days after study drug administration. 
Acceptable forms of contraception include double-barrier contraception or an insertable, 
injectable, transdermal, or combination oral contraceptive approved by applicable regulatory 
authorities. Note: The does not apply to women in only a same-sex relationship or women in a 
monogamous relationship with a surgically sterile partner. 
10. 
STATISTICAL CONSIDERATIONS 
10.1. 
General Considerations 
All data will be listed by subject and all safety and efficacy endpoints will be summarized by 
treatment group. Unless otherwise specified, Baseline is defined as the last observed 
measurement, whether scheduled or unscheduled, prior to HTX-011 administration.  
Continuous variables will be summarized using the number of subjects with data (n), mean, SD, 
median, minimum, and maximum. Selected continuous variable summaries will also include the 
SE. Categorical variables will be summarized using frequency counts and percentages. 


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10.2. 
Determination of Sample Size 
The sample size in this study was selected empirically without a formal statistical assumption. 
10.3. 
Analysis Populations 
Safety Population: All subjects who receive study drug will be included in the Safety Population. 
This population will be used for all summaries of efficacy and safety data. The actual treatment 
received will be used for analysis in this population. 
 
10.4. 
Statistical Analysis Methods 
10.4.1. 
Disposition and Demographics 
The number and percentage of subjects in the Safety Population will be summarized. Subject 
disposition, including the number of subjects screened, enrolled, dosed, completing the 
72-hour postoperative observation period, completing Day 28, and not completing Day 28 by 
reason for withdrawal will be summarized. 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 treatment group.  No statistical hypothesis testing will 
be performed.  For opioid rescue summaries, the proportion of subjects receiving no opioid 
rescue will be summarized as the proportion of subjects with a total IV MME dose = 0 over the 
relevant timeframe. 
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 
imputed via last observation carried forward (LOCF), in which the most recent postdose value is 
used for a subsequent missing value. For subjects who do not have a postdose value prior to their 
first missing value, the median of the postdose values at the relevant timepoint from subjects 
with observed data in the same treatment group will be used. Predose values will not be carried 
forward to postdose timepoints. In subjects who withdraw from the study prior to 72 hours, 
missing NRS pain intensity scores through 72 hours that were to be collected following 
withdrawal will be imputed via 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. 


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10.4.3. 
Safety Analysis 
All safety analyses will be carried out on the Safety Population. All safety data will be listed and 
summarized by treatment group. 
AEs that occur between the time the subject signs the ICF and the start of study drug 
administration will be considered pretreatment AEs. AEs that start during or after study drug 
administration, or AEs with an onset prior to study drug administration that worsen after study 
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. Changes from baseline in ECG results will 
be summarized. 
Wound healing assessment results will be summarized at each timepoint. 
10.5. 
Interim Analysis 
No formal interim analyses are planned. 
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. 
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 


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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. 
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 


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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). 
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 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. 


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13.3.2. 
Protocol 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 
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 in the US and outside the US 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 US regulations (21 CFR Part 54). In addition, the Investigator or 
subinvestigators must promptly notify the Sponsor if there are any reportable changes that occur 
during the 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: 
 


Protocol No: HTX-011-215 (Version 1) 
 
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 If there is a suspension of the study and further investigation shows that any death or 
3 non-fatal SAEs are determined by the Sponsor to be related to study drug and pose 
an unacceptable risk to the study subjects, the study will be terminated. 
 Discovery of an unexpected, significant, or unacceptable risk to the subjects. 
 Failure of the Investigator to comply with the protocol, GCP regulations and 
guidelines, or local requirements. 
 Insufficient adherence to protocol requirements or an unacceptably high rate of 
missing, erroneous, or improperly collected data. 
 Data are not sufficiently complete and/or evaluable. 
 Inadequate recruitment of subjects by the Investigator. 
 Sponsor decision. 
If the study is terminated early by the Sponsor, written notification documenting the reason for 
study termination will be provided to the Investigator and regulatory authorities. The Investigator 
will promptly inform the EC and provide the reason(s) for study termination. 
13.6. 
Publication and Information Disclosure Policy 
All information provided by the Sponsor and all data and information generated by the site as 
part of the study (other than a subject’s medical records) are the sole property of Heron 
Therapeutics, Inc. 
For clinical interventional studies in patients, Heron will post study results on websites such as 
https://clinicaltrials.gov/ and https://eudract.ema.europa.eu/ in accordance with FDA and 
European Union reporting rules. Regardless of study outcome, Heron commits to submit for 
publication results of its interventional clinical studies according to the prespecified plans for 
data analysis. Wherever possible, Heron also plans to submit for publication the results of any 
nonclinical or technology studies while protecting any proprietary information. 
Any publication or presentation of the results of this study may only be made in compliance with 
the provisions outlined in the executed Clinical Trial Agreement. Heron has developed a policy 
for the publication of scientific and clinical data that follows the recommendations of the 
International Committee of Medical Journal Editors (ICMJE), the CONSORT (Consolidated 
Standards of Reporting Trials) group and Good Publication Practice (GPP). A copy of this policy 
will be made available to the Investigator upon request. 
When the study is completed or prematurely terminated, the Sponsor or designee will ensure a 
Clinical Study Report is written in compliance with ICH E3 (Structure and Content of Clinical 
Study Reports) and submitted to the regulatory authorities, as required by the applicable 
regulatory requirement(s). Where required by applicable regulatory requirements, an Investigator 
signatory will be identified for the approval of the Clinical Study Report. The Investigator will be 
provided reasonable access to statistical tables, listings, and figures, as well as relevant reports, 
and will have the opportunity to review the complete study results. 


Protocol No: HTX-011-215 (Version 1) 
 
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14. 
REFERENCE LIST 
American Society of Anesthesiologists. (2015). "Standards for Basic Anesthetic Monitoring: 
Section 10.28.15." from http://www.asahq.org/quality-and-practice-management/standards-and-
guidelines. 
Apfelbaum, J. L., C. Chen, S. S. Mehta and T. J. Gan (2003). "Postoperative Pain Experience: 
Results from a National Survey Suggest Postoperative Pain Continues to Be Undermanaged." 
Anesthesia & Analgesia 97(2). 
Bailey, I. S., S. E. Karran, K. Toyn, P. Brough, C. Ranaboldo and S. J. Karran (1992). 
"Community surveillance of complications after hernia surgery." BMJ 304(6825): 469-471. 
Barnett, M. L., A. R. Olenski and A. B. Jena (2017). "Opioid-Prescribing Patterns of Emergency 
Physicians and Risk of Long-Term Use." New England Journal of Medicine 376(7): 663-673. 
Breivik, H., P. C. Borchgrevink, S. M. Allen, L. A. Rosseland, L. Romundstad, E. K. Hals, G. 
Kvarstein and A. Stubhaug (2008). "Assessment of pain." Br J Anaesth 101(1): 17-24. 
Cashman, J. N. and S. J. Dolin (2004). "Respiratory and haemodynamic effects of acute 
postoperative pain management: evidence from published data." Br J Anaesth 93(2): 212-223. 
Chan, E. Y., F. M. Blyth, L. Nairn and M. Fransen (2013). "Acute postoperative pain following 
hospital discharge after total knee arthroplasty." Osteoarthritis and Cartilage 21(9): 1257-1263. 
Coley, K. C., B. A. Williams, S. V. DaPos, C. Chen and R. B. Smith (2002). "Retrospective 
evaluation of unanticipated admissions and readmissions after same day surgery and associated 
costs." Journal of Clinical Anesthesia 14(5): 349-353. 
Dalury, D. F. (2016). "A state-of-the-art pain protocol for total knee replacement." Arthroplast 
Today 2(1): 23-25. 
EBA UEMS. (2016). "European Board of Anaesthesiology (EBA) Recommendations for 
Minimal Monitoring During Anaesthesia and Recovery." from http://www.eba-
uems.eu/PS/PS.html. 
EXPAREL USPI (2018). EXPAREL (bupivacaine liposome injectable suspension). San Diego, 
CA 92121: Pacira Pharmaceuticals, Inc. 
Fentanyl Citrate USPI (2012). Fentanyl Citrate injection. Lake Forest, IL 60045: Akorn, Inc. 
Gan, T. J., A. S. Habib, T. E. Miller, W. White and J. L. Apfelbaum (2014). "Incidence, patient 
satisfaction, and perceptions of post-surgical pain: results from a US national survey." Curr Med 
Res Opin 30(1): 149-160. 
Jarzyna, D., C. Jungquist, C. Pasero, J. Willens, A. Nisbet, L. Oakes, S. Dempsey, D. Santangelo 
and R. Polomano (2011). "American Society for Pain Management Nursing guidelines on 


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monitoring for opioid-induced sedation and respiratory depression." Pain management nursing : 
official journal of the American Society of Pain Management Nurses 12(3): 118-145.e110. 
Kehlet, H. and L. O. Andersen (2011). "Local infiltration analgesia in joint replacement: the 
evidence and recommendations for clinical practice." Acta Anaesthesiol Scand 55(7): 778-784. 
Kelley, T. C., M. J. Adams, B. D. Mulliken and D. F. Dalury (2013). "Efficacy of multimodal 
perioperative analgesia protocol with periarticular medication injection in total knee arthroplasty: 
a randomized, double-blinded study." J Arthroplasty 28(8): 1274-1277. 
Kessler, E. R., M. Shah, S. K. Gruschkus and A. Raju (2013). "Cost and Quality Implications of 
Opioid-Based Postsurgical Pain Control Using Administrative Claims Data from a Large Health 
System: Opioid-Related Adverse Events and Their Impact on Clinical and Economic Outcomes." 
Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy 33(4): 383-391. 
Lee, L. A., R. A. Caplan, L. S. Stephens, K. L. Posner, G. W. Terman, T. Voepel-Lewis and K. 
B. Domino (2015). "Postoperative Opioid-induced Respiratory DepressionA Closed Claims 
Analysis." Anesthesiology 122(3): 659-665. 
Lee, M. J., S. L. Daniels, J. R. L. Wild, T. R. Wilson, A. Jackson, C. K. Shun, A. Wheeler, R. 
West, E. M. Nofal, V. K. Proctor, M. Rigby, H. Burnett, R. Gaikwad, K. Madhbak, E. Flatt and 
F. Akram (2016). "Readmissions after general surgery: a prospective multicenter audit." Journal 
of Surgical Research 209: 53-59. 
Lynch, E. P., M. A. Lazor, J. E. Gellis, J. Orav, L. Goldman and E. R. Marcantonio (1997). 
"Patient Experience of Pain After Elective Noncardiac Surgery." Anesthesia & Analgesia 85(1). 
MARCAINE USPI (2015). MARCAINE (Bupivacaine Hydrochloride Injection). Hospira, Inc., 
Lake Forest, IL 60045 USA. 
Meissner, W., F. Coluzzi, D. Fletcher, F. Huygen, B. Morlion, E. Neugebauer, A. M. Pérez and 
J. Pergolizzi (2015). "Improving the management of post-operative acute pain: priorities for 
change." Current Medical Research and Opinion 31(11): 2131-2143. 
Misiolek, H., M. Cettler, J. Woron, J. Wordliczek, J. Dobrogowski and E. Mayzner-Zawadzka 
(2014). "The 2014 guidelines for post-operative pain management." Anaesthesiol Intensive Ther 
46(4): 221-244. 
MOBIC Tablets USPI (2016). MOBIC (meloxicam) tablets, for oral use. Ridgefield, CT 06877: 
Boehringer Ingelheim Pharmaceuticals, Inc. 
Oderda, G. M., T. J. Gan, B. H. Johnson and S. B. Robinson (2013). "Effect of Opioid-Related 
Adverse Events on Outcomes in Selected Surgical Patients." Journal of Pain & Palliative Care 
Pharmacotherapy 27(1): 62-70. 
Ramachandran, S. K., N. Haider, K. A. Saran, M. Mathis, J. Kim, M. Morris and M. O'Reilly 
(2011). "Life-threatening critical respiratory events: a retrospective study of postoperative 


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patients found unresponsive during analgesic therapy." Journal of Clinical Anesthesia 23(3): 
207-213. 
Shah, A., C. J. Hayes and B. C. Martin (2017). "Characteristics of Initial Prescription Episodes 
and Likelihood of Long-Term Opioid Use - United States, 2006-2015." MMWR Morb Mortal 
Wkly Rep 66(10): 265-269. 
Shirakami, G., Y. Teratani, T. Namba, H. Hirakata, M. Tazuke-Nishimura and K. Fukuda 
(2005). "Delayed discharge and acceptability of ambulatory surgery in adult outpatients 
receiving general anesthesia." Journal of Anesthesia 19(2): 93-101. 
Singla, N. K., P. J. Desjardins and P. D. Chang (2014). "A comparison of the clinical and 
experimental characteristics of four acute surgical pain models: Dental extraction, bunionectomy, 
joint replacement, and soft tissue surgery." PAIN 155(3): 441-456. 
Stephens, J., B. Laskin, C. Pashos, B. Pena and J. Wong (2003). "The burden of acute 
postoperative pain and the potential role of the COX-2-specific inhibitors." Rheumatology 
42(90003): 40-52. 
Svensson, I., B. Sjöström and H. Haljamäe (2000). "Assessment of Pain Experiences after 
Elective Surgery." Journal of Pain and Symptom Management 20(3): 193-201. 
Wheeler, M., G. M. Oderda, M. A. Ashburn and A. G. Lipman (2002). "Adverse events 
associated with postoperative opioid analgesia: A systematic review." The Journal of Pain 3(3): 
159-180. 
 
 
 




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


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




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APPENDIX E. INSTRUCTIONS FOR POSTOPERATIVE PAIN 
MANAGEMENT FOR SUBJECTS MEDICALLY READY 
FOR DISCHARGE 
The following text should be read by the Investigator or designee to the subject at the time of 
discharge: 
You have completed the initial part of the study which required you to stay at the facility. You 
are now being discharged to go home. You will come back here again for check-up visits on Day 
10 (approximately 1 week from now) and Day 28 (approximately 3½ weeks from now). 
While you are at home, if you experience any pain from your operation, please take up to 3 over-
the counter 200 mg ibuprofen (eg, Advil) every 6 hours as needed.  If this does not control your 
pain, after 3 hours please take 2 over- the-counter extra-strength (500 mg) acetaminophen 
tablets (eg, Tylenol, Panadol) every 6 hours as needed. Do not take more than 8 tablets 
(4000 mg) of acetaminophen 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. 
 


Signature Page for VV-CLIN-002721 v2.0
Signature Page for VV-CLIN-002721 v2.0
Approval
Erol Onel
Medical
31-Aug-2018 18:56:59 GMT+0000

SAP_001.pdf: 
Document Type:  
Statistical Analysis Plan 
Official Title:  
A Phase 2, Open-Label Study of HTX-011 in a Multimodal Analgesic 
Regimen for Decreased Opioid Use Following Unilateral Open Inguinal 
Herniorrhaphy 
NCT Number:  
NCT03695367 
Document Date:  
18-Oct-2018 
 


Clinical Study Report: HTX-011-215 
 
Heron Therapeutics, Inc. 
Phase 2 Herniorrhaphy Study for Opioid Elimination 
Confidential 
16.1.9. 
Documentation of Statistical Methods 
 
Statistical Analysis Plan Version 1.0 dated 18 October 2018 
 
Page 1 of 28


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-011-215 
A Phase 2, Open-Label Study of HTX-011 in a Multimodal Analgesic Regimen for 
Decreased Opioid Use Following Unilateral Open Inguinal Herniorrhaphy 
 
Prepared by: 
 
Heron Therapeutics, Inc. 
4242 Campus Point Court, Suite 200 
San Diego, CA 92121  
USA 
 
 
Version 1:  18 October 2018 
 
 
Upon review of this document, the undersigned approves the statistical analysis plan. The 
analysis methods are acceptable, and the table, listing, and figure shell production can begin. 
 
 
 
 
Approved by: 
 
 
 
Date:   
 
 
 
 
Vice President, Biometrics 
Heron Therapeutics, Inc. 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
  
Approved by: 
 
 
 
Date:   
 
 
 
Vice President, Clinical Research 
Heron Therapeutics, Inc. 
 
 
  
 
 
 
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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 
4.2. 
Assessments ..................................................................................................................8 
4.3. 
Endpoints ......................................................................................................................9 
4.3.1. 
Efficacy Endpoints ........................................................................................................9 
4.3.2. 
Safety Endpoints ...........................................................................................................9 
5. 
GENERAL STATISTICAL CONSIDERATIONS ....................................................10 
5.1. 
Sample Size ................................................................................................................10 
5.2. 
Randomization, Stratification, and Blinding ..............................................................10 
5.3. 
Analysis Populations ..................................................................................................11 
5.3.1. 
Safety Population ........................................................................................................11 
5.4. 
Other Important Considerations .................................................................................11 
5.4.1. 
Definition of Baseline .................................................................................................11 
5.4.2. 
Calculation of Change and Percent Change from Baseline ........................................11 
5.4.3. 
Study Day Calculation for Reporting Purposes ..........................................................11 
5.4.4. 
Start date/time of Study Drug Administration (Time 0) .............................................11 
5.4.5. 
72-Hour Postoperative Observation Period ................................................................11 
5.4.6. 
Visit Windows ............................................................................................................12 
5.4.7. 
Handling of Missing and Partial Data ........................................................................12 
6. 
SUBJECT DISPOSITION ..........................................................................................12 
7. 
DEMOGRAPHICS, CHARACTERISTICS, AND MEDICAL 
HISTORY ...................................................................................................................13 
7.1. 
Demographics and Baseline Characteristics ...............................................................13 
7.2. 
Medical History ..........................................................................................................13 
7.3. 
Protocol Deviations ....................................................................................................13 
8. 
TREATMENTS AND MEDICATIONS ....................................................................13 
8.1. 
Prior and Concomitant Medications ...........................................................................13 
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8.2. 
Surgery Procedure ......................................................................................................14 
8.3. 
Study Drug ..................................................................................................................14 
9. 
EFFICACY ANALYSIS ............................................................................................14 
9.1. 
Primary Efficacy Endpoint .........................................................................................14 
9.1.1. 
Primary Analysis ........................................................................................................14 
9.2. 
Secondary Efficacy Endpoints ....................................................................................15 
10. 
SAFETY ANALYSIS ................................................................................................17 
10.1. 
Adverse Events ...........................................................................................................17 
10.1.1. 
Incidence of Treatment Emergent Adverse Events ....................................................18 
10.1.2. 
Relationship of Adverse Events to Investigational Drug ...........................................18 
10.1.3. 
Severity of Adverse Event ..........................................................................................19 
10.1.4. 
Serious Adverse Events ..............................................................................................19 
10.1.5. 
Adverse Events Leading to Study Withdrawal ...........................................................19 
10.1.6. 
Opioid-related Adverse Events ...................................................................................19 
10.1.7. 
Local Inflammatory Adverse Events ..........................................................................20 
10.1.8. 
Potential Local Anesthetic Systemic Toxicity (LAST) related Adverse 
Events .........................................................................................................................20 
10.1.9. 
Death ...........................................................................................................................20 
10.2. 
Clinical Laboratory Evaluations .................................................................................21 
10.3. 
Hematology .................................................................................................................21 
10.3.1. 
Blood Chemistry .........................................................................................................21 
10.3.2. 
Urine Pregnancy Test and Urine Drug Screen ...........................................................22 
10.4. 
Vital Sign Measurements ............................................................................................22 
10.5. 
Electrocardiogram .......................................................................................................23 
10.6. 
Physical Examination .................................................................................................23 
10.7. 
Wound Healing Assessment .......................................................................................23 
11. 
INTERIM ANALYSIS ...............................................................................................24 
11.1. 
Interim Analysis ..........................................................................................................24 
11.2. 
Data Safety Monitoring Board ....................................................................................24 
12. 
REFERENCES ...........................................................................................................24 
APPENDIX 1. IMPUTATION OF PARTIAL AND MISSING DATES ..................................25 
APPENDIX 2. DOCUMENT REVISION HISTORY ...............................................................26 
 
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LIST OF TABLES 
Table 1.    Analgesic Windows and IV Morphine Milligram Equivalents for Opioid 
Rescue Medications in Preferred Terms .....................................................................16 
Table 2. 
Local Inflammatory Adverse Events by Preferred Term ...........................................20 
Table 3.  
Potential LAST-Related Adverse Events by Preferred Term .....................................20 
Table 4.   
Clinically Relevant Vital Signs Abnormalities ...........................................................23 
 
 
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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 
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-R 
Numeric Rating Scale at rest 
NSAID 
Nonsteroidal anti-inflammatory drug 
ORAE 
Opioid-related adverse event 
PT 
Preferred term 
RBC 
Red blood cell 
SAE 
Serious adverse event 
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Abbreviation 
Term 
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 
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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The secondary objectives are as follows: 
• To assess the total opioid use following HTX-011 as part of a multimodal 
analgesic regimen 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 that remain 
opioid-free through Day 10 and Day 28.  
• To assess the relationship between opioid use and severe pain. 
4. 
INVESTIGATIONAL PLAN 
4.1. 
Overall Study Design and Plan 
This is a Phase 2 open-label study in subjects undergoing unilateral open inguinal 
herniorrhaphy in up to 3 cohorts.  See the study protocol, Section 3.1.3 for a description of 
the inpatient scheduled analgesic regimen and the discharge/postoperative analgesic regimen 
for all cohorts. 
Cohort 1 
Approximately 30 subjects will be enrolled and dosed in one treatment group: 
• HTX-011 300 mg/9 mg (bupivacaine/meloxicam doses), 10.3 mL, via instillation into 
the surgical site. 
Optional Cohort 2 
At the Sponsor’s discretion upon completion of Cohort 1, Optional Cohort 2 may be initiated. 
If conducted, Optional Cohort 2 will be composed of approximately 30 subjects. Optional 
Cohort 2 would consist of the same required preoperative, intraoperative, and scheduled pain 
medication regimen as in Cohort 1 would be required with the intra-operative addition prior 
to wound closure of 1 dose of IV ketorolac as follows: 
• For subjects aged ≥65 years, Serum Creatinine >1.5, and/or weight <50 kg: 15 
mg. 
• For subjects aged <65 years and/or weight ≥50 kg: 30 mg. 
Optional Cohort 3 
At the Sponsor’s discretion upon completion of Optional Cohort 2, Optional Cohort 3 may be 
initiated. If conducted, Optional Cohort 3 will be composed of approximately 30 subjects. 
The specific multimodal analgesic regimen in Optional Cohort 3 will be determined by the 
Sponsor and included in a protocol amendment. 
4.2. 
Assessments 
Efficacy assessments will include the following: 
• Pain intensity scores using the NRS at rest (NRS-R). 
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• 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). 
• Physical examination. 
• Wound healing assessment. 
• Vital signs collections. 
4.3. 
Endpoints 
4.3.1. 
Efficacy Endpoints 
The primary efficacy endpoint is the following: 
• Proportion of subjects receiving no opioid rescue from 0-72 hours. 
 
The secondary efficacy endpoints are the following:  
• Total postoperative opioid consumption (in IV morphine milligram equivalents 
[IV MME]) through 72 hours. 
• Proportion of subjects receiving no opioid rescue over the following time 
intervals: 0-24 hours, 24-48 hours, 0-48 hours, 24-72 hours, 48-72 hours. 
• Proportion of subjects receiving no opioid rescue from 0-72 hours who receive no 
opioid rescue through Day 10, and through Day 28. 
• Proportion of subjects in severe pain (NRS-R ≥7) at any point in the first 72 hours 
postoperatively. 
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 Day 28. 
• Change from baseline in clinical laboratory results. 
• Change from baseline in ECG data. 
• Change from baseline in vital signs. 
• Wound healing assessment at 72 hours and on Day 10 and 28. 
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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 cohort, 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. 
All efficacy and safety data will be collected electronically. Datasets will be created using the 
Study Data Tabulation Model (SDTM) v. 1.4 or higher, conforming to the SDTM 
Implementation Guide (SDTMIG) v. 3.2 or higher. Datasets, tables, listings, and figures will 
be programmed using SAS® v. 9.4 or higher. All efficacy and safety data will be listed via 
the SDTM datasets and selected efficacy and safety data will be listed via programmed 
listings. 
5.1. 
Sample Size 
The sample size in this study was selected empirically without a formal statistical 
assumption. 
5.2. 
Randomization, Stratification, and Blinding 
This is an open-label study.   
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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. 
Definition of Baseline 
Baseline data are defined as the last observed measurement collected, whether scheduled or 
unscheduled, prior to the start of study drug administration.   
5.4.2. 
Calculation of Change and Percent Change from Baseline 
Change from Baseline to any timepoint t (Ct) is calculated as follows: 
 
Ct = Mt – MB, where: 
• Mt is the measurement of interest at timepoint t. 
• MB is the measurement of interest at Baseline. 
Percent change from Baseline to any timepoint (Pt) is calculated as follows: 
 
Pt = 100*(Ct/MB) 
5.4.3. 
Study Day Calculation for Reporting Purposes 
The following convention will be used to calculate study day for reporting purposes: 
• The study day of study drug administration is Study Day 1. 
• For measurements that are on or after the date of study drug administration:  
− 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. 
5.4.4. 
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. 
5.4.5. 
72-Hour Postoperative Observation Period 
The 72-hour postoperative observation period will be defined as the period of time from the 
start date/time of study drug administration to the date/time of NRS-R pain intensity score 
assessment at the nominal 72-hour postoperative timepoint.  
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Subjects who have a reported NRS-R pain intensity score at the nominal 72-hour 
postoperative timepoint will be considered as completing the 72-hour postoperative 
observation period. 
5.4.6. 
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. 
5.4.7. 
Handling of Missing and Partial Data 
The amount of missing data during the primary efficacy analysis period is expected to be 
very low due to the protocol-required 72-hour hospitalization of all subjects following 
surgery.   
For any data that is missing through 72 hours in subjects who complete the 72-hour 
postoperative observation period, the NRS-R 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-R 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-R pain 
intensity score observed prior to withdrawal will be used for post-withdrawal values through 
72 hours. Any missing NRS-R 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-R 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, and subjects not completing Day 28 by reason for withdrawal. Only 1 reason for 
study withdrawal will be recorded for each subject.   
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7. 
DEMOGRAPHICS, CHARACTERISTICS, AND MEDICAL 
HISTORY 
7.1. 
Demographics and Baseline Characteristics 
Demographics and baseline characteristics will be presented in tables using descriptive 
statistics. Demographics consist of age, age category, sex, race, and ethnicity. Baseline 
characteristics consist of weight, height, and body mass index (BMI). A subject’s age in 
years is calculated using the integer part of the difference in number of days between the date 
that informed consent is signed and date of birth divided by 365.25, or is recorded directly on 
the eCRF. The number and percentage of subjects in the following age categories will be 
presented: 18-44, 45-54, 55-64, 65-74, 75-84, and ≥ 85. 
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. 
• Randomization/blinding 
• 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 
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Day 1, or for which missing start and/or stop dates make it impossible to determine the prior 
or concomitant status, will be summarized as concomitant medications. 
All medications will be coded with the World Health Organization Drug Dictionary 
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. 
Average daily use and total use of protocol-specified postoperative analgesic medication will 
also be summarized using descriptive statistics for each analgesic (ibuprofen and 
acetaminophen) for hours 0-24, 0-48, and 0-72. 
8.2. 
Surgery Procedure 
The side of the body subject to the surgical procedure (left or right), type of mesh, and the 
duration of surgery will be summarized. Duration will be calculated as completion time 
minus start time, reported in minutes. In addition, summary statistics will be provided for 
length of incision in centimeters.  
8.3. 
Study Drug 
For all subjects, treatment will consist of a single dose of study drug.  As such, extent of 
exposure will be reported in the CSR as the number of subjects who received the study drug 
in the Safety Population.  A summary of treatment compliance will not be produced, as by 
definition it will be 100% for the Safety Population. 
9. 
EFFICACY ANALYSIS 
All efficacy summaries will be performed on the Safety Population and summarized within 
cohort and overall if optional Cohorts 2 or 3 are activated. 
All efficacy analyses will consist of reporting summary statistics in tables and figures. 
9.1. 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the proportion of subjects receiving no opioid rescue from 
0-72 hours. 
9.1.1. 
Primary Analysis 
The following steps will be implemented to identify opioid rescue medication during 0-72 
hours: 
1. Select concomitant medications that are coded as an opioid analgesic.  
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 5.4.5 for details). 
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The proportion of subjects receiving no opioid rescue medication from 0-72 hours will be 
summarized. 
9.2. 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints are: 
• Total postoperative opioid consumption (in IV morphine equivalents [IV MME]) 
through 72 hours. 
• Proportion of subjects receiving no opioid rescue over the following time 
intervals: 0-24 hours, 24-48 hours, 0-48 hours, 24-72 hours, 48-72 hours. 
• Proportion of subjects receiving no opioid rescue from 0-72 hours who receive no 
opioid rescue through Day 10, and through Day 28. 
• Proportion of subjects in severe pain (NRS-R ≥ 7) at any point in the first 72 
hours postoperatively. 
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).  
Table 1 displays the IV MME of selected opioid rescue medications. 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. 
 
 
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Table 1.    
Analgesic Windows and IV Morphine Milligram Equivalents for Opioid 
Rescue Medications in Preferred Terms 
Medication 
Route 
IV MME Factor 
Protocol Allowed 
CODEINE 
PO 
0.05 
 
 
HYDROMORPHONE HYDROCHLORIDE 
PO 
1.33 
 
 
HYDROMORPHONE HYDROCHLORIDE 
IV 
6.67 
 
 
FENTANYL 
IV 
50.00 
 
 
HYDROCODONE 
PO 
0.40 
 
 
MORPHINE 
IV 
1.00 
 
 
MORPHINE 
PO 
0.33 
 
 
MORPHINE 
IM 
1.00 
 
 
MORPHINE 
PR 
1.00 
 
 
OXYCODONE 
IV 
1.00 
 
 
OXYCODONE 
IM 
1.00 
 
 
OXYCODONE 
PO 
0.50 
 
 
PETHIDINE 
IV 
0.13 
 
 
TRAMADOL 
IV 
0.06 
 
 
TRAMADOL 
PO 
0.04 
 
 
 
Protocol-allowed postoperative rescue medications consist of oral (PO) immediate-release 
oxycodone (no more than 10 mg within a 4-hour period as needed) or IV morphine (no more 
than 10 mg within a 2-hour period as needed). Administration of other opioids or any other 
analgesics (eg, ketamine, pregabalin), local anesthetics, or anti-inflammatory agents (except 
as specified by the protocol) is prohibited, unless needed to treat an AE that occurs after 
signing the ICF, for pretreatment prior to a needle placement, or to decrease venous irritation 
(eg, caused by propofol, in which case no more than a single administration of lidocaine 1% 
20 mg IV may be administered). Combination opioid/non-opioid products (eg, Percocet) are 
not allowed. 
Analysis method 
Average daily use and total use of opioid rescue medication will be tabulated using 
descriptive statistics for each opioid and for overall opioids during the following periods: 
hours 0-24, hours 24-48, hours 0-48, hours 24-72, 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. 
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Proportion of subjects receiving no opioid rescue medication over the following time 
intervals: 0-24 hours, 24-48 hours, 0-48 hours, 24-72 hours, 48-72 hours 
The proportion of subjects receiving no opioid rescue medication over these time periods will 
be summarized.  The proportions of subjects receiving no opioid rescue medication from 0-
24, 0-48, and 0-72 hours will be plotted in a bar chart.  In addition, the proportions of 
subjects receiving no opioids from Day 1-10 and from Day 1-28 will be summarized.  The 
Day 10 and Day 28 opioid use data will come from the subject diary. 
Proportion of subjects receiving no opioid rescue medication from 0-72 hours who 
receive no opioid rescue through Day 10, and through Day 28 
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.   
Proportion of subjects in severe pain (NRS-R ≥ 7) at any point in the first 72 hours 
postoperatively 
Acute severe pain at rest will be assessed through 72 hours following surgery.  Proportions of 
subjects with an NRS-R score ≥ 7 at any time during hours 0-24, 0-48, and 0-72 will be 
summarized and plotted in a bar chart.  In addition, a line plot of NRS-R pain intensity scores 
from hours 0-72 will be produced. 
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, or any AE with an onset prior to study drug 
administration that worsens during or after study drug administration. An AE may be any 
unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a study drug, whether or not considered 
causally associated with the use of the study drug. Any abnormal laboratory value, 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. 
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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. 
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.   
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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 
Incidence of ORAEs will be presented separately as follows: 
• Incidence of ORAEs.  
• Incidence of ORAEs through the 72-hour postoperative observation period. 
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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 2). 
Table 2. 
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 3). 
Table 3.  
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.  
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. 
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10.2. 
Clinical Laboratory Evaluations 
Laboratory assessments will be performed by a central laboratory (hematology and serum 
chemistry) or locally (pregnancy test and drug screen). All summaries of central laboratory 
data will be based on the standard international (SI) units provided by the central lab. 
Associated laboratory parameters such as hepatic profile, renal function, and hematology 
values will be grouped and presented together. 
Summary tables for hematology and chemistry including actual values and change from 
Baseline values will be presented for clinical laboratory tests with numeric values. These 
tables will include each visit (Baseline, Hour 72, and Day 10), highest postdose value, lowest 
postdose value, and last postdose value.  Hematology will additionally include Hour 24. 
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 
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, 
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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 
1 before surgery, and post-treatment at 1, 1.5, 2, 4, 8, 12, 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 
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clinical relevant abnormalities in vital signs will be presented in data listing as well. The 
criteria for clinically relevant abnormalities are shown in Table 4.  
Table 4.   
Clinically Relevant Vital Signs Abnormalities 
Vital Sign 
Low 
High 
HR 
≤50 bpm and  ≥15 bpm decrease from 
Baseline 
≥120 bpm and  ≥15 bpm increase from Baseline 
SBP 
≤90 mmHg and  ≥20 mmHg decrease from 
Baseline 
≥160 mmHg and  ≥20 mmHg increase from 
Baseline 
DBP 
≤50 mmHg and  ≥15 mmHg decrease from 
Baseline 
≥100 mmHg and  ≥15 mmHg increase from 
Baseline 
Abbreviations: bpm, beats per minute; DBP, diastolic blood pressure; HR, heart rate; SBP, systolic blood 
pressure. 
 
10.5. 
Electrocardiogram 
 
12-lead ECG (triplicate) is performed at screening and at 4, 24, 48, and 72 hours.   ECG 
parameters include heart rate (beats/min), PR interval (ms), RR interval (ms), QRS interval 
(ms), QT interval (ms), and QTcF interval (ms). Overall interpretations of ECG results are 
also included.  
ECG assessments will be performed in triplicate, and the mean value of the observed 
triplicates will be used for each ECG parameter. Summary statistics of ECG parameters and 
change from Baseline in ECG parameters will be presented using descriptive statistics at 
each scheduled visit. Shift from baseline of overall ECG interpretation at each postoperative 
timepoint will also be provided.  
The number and percentage of subjects with clinically relevant abnormalities will be 
presented using summary table as well as data listing at each postoperative timepoint. 
• QTcF values > 450 ms, > 480 ms, and > 500 ms 
• Change from Baseline in QTcF values > 30 ms and > 60 ms 
• QT values > 500 ms 
10.6. 
Physical Examination 
Physical examination is performed at Screening, 72 hours, and early termination.  Physical 
examination data will be listed only. 
10.7. 
Wound Healing Assessment 
Wound healing assessment according to the Southampton Wound Scoring System (Bailey, 
Karran et al. 1992) is performed at 72 hours, on Day 10, and on Day 28.  A summary of 
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wound healing assessment results will be produced, showing the number and percentage of 
subjects at each visit by grade with subgrade breakdown.  
11. 
INTERIM ANALYSIS 
11.1. 
Interim Analysis 
No formal interim analyses are planned. 
11.2. 
Data Safety Monitoring Board 
An independent Data Safety Monitoring Board (DSMB) will not be involved with the 
conduct of this study. The Sponsor will review tables and listings of accumulating data 
approximately monthly to check enrollment, adherence to follow-up schedule, and ongoing 
safety results.   
12. 
REFERENCES 
Bailey, I. S., S. E. Karran, K. Toyn, P. Brough, C. Ranaboldo and S. J. Karran (1992). 
"Community surveillance of complications after hernia surgery." BMJ 304(6825): 469-471. 
 
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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 
18 October 2018 
Initial version, based on protocol version 1 (31 August 2018) 
 
 
 
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Signature Page for VV-TMF-36894 v1.0
Signature Page for VV-TMF-36894 v1.0
Reason for signing: Approved
Name: 
Role: B
Date of signature: 19-Oct-2018 19:29:50 GMT+0000
Reason for signing: Approved
Name: 
Role: C
perations
Date of signature: 19-Oct-2018 19:35:38 GMT+0000
SAP V1 HTX-011-215 18Oct2018 | VV-TMF-36894 | 1.0
Approved
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