Clinical trial NCT02504580
Conditions: Postoperative Pain
Sponsor: Heron Therapeutics
Start date: 2015-07-01; Completion date: 2017-04-01
Enrollment: 463 participants; Allocation: RANDOMIZED; Intervention model: FACTORIAL

Brief summary:
A Phase 2, Randomized, Pilot Study to Investigate the Safety, Efficacy, Pharmacokinetics and Bioavailability of HTX-011, HTX-002, or HTX-009 Administered Via Injection and/or Topical Application Following Unilateral Open Inguinal Herniorrhaphy

Detailed description:
This study includes multiple formulations for formulation selection of the fixed-combination product and for the factorial design assessment of the contribution of each component. HTX-011 is the initial formulation studied (HTX-011-19). HTX-011A is the second formulation studied (HTX-011-49). HTX-011B is the final formulation studied (HTX-011-56), which was also included in subsequent Phase 2b and Phase 3 studies. For the factorial design assessment, HTX-002, a bupivacaine-only formulation in the same HTX-011 proprietary polymer, and HTX-009, a meloxicam-only formulation in the same HTX-011 proprietary polymer, were evaluated.

Arms: arm 1: HTX-011 (bupivacaine/meloxicam), 200 mg/6 mg by injection. arm 2: HTX-011(bupivacaine/meloxicam), 400 mg/12 mg by injection. arm 3: HTX-011 (bupivacaine/meloxicam), 200 mg/6 mg by instillation. arm 4: HTX-011 (bupivacaine/meloxicam), 400 mg/12 mg by instillation. arm 5: HTX-011 (bupivacaine/meloxicam), 400 mg/12 mg by injection and instillation (combination). arm 6: Saline placebo by injection. arm 7: HTX-011A (bupivacaine/meloxicam), 200 mg/6 mg by injection. arm 8: HTX-011A (bupivacaine/meloxicam) 400 mg12 mg by injection. arm 9: HTX-011B (bupivacaine/meloxicam), 200 mg/6 mg by injection. arm 10: HTX-011B (bupivacaine/meloxicam), 400 mg/12 mg by injection. arm 11: Saline placebo by injection. arm 12: HTX-002, 200 mg by injection or instillation. arm 13: HTX-002, 400 mg by injection or instillation. arm 14: HTX-011B (bupivacaine/meloxicam), 200 mg/6 mg by instillation. arm 15: HTX-011B (bupivacaine/meloxicam), 400 mg/12 mg by instillation. arm 16: Saline placebo by instillation. arm 17: Bupivacaine HCI (Marcaine), 75 mg by injection. arm 18: HTX-011B (bupivacaine/meloxicam), 400 mg/13 mg via a combination of injection and instillation. arm 19: HTX-009, 12 mg by injection and instillation (combination). arm 20: HTX-011B (bupivacaine/meloxicam), 300 mg/9 mg by instillation. arm 21: Bupivacaine HCI (Marcaine), 75 mg by injection. arm 22: Saline placebo by injection.
Interventions: intervention 1: HTX-011 intervention 2: Placebo intervention 3: HTX-002 intervention 4: Bupivacaine HCI (Marcaine) intervention 5: HTX-011A intervention 6: HTX-011B intervention 7: HTX-009
Intervention descriptions: intervention 1: HTX-011 (bupivacaine/meloxicam) by injection. intervention 2: Saline placebo by injection. intervention 3: HTX-002, by injection or instillation (pooled). intervention 4: Bupivacaine HCI (Marcaine) by injection. intervention 5: HTX-011A (bupivacaine/meloxicam) by injection. intervention 6: HTX-011B (bupivacaine/meloxicam) by injection, instillation or combination. intervention 7: HTX-009 by injection and instillation (combination).

Protocol documents:
Prot_000.pdf: 
Document Type:  
Study Protocol 
Official Title:  
Phase 2, Randomized, Pilot Study to Investigate the Safety, Efficacy, 
Pharmacokinetics and Bioavailability of HTX-011, HTX-002, or HTX-
009 Administered Via Injection and/or Topical Application Following 
Unilateral Open Inguinal Herniorrhaphy 
NCT Number:  
NCT02504580 
Document Date:  
31-Jan-2017 
 


 
CLINICAL STUDY PROTOCOL 
PROTOCOL NUMBER HTX-011-C2015-202 
A Phase 2, Randomized, Pilot Study to Investigate the Safety, Efficacy, Pharmacokinetics 
and Bioavailability of HTX-011, HTX-002, or HTX-009 Administered Via Injection and/or 
Topical Application Following Unilateral Open Inguinal Herniorrhaphy 
 
Compound Name: 
HTX-011 (extended-release 2.5% bupivacaine and 0.075% 
meloxicam) 
HTX-002 (extended-release 2.5% bupivacaine) 
HTX-009 (extended-release 0.075% meloxicam) 
IND # 
125927 
Protocol Version: 
12 
Date of Protocol: 
31 January 2017 
Previous Versions: 
Version 1: 13 May 2015 
Version 2: 23 June 2015 
Version 3: 13 August 2015 
Version 4: 03 September 2015 
Version 5: 23 November 2015 
Version 6: 22 December 2015 
Version 7: 28 February 2016 
Version 8: 08 June 2016 
Version 9: 08 July 2016 
Version 10: 07 October 2016 
Version 11: 28 December 2016 
 
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. 




Protocol HTX-011-C2015-202, Version 12 
Page 3 of 83 
 
 
Heron Therapeutics, Inc. 
Confidential 
INVESTIGATOR AGREEMENT 
CLINICAL PROTOCOL HTX-011-C2015-202 
A Phase 2, Randomized, Pilot Study to Investigate the Safety, Efficacy, Pharmacokinetics 
and Bioavailability of HTX-011, HTX-002, or HTX-009 Administered Via Injection and/or 
Topical Application 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 therein. 
I will provide copies of the protocol and all information on the drug relating to the nonclinical and prior 
clinical experience which 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 drug and the conduct of the study. 
I agree to keep records on all subject information (i.e., 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) regulations. 
Principal Investigator: 
 
Address: 
 
Signature: 
 
Date: 
 


Protocol HTX-011-C2015-202, Version 12 
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Heron Therapeutics, Inc. 
Confidential 
SYNOPSIS 
Name of Sponsor/Company:  
Heron Therapeutics, Inc. 
Protocol Number:  HTX-011-C2015-202 
Name of Investigational Product:  
HTX-011 (extended-release 2.5% bupivacaine and 
0.075% meloxicam)  
• HTX-011-19 
• HTX-011-49 
• HTX-011-56 
HTX-002 (extended-release 2.5% bupivacaine) 
HTX-009 (extended-release 0.075% meloxicam)  
Protocol Title:  A Phase 2, Randomized, Pilot Study to 
Investigate the Safety, Efficacy, Pharmacokinetics and 
Bioavailability of HTX-011, HTX-002, or HTX-009 
Administered Via Injection and/or Topical Application 
Following Unilateral Open Inguinal Herniorrhaphy 
Name of Active Ingredients: 
• Bupivacaine and Meloxicam (HTX-011) 
• Bupivacaine (HTX-002) 
• Meloxicam (HTX-009) 
Phase of Development: 2 
Objectives:  
Part A: 
The primary objective for Part A is to evaluate the efficacy and duration of analgesia following administration 
of one of two doses of HTX-011-19 by different techniques. 
Parts B through G: 
The primary objective of Parts B through G will be to evaluate the efficacy and duration of analgesia following 
administration of HTX-011-49, HTX-011-56, HTX-002, HTX-009, bupivacaine (Marcaine), or normal saline. 
The secondary objectives that will be evaluated in Parts A through G are as follows:  
• 
To determine in Part A the optimal administration technique of study drug  
• 
To determine the safety and tolerability of HTX-011, HTX-002, and HTX-009 as evaluated through 
physical examination, vital signs, clinical laboratory tests, electrocardiograms (ECGs), and incidence of 
adverse events (AEs) and serious AEs (SAEs) 
• 
To evaluate the pharmacokinetic (PK) profiles of bupivacaine and/or meloxicam in HTX-011, HTX-002, 
and HTX-009 over 120 hours  
• 
To evaluate the analgesic effects of HTX-011, HTX-002, and HTX-009 over various intervals using a 
series of secondary efficacy endpoints for pain intensity (such as the patient’s global assessment of pain 
control, time to administration of first dose of rescue analgesia, and total and average daily rescue 
consumption) 
• 
To assess the effects of HTX-011, HTX-002, and HTX-009 on wound healing at 72 hours and on Days 10 
and 28 post-treatment 
• 
To evaluate nausea at 6, 24, 48, and 72 hours post-treatment 
• 
To evaluate the percentage of subjects pain free over time 
Methodology: This is a Phase 2, multi-center, single-dose, randomized study in adult subjects undergoing unilateral 
open inguinal herniorrhaphy.  The total duration of this study for each subject will be up to 88 days (from screening 
through the Day 60 follow-up phone call). 
Pretreatment Phase: 
Screening Period (Day -28 to Day -1): Subjects will be consented and screened. 
Treatment and Confinement Phase: 
Subjects will be confined from Day 0 to 72 hours after receiving study medication in this 7-part study comprising 
the following groups: 
 


Protocol HTX-011-C2015-202, Version 12 
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Heron Therapeutics, Inc. 
Confidential 
Name of Sponsor/Company:  
Heron Therapeutics, Inc. 
Protocol Number:  HTX-011-C2015-202 
Name of Investigational Product:  
HTX-011 (extended-release 2.5% bupivacaine and 
0.075% meloxicam)  
• HTX-011-19 
• HTX-011-49 
• HTX-011-56 
HTX-002 (extended-release 2.5% bupivacaine) 
HTX-009 (extended-release 0.075% meloxicam)  
Protocol Title:  A Phase 2, Randomized, Pilot Study to 
Investigate the Safety, Efficacy, Pharmacokinetics and 
Bioavailability of HTX-011, HTX-002, or HTX-009 
Administered Via Injection and/or Topical Application 
Following Unilateral Open Inguinal Herniorrhaphy 
Name of Active Ingredients: 
• Bupivacaine and Meloxicam (HTX-011) 
• Bupivacaine (HTX-002) 
• Meloxicam (HTX-009) 
Phase of Development: 2 
Part A 
108 subjects will be assigned  randomly to any 1 of 6 treatment cohorts:  
A) 200 mg (3.42 mL) HTX-011-19 by injection into the surgical wound (n=18 subjects) 
B) 400 mg (6.84 mL) HTX-011-19 by injection into the surgical wound (n=18 subjects) 
C) 200 mg (3.42 mL) HTX-011-19 by topical administration into the surgical wound (n=18 subjects) 
D) 400 mg (6.84 mL) HTX-011-19 by topical administration into the surgical wound (n=18 subjects) 
E) A combination  technique of 200 mg (3.42 mL) HTX-011-19 by injection into the surgical wound and 200 mg 
(3.42 mL) HTX-011-19 by topical administration into the surgical wound (n=18 subjects) 
F) 6.84 mL of saline solution by injection into the surgical wound (n=18 subjects) 
Part B 
Upon determining the optimal route of administration in Part A, 90 subjects in Part B will be assigned randomly to 
any 1 of 6 treatment cohorts:  
A) 200 mg (6.84 mL) HTX-011-49 via technique determined in Part A (n=15 subjects) 
B) 400 mg (13.68 mL) HTX-011-49 via technique determined in Part A (n=15 subjects) 
C) 200 mg (6.84 mL) HTX-011-56 via technique determined in Part A (n=15 subjects) 
D) 400 mg (13.68 mL) HTX-011-56 via technique determined in Part A (n=15 subjects) 
E) 6.84 mL of saline solution via technique determined in Part A (n=15 subjects) 
F) 13.68 mL of saline solution via technique determined in Part A (n=15 subjects) 
Part C 
Approximately 135 subjects in Part C will be assigned randomly to any 1 of 9 treatment cohorts: 
A) 200 mg (6.84 mL) HTX-002 by injection into the surgical wound (n=15 subjects) 
B) 400 mg (13.68 mL) HTX-002 by injection into the surgical wound (n=15 subjects) 
C) 6.84 mL of saline solution by injection into the surgical wound (n=15 subjects) 
D) 13.68 mL of saline solution by injection into the surgical wound (n=15 subjects) 
E) 200 mg (6.84 mL) HTX-011-56 via instillation (n=15 subjects) 
F) 400 mg (13.68 mL) HTX-011-56 via instillation (n=15 subjects) 
G) 200 mg (6.84 mL) HTX-002 via instillation (n=15 subjects) 
H) 400 mg (13.68 mL) HTX-002 via instillation (n=15 subjects) 
I) 
30 mL of 0.25% Marcaine without epinephrine via local infiltration (n=15 subjects) 
Part D 
Approximately 45 subjects will be assigned randomly to 1 of the following 3 treatment cohorts:  
A) 400 mg (13.68 mL) HTX-011-56 via a combination of injection and instillation and fentanyl 50 µg IV before 
wound closure (n=15 subjects) 
B) 400 mg (13.68 mL) HTX-011-56 via a combination of injection and instillation and fentanyl 100 µg IV before 


Protocol HTX-011-C2015-202, Version 12 
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Heron Therapeutics, Inc. 
Confidential 
Name of Sponsor/Company:  
Heron Therapeutics, Inc. 
Protocol Number:  HTX-011-C2015-202 
Name of Investigational Product:  
HTX-011 (extended-release 2.5% bupivacaine and 
0.075% meloxicam)  
• HTX-011-19 
• HTX-011-49 
• HTX-011-56 
HTX-002 (extended-release 2.5% bupivacaine) 
HTX-009 (extended-release 0.075% meloxicam)  
Protocol Title:  A Phase 2, Randomized, Pilot Study to 
Investigate the Safety, Efficacy, Pharmacokinetics and 
Bioavailability of HTX-011, HTX-002, or HTX-009 
Administered Via Injection and/or Topical Application 
Following Unilateral Open Inguinal Herniorrhaphy 
Name of Active Ingredients: 
• Bupivacaine and Meloxicam (HTX-011) 
• Bupivacaine (HTX-002) 
• Meloxicam (HTX-009) 
Phase of Development: 2 
wound closure (n=15 subjects) 
C) 400 mg (13.68 mL) HTX-011-56 via a combination of injection and instillation and no fentanyl before wound 
closure (n=15 subjects) 
Part E 
Approximately 20 subjects will be assigned randomly to 1 of the following 2 treatment cohorts:  
A) 13.68 mL of HTX-009 via a combination of injection and instillation (n=15 subjects) 
B) 13.68 mL of normal saline via a combination of injection and instillation (n=5 subjects) 
Subject safety will be monitored by regular assessments of vital signs, electrocardiographs (ECGs), physical 
examination, clinical laboratory tests, wound healing and photographs of the surgical site, and by collection of AEs 
and concomitant medications. 
Part F 
Approximately 20 subjects will be assigned randomly to 1 of the following 2 treatment cohorts: 
A) 13.68 mL of normal saline via instillation and fentanyl 50 µg IV before wound closure (n=15 subjects) 
B) 400 mg (13.68 mL) HTX-011-56 via instillation and fentanyl 50 µg IV before wound closure (n=5 subjects) 
Part G 
Approximately 35 subjects will be assigned randomly to 1 of the following 3 treatment cohorts: 
A) 300 mg (10.26 mL) of HTX-011-56 via instillation and 50 µg fentanyl IV before wound closure (n=15 subjects) 
B) 75 mg (30 mL) of 0.25% Marcaine without epinephrine via injection and 50 µg fentanyl IV before wound 
closure (n=15 subjects) 
C) 10.26 mL of normal saline via injection and 50 µg fentanyl IV before wound closure (n=5 subjects) 
Symptoms of CNS including those known to be associated with bupivacaine toxicity will be prospectively assessed 
at regular time points throughout the 72 hour clinic stay for perioral tingling, strange taste, muscle twitching, ringing 
in ears, seizure, bradycardia, and cardiac arrest, and by neurologic examination which will include a mental status 
exam and evaluation of cranial nerve, motor, sensory, and cerebellar function.  
Blood sample for pharmacokinetic analyses (PK) will be drawn prior to administration of the investigational 
product (IP), and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 18, 24, 30, 36, 48, 60, 72, 96, and 120 hours following 
administration of the IP. 
Efficacy evaluations will include collection of Pain Intensity scores, Patient Global Assessment of Pain Control, 
assessments of nausea, and use of analgesia rescue medicine.  
Post-Treatment Phase: 
Subjects will return to the clinic site at 96 and 120 hours post-administration of study drug and at Day 10 and Day 
28 for safety and efficacy evaluations, as follows: 


Protocol HTX-011-C2015-202, Version 12 
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Heron Therapeutics, Inc. 
Confidential 
Name of Sponsor/Company:  
Heron Therapeutics, Inc. 
Protocol Number:  HTX-011-C2015-202 
Name of Investigational Product:  
HTX-011 (extended-release 2.5% bupivacaine and 
0.075% meloxicam)  
• HTX-011-19 
• HTX-011-49 
• HTX-011-56 
HTX-002 (extended-release 2.5% bupivacaine) 
HTX-009 (extended-release 0.075% meloxicam)  
Protocol Title:  A Phase 2, Randomized, Pilot Study to 
Investigate the Safety, Efficacy, Pharmacokinetics and 
Bioavailability of HTX-011, HTX-002, or HTX-009 
Administered Via Injection and/or Topical Application 
Following Unilateral Open Inguinal Herniorrhaphy 
Name of Active Ingredients: 
• Bupivacaine and Meloxicam (HTX-011) 
• Bupivacaine (HTX-002) 
• Meloxicam (HTX-009) 
Phase of Development: 2 
Post-Confinement Phase: 
96 Hours: safety assessments of vital signs, ECG, collection of AEs and concomitant medications, and photographs 
of the surgical site.  A blood sample will be collected for PK.  Efficacy assessments will include collection of Pain 
Intensity scores and PGA evaluations.  
120 Hours: obtain blood sample for pharmacokinetic analysis only.  
Day 10: a physical examination, vital signs, ECGs collection of AEs and concomitant medications, assessment of 
wound healing, and photographs of the surgical site. 
Day 28: collection of AEs and concomitant medications, assessment of wound healing, and photographs of the 
surgical site. 
Day 60: subjects will receive a phone call from the study site to collect follow-up information on postoperative pain 
and pain medications. 
Number of Subjects: This study will enroll up to approximately 453 subjects (108 in Part A, 90 in Part B, 135 in 
Part C, 45 in Part D, 20 in Part E, 20 in Part F, and 35 in Part G). 
Number of study sites: up to 6 
Study country location: United States 
Criteria for inclusion: Subjects must meet all of the following criteria to be considered eligible to participate in the 
study: 
1. Be male or female 18 years of age or older 
2. Female subjects are eligible only if all of the following apply: 
o Not pregnant (female subject of child bearing potential must have a negative serum pregnancy test at 
screening and negative urine pregnancy test before surgery) 
o Not lactating 
o Not planning to become pregnant during the study 
o Be surgically sterile; or at least two years post-menopausal; or have a monogamous partner who is surgically 
sterile; or is practicing double-barrier contraception; or practicing abstinence (must agree to use double-
barrier contraception in the event of sexual activity); or using an insertable, injectable, transdermal, or 
combination oral contraceptive approved by the FDA for greater than 2 months prior to screening visits and 
commits to the use of an acceptable form of birth control for the duration of the study and for 30 days from 
completion of the study 
 
 


Protocol HTX-011-C2015-202, Version 12 
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Heron Therapeutics, Inc. 
Confidential 
Name of Sponsor/Company:  
Heron Therapeutics, Inc. 
Protocol Number:  HTX-011-C2015-202 
Name of Investigational Product:  
HTX-011 (extended-release 2.5% bupivacaine and 
0.075% meloxicam)  
• HTX-011-19 
• HTX-011-49 
• HTX-011-56 
HTX-002 (extended-release 2.5% bupivacaine) 
HTX-009 (extended-release 0.075% meloxicam)  
Protocol Title:  A Phase 2, Randomized, Pilot Study to 
Investigate the Safety, Efficacy, Pharmacokinetics and 
Bioavailability of HTX-011, HTX-002, or HTX-009 
Administered Via Injection and/or Topical Application 
Following Unilateral Open Inguinal Herniorrhaphy 
Name of Active Ingredients: 
• Bupivacaine and Meloxicam (HTX-011) 
• Bupivacaine (HTX-002) 
• Meloxicam (HTX-009) 
Phase of Development: 2 
Male:  
o Must be surgically sterile (biologically or surgically) or commit to the use of a reliable method of birth 
control for the duration of the study until at least 1 week after the administration of study medication 
3. Plan to undergo a unilateral inguinal herniorrhaphy 
4. Have the ability and be willing to comply with the study procedures 
5. Must be able to understand study procedures and give informed consent for the conduct for all study 
procedures, using an IRB approved consent form 
Criteria for Exclusion: Subjects will not be eligible to participate in the trial if any of the following criteria are 
met: 
1. Unwilling to sign informed consent or not willing or able to complete all study procedures 
2. Have a contraindication or be allergic to any medication to be used during the trial period  
3. Have clinically significant cardiac abnormalities, that in the opinion of the investigator would pose a health risk 
to the subject should they participate in the trial 
4. Have American Society of Anesthesiologists (ASA) Physical Status classification system category 4 or greater 
(Appendix E) 
5. Have clinically significant renal or hepatic abnormalities (defined as an AST or ALT > 3x ULN, creatinine 
> 2x ULN) 
6. Have another pre-existing painful condition that may confound pain assessments 
7. Have another surgery planned within 30 days of procedure, or presents with bilateral or recurrent inguinal 
hernia, other hernia presentations, or hernias with large scrotal component that would be difficult to reduce 
surgically.  Note: Subject may present with bilateral hernia; however subject may be scheduled to only have 
unilateral repair while participating in this study  
8. Have a known or suspected history of alcohol or drug abuse, or a positive drug screen 
9. Currently taking analgesics for a chronically painful condition, or has taken long acting opioids within 3 days 
of surgery, or taken any opioids within 24 hours of scheduled surgery for this study 
10. Subjects with documented sleep apnea or are on home continuous positive airway pressure (CPAP) 
11. Female subjects who are pregnant (positive pregnancy test at screening or on the day of surgery) 
12. Subjects who are receiving oxygen therapy at the time of screening 
13. Have participated in a clinical trial within 30 days of planned surgery 
14. Have a body mass index (BMI) > 39 kg/m2 


Protocol HTX-011-C2015-202, Version 12 
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Heron Therapeutics, Inc. 
Confidential 
Name of Sponsor/Company:  
Heron Therapeutics, Inc. 
Protocol Number:  HTX-011-C2015-202 
Name of Investigational Product:  
HTX-011 (extended-release 2.5% bupivacaine and 
0.075% meloxicam)  
• HTX-011-19 
• HTX-011-49 
• HTX-011-56 
HTX-002 (extended-release 2.5% bupivacaine) 
HTX-009 (extended-release 0.075% meloxicam)  
Protocol Title:  A Phase 2, Randomized, Pilot Study to 
Investigate the Safety, Efficacy, Pharmacokinetics and 
Bioavailability of HTX-011, HTX-002, or HTX-009 
Administered Via Injection and/or Topical Application 
Following Unilateral Open Inguinal Herniorrhaphy 
Name of Active Ingredients: 
• Bupivacaine and Meloxicam (HTX-011) 
• Bupivacaine (HTX-002) 
• Meloxicam (HTX-009) 
Phase of Development: 2 
Investigational product: 
HTX-011 is a sterile, viscous, extended-release, fixed-ratio combination of bupivacaine and meloxicam to be 
administered topically or via injection into the surgical site for the prevention of postoperative pain.  The term 
“HTX-011” is used to represent study medication.  There are several formulations of HTX-011; HTX-011-19, 
HTX-011-49, and HTX-011-56 will be the formulations used for this study. 
HTX-002 is a sterile, viscous, extended-release formulation of bupivacaine to be locally administered into the 
surgical site for the prevention of postoperative pain. 
HTX-009 is a sterile, viscous, extended-release formulation of meloxicam to be locally administered into the 
surgical site for the prevention of postoperative pain. 
The vehicle formulation for HTX-011-19 is tri[ethylene glycol] based poly[orthoester] polymer with N-methyl-2-
pyrrolidone (NMP) and maleic acid excipients. 
The vehicle formulation for HTX-011-49, HTX-011-56, HTX-002, and HTX-009 is tri[ethylene glycol] based 
poly[orthoester] polymer with dimethyl sulfoxide, glycerol triacetate, and maleic acid excipients. 
This study is being conducted to evaluate the safety and analgesic efficacy of HTX-011, HTX-002, and HTX-009 in 
subjects following unilateral herniorrhaphy.  All formulations will be supplied by the sponsor for administration to 
subjects according to their randomization.  The calculated doses based on the mass of HTX-011 are as follows: 
HTX-011-19 
200 mg HTX-011-19: 
58.5 mg bupivacaine and 1.8 mg of meloxicam  = 1 mL HTX-011-19  
200.1 mg bupivacaine and 6.0 mg of meloxicam = 3.42 mL HTX-011-19  
 
400 mg HTX-011-19: 
58.5 mg bupivacaine and 1.8 mg of meloxicam = 1 mL HTX-011-19  
400.1 mg bupivacaine and 12.0 mg of meloxicam =  6.84 mL HTX-011-19  
 
HTX-011-49 
200 mg HTX-011-49: 
29.25 mg bupivacaine and 0.88 mg of meloxicam = 1 mL HTX-011-49 
200.1 mg bupivacaine and 6.0 mg of meloxicam  = 6.84 mL HTX-011-49 
 
400 mg HTX-011-49: 
29.25 mg bupivacaine and 0.88 mg of meloxicam = 1 mL HTX-011-49 
400.1 mg bupivacaine and 12.0 mg of meloxicam = 13.68 mL HTX-011-49 
 
 


Protocol HTX-011-C2015-202, Version 12 
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Heron Therapeutics, Inc. 
Confidential 
Name of Sponsor/Company:  
Heron Therapeutics, Inc. 
Protocol Number:  HTX-011-C2015-202 
Name of Investigational Product:  
HTX-011 (extended-release 2.5% bupivacaine and 
0.075% meloxicam)  
• HTX-011-19 
• HTX-011-49 
• HTX-011-56 
HTX-002 (extended-release 2.5% bupivacaine) 
HTX-009 (extended-release 0.075% meloxicam)  
Protocol Title:  A Phase 2, Randomized, Pilot Study to 
Investigate the Safety, Efficacy, Pharmacokinetics and 
Bioavailability of HTX-011, HTX-002, or HTX-009 
Administered Via Injection and/or Topical Application 
Following Unilateral Open Inguinal Herniorrhaphy 
Name of Active Ingredients: 
• Bupivacaine and Meloxicam (HTX-011) 
• Bupivacaine (HTX-002) 
• Meloxicam (HTX-009) 
Phase of Development: 2 
HTX-011-56 
200 mg HTX-011-56: 
29.25 mg bupivacaine and 0.88 mg of meloxicam = 1 mL HTX-011-56 
200.1 mg bupivacaine and 6.0 mg of meloxicam =  6.84 mL HTX-011-56  
 
300 mg HTX-011-56:  
29.25 mg bupivacaine and 0.88 mg of meloxicam = 1 mL HTX-011-56 
299.8 mg bupivacaine and 9.0 mg of meloxicam =  10.26 mL HTX-011-56 
 
400 mg HTX-011-56: 
29.25 mg bupivacaine and 0.88 mg of meloxicam = 1 mL HTX-011-56 
400.1 mg bupivacaine and 12.0 mg of meloxicam  = 13.68 mL HTX-011-56 
 
HTX-002 and HTX-009 are similar formulations to HTX-011-56 except that they contain only bupivacaine or 
meloxicam, respectively, at the same concentration as the active pharmaceutical product. 
Reference therapy: Normal saline solution (saline placebo) and 0.25% Marcaine without epinephrine 
Duration of treatment: Each subject will receive a single dose of study medication intra-operatively.  
Overview: Subjects will participate in the screening visit within 28 days of the scheduled surgery.  At that time, 
medical history, vital signs, physical examination, clinical laboratory tests, drug and alcohol screening, 12-lead 
ECG testing and collection of prior and concomitant medications, and a pregnancy test will be performed.  ASA 
classification and assessment of PONV risk factors will be assessed.  Review of inclusion/exclusion criteria 
eligibility, along with training the subject on pain assessment and placebo response will be performed. 
On day of surgery, Day 0, subjects will be reassessed for eligibility and undergo the index procedure under general 
anesthesia.  No epidural or spinal anesthesia will be allowed, nor will any local anesthetic infiltration other than the 
administration of the IP or control be permitted.  No prophylactic antiemetic, local anesthetics, or analgesic 
medications are allowed other than those used with general anesthesia.   
Subjects will be dosed in each cohort as described above.  Start and stop time of dosing will be recorded.  Dosing 
stop time will be considered T0. 
Subjects will be transferred to the post-anesthesia care unit and observed according to institutional standards.  While 
in the unit, subjects may receive morphine IV for pain control as needed as per local practice. 
A photograph of the surgical wound will be taken immediately after surgery, at 48, 72, and 96 hours, and at Days 10 
and 28. 
When subjects have met post-anesthesia care unit discharge criteria, they may be discharged to the clinic floor 


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Name of Sponsor/Company:  
Heron Therapeutics, Inc. 
Protocol Number:  HTX-011-C2015-202 
Name of Investigational Product:  
HTX-011 (extended-release 2.5% bupivacaine and 
0.075% meloxicam)  
• HTX-011-19 
• HTX-011-49 
• HTX-011-56 
HTX-002 (extended-release 2.5% bupivacaine) 
HTX-009 (extended-release 0.075% meloxicam)  
Protocol Title:  A Phase 2, Randomized, Pilot Study to 
Investigate the Safety, Efficacy, Pharmacokinetics and 
Bioavailability of HTX-011, HTX-002, or HTX-009 
Administered Via Injection and/or Topical Application 
Following Unilateral Open Inguinal Herniorrhaphy 
Name of Active Ingredients: 
• Bupivacaine and Meloxicam (HTX-011) 
• Bupivacaine (HTX-002) 
• Meloxicam (HTX-009) 
Phase of Development: 2 
where they will be housed until 72 hours post Time 0 and discharge procedures are performed.  
Pain scores at rest will be assessed utilizing an 11 point (0–10) numerical pain rating scale (NPRS) 1, 2, 78, 84, and 
96 hours after administration of study medication (Time 0). In this NPRS scale, 0-no pain experienced and 10-worst 
pain imaginable. 
Pain scores will be measured on movement (sitting up from a supine position) starting at Hour 4 and measured at 6, 
8, 10, 12, 14, 18, 24, 30, 36, 42, 48, 54, 60, and 72 hours.  Once subjects can tolerate oral medication, subjects may 
receive oral oxycodone or other comparable analgesic, as required for breakthrough pain every four to six hours as 
needed.  All medications taken by the subject and administered during surgery will be recorded and all adverse 
events noted throughout the study period.  Patients may receive acetaminophen 1000 mg for pain that is grade 4 or 
lower.  A daily dose of acetaminophen must not exceed 4 grams (4000 mg) per day. 
Vital signs will be measured at Screening, Baseline and at 1, 2, 4, 6, 12, 18, 24, 36, 48, 60, 72, and 96 hours after 
administration of study medication (Time 0) and at Day 10 visit.  
Subjects will have a 12-lead ECG performed at screening, at baseline (i.e., at check-in on Day 0) and at 24, 48, 72, 
and 96 hours post-treatment.  Study personnel will assess subjects for adverse events which will include a 
neurologic evaluation for potential bupivacaine toxicity. 
Blood PK samples will be drawn prior to administration of the investigational product (IP), and at 0.5, 1, 1.5, 2, 3, 4, 
6, 8, 10, 12, 18, 24, 30, 36, 48, 60, 72, 96, and 120 hours post-treatment. 
The subject will be assessed on Days 10 at the clinic by physical exam, 12-lead ECG, vital signs, and the wound 
assessed for healing and at Day 28 assessed for wound healing.  Any adverse events and concomitant medications 
will be collected. 
Subjects will receive a phone call from the study site on Day 60 and will be asked if they have any current pain 
related to the operation and to rate their pain intensity over the previous 24 hours using the NRS. Subjects will also 
be asked about their use of any pain medication over the previous 24 hours to treat pain related to the operation. 
Efficacy:  
• The primary efficacy endpoint will be the summed pain intensity score (SPI), SPI0-24. 
Secondary efficacy endpoints include: 
• SPI at various other time points (SPI0-6, SPI0-12, SPI12-24, SPI24-48, SPI0-48, SPI48-72, SPI0-72, SPI72-96 and SPI0-96). 
• The Patient Global Assessment (PGA) of pain control at 24, 48, 72, and 96 hours post-treatment. 
• Time to administration of first dose of rescue analgesia. 
• Total and average daily rescue consumption over 24, 48, 72, and 96 hours post-treatment. 
• Mean nausea assessment scores at 6, 24, 48, and 72 hours post-treatment. 
• The percentage of subjects who remain pain free (Numerical Pain Rating Scale ≤1) at 72 hours and at 96 hours 


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Name of Sponsor/Company:  
Heron Therapeutics, Inc. 
Protocol Number:  HTX-011-C2015-202 
Name of Investigational Product:  
HTX-011 (extended-release 2.5% bupivacaine and 
0.075% meloxicam)  
• HTX-011-19 
• HTX-011-49 
• HTX-011-56 
HTX-002 (extended-release 2.5% bupivacaine) 
HTX-009 (extended-release 0.075% meloxicam)  
Protocol Title:  A Phase 2, Randomized, Pilot Study to 
Investigate the Safety, Efficacy, Pharmacokinetics and 
Bioavailability of HTX-011, HTX-002, or HTX-009 
Administered Via Injection and/or Topical Application 
Following Unilateral Open Inguinal Herniorrhaphy 
Name of Active Ingredients: 
• Bupivacaine and Meloxicam (HTX-011) 
• Bupivacaine (HTX-002) 
• Meloxicam (HTX-009) 
Phase of Development: 2 
after study drug administration. 
Pharmacokinetics:  
The plasma PK parameters for bupivacaine and meloxicam will be derived by non-compartmental analysis of the 
plasma concentration-time profiles.  The following pharmacokinetic endpoints have been defined: 
• The area under the plasma concentration-time curve from time zero to time t of the last measured concentration 
above the limit of quantification (AUClast) 
• The area under the plasma concentration-time curve from zero to infinity (AUCinf) 
• The maximum plasma concentration (Cmax) 
• The time to reach maximum plasma concentration (Tmax) 
• The terminal elimination rate constant (λZ) with the respective half-life (t½) 
Safety: 
The safety endpoints will include the following: 
• wound assessment findings  
• vital signs 
• clinical laboratory tests, including routine blood chemistry and hematology 
• ECG findings 
• AEs and SAEs 
Statistical methods: 
Sample size determination:  The sample size for this study was selected empirically without a formal statistical 
assumption. 
Efficacy analysis: A comprehensive statistical analysis plan will be developed for this study.  Demographic and 
baseline characteristics will be summarized descriptively by treatment group.  Efficacy endpoints will be analyzed 
using ANOVA, chi-square tests, and log-rank tests, as appropriate.   
The efficacy data for all sums scores will be analyzed via analysis of variance via contrast statements for all 
pairwise and pooled group comparisons.   
Pharmacokinetic analysis: 
The PK parameters for bupivacaine and meloxicam will be calculated using non-compartmental analysis and 
summarized for formulations of HTX-011, HTX-002, HTX-009, and Marcaine. 
Safety analysis: The Medical Dictionary for Regulatory Activities (Version 16 or higher) will be used to classify all 
AEs/SAEs with respect to system organ class and preferred term.  AEs/SAEs will be summarized by treatment.  


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Name of Sponsor/Company:  
Heron Therapeutics, Inc. 
Protocol Number:  HTX-011-C2015-202 
Name of Investigational Product:  
HTX-011 (extended-release 2.5% bupivacaine and 
0.075% meloxicam)  
• HTX-011-19 
• HTX-011-49 
• HTX-011-56 
HTX-002 (extended-release 2.5% bupivacaine) 
HTX-009 (extended-release 0.075% meloxicam)  
Protocol Title:  A Phase 2, Randomized, Pilot Study to 
Investigate the Safety, Efficacy, Pharmacokinetics and 
Bioavailability of HTX-011, HTX-002, or HTX-009 
Administered Via Injection and/or Topical Application 
Following Unilateral Open Inguinal Herniorrhaphy 
Name of Active Ingredients: 
• Bupivacaine and Meloxicam (HTX-011) 
• Bupivacaine (HTX-002) 
• Meloxicam (HTX-009) 
Phase of Development: 2 
Changes in vital signs at each post dosing time point will be summarized by treatment using descriptive statistics 
without formal statistical tests.  The number and proportion of subjects with abnormal ECG findings at each 
assessment will be tabulated by treatment group. 


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TABLE OF CONTENTS 
SPONSOR DETAILS ................................................................................................................2 
INVESTIGATOR AGREEMENT.............................................................................................3 
SYNOPSIS .................................................................................................................................4 
TABLE OF CONTENTS .........................................................................................................14 
ABBREVIATIONS AND DEFINITIONS ..............................................................................19 
1. 
INTRODUCTION ..........................................................................................................21 
2. 
STUDY OBJECTIVES ..................................................................................................23 
3. 
INVESTIGATIONAL PLAN ........................................................................................24 
3.1. 
Overall Study Design ...................................................................................................24 
3.2. 
Rationale for Study Design and Control Groups .........................................................24 
4. 
STUDY POPULATION ................................................................................................26 
4.1. 
Inclusion Criteria .........................................................................................................26 
4.2. 
Exclusion Criteria ........................................................................................................26 
4.3. 
Discontinuation of Subjects .........................................................................................27 
4.3.1. 
Procedures for Withdrawal ....................................................................................27 
4.3.2. 
Replacement of Subjects ........................................................................................27 
4.4. 
Lifestyle Guidelines .....................................................................................................28 
4.4.1. 
Confinement ...........................................................................................................28 
4.5. 
Surgical Procedure .......................................................................................................28 
4.5.1. 
Anesthesia Protocol and Administration of Study Medication ..............................29 
4.5.1.1. 
Anesthesia ........................................................................................................29 
4.5.1.2. 
Study Drug Administration (Parts A, B, C, F, and G) .....................................29 
4.5.1.3. 
Study Drug Administration (Parts D and E) ....................................................30 
4.5.2. 
Identity of Study Medication .................................................................................30 
4.5.2.1. 
HTX-011, HTX-002, and HTX-009 Dose Calculations ..................................32 
4.6. 
Method of Assigning Subjects to Treatment Groups ...................................................34 
4.7. 
Selection of Doses........................................................................................................36 
4.8. 
Blinding and Unblinding of Study Medications ..........................................................36 
4.9. 
Treatment Compliance .................................................................................................36 
4.10. Drug Accountability.....................................................................................................37 
4.11. Packaging, Labeling, and Storage ................................................................................37 
4.11.1. 
Study Drug Packaging ...........................................................................................37 
4.11.2. 
Study Drug Labeling ..............................................................................................37 


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4.12. Prior and Concomitant Medications ............................................................................37 
4.13. Prohibited Medications ................................................................................................38 
4.14. Concomitant Interventions and Procedures .................................................................38 
4.15. Rescue Medication .......................................................................................................38 
5. 
STUDY PROCEDURES ................................................................................................40 
5.1. 
Order of Study Procedures ...........................................................................................40 
5.2. 
Demographic and Efficacy Assessments .....................................................................40 
5.2.1. 
Demographics ........................................................................................................40 
5.2.2. 
Medical History .....................................................................................................40 
5.2.3. 
Physical Examination.............................................................................................41 
5.2.4. 
Pain Intensity (PI) ..................................................................................................41 
5.2.5. 
Patient Global Assessment of Pain Control (PGA) ...............................................42 
5.2.6. 
Nausea Assessment ................................................................................................42 
5.3. 
Safety Assessments Description ..................................................................................42 
5.3.1. 
Clinical Laboratory Tests .......................................................................................42 
5.3.2. 
Vital Sign Measurements .......................................................................................43 
5.3.3. 
12-Lead Electrocardiogram (ECG) ........................................................................43 
5.3.4. 
Surgical Wound Healing Evaluation .....................................................................43 
5.3.5. 
Blood Sampling for Bupivacaine/Meloxicam Pharmacokinetics Analysis ...........43 
5.3.6. 
Assessment of Adverse Events ..............................................................................44 
5.3.6.1. 
Procedures for Blood Sampling and Further Handling for PK Analysis .........44 
5.3.6.2. 
Bioanalysis of Bupivacaine and Meloxicam ....................................................44 
5.3.6.3. 
Pharmacokinetic Analysis ................................................................................44 
5.4. 
Assessments by Visit ...................................................................................................45 
5.4.1. 
Screening Visit .......................................................................................................45 
5.4.2. 
Day 0 Check-in and Surgery ..................................................................................45 
5.4.3. 
Day 0 (Treatment) – Day 5 ....................................................................................46 
5.4.4. 
Day 10 ± 2, and Day 28 ± 2 (Follow-Up Procedures) ...........................................46 
5.4.5. 
Day 60 Follow-Up Phone Call (±8 days) ..............................................................47 
5.4.6. 
Early Termination (ET) Procedures .......................................................................47 
5.4.7. 
Unscheduled Visits ................................................................................................47 
5.5. 
Appropriateness of Assessments..................................................................................47 
6. 
ADVERSE EVENTS, SERIOUS ADVERSE EVENTS, AND SERIOUS 
SUSPECTED ADVERSE REACTIONS .......................................................................48 
6.1. 
Definition of an Adverse Event ...................................................................................48 
6.2. 
Definition of a Serious Adverse Event ........................................................................49 


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6.2.1. 
Serious Adverse Events That Occur Before Administration of Study 
Medication .............................................................................................................49 
6.2.2. 
Serious Adverse Events That Occur After Study Completion ...............................49 
6.3. 
Definition of a Suspected Adverse Reaction ...............................................................49 
6.4. 
Definition of a Serious Suspected Adverse Reaction ..................................................50 
6.5. 
Recording and Evaluating Adverse Events and Serious Adverse Events ....................50 
6.5.1. 
Assessment of Intensity .........................................................................................50 
6.5.2. 
Assessment of Causality ........................................................................................50 
6.5.3. 
Assessment of Outcome .........................................................................................51 
6.5.4. 
Assessment of Expectedness..................................................................................51 
6.6. 
Follow-up of Adverse Events and Serious Adverse Events ........................................52 
6.7. 
Prompt Reporting of Serious Adverse Events to the Sponsor .....................................52 
6.8. 
Regulatory Reporting Requirements ............................................................................53 
6.9. 
Precautions ...................................................................................................................53 
7. 
STATISTICAL METHODOLOGY ..............................................................................55 
7.1. 
Determination of Sample Size .....................................................................................55 
7.2. 
Study Endpoints ...........................................................................................................55 
7.2.1. 
Efficacy Endpoints .................................................................................................55 
7.2.2. 
Pharmacokinetic Endpoints ...................................................................................55 
7.2.3. 
Safety Endpoints ....................................................................................................55 
7.3. 
General Considerations for Statistical Analysis ..........................................................56 
7.3.1. 
Analysis Datasets ...................................................................................................56 
7.3.2. 
Test Hypothesis and P Value Justification ............................................................56 
7.3.3. 
Procedures for Handling Missing Data ..................................................................56 
7.3.3.1. 
PI Score Before and After Analgesic Rescue Medication ...............................56 
7.3.3.2. 
Other Missing PI Score(s) ................................................................................56 
7.3.4. 
Derived Variables ..................................................................................................57 
7.3.4.1. 
Study Population Summaries ...........................................................................57 
7.3.5. 
Disposition .............................................................................................................57 
7.3.6. 
Demographics ........................................................................................................57 
7.3.7. 
Protocol Violations ................................................................................................57 
7.3.8. 
Treatment Compliance ...........................................................................................57 
7.3.9. 
Prior and Concomitant Medications ......................................................................57 
7.4. 
Efficacy Analysis .........................................................................................................58 


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7.4.1. 
SPI and PI Analyses ...............................................................................................58 
7.4.2. 
Time to First Dose of Rescue Medication .............................................................58 
7.4.3. 
Patient Global Assessment (PGA) of Pain Control ...............................................58 
7.4.4. 
Proportion of Subjects Requiring Rescue Medication ...........................................58 
7.4.5. 
Nausea Assessments ..............................................................................................58 
7.4.6. 
Opioid Consumption and Symptoms Associated with Opioid Use .......................58 
7.4.7. 
Subgroup Analyses for Efficacy ............................................................................58 
7.5. 
Safety and Tolerability Evaluations .............................................................................58 
7.5.1. 
Adverse Events ......................................................................................................58 
7.5.2. 
Clinical Laboratory Tests .......................................................................................59 
7.5.3. 
Vital Sign Measurements .......................................................................................59 
7.5.4. 
Electrocardiograms ................................................................................................59 
7.5.5. 
Subgroup Analyses for Safety Endpoints ..............................................................59 
7.6. 
Pharmacokinetic Analysis ............................................................................................59 
7.7. 
Interim Evaluation .......................................................................................................59 
8. 
STUDY ADMINISTRATION .......................................................................................60 
8.1. 
Regulatory and Ethical Considerations ........................................................................60 
8.1.1. 
Regulatory Authority Approval .............................................................................60 
8.1.2. 
Ethical Conduct of the Study and Ethics Approval ...............................................60 
8.1.2.1. 
Ethics Committees ...........................................................................................60 
8.1.2.2. 
General Considerations ....................................................................................61 
8.1.3. 
Informed Consent...................................................................................................61 
8.1.4. 
Investigator Reporting Requirements ....................................................................62 
8.2. 
Study Monitoring .........................................................................................................62 
8.3. 
Quality Assurance ........................................................................................................62 
8.4. 
Study and Site Closure .................................................................................................62 
8.5. 
Records Retention ........................................................................................................63 
8.5.1. 
Health Insurance Portability and Accountability Act of 1996 ...............................63 
8.5.2. 
Financial Disclosure...............................................................................................63 
8.5.3. 
Access to Original Records ....................................................................................63 
8.5.4. 
Archiving of Study-Related Documents ................................................................63 
8.6. 
Provision of Study Results and Information to Investigators ......................................64 
8.7. 
Information Disclosure and Inventions ........................................................................64 
8.7.1. 
Ownership ..............................................................................................................64 
8.7.2. 
Confidentiality .......................................................................................................64 
8.7.3. 
Publication .............................................................................................................65 


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8.7.4. 
Data Management ..................................................................................................65 
8.7.5. 
Data Security ..........................................................................................................65 
8.8. 
Subject Tracking ..........................................................................................................66 
9. 
REFERENCES ...............................................................................................................67 
10. 
APPENDICES ................................................................................................................68 
 
LIST OF APPENDICES 
Appendix A: 
OVERVIEW OF STUDY SCHEDULE ....................................................68 
Appendix B: 
INVESTIGATOR OBLIGATIONS ..........................................................72 
Appendix C: 
STUDY-SPECIFIC INFORMATION .......................................................74 
Appendix D: 
BMI CALCULATION...............................................................................78 
Appendix E: 
AMERICAN SOCIETY OF ANESTHESIOLOGISTS PHYSICAL 
STATUS CLASSIFICATION SYSTEM ..................................................79 
Appendix F: 
WOUND SITE EVALUATION ................................................................80 
Appendix G: 
BUPIVACAINE TOXICITY EVALUATION..........................................81 
Appendix H: 
INSTRUCTIONS FOR TAKING PHOTOGRAPHS OF SURGICAL 
WOUND AFTER HERNIORRHAPHY ...................................................82 
Appendix I: 
DAY 60 FOLLOW-UP PHONE CALL ....................................................83 
 
 


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ABBREVIATIONS AND DEFINITIONS 
AE 
adverse event 
ANOVA 
analysis of variance 
APAP 
acetyl-para-aminophenol (Acetaminophen) 
API 
active pharmaceutical ingredient 
ASA 
American Society of Anesthesiology 
AUC 
area under the plasma concentration-time curve 
BA 
bioavailability 
BE 
bioequivalence 
BMI 
body mass index 
bpm 
beats per minute 
CFR 
Code of Federal Regulations  
Cmax 
maximum plasma concentration 
DMSO 
dimethyl sulfoxide 
ECG 
electrocardiogram 
eCRF 
electronic Case Report Form 
ET 
early termination 
GCP 
Good Clinical Practice 
HEENT 
head, eyes, ears, nose and throat 
HIV 
human immunodeficiency virus 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug 
IP 
Investigational Product 
IRB 
Institutional Review Board 
ITT 
intent-to-treat 
iv 
intravenous 
kg 
kilogram 
L 
liters 
LC-MS/MS 
liquid chromatography – tandem mass spectrometry 
LMA 
laryngeal mask airway 
LOCF 
last observation carried forward 
MAOIs 
monoamine oxidase inhibitors  
mg 
milligram 
min 
minute 


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mITT 
modified intend-to-treat  
NNRS 
Nausea Numeric Rating Scale 
NPRS 
Numerical Pain Rating Scale 
NRS 
Numeric Rating Scale 
NSAIDs 
non-steroidal anti-inflammatory drugs 
PCP 
phencyclidine  
PGA 
Patient Global Assessment 
PI 
pain intensity 
PK 
pharmacokinetic 
po 
by mouth, orally 
PONV 
postoperative nausea and vomiting  
PRN 
when necessary 
SAE 
serious adverse event 
SNRIs 
serotonin-norepinephrine reuptake inhibitors  
SPI 
summed pain intensity 
SpO2 
peripheral oxygen saturation 
SSRI 
selective serotonin reuptake inhibitor 
t½  
half-life 
TCAs 
tricyclic antidepressants 
TEG-POE 
tri(ethylene glycol) poly(orthoester) 
Tmax 
time to reach maximum plasma concentration 
T0 
Time 0 
VS 
vital signs 
WBC 
white blood cell  
WHO 
World Health Organization 
WLOCF 
windowed last observation carried forward  
λZ 
terminal elimination rate constant 
 


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1. 
INTRODUCTION 
The use of local anesthetics within a surgical wound, i.e., “wound infiltration,” has found 
extensive use in a vast number of patients (Renck 1994).  Medical opinion suggests that such 
infiltration with local anesthetics may be a relatively simple and safe means to reduce post-
operative pain (Moiniche, Mikkelsen et al. 1998).  The major limitation of the current local 
anesthetics used for infiltration is the limited duration of effect (6–12 hours) that is observed 
following surgery (Kehlet and Andersen 2011).  In recent years there has been a dramatic 
increase in day-case surgery.  In this patient population it is estimated that 30 to 40% of the 
patients suffer from moderate to severe pain during the first 24 to 48 hours.  The development of 
a long-acting local anesthetic formulation for this patient population would be of clinical 
significance (Rawal 2001). 
While non-steroidal anti-inflammatory drugs (NSAIDs) have long been used in the treatment of 
post-operative pain (Moote 1992), there is early evidence that there may be a synergistic 
interaction between local anesthetics and non-steroidal anti-inflammatory compounds when 
locally administered (Ortiz, Castañeda-Hernández et al. 2011).  The Sponsor has identified a 
combination of bupivacaine and low dose meloxicam in a sustained release formulation (HTX-
011), intended for the management of post-operative pain via wound infiltration that has 
demonstrated positive results in a non-clinical model of post-surgical pain and in an initial study 
in healthy volunteers with its first formulation HTX-011-19.  HTX-011 with the appropriate 
amount and combination of excipients has been selected for further clinical development.  Three 
distinctly different formulations of HTX-011 have been composed for clinical evaluation: 
• HTX-011-19: the vehicle formulation is tri[ethylene glycol] based poly[orthoester] 
polymer with N-methyl-2-pyrrolidone (NMP) and maleic acid. 
• HTX-011-49 the vehicle formulation is tri[ethylene glycol] based poly[orthoester] 
polymer with dimethyl sulfoxide (DMSO), glycerol triacetate, and maleic acid. 
• HTX-011-56: the vehicle formulation is tri[ethylene glycol] based poly[orthoester] 
polymer with DMSO, glycerol triacetate, and maleic acid. 
The three formulations differ from each other solely on the basis of either the percentage content 
of the active ingredients (bupivacaine and meloxicam) and or the percentage content of 
excipients comprising the vehicle formulation.  The two newer formulations, HTX-011-49 and 
HTX-011-56, were developed and incorporate two new excipients: these formulations improve 
the ease of delivery while maintaining the pharmacokinetic and pharmacodynamic properties of 
HTX-011-19. 
The Sponsor has also developed 2 formulations, HTX-002 and HTX-009, which are similar  in 
pharmaceutical composition to HTX-011-56 except that they contain only bupivacaine or 
meloxicam, respectively, as the active pharmaceutical ingredient (API).  Exploratory studies 
evaluating the antinociceptive effect in a post-operative pain model in domestic piglets and 
cross-over PK studies in the beagle dogs demonstrate that the primary pharmacodynamics and 
PK characteristics for HTX-002 are similar to that of HTX-011-56.  Both the active ingredients 
(bupivacaine and meloxicam) and the identical biochronomer polymer vehicle have been studied 
in humans. 




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2. 
STUDY OBJECTIVES 
The primary objective for Part A is to evaluate the efficacy and duration of analgesia following 
administration of one of two doses of HTX-011-19 by different techniques. 
The primary objective of Parts B through G will be to evaluate the efficacy and duration of 
analgesia following administration of HTX-011-49, HTX-011-56, HTX-002, HTX-009, 
bupivacaine (Marcaine), or normal saline. 
The secondary objectives to be evaluated in Parts A through G are as follows: 
• To determine in Part A the optimal administration technique of study drug  
• To determine the safety and tolerability of HTX-011, HTX-002, and HTX-009 as 
evaluated through physical examination, vital signs, clinical laboratory tests, ECGs, and 
incidence of adverse events (AEs) and serious AEs (SAEs) 
• To evaluate the pharmacokinetic (PK) profiles of bupivacaine and/or meloxicam in  
HTX-011, HTX-002, and HTX-009 over 120 hours  
• To evaluate the analgesic effects of HTX-011, HTX-002, and HTX-009 over various 
intervals using a series of secondary efficacy endpoints for pain intensity (such as the 
patient’s global assessment of pain control, time to administration of first dose of rescue 
analgesia, and total and average daily rescue consumption) 
• To assess the effects of HTX-011, HTX-002, and HTX-009 on wound healing at 72 hours 
and on Days 10 and 28 post-treatment 
• To evaluate nausea at 6, 24, 48, and 72 hours post-treatment 
• To evaluate the percentage of subjects pain free over time 


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3. 
INVESTIGATIONAL PLAN 
3.1. 
Overall Study Design 
This is a Phase 2, multi-center, single-dose, randomized, study in adult subjects undergoing 
unilateral open inguinal herniorrhaphy.  The study will enroll up to approximately 453 subjects. 
Subjects at least 18 years of age requiring unilateral open inguinal herniorrhaphy will be 
screened for participation at the study sites in the United States within 28 days of the planned 
surgery.  After signing the informed consent, subjects will be assessed for medical history, 
PONV risk factors, physical examination, baseline clinical laboratory tests, drug and alcohol 
screen, 12 lead electrocardiogram (ECG), pregnancy testing, vital sign measurements, and they 
will undergo pain and placebo assessment training during the screening visit. 
On the day of surgery (Day 0), after having been reassessed for eligibility, subjects will undergo 
a unilateral open inguinal herniorrhaphy under general anesthesia.  No epidural or spinal 
anesthesia will be allowed, nor will any local anesthetic infiltration, other than the administration 
of the investigational product (IP), be permitted.  No prophylactic antiemetic, local anesthetics, 
or analgesic medications are allowed at any time.  A single dose of study drug (either HTX-011, 
HTX-002, HTX-009, Marcaine, or saline, according to a randomization schedule) will be 
administered.  Start and stop time of dosing will be recorded.  Dosing stop time will be 
considered Time 0. 
Following the completion of surgery and immediate postoperative recovery stay, subjects will be 
transferred to the unit.  Staff members at the unit will be blinded to study treatment.  Subjects 
will stay at the unit for approximately 72 hours after the administration of study medication and 
will return to the unit 96 and 120 hours after the administration of study medication to complete 
additional assessments.  Subjects will be scheduled to return on Day 10 for additional efficacy 
and safety assessments and Day 28 for an assessment of wound healing and collection of AEs 
and concomitant medications.  Part A of the study will determine the optimal technique of 
administration of study drug.  Efficacy assessments will include pain intensity scoring, use of 
rescue medication, Patient Global Assessment (PGA) of pain control, and assessments of nausea, 
and use of analgesia rescue medicine.  Safety assessments will include monitoring of AEs, 
physical examinations, vital sign measurements, clinical laboratory tests, ECGs, and wound 
healing assessments and photographs of the surgical site.  Blood samples will be obtained to 
assess meloxicam and bupivacaine pharmacokinetics. Subjects will also receive a phone call 
from the study site on Day 60 to collect follow-up information on postoperative pain and pain 
medications. 
3.2. 
Rationale for Study Design and Control Groups 
This study will evaluate the efficacy and safety of three formulations of the combination of a 
known local anesthetic, bupivacaine, and a known anti-inflammatory drug, meloxicam 
(HTX-011), via different administration techniques (injection into the surgical wound and/or 
topical administration into the surgical wound).   




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4. 
STUDY POPULATION 
4.1. 
Inclusion Criteria 
Subjects must meet all of the following criteria to be considered eligible to participate in the 
study: 
1. Be male or female 18 years of age or older 
2. Female subjects are eligible only if all of the following apply: 
o Not pregnant (female subject of child bearing potential must have a negative serum 
pregnancy tests at screening and negative urine pregnancy test before surgery) 
o Not lactating 
o Not planning to become pregnant during the study 
o Be surgically sterile; or at least two year post-menopausal; or have a monogamous 
partner who is surgically sterile; or is practicing double-barrier contraception; or 
practicing abstinence (must agree to use double-barrier contraception in the event of 
sexual activity); or using an insertable, injectable, transdermal, or combination oral 
contraceptive approved by the FDA for greater than 2 months prior to screening visits 
and commits to the use of an acceptable form of birth control for the duration of the 
study and for 30 days from completion of the study 
Male:  
o Must be surgically sterile (biologically or surgically) or commit to the use of a 
reliable method of birth control for the duration of the study until at least 1 week after 
the administration of study medication 
3. Plan to undergo a unilateral inguinal herniorrhaphy 
4. Have the ability and be willing to comply with the study procedures 
5. Must be able to understand study procedures and give informed consent for the conduct 
for all study procedures, using an IRB approved consent form 
4.2. 
Exclusion Criteria 
Subjects who meet any of the following criteria will be excluded from participating in the study: 
1. Unwilling to sign informed consent or not willing or able to complete all study 
procedures 
2. Have a contraindication or be allergic to any medication to be used during the trial period 
3. Clinically significant cardiac abnormalities that in the opinion of the investigator would 
pose a health risk to the subject should they participate in the trial 


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4. Have American Society of Anesthesiologist (ASA) Physical Status classification system 
category 4 or greater (Appendix E) 
5. Have clinically significant renal or hepatic abnormalities (defined as an AST or ALT 
> 3x ULN, creatinine > 2x ULN) 
6. Have another  pre-existing painful condition that may confound pain assessments 
7. Have another surgery planned within 30 days of procedure, or presents with bilateral or 
recurrent inguinal hernias, other hernia presentations, or hernias with large scrotal 
component that would be difficult to reduce surgically.  Note: Subject may present with 
bilateral hernia: however, subject may be scheduled to only have unilateral repair while 
participating it this study 
8. Have a known or suspected history of alcohol or drug abuse or a positive drug screen 
9. Currently taking analgesics for a chronically painful condition, or has taken long acting 
opioids within 3 days of surgery, or taken any opioids within 24 hours of surgery for this 
study 
10. Subjects with documented sleep apnea or are on home continuous positive airway 
pressure (CPAP) 
11. Female subjects who are pregnant (positive pregnancy test at screening or on the day of 
surgery) 
12. Subjects who are receiving oxygen therapy at the time of screening 
13. Have participated in a clinical trial within 30 days of planned surgery 
14. Have a body mass index (BMI) > 39 kg/m2 
4.3. 
Discontinuation of Subjects 
4.3.1. 
Procedures for Withdrawal 
A subject may be discontinued 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.  Subjects 
who withdraw consent or who are discontinued from the study before completing the protocol 
specified duration of treatment should be encouraged to complete the early termination 
assessments.  Subjects will be encouraged to agree to be followed for up to 28 days after 
receiving study medication.  The date the subject is withdrawn and the primary reason for 
discontinuation will be recorded in the subject’s electronic case report form (eCRF). 
4.3.2. 
Replacement of Subjects 
Subjects who discontinue from this study between 24 and 72 hours post-treatment may be 
replaced in this study after discussion with the investigator and at the discretion of the Sponsor. 


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Any subject who is randomly assigned to study drug but who discontinues the study prior to the 
study drug administration will be replaced by the next study subject who meets the study entry 
criteria.  The replacement subject will be assigned to the same study drug that was intended for 
the subject being replaced. 
4.4. 
Lifestyle Guidelines 
4.4.1. 
Confinement 
Prior to the surgical procedure (Day 0), subjects will arrive at the study clinic in sufficient time 
to prepare for the procedure and confirm eligibility to participate in the study.  In Part A of the 
study, appropriately qualified subjects will be assigned randomly to one of 5 treatment cohorts of 
HTX-011-19 or to saline during the unilateral open inguinal herniorrhaphy procedure.  In Part B, 
subjects will be assigned randomly to one of 4 treatment groups of either HTX-011-49 or HTX-
011-56 or to saline, via the technique that was determined to be optimal in Part A.  In Part C, 
subjects will be assigned randomly to one of the 9 treatment groups of HTX-002 or HTX-011, 
Marcaine, or to saline.  In Part D, subjects will be assigned randomly to one of the 3 treatment 
groups of HTX-011-56 with or without fentanyl administration at the conclusion of the case and 
before study drug administration.  In Part E, subjects will be assigned randomly to one of the 2 
treatment groups of HTX-009 or normal saline.  In Part F, subjects will be assigned randomly to 
one of the 2 treatment groups of HTX-011-56 or normal saline with fentanyl administration at 
the conclusion of the case and before study drug administration. In Part G, subjects will be 
assigned randomly to one of the 3 treatment groups of HTX-011-56, Marcaine, or normal saline 
with fentanyl administration at the conclusion of the case and before study drug administration.  
(See Section 4.6 for more information on treatment cohorts for each part of the study.)  Subjects 
will be discharged from the study clinic on Day 3, about 72 hours after receiving study 
medication.  They will be scheduled to return to the study clinic 24 hours later, i.e., 
approximately 96 hours, and at 120 hours after receiving study medication. 
Bathroom privileges will be restricted during the postoperative confinement period.  Following 
completion of the surgery, subjects will be restricted to use of a bedpan, bedside commode, or 
bathroom privileges via wheelchair through completion of 12-hour assessments; bathroom 
privileges may be loosened at any time at the discretion of the investigator.  While confined at 
the study clinic following surgery, subjects will be required to remain resting in bed at least 5 
minutes prior to any pain intensity assessment.  Subjects will be allowed to ambulate according 
to standard postoperative care instructions. 
4.5. 
Surgical Procedure  
On the day of surgery (Day 0), subjects will undergo unilateral open inguinal hernia with tension 
free technique using implanted mesh.  Surgeries should be scheduled so as to allow for all 
surgical procedures to be completed by approximately 5:00 pm on the day of surgery. 


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4.5.1. 
Anesthesia Protocol and Administration of Study Medication 
4.5.1.1. 
Anesthesia 
The anesthetic protocol below is a guide that should be followed to minimize inter-subject 
variability to the greatest extent possible.  However, it is understood that hemodynamic 
fluctuations and other intraoperative events may necessitate some deviation from the standard 
regimen. 
The surgery will be performed under general anesthesia according to local practices; for 
example, inducing sedation with up to 2 mg midazolam is permitted, or induction with propofol 
(and lidocaine to decrease injection pain from propofol is permitted), and fentanyl should be 
limited to no more than 100 micrograms.  Should intubation be required, non-depolarizing 
muscle relaxants may be used and reversed, if needed, per local practice.  Laryngeal mask airway 
(LMA) placement is preferred over intubation.  Succinylcholine is not permitted.  Volatile 
anesthetics are to be used for maintenance of anesthesia, and nitrous oxide is not permitted.  No 
epidural or spinal anesthesia will be allowed, nor will any local anesthetic infiltration, other than 
the administration of the IP, be permitted.  No prophylactic antiemetics, local anesthetics, or 
analgesic medications are allowed at any time. 
4.5.1.2. 
Study Drug Administration (Parts A, B, C, F, and G) 
Once the hernia repair is completed, study medication will be administered by local 
administration into the surgical site utilizing either the technique of wound infiltration 
(“injection”), instillation (“topical”), or both, depending on the study group assignment. 
Wound Infiltration 
For subjects receiving wound infiltration of study drug only: 
• Approximately 1/3 of the study drug is placed into the upper third of subcutaneous tissue 
just above the level of the fascia,  
• Approximately 1/3 is placed immediately underneath the aponeurosis of the external 
oblique above the inguinal canal (taking care to avoid the nerves), and  
• Approximately 1/3 is placed into the canal itself 
For the first two steps, it is expected that a number of intrusions of the needle will be necessary 
to cover the area. 
Instillation 
For subjects receiving the topical administration dosing cohort, the study drug is prepared in the 
syringe and then evenly applied throughout the surgical wound prior to closure at both the level 
below and the level above the fascia. 


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Both 
For subjects receiving both wound infiltration and instillation, both of the above steps are to be 
followed. 
In all cases, start and stop time of dosing will be recorded; dosing stop time will then be 
considered Time 0 (T0).  Details of an 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. 
4.5.1.3. 
Study Drug Administration (Parts D and E) 
Once the hernia repair is completed, study drug will be administered by local administration into 
the surgical site using a “combination” technique comprising both wound infiltration 
(“injection”) and instillation (“topical”). 
Use approximately ½ the study drug for wound infiltration. This portion of study drug 
should be administered as follows: 
• Approximately 1/3 of the study drug is placed into the subcutaneous tissue just above the 
level of the fascia. 
• Approximately 1/3 is placed immediately underneath the aponeurosis of the external 
oblique above the inguinal canal (taking care to avoid the nerves). 
• Approximately 1/3 is placed into the canal. 
For the first two steps, it is expected that a number of intrusions of the needle will be necessary 
to cover the area. 
Use the remaining amount of study drug for instillation: 
The study drug is prepared in the syringe and then evenly applied throughout the surgical wound 
prior to closure at both the level below and the level above the fascia. 
In all cases, start and stop time of dosing will be recorded; dosing stop time will then be 
considered Time 0 (T0).  Details of an 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. 
4.5.2. 
Identity of Study Medication 
Study drug is defined as HTX-011 (HTX-011-19, HTX-011-49, HTX-011-56), HTX-002, HTX-
009, Marcaine, or normal saline. 
HTX-011 
HTX-011 is a sterile, viscous, extended-release, fixed-ratio combination of bupivacaine and 
meloxicam to be administered via injection into the surgical site for the prevention of 
postoperative pain.  There will be three HTX-011 formulations used in this study, HTX-011-19, 
HTX-011-49, and HTX-011-56. 


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The specific gravity of all formulations is approximately 1.17 g/mL.  A mass of 1000 mg of 
HTX-011, therefore, is equivalent to a volume of 0.855 mL. 
The vehicle formulation for HTX-011-19 is tri[ethylene glycol] based poly[orthoester] polymer 
with N-methyl-2-pyrrolidone (NMP) and maleic acid.  Each mL of HTX-011-19 contains 58.5 
mg bupivacaine base and 1.8 mg of meloxicam.  The proposed drug product contains 5.00% w/w 
bupivacaine base, 0.15% meloxicam, in 79.25% w/w AP135 and 0.60% w/w maleic acid and 
15% w/w NMP. 
The vehicle formulation for HTX-011-49 is tri[ethylene glycol] based poly[orthoester] polymer 
with dimethyl sulfoxide (DMSO), glycerol triacetate, and maleic acid.  One mL of HTX-011-49 
contains 29.25 mg bupivacaine base and 0.88 mg of meloxicam.  The proposed drug product 
contains 2.50% w/w bupivacaine base, 0.075% w/w meloxicam, in 54.275% w/w AP135 and 
0.15% w/w maleic acid, 8.00% w/w DMSO, and 35% w/w glycerol triacetate (or triacetin). 
The vehicle formulation for HTX-011-56 is tri[ethylene glycol] based poly[orthoester] polymer 
with dimethyl sulfoxide, glycerol triacetate, and maleic acid.  One mL of HTX-011-56 contains 
29.25 mg bupivacaine base and 0.88 mg of meloxicam.  The proposed drug product contains 
2.5% w/w bupivacaine base and 0.075% w/w meloxicam in 62.375% w/w tri(ethylene glycol) 
poly(orthoester) (TEG-POE), 10.00% (w/w) DMSO, 25.00% w/w glycerol triacetate, and 0.05% 
w/w maleic acid.   
HTX-002 
HTX-002 has a similar composition as HTX-011-56 except that it contains only bupivacaine as 
the API.  The vehicle formulation for HTX-002 is tri[ethylene glycol] based poly[orthoester] 
polymer with DMSO, glycerol triacetate, and maleic acid.  One mL of HTX-002 contains 29.25 
mg bupivacaine base.  The proposed drug product contains 2.5% (w/w) bupivacaine base in 
62.45% (w/w) tri(ethylene glycol) poly(orthoester) (TEG-POE), 10.00% (w/w) DMSO, 25.00% 
glycerol triacetate, and 0.05% (w/w) maleic acid. 
HTX-009 
HTX-009 has a similar composition as HTX-011-56 except that it contains only meloxicam as 
the API.  The vehicle formulation for HTX-009 is tri[ethylene glycol] based poly[orthoester] 
polymer with DMSO, glycerol triacetate, and maleic acid.  One mL of HTX-009 contains 0.88 
mg of meloxicam.  The proposed drug product contains 0.075% w/w meloxicam in 64.92% w/w 
tri(ethylene glycol) poly(orthoester) (TEG-POE), 10.00% (w/w) DMSO, 25.00% w/w glycerol 
triacetate.  
HTX-011, HTX-002, and HTX-009 formulations will be provided by the Sponsor. 
Normal saline and 0.25% Marcaine without epinephrine for injection should be provided by the 
site.  


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4.5.2.1. 
HTX-011, HTX-002, and HTX-009 Dose Calculations 
The calculated doses based on the mass of HTX-011, HTX-002, and HTX-009 are as follows: 
HTX-011-19 
200 mg HTX-011-19: 
58.5 mg bupivacaine and 1.8 mg of meloxicam = 1 mL HTX-011-19  
200.1 mg bupivacaine and 6.0 mg of meloxicam = 3.42 mL HTX-011-19  
 
400 mg HTX-011-19: 
58.5 mg bupivacaine and 1.8 mg of meloxicam = 1 mL HTX-011-19  
400.1 mg bupivacaine and 12.0 mg of meloxicam = 6.84 mL HTX-011-19  
 
HTX-011-49 
200 mg HTX-011-49: 
29.25 mg bupivacaine and 0.88 mg of meloxicam = 1 mL HTX-011-49 
200.1 mg bupivacaine and 6.0 mg of meloxicam = 6.84 mL HTX-011-49 
 
400 mg HTX-011-49: 
29.25 mg bupivacaine and 0.88 mg of meloxicam = 1 mL HTX-011-49 
400.1 mg bupivacaine and 12.0 mg of meloxicam = 13.68 mL HTX-011-49 
 
HTX-011-56 
200 mg HTX-011-56: 
29.25 mg bupivacaine and 0.88 mg of meloxicam = 1 mL HTX-011-56 
200.1 mg bupivacaine and 6.0 mg of meloxicam = 6.84 mL HTX-011-56  
 


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300 mg HTX-011-56:  
29.25 mg bupivacaine and 0.88 mg of meloxicam = 1 mL HTX-011-56 
299.8 mg bupivacaine and 9.0 mg of meloxicam = 10.26 mL HTX-011-56 
 
400 mg HTX-011-56: 
29.25 mg bupivacaine and 0.88 mg of meloxicam = 1 mL HTX-011-56 
400.1 mg bupivacaine and 12.0 mg of meloxicam = 13.68 mL HTX-011-56 
 
HTX-002 
200 mg HTX-002: 
29.25 mg bupivacaine = 1 mL HTX-002  
200.1 mg bupivacaine = 6.84 mL HTX-002   
 
400 mg HTX-002: 
29.25 mg bupivacaine = 1 mL HTX-002 
400.1 mg bupivacaine = 13.68 mL HTX-002 
 
HTX-009 
0.88 mg of meloxicam = 1 mL HTX-009 
12.0 mg of meloxicam = 13.68 mL HTX-009  
Refer to the Pharmacy Manual for details on the preparation of study medication for 
administration to subjects enrolled in the study. 


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4.6. 
Method of Assigning Subjects to Treatment Groups 
In Part A, 108 subjects will be assigned randomly to treatment with HTX-011-19 or with saline 
according to the randomization scheme, to 1 of 6 treatment cohorts: 
A. 200 mg (3.42 mL) HTX-011-19 by injection into the surgical wound (n=18 subjects) 
B. 400 mg (6.84 mL) HTX-011-19 by injection into the surgical wound (n=18 subjects) 
C. 200 mg (3.42 mL) HTX-011-19 by topical administration into the surgical wound 
(n=18 subjects) 
D. 400 mg (6.84 mL) HTX-011-19 by topical administration into the surgical wound 
(n=18 subjects) 
E. A combination of 200 mg (3.42 mL) HTX-011-19 by injection into the surgical wound 
and 200 mg (3.42 mL) HTX-011-19 by topical administration into the surgical wound 
(n=18 subjects) 
F. 6.84 mL of saline solution by injection into the surgical wound (n=18 subjects) 
Upon determination of the optimal route of administration in Part A, 90 subjects in Part B will be 
assigned randomly to any 1 of 6 treatment cohorts: 
A. 200 mg (6.84 mL) HTX-011-49 via technique determined in Part A (n=15 subjects) 
B. 400 mg (13.68 mL) HTX-011-49 via technique determined in Part A (n=15 subjects) 
C. 200 mg (6.84 mL) HTX-011-56 via technique in Part A (n=15 subjects) 
D. 400 mg (13.68 mL) HTX-011-56 via technique determined in Part A (n=15 subjects) 
E. 6.84 mL of saline solution via technique determined in Part A (n=15 subjects) 
F. 13.68 mL of saline solution via technique determined in Part A (n=15 subjects) 
Approximately 135 subjects in Part C will be assigned randomly to any 1 of 9 treatment cohorts: 
A. 200 mg (6.84 mL) HTX-002 by injection into the surgical wound (n=15 subjects) 
B. 400 mg (13.68 mL) HTX-002 by injection into surgical wound (n=15 subjects) 
C. 6.84 mL of saline solution by injection into the surgical wound (n=15 subjects) 
D. 13.68 mL of saline solution by injection into the surgical wound (n=15 subjects) 
E. 200 mg (6.84 mL) HTX-011-59 via instillation (n=15 subjects) 


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F. 400 mg (13.68 mL) HTX-011-59 via instillation (n=15 subjects) 
G. 200 mg (6.84 mL) HTX-002 via instillation (n=15 subjects) 
H. 400 mg (13.68 mL) HTX-002 via instillation (n=15 subjects) 
I. 30 mL of 0.25% Marcaine without epinephrine via infiltration (n=15 subjects) 
Approximately 45 subjects in Part D will be assigned randomly to 1 of the following 3 treatment 
cohorts:  
A. 400 mg (13.68 mL) HTX-011-56 via a combination of injection and instillation and 
fentanyl 50 µg IV before wound closure (n=15 subjects) 
B. 400 mg (13.68 mL) HTX-011-56 via a combination of injection and instillation and 
fentanyl 100 µg IV before wound closure (n=15 subjects) 
C. 400 mg (13.68 mL) HTX-011-56 via a combination of injection and instillation and no 
fentanyl before wound closure (n=15 subjects) 
Approximately 20 subjects in Part E will be assigned randomly to 1 of the following 2 treatment 
cohorts:  
A. 13.68 mL of HTX-009 via a combination of injection and instillation (n=15 subjects) 
B. 13.68 mL of normal saline via a combination of injection and instillation (n=5 subjects) 
Approximately 20 subjects in Part F will be assigned randomly to 1 of the following 2 treatment 
cohorts: 
A. 13.68 mL of normal saline via instillation and fentanyl 50 µg IV before wound closure 
(n=15 subjects) 
B. 400 mg (13.68 mL) HTX-011-56 via instillation and fentanyl 50 µg IV before wound 
closure (n=5 subjects) 
Approximately 35 subjects in Part G will be assigned randomly to 1 of the following 3 treatment 
cohorts:  
A. 300 mg (10.26 mL) of HTX-011-56 via instillation and fentanyl 50 µg IV before wound 
closure (n=15 subjects) 
B. 75 mg (30 mL) of 0.25% Marcaine without epinephrine via injection and fentanyl 50 µg 
IV before wound closure (n=15 subjects) 
C. 10.26 mL of normal saline via injection and fentanyl 50 µg IV before wound closure 
(n=5 subjects) 


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All study doses administered will be according to the original treatment assignment.  Only the 
site staff directly involved in the surgery and the unblinded pharmacy staff will have access to 
the randomization scheme. 
Subject and site staff involved in the post-surgical assessments of safety and efficacy will not 
have access to the randomization scheme and will be blinded to study treatment.  
4.7. 
Selection of Doses 
To ensure analgesic efficacy is demonstrated and to better understand the dose response effect of 
the HTX-011 formulations, 3 dose levels (200, 300, and 400 mg) will be evaluated in this study. 
HTX-011 doses up to 600 mg have been evaluated in previous and ongoing clinical studies and 
have been generally well tolerated.  
In a placebo-controlled Phase 1 clinical trial, single doses of 100 mg, 200 mg, and 400 mg of 
HTX-011-19, and single doses of 100 mg and 200 mg mL of HTX-011-49 were administered to 
healthy adult volunteers.  HTX-011 elicited the desired pharmacokinetic profile for both 
bupivacaine and meloxicam.  Therapeutically relevant plasma bupivacaine levels were sustained 
for 2 to 3 days in the absence of large initial peak plasma concentrations that can be observed 
with commercially available formulations of the drug.  The anesthetic effects of HTX-011 
persisted through 96 hours, which closely correlated with plasma bupivacaine concentrations.  
All five doses were well-tolerated with no serious adverse events, clinically relevant ECG or 
laboratory changes, or premature discontinuations.  Mild redness and bruising were seen at some 
injection sites due to the subcutaneous administration of the product in this healthy volunteer 
study. 
4.8. 
Blinding and Unblinding of Study Medications 
Since HTX-011, HTX-002, and HTX-009 formulations are colored and viscous solutions 
whereas saline and Marcaine are not, and the volume administered varies with dose, this renders 
obsolete any double-blinded study drug administration.  Therefore, the site’s surgical and 
pharmacy staff will not be blinded to the study medication administered.  However, the conduct 
of the study will be observer blind.  Once surgery is completed and subjects have been 
transferred to the clinical unit, all site staff in the clinical unit involved in the assessment of 
safety and efficacy will be blinded to the treatment assignment, and (s)he will remain masked to 
treatment assignments throughout the conduct of this study.  The study blind may be broken only 
if the safety of a subject is at risk and the treatment plan for that subject depends on which study 
medication he or she received.  If knowledge of the treatment assignment is absolutely necessary 
for the management of a subject’s safety, the investigator must contact the medical monitor for 
unblinding information.  If a subject’s data are unblinded without the prior knowledge of the 
sponsor, the investigator must notify the sponsor as soon as possible and no later than the next 
business morning.  All circumstances surrounding a premature unblinding must be clearly 
documented. 
4.9. 
Treatment Compliance 
Since study medication is being administered as a component of the surgical procedure, a lack of 
treatment compliance is not expected.  The exact date, time, and dose of study medication 


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administration will be recorded in the subject’s eCRF.  It is important that all study medication is 
administered and that the syringes are emptied. 
4.10. Drug Accountability 
The investigator (or designee) will sign for the study medications when they are received.  The 
study medication must be handled and stored as described in the pharmacy manual and dispensed 
only to those subjects formally entered into the study. 
At the completion of the study and after reconciliation of all delivery and usage records, any 
unused study medication supplied by the sponsor will be returned to the sponsor (or designee) or 
destroyed per written instructions from the sponsor. 
4.11. Packaging, Labeling, and Storage 
All study medication (HTX-011, HTX-002, and HTX-009) will be prepared by the sponsor or 
the sponsor’s designee.  All study medication will be dispensed by the investigator or a person 
under his/her supervision and will be administered by the individual performing the surgery. 
4.11.1. 
Study Drug Packaging  
HTX-011, HTX-002, HTX-009 will be packed and dispatched in refrigerated shipping containers 
with a temperature monitor enclosed.  The lot number and a manufacturing date will be 
provided. 
4.11.2. 
Study Drug Labeling 
HTX-011, HTX-002, HTX-009 labeling will comply with federal applicable laws and 
regulations.  At the minimum, the following information will be provided: 
• Study number (HTX-011-C2015-202) 
• Drug identification 
• Name, address, and telephone number of sponsor or manufacturer 
• Lot number 
• Contents of Package 
• Storage conditions 
• CAUTION: New Drug – Limited by United States Law to Investigational Use Only 
All HTX-011, HTX-002, and HTX-009 formulations at the study site(s) should be stored in a 
refrigerator at 2–8oC.  The refrigerator should be in a locked area with restricted access.  A 
temperature log or chart should be maintained to monitor the environment at the study site. 
4.12. Prior and Concomitant Medications 
All medications and other treatments taken by subjects within 30 days before dosing and during 
the study will be recorded in the eCRF. 


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All chronic medications that have not been at a stable dose for at least 30 days prior to the 
scheduled surgery procedure will be prohibited.  
4.13. Prohibited Medications 
The following medications are prohibited throughout the study: anticonvulsants, monoamine 
oxidase inhibitors (MAOIs), tricyclic antidepressants (TCAs), neuroleptics, or serotonin-
norepinephrine reuptake inhibitors (SNRIs), gabapentin, and pregabalin, and administration of 
any of these agents, while participating in the study will disqualify the subject from the efficacy 
evaluation. 
Selective serotonin reuptake inhibitor (SSRI) treatments are allowed if taken for at least 30 days 
before the screening period of the study at an unchanged stable dose. 
Analgesic medications other than those pre-specified for post-randomization rescue use 
(Section 4.15) are prohibited during the period from T0 to T72 and the prohibited medications 
include, but are not limited to: hydromorphone, hydrocodone, codeine, fentanyl, meperidine, 
tramadol, opioid combinations, and NSAIDs.  Aspirin (acetylsalicylic acid) is also prohibited 
excluding low dose ASA for cardiac prophylaxis. 
Sedatives (including benzodiazepines) used as minor tranquilizers or hypnotics are not allowed 
unless approved by the investigator and the Sponsor’s medical monitor. 
Agents 
for 
post-surgical 
nausea 
prophylaxis, 
including 
5-HT3 
receptor 
blockers 
(e.g., ondansetron), scopolamine, dexamethasone, or haloperidol, are prohibited during or upon 
completion of the surgical procedure.  Anti-nausea medication will only be administered during 
the post-operative period for any of the following: (1) subject records a score of ≥ 5 on the 
nausea numeric rating scale; (2) subject is actively vomiting; (3) subject requests anti-nausea 
medication. 
Note: Midazolam 1–2 mg IV may be administered preoperatively for anxiolysis. 
4.14. Concomitant Interventions and Procedures 
All interventions or procedures, whether diagnostic or therapeutic, and concomitant medications 
used for these interventions will be recorded in the eCRF, along with time, date, and reason for 
the intervention or procedure.  If an intervention or procedure is implemented to treat an AE, the 
event must be recorded as an AE, along with all relevant information. 
4.15. Rescue Medication 
Study investigators will review the HTX-011/HTX-002 Investigator’s Brochure so as to be 
aware of the safety related events which may be anticipated with its use.  Investigators will be 
versed in the latest standard of care guidelines.  A fully stocked emergency crash cart, oxygen, 
and personnel trained in emergency resuscitation will be available at the study center at all times 
during the confinement period.  Pain intensity assessments (NPRS) must be completed prior to 
each dose of rescue medication. 


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Rescue analgesia (from T0 to T72) will be available to subjects with inadequately controlled pain 
symptoms.  The approved rescue regimen will be morphine 2 mg IV bolus doses by titration as 
needed in the post-anesthesia care area.  Once effective analgesia has been reached using the 
morphine administered, subjects will be transitioned to oral oxycodone 10 mg every 4–6 hours, 
as needed for analgesia.  Additional morphine 2 mg IV every 2 hours may be administered for 
inadequate analgesia with oxycodone.  A subject who indicates a PI score that is ≤ 4 may be 
given acetaminophen 1000 mg for analgesia; however, a daily dose of acetaminophen must not 
exceed 4 grams (4000 mg). 
Efforts should be made to encourage subjects to wait at least 60 minutes after the end of study 
drug administration prior to receiving rescue medication.  Subjects do not need to have a 
qualifying pain score to receive rescue analgesia; however, whenever possible staff should try to 
ensure that rescue analgesia is administered only when the numerical pain intensity rating score 
prior to rescue is NPRS ≥ 4. 
Between T72 (i.e., after discharge from the research unit) and T96, pain medication (if needed) 
will be prescribed according to the investigator’s discretion and institutional standard of care. 
After T96, PI scores will not be recorded: subjects may resume standard of care pain medication 
as advised by their surgeon.  This may include, but is not limited to, ibuprofen, acetaminophen, 
opioids, or opiate/APAP combo medication, if still needed.  The name, dose, reason, route, and 
time of administration of analgesics consumed after T96 will be recorded at the time of Day 10 
visit to the study center. 
Subjects who do not achieve adequate analgesia from the rescue regimen or experience 
intolerable opioid-related side effects will be discontinued from study drug efficacy evaluations, 
and they can be administered the standard of care regimen of analgesics.  However, the subject 
must remain in the study for all planned visits (i.e., safety evaluations and for obtaining PK 
blood samples) until completion of participation in the study or early termination from the study 
for any other reason. 


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5. 
STUDY PROCEDURES 
A schedule of study procedures for overall study assessments and day-of-dosing assessments is 
provided in Appendix A. 
5.1. 
Order of Study Procedures 
The order of the procedures to be performed at any scheduled time will be as follows (where 
appropriate): 
1. Pain Intensity 
2. PGA 
3. Nausea assessment 
4. Vital signs 
5. 12-Lead ECG 
6. Physical Examination (± 30 minutes at 72 hours) 
7. Blood draw for PK and blood chemistry 
8. Wound assessment (Appendix F) 
9. Bupivacaine Toxicity Evaluation (Appendix G) 
10. Photographs of wound site (Appendix H) 
Study procedures have a ± 15 minutes window unless otherwise stated. 
5.2. 
Demographic and Efficacy Assessments 
5.2.1. 
Demographics 
Demographic information will be collected during screening visit including age, sex, ethnicity, 
race, weight, height, and BMI. 
5.2.2. 
Medical History 
The investigator or designee will document each subject’s medical history (including PONV risk 
factors; Appendix C.3) during the screening visit.  Medical history will be obtained through 
subject interview.  A review of the subject’s medical records from their primary care physician 
will not be conducted.  Medical history will be updated on Day 0 when the subject reports for 
surgery, and the subject will be interviewed to confirm that they continue to meet the required 
study inclusion and exclusion criteria. 


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5.2.3. 
Physical Examination 
The investigator or designee will perform a physical examination (HEENT, cardiovascular, 
respiratory, gastrointestinal, neurological, dermatologic, and musculoskeletal systems) during the 
screening visit, at admission (Day 0) to the study site on the day of surgery, at 72 hours post 
dosing, and at the Day 10 visit.  Body weight and height will be measured, and BMI 
(Appendix D) will be calculated during the screening visit; all other physical examinations will 
include weight only.  Weight does not need to be measured at 72 hours after administration of 
study medication. 
The neurologic examination includes a mental status exam and evaluation of cranial nerve, 
motor, sensory, and cerebellar function.  In addition, the findings will be summarized in a 
neurologic assessment.  The examiner will be asked to record whether the subject’s overall 
neurologic status is better, worse, or the same. 
The study investigator should perform a physical examination (the extent of which is determined 
by the study investigator) at any time during the study if indicated by change in a subject’s 
condition. 
5.2.4. 
Pain Intensity (PI) 
PI will be assessed by the subject for their current pain according to an 11-point NPRS (0-10) 
where 0 equates to no pain and 10 equates to the worst pain imaginable.  PI scores will be 
measured two ways: on movement and at rest. 
PI scores will be assessed utilizing an 11 point (0–10) numerical pain rating scale (NPRS) at the 
following time points: 1, 2, 4, 6, 8, 10, 12, 14, 18, 24, 30, 36, 42, 48, 54, 60, 72, 78, 84, and 
96 hours post study drug administration.  Assessments performed at 78 and 84 hours will be 
performed by subjects on an out subject basis.  PI assessments scheduled between 24:00 and 
06:00 must be collected, even if subjects are asleep at the time of the assessment.   
Pain scores will be measured on movement (sitting up from a supine position) starting at Hour 4 
and measured at 6, 8, 10, 12, 14, 18, 24, 30, 36, 42, 48, 54, 60, and 72 hours. 
Pain Scores will be measured at rest at 1, 2, 78, 84, and 96 hours after administration of study 
medication.  The pain score will be measured after the patient has been supine for a minimum of 
5 minutes and a resting pain score has been obtained. 
There will be a ± 15 minute window allowed for the collection of each PI assessment unless 
otherwise stated. 
PI will also be assessed within 5 minutes prior to administration of each dose of rescue analgesia 
and at time of early discontinuation (should it occur and only if the subject was discontinued 
prior to 96 hour). 


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5.2.5. 
Patient Global Assessment of Pain Control (PGA) 
Subjects will be asked to evaluate the performance of their study medication as a pain treatment 
in response to the following inquiry: “Overall, please rate how well your pain has been 
controlled during the last 24, 48, 72, and 96 hours since you received study medication?: 0-poor, 
1-fair, 2-good, 3-very good, or 4-excellent.” 
The PGA of pain control will be completed at 24, 48, 72, and 96 hours after study medication 
administration and at time of early discontinuation (should it occur and only if the subject was 
discontinued prior to 96 hours post-treatment). 
5.2.6. 
Nausea Assessment 
Nausea will be assessed during the study using an 11-point NRS where 0 equates to no nausea 
and 10 equates to the worst nausea imaginable.  Assessment of nausea will be completed by 
subjects at the following time points: 6, 24, 48, and 72 hours within a ± 15 minute window 
unless otherwise stated. 
5.3. 
Safety Assessments Description 
5.3.1. 
Clinical Laboratory Tests 
During the screening visit, on Day 0 during check-in, at 72 (± 1) hours following study drug 
administration, and in the event of subject early discontinuation, subjects will have blood 
samples collected for routine clinical laboratory testing as follows: 
• hematology: complete blood count consisting of white blood cell (WBC) and red blood 
cell count, platelet count, hemoglobin, hematocrit, and differential counts (total 
neutrophils, eosinophils, basophils, lymphocytes, and monocytes) 
• clinical chemistry tests: urea, glucose, creatinine, sodium, potassium, chloride, 
bicarbonate, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, 
total bilirubin, direct bilirubin, gamma-glutamyltransferase, lactate dehydrogenase, 
calcium, total protein, magnesium, phosphate, albumin, and uric acid 
Additional urine or blood samples will be collected and tested as follows: 
• urine drug screen and alcohol breath test at the screening visit, and during admission to 
the study unit on Day 0.  Urine drug screen will include screening of (at minimum): 
cocaine, marijuana, opiates/opioids, amphetamines, methamphetamines, phencyclidine 
(PCP), benzodiazepines, barbiturates, methadone, and oxycodone. 
• serum pregnancy test at the screening visit, and a urine pregnancy test at check-in on Day 
0 (female subjects of child bearing potential only). 
Screening laboratory results will be used for assessing eligibility for randomization.  Clinical 
laboratory test done on Day 0 prior to surgery will be used as baseline reference and not for 
assessing study randomization eligibility. 


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5.3.2. 
Vital Sign Measurements 
Resting vital signs will include resting blood pressure, resting pulse, respiratory rate, oral 
temperature, and peripheral oxygen saturation (SpO2).  Resting tests must be obtained after 
resting (seated/supine) for ≥ 5 minutes. 
After the administration of study medication, subjects will have vital signs (resting only) 
measured and recorded at the following times: 1, 2, 4, 6, 12, 18, 24, 36, 48, 60, 72, and 96 hours 
and at the Day 10 visit.  Vital signs will have a collection window of ± 15 minutes unless 
otherwise stated. 
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. 
5.3.3. 
12-Lead Electrocardiogram (ECG) 
A 12-lead ECG will be performed after the subject has been supine for at least 5 minutes and will 
be completed for all subjects at screening, at check-in on Day (0) and at 24, 48, 72, 96 hours, and 
at the Day 10 visit and at time of early discontinuation.  12-lead ECG will be used to exclude 
subjects with a clinically significant abnormal ECG. 
The findings (i.e., classification as “normal,” “abnormal not clinically significant,” or “abnormal 
clinically significant [including heart block]”) will be recorded in the subject’s eCRF.  The ECG 
tracings will not be collected for Data Management. 
5.3.4. 
Surgical Wound Healing Evaluation 
The wound evaluator will be a blinded investigator or will be other medically qualified clinical 
site personnel  (S)he and will assess the surgical site to determine if healing is normal or 
abnormal at 72 hours, Day 10, and Day 28 or Early Termination, and record observations 
(Appendix F) on the appropriate eCRF and source document.  Normal is defined as expected 
post-surgical findings as assessed by a blinded investigator or other medically qualified clinical 
site personnel, including but not limited to wound dry, no dehiscence, no erythema, no drainage, 
mild bruising, oozing, and swelling.  A normal finding will not be recorded as an AE. 
Photographs of the subject’s surgical site will be taken immediately after surgery, 48 and 
72 hours, Day 10, and Day 28 (Appendix H).  If a wound is assessed as having an abnormal and 
unexpected post-surgical finding, the finding will be recorded as an AE. 
5.3.5. 
Blood Sampling for Bupivacaine/Meloxicam Pharmacokinetics Analysis 
Blood samples for the pharmacokinetic analysis of bupivacaine and meloxicam will be collected 
at the following times: prior to surgery, and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 18, 24, 30, 36, 48, 
60, 72, 96, and 120 hours after study medication administration (± 15 minutes unless otherwise 
stated). 


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5.3.6. 
Assessment of Adverse Events 
Physical examinations including neurologic and cardiovascular evaluations will be performed to 
determine if there are any changes in the patient’s condition from baseline as noted in the 
schedule of events.  Close attention should be given to conditions that may represent reported 
toxicities associated with bupivacaine including, but not limited to, perioral tingling, strange 
taste, visual and auditory disturbances, muscle twitching, seizure, acidosis, shortness of breath, 
bradycardia (heart rate < 50 bpm with symptoms), hypotension (BP < 90 mmHg or symptomatic 
decrease from baseline), low oxygen saturation (≤ 90% for ≥ 1 minute), and cardiac arrest.  
Adverse events and any interventions will be documented in the eCRF. 
5.3.6.1. 
Procedures for Blood Sampling and Further Handling for PK Analysis 
Blood samples for the assay of bupivacaine and meloxicam will be taken in Li-Heparin 
collection tubes (BD Vacutainer cat no 367886; 13 x 100 mm x 6.0 mL BD Vacutainer plus 
plastic plasma tube, additive lithium heparin).  Tube volume should allow collection of 6 mL 
blood.  Blood samples will be stored at approximately 4°C on ice until further processing which 
should start within 30 minutes after blood collection.  Processing of blood to plasma concerns 
centrifugation at 1500 g at a temperature between 0°C and 4°C and subsequent pipetting of the 
plasma layer into cryovial sample tubes for a maximum of 15 minutes.  Plasma will be equally 
divided over 2 of these tubes.  Samples/tubes will be deep frozen (at approximately -20°C) prior 
to shipment to the central laboratory. 
Blood samples and derived plasma samples must be properly labeled at every stage of the 
process.  Refer to the Laboratory Manual for more details. 
5.3.6.2. 
Bioanalysis of Bupivacaine and Meloxicam 
The concentrations of bupivacaine and meloxicam in plasma will be determined using validated 
LC-MS/MS assays.  Concentrations will be calculated by interpolation from a calibration curve.  
Quality control samples will be analyzed throughout the study.  Their measured concentrations 
will be used to determine between-run, overall precision, and accuracy of the analyses. 
5.3.6.3. 
Pharmacokinetic Analysis 
The plasma PK parameters for bupivacaine and meloxicam will be derived by noncompartmental 
analysis of the plasma concentration-time profiles.  The following pharmacokinetic endpoints 
will be defined: 
• The area under the plasma concentration-time curve from time zero to time t of the last 
measured concentration above the limit of quantification (AUClast) 
• The area under the plasma concentration-time curve from zero to infinity (AUCinf) 
• The maximum plasma concentration (Cmax) 
• The time to reach maximum plasma concentration (Tmax) 
• The terminal elimination rate constant (λZ) with the respective half-life (t½) 


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5.4. 
Assessments by Visit 
5.4.1. 
Screening Visit 
Subjects meeting the eligibility criteria listed in Sections 4.1 and 4.2 may be enrolled in the study 
after the nature and purpose of the protocol have been explained to them and they have 
voluntarily granted written informed consent to participate.  All subjects will have a screening 
evaluation within 28 days before surgery (Day 0).  After informed consent is obtained, the 
following procedures will be performed at the screening visit for all subjects: 
• Demographics and medical history 
• Measurement of resting vital signs  
• 12-lead ECG  
• Physical examination including height, weight, and BMI  
• Clinical laboratory tests and serology  
• Drug and alcohol screen  
• Serum pregnancy test for women of childbearing potential 
• Review of inclusion/exclusion criteria eligibility 
• ASA Classification Assessment 
• Assessment of PONV risk factors 
• Training on pain assessment and placebo response 
• Prior and concomitant medications (within 30 days of D0) 
5.4.2. 
Day 0 Check-in and Surgery 
The following assessments will be conducted on the day of admission (Day 0, prior to surgery) 
for all subjects: 
• Review of inclusion/exclusion criteria eligibility 
• Medical history update  
• Measurement of resting vital signs  
• 12-lead ECG  
• Physical examination, including weight only 
• Clinical laboratory tests  
• Drug and alcohol screen  
• Urine pregnancy test 
• Training reminders on pain assessments and placebo response 
• Blood draw for PK analysis of bupivacaine and meloxicam 
• Prior and concomitant medications (within 30 days of D0) 
• Neurologic Exam 
• Monitoring of Serious Adverse Events 
• Use of Rescue Medication 
Subjects who continue to meet eligibility criteria will undergo primary unilateral open inguinal 
herniorrhaphy.  Subjects who don’t experience a clinically significant event during surgery (e.g., 
excessive bleeding, hemodynamic instability) that would render the subject medically unstable or 


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complicate their postsurgical course will be administered study medication according to the 
randomization scheme. 
In Part D, F, and G, subjects will be administered fentanyl IV at the end of surgery and before 
study drug administration according to the randomization scheme (see Section 4.6).  Fentanyl 
will be administered per the product label instructions. 
5.4.3. 
Day 0 (Treatment) – Day 5  
The following assessments will be conducted during the treatment phase on Days 0 – 5 
subsequent to the administration of study medication: 
• PI assessments  
• PGA evaluations 
• Assessment of NRS for nausea 
• Measurement of resting vital signs  
• 12-lead ECG 
• Blood samples for PK  
• Physical examination (weight not required at the 72 hour exam) 
• Clinical laboratory tests (72 hour only) 
• Monitoring of AEs and concomitant medications  
• Use of Rescue Medication 
• Assessment of wound healing (72 hour only) 
• Bupivacaine Toxicity and Neurological Assessment (8, 16, 24, 48, and 72 hours only) 
• Photographs of the surgical site will be taken at 48, 72, and 96 hours 
One hour after administration of study medication (T0) assessments will be completed if the 
subject is awake and alert. 
Rescue analgesia will be available to subjects with inadequately controlled pain symptoms 
during the treatment phase on Days 0 until T72.  After T72, subjects may resume standard of 
care pain medication as advised by their surgeon. 
5.4.4. 
Day 10 ± 2, and Day 28 ± 2 (Follow-Up Procedures) 
The following procedures will be conducted for all subjects during the Day 10 and 28 visits. 
• Physical examination, including weight only (Day 10 only) 
• 12-lead ECG (Day 10 only) 
• Measurement of resting vital signs (Day 10 only) 
• Monitoring of AEs and concomitant medications  
• Assessment of wound healing for healing, and discoloration 
• Photograph of the surgical site 
Clinically significant adverse events, examination, or test results will be followed until 
appropriate resolution can be documented. 


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5.4.5. 
Day 60 Follow-Up Phone Call (±8 days) 
Subjects will receive a phone call from the study site.  Subjects will be asked if they have any 
current pain related to the operation.  Subjects will also be asked to think about the previous 
24 hours and to rate their pain intensity related to the operation using the NRS, and to report any 
medication(s) to treat the pain (name, dose, and route).  See Appendix I for details on the 
information to be collected.  The results will be recorded in source documents. 
5.4.6. 
Early Termination (ET) Procedures 
Subjects who discontinue participation or who are discontinued prior to the Day 28 visit will be 
asked to complete ET procedures, including: 
• PI assessment (only if the subject was discontinued prior to 96 hour) 
• PGA assessment (only if the subject was discontinued prior to 96 hour) 
• Assessment of nausea NRS 
• Measurement of resting vital signs  
• 12-lead ECG 
• Physical examination, including weight only 
• Clinical laboratory tests 
• Assessment of AEs and review of concomitant medications 
• Assessment of wound healing 
• Bupivacaine Toxicity and Neurological Assessment (only if the subject was discontinued 
prior to 72 hour) 
5.4.7. 
Unscheduled Visits  
Unscheduled visits should be performed on an ‘as-needed’ basis if a subject’s medical situation 
warrants it.  For each unscheduled visit, the following will be recorded: 
• Assessment of any new AEs. 
• Assessment of concomitant medications. 
• A blood sample draw (to be used for determination of bupivacaine levels) when the 
unscheduled visit(s) is precipitated by AE(s) associated with neurologic or cardiac 
symptoms. 
5.5. 
Appropriateness of Assessments 
The efficacy measures utilized in this study are commonly used in clinical studies performed in 
acute postoperative pain populations.  The timing of assessments is intended to evaluate the time 
to onset of analgesia, duration of effect, and magnitude of benefit. 
Safety measures used in this study are standard for clinical trials of investigational medications. 


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6. 
ADVERSE EVENTS, SERIOUS ADVERSE EVENTS, AND SERIOUS SUSPECTED 
ADVERSE REACTIONS 
The investigator is responsible for the detection and documentation of events meeting the criteria 
and definition of an AE, SAE, or serious suspected adverse reaction as provided in this protocol.  
During the study, when there is a safety evaluation, the investigator or site staff will be 
responsible for detecting AEs and SAEs, as detailed in this section of the protocol. 
6.1. 
Definition of an Adverse Event 
An AE is defined as any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related. 
An AE may be any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a study medication, whether or not 
considered causally associated with the use of the study medication.  Any abnormal laboratory 
value deemed clinically significant by the investigator, regardless of causal relationship, must be 
reported as an AE. 
Examples of an AE include the following: 
• significant or unexpected worsening or exacerbation of the condition or indication under 
study 
• exacerbation of a chronic or intermittent preexisting condition, including either an 
increase in frequency or intensity of the condition (e.g., 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 medication or 
a concurrent medication (overdose per se should not be reported as an AE or SAE, unless 
nonserious or serious sequelae occur) 
The following examples are not considered AEs: 
• medical or surgical procedure (e.g., endoscopy, appendectomy), although the condition 
that leads to the procedure is an AE 
• anticipated day to day fluctuations of preexisting disease(s) or condition(s) (including 
laboratory values) present or detected at the start of the study that do not worsen 
• the disease or disorder being studied, or expected progression, signs, or symptoms of the 
disease or disorder being studied, unless they become more severe or occur with a greater 
frequency than expected for the subject’s condition 
• transient paresthesia that are considered to be clinically normal (would be expected to 
occur as a long-acting local anesthetic wears off) 
All AEs, whether volunteered, elicited, or noted on physical examination and regardless of 
causality or seriousness, will be assessed and recorded in the eCRF beginning after 
administration of study medication through the Day 10 study visit. 


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6.2. 
Definition of a Serious Adverse Event 
An SAE is defined as any event that meets the following criteria: 
• It results in death or is life-threatening (i.e., presents 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.) 
• It results in persistent or substantial disability or incapacitation.  (This criterion is not 
intended to include experiences of relatively minor medical significance such as 
uncomplicated headache, diarrhea, or sprained ankle.) 
• It results in hospitalization. 
• It results in prolongation of an existing hospitalization. 
• It is a congenital anomaly or birth defect. 
• It requires medical or surgical intervention to prevent any of the above outcomes. 
Medical and scientific judgment should be exercised in determining whether an AE is serious 
when considering important medical events that may not be immediately life-threatening or 
result in death or hospitalization but may jeopardize the subject or may require intervention to 
prevent any of the other outcomes listed.  Examples of such medical events that may also be 
considered serious include, but are not limited to, intensive treatment in an emergency room or at 
home for allergic bronchospasm, blood dyscrasias, or convulsions that do not result in 
hospitalization. 
Hospitalization for elective treatment of a preexisting condition that did not worsen from 
baseline does not meet the definition of an SAE. 
Social or convenience admission to a hospital or prolongation of a hospitalization for social or 
convenience reasons not associated with the occurrence of an AE does not meet the definition of 
an SAE. 
6.2.1. 
Serious Adverse Events That Occur Before Administration of Study Medication 
Before administration of study medication, only SAEs assessed by the investigator as related to 
study participation (e.g., related to study procedures or a change in existing therapy) will be 
transcribed onto the SAE reporting form and reported to the sponsor. 
6.2.2. 
Serious Adverse Events That Occur After Study Completion 
If an investigator becomes aware of an SAE or death that occurs in a subject more than 28 days 
of the subject’s last study visit and that investigator considers the event to be related to the study 
medication, the investigator is obligated to report the SAE to the sponsor as outlined in 
Section 6.7. 
6.3. 
Definition of a Suspected Adverse Reaction  
A suspected adverse reaction is defined as any adverse event for which there is a reasonable 
possibility that the adverse event was caused by the study drug.  For the purposes of IND safety 
reporting, “reasonable possibility” means there is evidence to suggest a causal relationship 


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between the drug and the adverse event.  A suspected adverse reaction implies a lesser degree of 
certainty about causality than adverse reaction, which means any adverse event caused by a drug. 
6.4. 
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 6.2; i.e. death, life-threatening, 
causes or prolongs inpatient hospitalization, causes a persistent of significant incapacity or 
substantial disruption of the ability to conduct normal life functions, or a congenital 
abnormality/birth defect. 
6.5. 
Recording and Evaluating Adverse Events and Serious Adverse Events 
The investigator will attempt to establish a diagnosis of the event on the basis of signs, 
symptoms, or other clinical information.  In such cases, the diagnosis, not the individual signs or 
symptoms, should be documented as the AE or SAE. 
6.5.1. 
Assessment of Intensity 
The investigator will make an assessment of intensity for each AE and SAE reported during the 
study, using his or her clinical judgment.  The intensity of each AE and SAE recorded in the 
eCRF should be assigned to one of the following categories: 
• mild: an event that is easily tolerated by the subject, causes minimal discomfort, and does 
not interfere with everyday activities 
• moderate: an event that is sufficiently discomforting to interfere with normal everyday 
activities 
• severe: an event that prevents normal everyday activities 
An AE that is assessed as severe should not be confused with an SAE.  Severity is a term used to 
describe the intensity of a specific event, and both AEs and SAEs can be assessed as severe.  The 
event itself, however, may be of relatively minor medical significance (such as a severe 
headache).  This is not the same as serious, which is based on the subject’s or event’s outcome or 
on action criteria usually associated with events that pose a threat to a subject’s life or 
functioning (see Section 6.2). 
6.5.2. 
Assessment of Causality 
The investigator is obligated to use his or her clinical judgment to assess the relationship 
between the study medication and the occurrence of each AE or SAE.  For this study, adverse 
events that are considered by the Investigator to have a Possible, Probable, or Definite 
relationship to the investigational product are considered to be “related” to the investigational 
product; unlikely and unrelated are considered to be “not related” to the investigational product.  
Sponsor assessment of causality may differ from Investigator assessment in accordance with 
FDA guidance, Safety Reporting Requirements for INDs and BA/BE studies. 
The investigator will assess the relationship to the study medication by using the following 
criteria: 


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• Definitely Related: An AE has a strong temporal relationship to the study drug.  The AE 
is most likely explained by study drug.  Dechallenge and rechallenge (if possible) are 
positive.  The AE is consistent with a known response to the study drug.  Another 
etiology is unlikely or significantly less likely. 
• Probably Related: An AE has a strong temporal relationship to the study drug.  The AE is 
more likely explained by study drug than by another cause.  Dechallenge (if performed) 
is positive. 
• Possibly Related: An AE has a reasonable temporal relationship to study drug.  The AE 
could have been due to another equally likely cause.  Dechallenge is positive. 
• Not Related: The subject did not receive the study drug OR the AE has no temporal 
relationship to study drug OR the AE has a much more likely alternate etiology OR the 
AE is due to an underlying or concurrent illness or effect of another drug. 
Even in situations in which minimal information is available for the initial SAE report, it is 
important that the investigator always make an assessment of causality for every event before 
transmitting the SAE reporting form and completing the AE eCRF page(s).  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 reporting form and AE eCRF page(s) accordingly. 
6.5.3. 
Assessment of Outcome 
All SAEs must be followed until they are resolved, the condition stabilizes, the events are 
otherwise explained, or the subject is lost to follow-up.  The investigator will assess the outcome 
of the event by using the following terms: 
• Resolved: The event resolved or the subject recovered without sequelae.  An event (either 
serious or nonserious) occurred and had an endpoint, and the subject experienced no 
restrictions.  Examples include stent placement for coronary artery disease (a device 
implanted is not a sequela), an appendectomy (a scar is not a sequela), a postoperative 
wound infection, or an upper respiratory tract infection. 
• Resolved with sequelae: The event has at least one secondary outcome that may result in 
permanent disability, functional limitation, or both.  Such sequelae are usually limited to 
SAEs.  Examples include hip replacement resulting in foot drop (foot drop is not the 
intended outcome but is a risk of surgery), stroke resulting in paralysis, or emboli 
formation after a bacterial infection resulting in a renal infarct and loss of renal function. 
• Not resolved: At the end of the study, a nonserious event either has not changed in 
intensity or may not have recovered to baseline values, and the outcome is unknown.  
Examples include headache, low-grade fever, or nausea. 
• Unknown: The subject has withdrawn from the study prematurely or is lost to follow-up, 
and the status of the event is unknown. 
• Death 
6.5.4. 
Assessment of Expectedness 
For the purposes of IND safety reporting, adverse events and suspected adverse events should be 
assessed as being expected or unexpected.  An AE or suspected adverse reaction is considered 


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unexpected if it is not listed in the investigator brochure or is not listed at the specificity or 
severity that has been observed; or, if an investigator brochure is not required or available, is not 
consistent with the risk information described in the general investigational plan or elsewhere in 
the current application. 
6.6. 
Follow-up of Adverse Events and Serious Adverse Events 
Nonserious AEs will be followed after the last scheduled study visit until an appropriate 
resolution can be documented. 
After the occurrence of an AE or SAE, the investigator is required to follow each subject 
proactively and provide further information on the subject’s condition.  All AEs and SAEs 
documented at a previous visit or contact and designated as ongoing and will be reviewed at 
subsequent visits or contacts. 
SAEs will be followed until the event resolves, the condition stabilizes, the event is otherwise 
explained, or the subject is lost to follow-up.  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 on the originally completed SAE reporting form 
and entered into the eCRF pages, with all changes signed and dated by the investigator.  The 
updated SAE reporting form should be resubmitted to the sponsor within the time frames 
outlined in Section 6.7. 
6.7. 
Prompt Reporting of Serious Adverse Events to the Sponsor 
Once the investigator determines that an event meets the protocol definition of an SAE, he or she 
must notify the sponsor within 24 hours. 
ANY SAE OR ANY OUTCOME OF DEATH DUE TO ANY CAUSE WHICH OCCURS 
DURING THE COURSE OF THIS STUDY, REGARDLESS OF RELATIONSHIP TO STUDY 
MEDICATION, MUST BE REPORTED TO THE SPONSOR IMMEDIATELY (within 24 
hours). 
COMPLETE THE SAE DETAILS REPORTING FORM AND FORWARD BY E-MAIL TO 
THE FOLLOWING SPONSOR CONTACT: 
Medical Monitor 
 
Name: 
Gilad Gordon, MD 
Address: 
4242 Campus Point Court, Suite 200 
San Diego, CA 92121 
USA 
Telephone Number: 
1-303-517-6212 
Fax Number: 
1-858-251-4401 
E-Mail Address: 
htx011safety@herontx.com 
 
 


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In the initial e-mail, 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. 
E-mail transmission is the preferred method to transmit SAE information.  In rare circumstances 
and in the absence of e-mail 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 reporting form and eCRF pages within 
the time frames outlined. 
If the investigator does not have all information regarding an SAE, he or she must not wait to 
receive additional information before notifying the sponsor of the event.  The form must be 
updated when additional information is received.  Follow-up information received on all SAEs 
must be forwarded to the sponsor by using the same procedure and timelines as for an initial 
report. 
6.8. 
Regulatory Reporting Requirements 
The investigator must promptly report all SAEs to the sponsor in accordance with the procedures 
detailed in Section 6.7, “Prompt Reporting of Serious Adverse Events to the Sponsor.”  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 reaction 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 medication, 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 IRB or IEC. 
6.9. 
Precautions 
Any subject who becomes pregnant during the study must be discontinued immediately but 
should be followed through delivery or termination of the pregnancy.  A subject should also 
notify the investigator if she becomes pregnant within 28 days after receiving study medication.  


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The sponsor must be notified of all pregnancies reported to the investigator (see Section 6.7 for 
contact information). 


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7. 
STATISTICAL METHODOLOGY 
7.1. 
Determination of Sample Size 
The sample size of up to approximately 453 subjects (108 subjects for Part A, 90 subjects for 
Part B, 135 subjects for Part C, 45 for Part D, 20 for Part E, 20 for Part F, and 35 for Part G) for 
this study was selected empirically without a formal statistical assumption. 
7.2. 
Study Endpoints 
7.2.1. 
Efficacy Endpoints 
The primary efficacy endpoint will be the SPI0-24. 
Secondary efficacy variables will include the following: 
• SPI at various other time points (SPI0-6, SPI0-12, SPI12-24, SPI24-48, SPI0-48, SPI48-72, SPI0-72, 
SPI72-96, and SPI0-96). 
• The Patient global assessment (PGA) of pain control at 24, 48, 72, and 96 hours post-
treatment. 
• Time to administration of first dose of rescue analgesia. 
• Total and average daily rescue consumption over 24, 48, 72, and 96 hours post-treatment. 
• Mean nausea assessment scores at 6, 24, 48, and 72 hours post-treatment. 
• The percentage of subjects who remain pain free (Numerical Pain Rating Scale ≤ 1) at 72 
hours and at 96 hours after study drug administration.  
7.2.2. 
Pharmacokinetic Endpoints 
The plasma PK parameters for bupivacaine and meloxicam will be derived by non-
compartmental analysis of the plasma concentration-time profiles.  The following 
pharmacokinetic endpoints have been defined: 
• The area under the plasma concentration-time curve from time zero to time t of the last 
measured concentration above the limit of quantification (AUClast) 
• The area under the plasma concentration-time curve from zero to infinity (AUCinf) 
• The maximum plasma concentration (Cmax) 
• The time to reach maximum plasma concentration (Tmax) 
• The terminal elimination rate constant (λZ) with the respective half-life (t½) 
7.2.3. 
Safety Endpoints 
The safety endpoints will include the following: 
• wound assessment findings  
• vital signs 
• clinical laboratory tests, including routine blood chemistry and hematology 


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• ECG findings 
• AEs and SAEs 
7.3. 
General Considerations for Statistical Analysis 
7.3.1. 
Analysis Datasets  
Intent-to-Treat (ITT) Analysis Set: The ITT set will include all subjects who are randomized to 
receive study medication. 
Efficacy Set: The efficacy analysis set will include all subjects who are randomized to receive 
study medication and have recorded at least one post dosing PI scores.  This analysis set is noted 
as the modified Intend-to-Treat (mITT) set. 
Safety Set: The safety set will include all treated subjects and will be used for safety and 
tolerability assessments. 
7.3.2. 
Test Hypothesis and P Value Justification 
The null hypothesis is that there is no difference between each comparison (pairwise or pooled 
group comparison).  The alternative hypothesis is there is a difference for the comparison. 
Each pairwise or pooled group comparison will be evaluated via 2-sided 2-sample t-test at the 
0.05 level of significance.  Nominal p value will be reported without adjustment for multiplicity. 
7.3.3. 
Procedures for Handling Missing Data  
Unless indicated otherwise (see Section 7.3.3.1 and 7.3.3.2), no imputation will be done for 
missing data. 
7.3.3.1. 
PI Score Before and After Analgesic Rescue Medication 
All subjects are expected to assess their postoperative pain intensity according to the pain 
intensity schedule; those PI assessments are referenced as the scheduled PIs.  Subjects who 
require rescue analgesia are expected to report their pain intensity immediately before taking the 
rescue medication; this PI is referenced as the pre-rescue PI.  The duration of analgesic effect 
will be determined for the rescue medication (e.g., the analgesic window for one oxycodone 10 
mg tablet is 6 hours); this analgesic duration is referenced as the analgesic window of this rescue 
medication.  When the assessment of a scheduled PI is done after the rescue medication and the 
time is within the analgesic window (inclusive) of the rescue medication, the scheduled PI score 
will be replaced by the pre-rescue PI score for the purpose of efficacy analysis.  This method is 
referenced as the Windowed Last Observation Carried Forward (WLOCF).  The original 
scheduled PI scores will be displayed on data listing along with the “imputed” PI score. 
7.3.3.2. 
Other Missing PI Score(s) 
After the scheduled PI scores are appropriately replaced by the pre-rescue PI score for all 
subjects who had rescue medication based on the WLOCF method, if there are additional time 


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points where the PI scores are missing, the standard LOCF method will be used to impute the 
missing PI score.  All imputed PI scores will be clearly marked on data listings. 
Additional missing data imputation methods may be used to assess the robustness of the efficacy 
data.  The details will be discussed in the statistical analysis plan for the study. 
7.3.4. 
Derived Variables 
Prior to data base lock, a complete statistical analysis plan will be developed which will describe 
in detail the calculation of all efficacy variables. 
7.3.4.1. 
Study Population Summaries 
Population summaries will be provided for the safety analysis set included in this study. 
7.3.5. 
Disposition 
The summary tables will provide frequency counts for subject disposition (all treated subjects, 
subjects who completed the study, subjects who discontinued from the study, and reason for 
discontinuation) by treatment group and study overall. 
Disposition in terms of number of subjects excluded from each analysis sets (mITT, safety) will 
also be provided by treatment groups and study overall. 
7.3.6. 
Demographics 
The demographic summary will include descriptive statistics for age, sex, race, weight, height, 
and BMI for the overall and by treatment group.  
7.3.7. 
Protocol Violations 
All protocol violations and deviations will be identified.  Tabulation may be provided if data is 
warranted. 
7.3.8. 
Treatment Compliance 
Since study medication is administered intra-operatively, no formal summary of treatment 
compliance will be produced. 
7.3.9. 
Prior and Concomitant Medications 
All prior and concomitant medications will be tabulated for the overall study population.  Prior 
and concomitant medications will be coded to the therapeutic drug classes and generic drug 
names using the World Health Organization (WHO) drug classifications version 1Q2013 or 
higher. 


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7.4. 
Efficacy Analysis 
7.4.1. 
SPI and PI Analyses 
The analyses of the primary and all secondary endpoints will be described in the statistical 
analysis plan. 
7.4.2. 
Time to First Dose of Rescue Medication 
A description of the analysis of time to first dose of rescue medication will be presented in the 
Statistical Analysis Plan. 
7.4.3. 
Patient Global Assessment (PGA) of Pain Control 
Number and percent of subjects in each global pain control category (0-poor, 1-fair, 2-good, 3-
very good, or 4-excellent) will be tabulated by treatment group.  The difference between the 
groups in global pain control will be evaluated based on proportion of subjects rated their pain 
control as good, very good, or excellent using Fisher’s exact test. 
7.4.4. 
Proportion of Subjects Requiring Rescue Medication  
The analysis will evaluate the relative risk (each HTX-011 formulation vs. saline, each HTX-011 
formulation vs. Marcaine, HTX-011-56 vs. HTX-002, and HTX-009 vs. saline) to require rescue 
medications during the treatment phase of the study.  Proportion of subjects that used rescue 
medications at least once will be tabulated by treatment group; treatment group differences will 
be assessed as described in the Statistical Analysis Plan. 
7.4.5. 
Nausea Assessments 
The mean nausea assessment scores at 6, 24, 48, and 72 hours will be calculated, and the analysis 
of the data will be described in the Statistical Analysis Plan. 
7.4.6. 
Opioid Consumption and Symptoms Associated with Opioid Use  
Average daily opioid use will be calculated for each 24 hour period post study medication 
administration.  Subjects who did not use any opioid during a period will be assigned to “0.”  
Average daily opioid data will be tabulated by treatment group with descriptive statistics. 
7.4.7. 
Subgroup Analyses for Efficacy 
No subgroup analysis for efficacy endpoints is planned. 
7.5. 
Safety and Tolerability Evaluations 
7.5.1. 
Adverse Events 
The Medical Dictionary for Regulatory Activities (Version 16 or higher) will be used to classify 
all AEs with respect to system organ class and preferred term. 


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Three types of summaries will be produced for the AE summary: 
1. an overall summary of AEs: number of subjects with at least one event and number of 
events for all AEs and SAEs 
2. a summary table of AEs and SAEs by system organ class and preferred term and severity 
3. a summary table of AEs and SAEs by preferred terms in descending order of total 
incidence 
AEs will be tabulated by treatment group.  AEs that lead to premature discontinuation from the 
study or to death will be listed separately via data listings. 
7.5.2. 
Clinical Laboratory Tests 
Laboratory values will be collected at screening, Day 0 during check-in, 72 hours, and ET.  
Observed values at each time point and change from baseline (Day 0) at the end of study will be 
summarized for the by treatment group without formal statistical testing. 
7.5.3. 
Vital Sign Measurements 
Resting vital sign values at each time point collected will be summarized by treatment without 
formal statistical testing. 
7.5.4. 
Electrocardiograms 
The number and proportion of subjects with abnormal ECG findings at each time point collected 
will be tabulated by treatment group.  A data listing will be provided for subjects with changes 
from normal at baseline to abnormal and clinically significant after baseline by treatment. 
7.5.5. 
Subgroup Analyses for Safety Endpoints 
No subgroup analysis is planned for safety endpoints. 
7.6. 
Pharmacokinetic Analysis 
The PK parameters for bupivacaine and/or meloxicam will be calculated using 
non-compartmental analysis and summarized for formulations of HTX-011, HTX-002, HTX-
009, and for Marcaine. 
7.7. 
Interim Evaluation 
An evaluation of the data in Part A will be used to determine the optimal technique of 
administration of study drug for Part B and Part C.  An evaluation of the data in Part B is also 
planned to determine which formulation/dose to be used for Part C. 


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8. 
STUDY ADMINISTRATION 
8.1. 
Regulatory and Ethical Considerations 
8.1.1. 
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. 
8.1.2. 
Ethical Conduct of the Study and Ethics Approval 
This study will be conducted according to GCP; US 21 Code of Federal Regulations (CFR) Part 
50 (Protection of Human Subjects); US 21 CFR Part 56 (IRBs); US 21 CFR Part 54 (Financial 
Disclosure); International Conference on Harmonisation (ICH) Guidance for Industry, E6 GCP: 
Consolidated Guidance; the Nuremberg Code; and, where applicable the principles of the 
Declaration of Helsinki (Recommendations guiding Medical Doctors in Biomedical Research 
Involving Human Subjects), and with the NH&MRC National Statement on Ethical Conduct in 
Human Research (2007). 
8.1.2.1. 
Ethics Committees 
The investigator (or sponsor, where applicable) is responsible for ensuring that this protocol, the 
site’s informed consent form, and any other information that will be presented to potential 
subjects (e.g., advertisements or information that supports or supplements the informed consent 
form) are reviewed and approved by the appropriate IRB or IEC.  The investigator agrees to 
allow the IRB or IEC direct access to all relevant documents.  The IRB or IEC must be 
constituted in accordance with all applicable regulatory requirements.  The sponsor will provide 
the investigator with relevant documents or data needed for IRB or IEC review and approval of 
the study.  Before investigational products can be shipped to the site, the sponsor must receive 
copies of the IRB or IEC approval, the approved informed consent form, and any other 
information that the IRB or IEC has approved for presentation to potential subjects. 
If the protocol, the informed consent form, or any other information that the IRB or IEC has 
approved for presentation to potential subjects is amended during the study, the investigator is 
responsible for ensuring that the IRB or IEC reviews and approves, where applicable, these 
amended documents.  The investigator must follow all applicable regulatory requirements 
pertaining to the use of an amended informed consent form, including obtaining IRB or IEC 
approval of the amended form, before new subjects consent to take part in the study using the 
new version of the form.  The investigator must promptly forward to the sponsor copies of the 
IRB or IEC approval of the amended informed consent form or other information and the 
approved amended informed consent form or other information.  IRB or IEC approval of the 
consent forms must be obtained in addition to the approval given for the clinical study.  
Regulatory review and approval may be required in some countries before IRB or IEC approval 
can be sought. 


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8.1.2.2. 
General Considerations 
The ethical standards defined within GCP are intended to ensure the following: 
• Human subjects are provided with an adequate understanding of the possible risks of 
their participation in the study, and they have a free choice to participate or not. 
• The study is conducted with diligence and in conformance with the protocol in such a 
way as to ensure the integrity of the findings. 
• The potential benefits of the research justify the risks. 
Heron Therapeutics, Inc. is the sponsor of study HTX-011-C2015-202.  The sponsor (or its 
designee) is responsible for all of the following: 
• selecting qualified investigators 
• providing investigators with the information they need to conduct the investigation 
properly 
• ensuring proper monitoring of the investigation 
• ensuring that appropriate regulatory agencies and all participating investigators are 
properly informed of significant new information regarding AEs or risks associated with 
HTX-011, HTX-002, or HTX-009. 
8.1.3. 
Informed Consent 
The sponsor (or its designee) will provide investigators with a multicenter informed consent 
form 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 informed consent form must be accepted by the sponsor and 
approved by the IRB or IEC.  Investigators must provide the sponsor with an unsigned copy of 
the final informed consent form before and after it is approved by the IRB or IEC.  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 informed consent form, the sponsor 
will provide investigators with a revised informed consent form.  The IRB or IEC must provide 
written approval of any revisions to the informed consent form in advance of its use. 
Investigators must provide subjects 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, and possible risks. 
All information in the informed consent form should be provided in a language (whether written 
or spoken) that is as nontechnical as practical and that is understandable to the subjects. 
Before written 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 (or his or her legally authorized representative). 


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Before a subject undergoes procedures specific to the protocol, the informed consent form must 
be signed and dated by the subject (or his or her legally authorized representative) and any other 
signatories as required by the IRB or IEC. 
If a subject (or legally authorized representative) cannot read, a short form approved by the IRB 
or IEC may be used.  Only the short form itself is to be signed by the subject or the 
representative.  However, the witness shall sign both the short form and a copy of the summary, 
and the person actually obtaining the consent shall sign the copy of the summary in accordance 
with 21 CFR 50.27 (b2). 
After all required signatures have been obtained, a copy of the informed consent form should be 
provided to the subject, and the original must be kept on file at the site and made available for 
review by the sponsor.  Documentation of the informed consent discussion must be noted in the 
subject’s case history. 
8.1.4. 
Investigator Reporting Requirements 
The investigator is responsible for completing and maintaining adequate and accurate eCRFs and 
source documentation.  Source documentation constitutes original records (first point of entry, 
either hard copy or electronic), which may include progress notes, medication administration 
records, operation reports, laboratory reports, discharge summaries, and so on. 
8.2. 
Study Monitoring 
The sponsor (or its designee) is responsible for ensuring the proper conduct of the study with 
regard to subject protection, ethics, protocol adherence, site procedures, and integrity of the data.  
At regular intervals during the study, the sponsor’s study monitors will contact the study site via 
visits to the site, telephone calls, and letters in order to review study progress and 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, use of concomitant therapy by 
subjects, AE and SAE documentation and reporting, and quality of data. 
8.3. 
Quality Assurance 
The sponsor, a regulatory authority, or an IRB representative may visit the study site at any time 
during the study or after completion of the study to perform audits or inspections.  The purpose 
of a sponsor audit or regulatory inspection is to examine systematically and independently all 
study related activities and documents to determine whether these activities were conducted 
according to the protocol, GCP, ICH guidelines, and any other applicable regulatory 
requirements.  Investigators should contact the sponsor immediately if contacted by a regulatory 
agency about an inspection at their site. 
8.4. 
Study and Site Closure 
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 the study site should be 


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closed, this action may be taken after appropriate consultation between the sponsor and 
investigator.  Conditions that may warrant termination of the study include, but are not limited 
to, the following: 
• discovery of an unexpected, serious, or unacceptable risk to the subjects enrolled in the 
study 
• submission of knowingly false information from the research facility to the sponsor, 
study monitor, or regulatory agencies 
• failure of the investigator to comply with GCP (e.g., ICH guidelines, regulatory agency 
guidelines) 
• insufficient adherence to protocol requirements or an unacceptably high rate of missing, 
erroneous, or improperly collected data 
• evidence from the blinded data of sufficient technical problems with the study that one 
could believe with a high degree of certainty that subjects are being exposed to the 
investigational drug without a realistic expectation of evaluable data 
• a decision on the part of the sponsor to suspend or discontinue testing evaluation or 
development of the product 
• failure of the investigator to enroll subjects into the study at an acceptable rate 
8.5. 
Records Retention 
8.5.1. 
Health Insurance Portability and Accountability Act of 1996 
The investigator agrees to comply with all applicable federal, state, and local laws and 
regulations relating to the privacy of subjects’ health information, including, but not limited to, 
the Standards for Individually Identifiable Health Information, 45 CFR Parts 160 and 164 (the 
Health Insurance Portability and Accountability Act of 1996 privacy regulation).  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 and in a form satisfactory to the sponsor. 
8.5.2. 
Financial Disclosure 
Financial disclosure is required for this study. 
8.5.3. 
Access to Original Records 
Regulatory authorities expect that monitors, auditors, and representatives of national and 
international government regulatory agency bodies have access to original source documentation 
(see examples in Section 8.1.4) to ensure data integrity.  “Original” in this context is defined as 
the first documentation of an observation and does not differentiate between hard copy and 
electronic records. 
8.5.4. 
Archiving of Study-Related Documents 
Records related to this clinical study must be retained either for at least 2 years after the last 
approval of a marketing application in an ICH region and until there are no pending or 


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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.  The sponsor 
will notify the investigator as to when these documents no longer need to be retained for this use. 
8.6. 
Provision of Study Results and Information to Investigators 
When a clinical study report is completed, the sponsor will provide the major findings of the 
study to the investigators. 
In addition, details of the study treatment assignment will be provided to the investigators to 
enable them to review the data to determine the outcome of the study for their subjects. 
The sponsor may list and summarize the results from coded samples by subject number in the 
clinical study report.  In this event, the investigator and study staff would have access to the 
research results and would be able to link the results to a particular subject.  The investigator and 
study staff would be directed to hold this information confidentially. 
8.7. 
Information Disclosure and Inventions 
8.7.1. 
Ownership 
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. 
All rights, title, and interests in any inventions, know how, or other intellectual or industrial 
property rights that are conceived or reduced to practice by site staff during the course of or as a 
result of the study are the sole property of Heron Therapeutics, Inc. and are hereby assigned to 
Heron Therapeutics, Inc. 
If a written contract is executed between Heron Therapeutics, Inc. and the study site for the 
conduct of the study and that contract includes ownership provisions inconsistent with this 
statement, that contract’s ownership provisions shall apply rather than this statement. 
8.7.2. 
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 other 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.  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 
IEC or IRB 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 8.7.3.  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. 


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8.7.3. 
Publication 
For multicenter studies, the first publication or disclosure of study results shall be a complete, 
joint, multicenter publication or disclosure coordinated by Heron Therapeutics, Inc.  Thereafter, 
any secondary publications will reference the original publication(s).  If no multicenter 
publication is submitted for publication within 18 months of study database hard lock, then the 
site shall be free to disclose its own results, subject to sponsor rights under Section 8.7.1. 
Before submitting material for publication, presentation, or use for instructional purposes, or 
before otherwise disclosing the study results generated by the site (collectively, a “publication”), 
the investigator shall provide Heron Therapeutics, Inc. with a copy of the proposed publication 
and allow Heron Therapeutics, Inc. a period of at least 90 days to review the proposed 
publication.  Proposed publications shall not include either Heron Therapeutics, Inc. confidential 
information (other than the study results) or the personal data (such as name or initials) of any 
subject. 
At Heron Therapeutics, Inc.’s request, the submission or other disclosure of a proposed 
publication will be delayed a further 90 days to allow Heron Therapeutics, Inc. to seek patent or 
similar protection of any inventions, know-how, or other intellectual or industrial property rights 
disclosed in the proposed publication. 
If a written contract is executed for the conduct of the study and that contract includes 
publication provisions inconsistent with this statement, that contract’s publication provisions 
shall apply rather than this statement. 
8.7.4. 
Data Management 
The investigator (or designee) will enter subject data by using the eCRF defined by Heron 
Therapeutics, Inc. or its designee.  Clinical data management will be performed in accordance 
with applicable Heron Therapeutics, Inc. standards and data cleaning procedures.  Database 
freeze will occur when data management quality-control procedures are completed. 
In addition, validated laboratory data will be transmitted electronically from the clinical 
laboratory to Heron Therapeutics, Inc. or its designee. 
The investigator or designee must record all required data using the previously specified data 
collection method defined by Heron Therapeutics, Inc. or its designee.  An explanation must be 
documented for any critical data points.  The investigator must sign and date a declaration in the 
eCRF attesting that he or she is responsible for the quality of all data recorded and that the data 
represent a complete and accurate record of each subject’s participation in the study. 
8.7.5. 
Data Security 
Access to the data will be strictly controlled. 


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8.8. 
Subject Tracking 
Drug accountability logs, a subject identification log (to be retained by the investigator only), 
and a subject enrollment log will be used to track subject participation in the study. 
 


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9. 
REFERENCES 
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. 
Moiniche, S., S. Mikkelsen, J. Wetterslev and J. B. Dahl (1998). "A qualitative systematic 
review of incisional local anaesthesia for postoperative pain relief after abdominal operations." 
Br J Anaesth 81(3): 377-383. 
Moote, C. (1992). "Efficacy of nonsteroidal anti-inflammatory drugs in the management of 
postoperative pain." Drugs 44 Suppl 5: 14-29; discussion 29-30. 
Ortiz, Mario I., Gilberto  Castañeda-Hernández, Jeannett A.  Izquierdo-Vega and Héctor A.  
Ponce-Monter (2011). "Peripheral synergistic interaction between lidocaine and lumiracoxib on 
the 1% formalin test in rats." The Open Pain Journal 4: 8-14. 
Rawal, N. (2001). "Analgesia for day-case surgery." Br J Anaesth 87(1): 73-87. 
Renck, H. (1994). "Wound infiltration with local anaesthetics." Acta Anaesthesiol Scand 38(1): 
2-6. 
 
 
 


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10. 
APPENDICES 
Appendix A: 
OVERVIEW OF STUDY SCHEDULE 
Table 1: 
SCREENING 
Procedure 
Day -28 to Day -1 
Screening 
Informed Consent 
X 
Eligibility Assessment 
X 
Demographics and Medical History 
X 
Assessment of PONV Risk Factors 
X 
ASA Classification Assessment 
X 
Physical Examination 
X 
Pregnancy Test  
(female subjects of child bearing potential only) 
Xserum 
Urine Drug Screen 
X 
Alcohol Breath Test 
X 
Clinical Laboratory Tests a 
X 
Vital Signs b 
X 
BMI Determination 
X 
12-lead ECG 
X 
Pain Training 
X 
Prior and Concomitant Medication c 
X 
Serious Adverse Event Monitoring d 
X 
a Laboratory tests will include hematology and chemistry screenings in all subjects.  Results will determine subject 
eligibility for the study. 
b Resting vital signs (VS) will be collected at screening.  Resting VS include: resting blood pressure, resting pulse, 
respiratory rate, oral temperature and SpO2.  Resting tests must be obtained after resting (seated/reclined) for ≥ 5 
minutes. 
c ConMeds taken within 30 days before dosing will be recorded. 
d SAEs will be reported if considered related to study participation. 
 
 


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Appendix A: 
OVERVIEW OF STUDY SCHEDULE 
Table 2: 
DAY 0 PRIOR TO SURGERY AND SURGERY 
 
Day 0 
Prior to Surgery 
Surgery 
Eligibility Assessment 
X 
 
Demographics and Medical History 
X 
 
Physical Examination c 
X 
 
Pregnancy Test  
(female subjects of child bearing potential only) 
Xurine 
 
Urine Drug Screen 
X 
 
Alcohol Breath Test 
X 
 
Clinical Laboratory Tests a 
X d 
 
Vital Signs b 
X 
 
12-lead ECG 
X  
 
Pain Training 
X 
 
Blood Draw for PK 
X d 
 
Neurologic Exam 
X 
 
Surgery Procedure 
 
X 
Study Drug Administration 
 
X 
Prior and Concomitant Medication f 
X 
 
Serious Adverse Event Monitoringg 
X 
X 
a Laboratory tests will include hematology and chemistry and will be used as baseline reference and not for 
determining subject eligibility. 
b Resting vital signs (VS) will be collected at screening and check-in only, all other assessments will include resting 
VS only.  Resting VS include: resting blood pressure, resting pulse, respiratory rate, oral temperature and SpO2.  
Resting tests must be obtained after resting (seated/reclined) for ≥ 5 minutes.  VS will have a ± 15 minute window. 
c Physical examination will include weight only but not height or BMI. 
d Baseline laboratory samples can be collected prior to surgery. 
f ConMeds taken within 30 days before dosing will be recorded 
g SAEs that occur before study drug administration will be reported only if considered related to study participation.  
After study drug administration, all SAEs that occur through Day 28 post-treatment must be reported. 


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Appendix A: 
OVERVIEW OF STUDY SCHEDULE 
Table 3: 
POST STUDY MEDICATION ADMINISTRATION 
 
Day 0 to 5 
D10 
(±2d) 
D28 
(±2d) 
D60 
(±8d) 
Post Study Drug Administration Time Points (hrs) 
0.5 
1f 
1.5 
2 
3 
4 
6 
8, 10, 12 
14 
18 
24 
30 
36 
42 
48g 
54g 
60g 
72g 
78g 
84g 
96g 
120  
Confinement 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
Physical Examination 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xg 
 
 
 
 
Xc  
 
 
Clinical Laboratory 
Tests a 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Vital Signs b 
 
X 
 
X 
 
X 
X 
X (12hr  
only) 
 
X 
X 
 
X 
 
X 
 
X 
X 
 
 
X 
 
X  
 
 
12-lead ECG 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
X  
 
 
Pain Intensity (PI) 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
PGA of Pain Control  
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
Use of Rescue 
Medication 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Xe 
Xe 
 
PK Blood Draws 
(±15 min) 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
 
X 
X 
 
 
X 
X g 
 
 
 
Numerical Rating 
Scale for Nausea 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
Assessment of 
Wound Healing 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
X 
 
Photos  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
X 
 
 
Bupivacaine Toxicity 
and Neurological 
Assessment 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
AE Monitoring d 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
Phone Call h 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Abbreviations: AE, adverse event; D, day; ECG, electrocardiogram; hr(s), hour(s); min, minutes; PK, pharmacokinetics. 
a Laboratory tests will include hematology and chemistry. 


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b Resting VS only.  Resting VS include: resting blood pressure, resting pulse, respiratory rate, oral temperature and SpO2.  Resting tests must be obtained after resting (seated/supine) for ≥ 5 minutes. 
c Physical examination will include weight only, but not height or BMI.  Weight not required at 72 hour exam. 
d AEs will be monitored after administration of study medication through the Day 10 study visit.  SAEs will be monitored through Day 28. 
e Subjects may resume standard of care pain medication as advised by their surgeon after the 72 hour study visit. 
f 1 hour assessments to be completed if subject is awake and alert. 
g ± 30 minutes for 72hr Physical Exam, ± 60 minutes for the 48, 54, 60 and 72 hr assessments, and ± 4 hours for the 96 and 120 hr assessments 
h Subjects will receive a phone call from the study site on Day 60 (±8 days). Subjects will be asked if they have any current pain related to the operation. Subjects will also be asked to think about the 
previous 24 hours and to rate their pain intensity related to the operation using the NRS and to report any medication(s) taken to treat the pain (name, dose, and route). 


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Appendix B: 
INVESTIGATOR OBLIGATIONS 
As an investigator, you are responsible for ensuring that the study is conducted according to 
the protocol, the signed Statement of Investigator, and all applicable regulations. 
Debarment 
Individuals ineligible to conduct or be involved with clinical studies, including those 
ineligible as a result of debarment under the Generic Drug Enforcement Act of 1992, will not 
be allowed to conduct or work on studies sponsored by Heron Therapeutics, Inc.  You are 
required to disclose immediately to the sponsor, in writing, if any person involved in the 
conduct of the study is debarred pursuant to a hearing by FDA under this antifraud law or if 
any proceeding for debarment is pending or is (to the best of your knowledge) threatened. 
Institutional Review Board 
You are required to obtain initial and continuing review and approval by an IRB or IEC that 
complies with the requirements specified in 21 CFR Part 56.  Before initiating the trial, you 
must have written approval from the IRB or IEC for the protocol, informed consent form, 
subject recruitment procedures (e.g., advertisements), and any other written information to be 
provided to the subjects.  You must submit the Investigator’s Brochure and any updates to 
the IRB or IEC for review.  The IRB or IEC must also provide written approval of any 
amendments to the protocol that affect the conduct of the study and any changes to the 
informed consent form in advance of use.  If the duration of the study is longer than 1 year, 
reapproval by the IRB or IEC must be obtained on a yearly basis (or at more frequent 
intervals if required by the IRB or IEC).  All IRB or IEC approvals must be forwarded to the 
sponsor. 
You must provide reports of all SAEs from your site to the IRB or IEC.  You are also 
responsible for providing the IRB or IEC with Safety Reports of any SAEs from any other 
study conducted with the study medication.  The latter will be provided to you by the 
sponsor. 
Confidentiality and Safety of Subjects 
You are responsible for protecting the rights, safety, and welfare of subjects under your care 
and for the control of the drug(s) under investigation. 
You are responsible for keeping a record of all screened subjects, including full names and 
last known addresses.  All subjects will be identified on the eCRFs by initials and subject 
numbers.  Demographic information including date of birth, sex, and race will also be 
recorded on the eCRFs.  Confidentiality of subject data will be maintained in accordance 
with local laws. 
In addition to your responsibilities for reporting AEs identified during the course of a 
subject’s participation in the study, you must also report any SAEs that occur within 28 days 
after the last dose of study medication (regardless of relationship to study medication) and 


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any serious adverse drug reactions (SAEs for which you consider that there is a reasonable 
possibility that the study medication caused the response) that you become aware of at any 
time (even if the event occurs more than 28 days after the subject’s last exposure to study 
medication).  This obligation is in addition to any protocol-specified requirement for 
reporting AEs occurring after the last dose of study medication.  Please refer to Sections 6.7 
and 6.8 of this protocol for contact information and SAE reporting requirements. 
Study-Related Records 
You are required to maintain complete and accurate study documentation in compliance with 
current GCP standards and all applicable federal, state, and local laws, rules, and regulations 
related to the conduct of a clinical study. 
You are required to make all study documentation promptly available for inspection, review, 
or audit at your study site upon request by the sponsor, its representatives, or any appropriate 
regulatory agencies. 
Accountability of the Investigational Product 
You or your designee (i.e., the pharmacist) is responsible for accountability of the 
investigational product at the site.  You or your designee must maintain records of the 
product’s delivery to the site, inventory at the site, use by each subject, and the return to the 
sponsor or alternative disposition of any unused product.  These records must include dates; 
quantities; batch, serial, or lot numbers; and expiration dates (if applicable). 
You should ensure that the investigational product is used only in accordance with the 
protocol. 
 
 


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Appendix C: 
STUDY-SPECIFIC INFORMATION 
Appendix C.1: 
Pain Intensity Assessments 
PAIN INTENSITY- NUMERICAL PAIN RATING SCALE (NPRS) 
On a scale of 0–10, please rate your pain by marking an ‘X” in the appropriate box that 
best describes your pain NOW. 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No Pain 
 
 
 
 
 
 
 
 
 
Worst Pain 
Imaginable 
 
 
 


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Appendix C.2.: 
Patient Global Assessment (PGA) of Pain Control  
The following question will be answered by the subject 24, 48, 72, and 96 hours after study 
treatment initiation: 
“Overall, please rate how well your pain has been controlled during the last 24 (48, 72, 
96) hours since you received study medication?” 
 
Response to each question will be:  (Check (√) one box) 
  Poor (0) 
  Fair (1) 
  Good (2) 
  Very Good (3) 
  Excellent (4) 
 
 


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Appendix C.3: 
Risk Factors for Postoperative Nausea and Vomiting 
• Past history of postoperative nausea and vomiting and/or motion sickness 
• Habitual nonsmoking status 
• Female sex 
• Expected to receive opioid analgesia postoperatively. 
 
 


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Appendix C.4: 
Nausea Numerical Rating Scale 
At 6, 24, 48, and 72 hours after the administration of study medication, subjects will answer 
the following question: 
On a scale of 0–10, please rate your nausea by marking an ‘X” in the appropriate box 
that best describes your nausea level NOW. 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No 
Nausea 
 
 
 
 
 
 
 
 
 
Worst 
Nausea 
Imaginable  
 
 
 


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Appendix D: 
BMI CALCULATION 
Body Mass Index Calculations 
 
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 E: 
AMERICAN SOCIETY OF ANESTHESIOLOGISTS 
PHYSICAL STATUS CLASSIFICATION SYSTEM 
I 
Normal healthy subject 
II  
Subject with mild systemic disease; no functional limitation – e.g. smoker with well-
controlled hypertension 
III  
Subject with severe systemic disease; definite functional impairment – e.g. diabetes 
and angina with relatively stable disease, but requiring therapy 
IV 
Subject with severe systemic disease that is a constant threat to life – e.g. diabetes 
and angina and congestive heart failure; subjects with dyspnea on mild exertion and 
chest pain 
V 
Unstable moribund subject who is not expected to survive 24 hours with or without 
operation 
VI 
Brain dead subject whose organs are removed for donation to another 
E 
Emergency operation of any type, which is added to any of the above six categories, 
an in ASA II E 
 
 
 


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Appendix F: 
WOUND SITE EVALUATION 
WOUND SITE EVALUATION 
Timepoint: 
 72 Hour  
 Day 10 
 Day 28 
NOT DONE   
 
Normal 
(Expected 
Post-
Surgical 
Findings) 
Abnormal 
Not Done 
Please Describe Abnormalities 
Wound Site 
 
 
 
 
Other, specify: 
____________ 
 
 
 
 
• Normal expected post-surgical findings is defined as but is not limited to: wound dry, 
no dehiscence, no erythema, no drainage, and swelling consistent with expected post-
surgery findings. 
• Abnormal findings should be recorded as adverse events. 
 
 
 
 
Investigator’s Signature 
 
Date 
 
 


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Appendix G: 
BUPIVACAINE TOXICITY EVALUATION 
 
Time point: 
 24 Hour  
 48 Hour  
 72 Hour  
NOT DONE   
 
 
Absent 
Present 
Describe Abnormalities and note if 
clinically significant 
Perioral tingling 
 
 
 
Strange taste 
 
 
 
Muscle twitching 
 
 
 
Ringing in ears 
 
 
 
Seizure 
 
 
 
Bradycardia 
 
 
 
Cardiac Arrest 
 
 
 
Abnormal findings should be recorded as adverse events if determined to be clinically 
significant. 
 
 
 
Investigator’s Signature 
 
Date 
 


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Appendix H: 
INSTRUCTIONS FOR TAKING PHOTOGRAPHS OF 
SURGICAL WOUND AFTER HERNIORRHAPHY 
Materials 
• Camera (specify type and model).  Identify camera settings. 
• ID tag: Complete for Protocol#, Subject #, Study  Hour or Day, Date, Time, and area 
photographed  
• Adhesive Backed Decal (on a roll) ruler  
 
1. Ensure the batteries in the camera are charged.  If low, replace the batteries prior to 
using the camera. 
2. Expose the area to be photographed. 
3. Remove any dressing and place the completed ID tag and adhesive backed ruler decal 
adjacent to the area to be photographed, taking care not to obscure any area of the 
wound. 
4. Ensure that Protocol #, Subject #, Study Hour or Day, Date, Time, and area being 
photographed are documented for reference purposes in the photograph. 
5. At each photographic time point (immediately after surgery, 48, 72, and 96 hours, and 
Days 10 and 28) take 3 photos from different angles clearly showing the surgical 
incision in the hope that there will be at least one taken from each view that best 
represents the wound area. 
 


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Appendix I: 
DAY 60 FOLLOW-UP PHONE CALL  
Subjects will receive a follow-up phone call from the site on Day 60 (± 8 days). Sites will 
attempt to contact subjects at least twice to complete this assessment; attempts must be 
recorded, including the phone number called, in source documents.  
During the Day 60 call, subjects will be asked the following questions. The results will be 
recorded in source documents. 
1. Are you having any pain related to the operation? 
Yes/No 
2. Thinking about the past 24 hours, on a scale of 0 – 10 with 0 being no pain and 10 
being the worst possible pain, what is your pain related to the operation? 
0 – 10 
3. Thinking about the past 24 hours, have you taken any medication(s) to treat pain 
related to the operation? 
Yes/No 
4. If you answered Yes to Question 3, what medications (name, dose, and route) have 
you taken? 
 
 
 
Enter “N/A” if not applicable 
 
 



SAP_001.pdf: 
Document Type:  
Statistical Analysis Plan 
Official Title:  
Phase 2, Randomized, Pilot Study to Investigate the Safety, Efficacy, 
Pharmacokinetics and Bioavailability of HTX-011, HTX-002, or HTX-
009 Administered Via Injection and/or Topical Application Following 
Unilateral Open Inguinal Herniorrhaphy 
NCT Number:  
NCT02504580 
Document Date:  
24-Mar-2017 
 


Heron Therapeutics, Inc. 
Statistical Analysis Plan
HTX-011-C2015-202 
 
Version 1.0; 24 March 2017
 
 
Confidential 
Page 1 of 47
 
  
 
Statistical Analysis Plan 
Heron Therapeutics, Inc. 
HTX-011-C2015-202 
 
 
 
A Phase 2, Randomized, Pilot Study to Investigate the Safety, Efficacy, 
Pharmacokinetics and Bioavailability of HTX-011, HTX-002, or HTX-009 Administered 
Via Injection and/or Topical Application Fol owing Unilateral Open Inguinal 
Herniorrhaphy 
Protocol Version: 12 0 31JAN2017 
 
 
 
 
 
Sponsor:  
       Heron Therapeutics, Inc. 
    
                   4242 Campus Point Court, Suite 200  
                               San Diego, CA 92121 
Version: 
       1.0 
Date of Creation: 29 June 2016 
Last Updated:      24 March 2017 
 
HTX-011-202 SAP V1 24Mar2017 | VV-TMF-05704 | 1.0
Approved
Downloaded by System  on 3/7/2018




Heron Therapeutics, Inc.  
Statistical Analysis Plan
HTX-011-C2015-202 
 
Version 1.0; 24 March 2017
 
 
Confidential 
Page 3 of 47
 
TABLE OF CONTENTS 
 
ABBREVIATIONS ............................................................................................................5 
1 
INTRODUCTION ......................................................................................................7 
2 
STUDY OBJECTIVES ..............................................................................................8 
3 
STUDY DESIGN ........................................................................................................9 
3.1 
Overall Study Design .............................................................................................9 
3.2 
Treatment and Schedule of Assessments ...........................................................10 
4 
STUDY ENDPOINTS ..............................................................................................15 
4.1 
Efficacy Endpoints ...............................................................................................15 
4.2 
Safety Endpoints ..................................................................................................15 
 
Adverse Events ................................................ ..............................................16 
 
Nausea Assessments ............................................ ........................................16 
 
Vital Signs ......................................................... ........ ...................................16 
 
Laboratory Parameters ..............................
..... .......................................16 
 
Electrocardiograms................................... ....................................................17 
 
Wound Healing Assessments ........................................................................17 
 
Bupivacaine Toxicity ............................
...................................................17 
 
Liver Function ................................... ..........................................................17 
 
Neurological Exams .................... .................................................................17 
5 
DATA QUALITY ASSURANCE .... .......................................................................17 
6 
POPULATIONS DEFINED ........
..... ................................................................18 
6.1 
Sample Size Determination .. ........ ....................................................................18 
7 
STATISTICAL METHODS AND DATA CONSIDERATIONS.........................18 
7.1 
General Considerations ....... ............................................................................18 
 
Standard Calculations .. ..............................................................................21 
7.2 
Analysis Datasets .. .....
..... ...........................................................................21 
7.3 
Disposition of Subjects and Protocol Violations ...............................................22 
7.4 
Demographic and Other Baseline Characteristics ............................................22 
7.5 
Prior and Concomitant Medications ..................................................................22 
7.6 
Treatment Compliance and Extent of Exposure ..............................................23 
7.7 
Efficacy Analysis ..................................................................................................23 
 
Primary Efficacy Endpoint Analysis Methods ............................................24 
7.7.2 
Secondary Efficacy Endpoint Analysis Methods ........................................25 
7.7.3 
Exploratory Analyses.....................................................................................27 
7.8 
Data Imputation and Adjustment ......................................................................28 
7.8.1 
PI Assessments ...............................................................................................28 
7.8.2 
Other Assessments .........................................................................................29 
7.9 
Safety Analysis .....................................................................................................29 
 
Adverse Events ...............................................................................................29 
 
Nausea Assessments .......................................................................................30 
 
Clinical Laboratory Tests..............................................................................30 
 
Vital Sign Measurements ..............................................................................30 
 
Electrocardiograms........................................................................................31 
 
Physical Examinations ...................................................................................31 
HTX-011-202 SAP V1 24Mar2017 | VV-TMF-05704 | 1.0
Approved
Downloaded by System  on 3/7/2018


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Statistical Analysis Plan
HTX-011-C2015-202 
 
Version 1.0; 24 March 2017
 
 
Confidential 
Page 4 of 47
 
 
Wound Healing Assessments ........................................................................31 
 
Bupivacaine Toxicity .....................................................................................31 
 
Liver Function ................................................................................................31 
7.9.10 
Neurological Exam .........................................................................................32 
8 
INTERIM ANALYSIS .............................................................................................32 
9 
CHANGE FROM ANALYSIS PLANNED IN PROTOCOL ...............................32 
10 REFERENCES .........................................................................................................33 
List of tables, figures and data listings ...........................................................................34 
 
 
List of Tables 
Table 1: 
Protocol Revision History ..........................................................................7 
Table 2: 
Cohorts for each Part ..............................................................................10 
Table 3: 
Screening ...................................................
............................................11 
Table 4: 
Prior to Surgery and Surgery (Day 0)...... .... ......................................12 
Table 5: 
Post Study Medication Administration (Days 0-5) ...............................13 
Table 6: 
Analgesic Windows and Morphine Milligram Equivalencies ..............27 
Table 7: 
Criteria for Abnormal Vital Signs.. .... .... ...........................................31 
Table 8: 
Criteria for Abnormal Liver Function ..................................................31 
  
 
 
 
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ABBREVIATIONS  
Abbreviation 
Definition 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
ANOVA 
analysis of variance 
AST 
aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
AUC 
area under the curve 
BMI 
body mass index 
BPM 
beats per minute 
CI 
confidence interval 
CRF 
case report form 
CS 
clinically significant 
CSR 
clinical study report 
DBP 
diastolic blood pressure 
ECG 
electrocardiogram 
ICH 
International Conference on Harmonisation 
IP 
investigational product 
ITT 
Intent-to-Treat 
IV 
intravenous 
LOCF 
last observation carried forward 
LSMD  
least-squares mean difference 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
modified Intend-to-Treat  
MME 
morphine milligram equivalency 
NCS 
not clinically significant 
NRS 
numeric rating scale 
PACU 
post anesthesia care unit 
PGA 
Patient Global Assessment 
PI 
pain intensity 
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Abbreviation 
Definition 
PK 
pharmacokinetic 
PONV 
postoperative nausea and vomiting 
PT 
preferred term 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SBP 
systolic blood pressure 
SD 
standard deviation 
SEM 
standard error of the mean 
SOC 
system organ class 
SPI 
summed pain intensity 
SpO2 
peripheral oxygen saturation 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 
WHO 
World Health Organization 
WLOCF 
windowed last observation carried forward  
 
 
 
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1 INTRODUCTION  
This statistical analysis plan (SAP) describes the planned statistical analysis and reporting of the clinical 
study HTX-011-C2015-202 titled “A Phase 2, Randomized, Pilot Study to Investigate the Safety, 
Efficacy, Pharmacokinetics and Bioavailability of HTX-011, HTX-002, or HTX-009 Administered Via 
Injection and/or Topical Application Following Unilateral Open Inguinal Herniorrhaphy”. This SAP does 
not include the planned analysis and reporting of the pharmacokinetic (PK) assessments in the study; 
these will be presented in a separate document. 
Table 1: 
Protocol Revision History 
Protocol Revision Chronology: 
Protocol Version 1 
13 May 2015 
Original protocol submitted to FDA 
Protocol Version 2 
23 Jun 2015 
Updates predominantly administrative 
Protocol Version 3 
13 Aug 2015 
HTX-011-49 to replace HTX-011-19 if available, additional PK 
time point (120 hours) 
Protocol Version 4 
03 Sep 2015 
Removal of Mesh and HTX-011-49 
Protocol Version 5 
23 Nov 2015 
Reintroduction of Mesh  
Protocol Version 6 
22 Dec 2015 
Addition of HTX-011-49 and clarification of dosing 
Protocol Version 7 
28 Feb 2016 
Addition of HTX-011-56 and separation of study into Part A and 
Part B 
Protocol Version 8 
08 Jun 2016 
Addition of two HTX-002 injection cohorts and two HTX-011-56 
topical cohorts as Part C 
Protocol Version 9 
08 Jul 2016 
Addition of two HTX-002-013 topical cohorts and Marcaine to 
Part C  
Protocol Version 10 
07 O t 2016 
Addition of three HTX-011-56 cohorts, with/without fentanyl 
injection as Part D, and 2 cohorts of HTX-009 or saline placebo as 
Part E 
Protocol Version 11 
28 Dec 2016 
Addition of Part F; saline placebo or 400 mg HTX-56 via 
instillation, with 50 µg fentanyl IV. Terminology changed from 
“Topical” to “Instillation”. 
Protocol Version 12 
31 Jan 2017 
Addition of 3 Part G cohorts; saline + fentanyl, 75 mg Marcaine 
without epinephrine + fentanyl, and 300 mg HTX-011-56 + 
fentanyl.  
Note:  This SAP may not be revised with every amendment of the study protocol.  
This SAP was based on protocol version 12, issued 31 January 2017, and was prepared prior to database 
lock to provide full details to be presented in the clinical study report (CSR). Revisions can be made to 
this SAP while the study is ongoing, but the SAP must be finalized before the database is locked. Any 
changes between the statistical methods provided in the clinical study protocol and this SAP will be 
explained herein; any changes or deviations from this SAP relative to the final analysis will be fully 
documented in the CSR, including the rationale. 
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The present Phase 2 study is designed to evaluate the efficacy and duration of analgesia following 
administration of HTX-011, HTX-002, or HTX-009. There are 7 parts to this study. Part A will evaluate 2 
administration techniques and 2 dose levels of the HTX-011-19 formulation applied into the surgical site 
following unilateral open inguinal herniorrhaphy. Upon the completion of Part A, one of the two 
administration techniques will be chosen for Part B. Part B will evaluate the efficacy and safety of the 
HTX-011-49 and HTX-011-56 formulations at 2 dose levels via administration of the preferred technique 
as determined in Part A. Part C will evaluate the efficacy and duration of analgesia following 
administration of HTX-011-56 and HTX-002, at 2 dose levels, with two administration techniques in 
comparison to normal saline and MarcaineTM.  Part D will evaluate the efficacy and duration of analgesia 
following administration of 400 mg HTX-011-56 with or without fentanyl at the end of surgery via 
combination administration. Part E will evaluate the efficacy and duration of analgesia following 
administration of HTX-009 or saline placebo. Part F will evaluate the efficacy and duration of analgesia 
following administration of 400 mg HTX-011-56 with fentanyl at the end of surgery via instillation 
administration, and Part G will evaluate the efficacy and duration of analgesia following administration of 
300 mg HTX-011-56 with fentanyl IV or Marcaine (without epinephrine) with fentanyl IV at the end of 
surgery via injection administration before wound closure. 
Saline placebo groups are included in each part to match part-specific administration methods. 
Efficacy assessments are intended to characterize the analgesic time action curve and the magnitude of 
analgesic effect of multiple dosing techniques and formulations of HTX-011, HTX-002, and HTX-009. In 
addition, the study will further characterize the safety and PK profiles of all formulations of HTX-011, 
HTX-002, and HTX-009. 
2 STUDY OBJECTIVES 
The primary objective for Part A is to evaluate the efficacy and duration of analgesia following 
administration of one of two doses of HTX-011-19 by two different techniques.  
The primary objective of Parts B th ough G will be to evaluate the efficacy and duration of analgesia 
following administration of HTX-011-49, HTX-011-56, HTX-002, HTX-009, bupivacaine (Marcaine), or 
normal saline. 
The secondary objectives to be evaluated in Parts A through G are as follows: 
 
 To determine in Part A the optimal administration technique of study drug 
 
 To determine the safety and tolerability of HTX-011, HTX-002, and HTX-009 as 
evaluated through physical examination, vital signs, clinical laboratory tests, electrocardiograms 
(ECGs), and incidence of adverse events (AEs) and serious AEs (SAEs) 
 
 To evaluate the PK profiles of bupivacaine and/or meloxicam in HTX-011, HTX-002, and HTX-
009 over 120 hours 
 
 To evaluate the analgesic effects of HTX-011, HTX-002, and HTX-009 over various 
intervals using a series of secondary efficacy endpoints for pain intensity (such as the 
patient’s global assessment [PGA] of pain control, time to administration of first dose of rescue 
analgesia, and total and average daily rescue consumption) 
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 To assess the effects of HTX-011, HTX-002, and HTX-009 on wound healing at 72 hours 
and on Days 10 and 28 post-treatment 
 
 To evaluate nausea at 6, 24, 48, and 72 hours post-treatment 
 To evaluate the percentage of subjects who are pain free over time   
3 STUDY DESIGN 
3.1 
Overall Study Design 
This is a Phase 2, multicenter, single-dose, randomized study in adult subjects undergoing unilateral open 
inguinal herniorrhaphy. The study will enroll up to approximately 453 subjects.  
Male and female subjects at least 18 years of age requiring unilateral open inguinal herniorrhaphy will be 
screened for participation at the study sites in the United States within 28 days of the planned surgery. 
After signing the informed consent form, subjects will be assessed for medical history, postoperative 
nausea and vomiting (PONV) risk factors, physical examination, baseline clinical laboratory tests, drug 
and alcohol screen, 12 lead electrocardiogram (ECG), pregnancy testing, vital sign measurements. 
Additionally, they will undergo pain and placebo assessment training during the screening visit. 
On the day of surgery (Day 0), after having been reassessed for eligibility, subjects will undergo a 
unilateral open inguinal herniorrhaphy und r general anesthesia. No epidural or spinal anesthesia will be 
allowed, nor will any local anesthetic infiltration, other than the administration of the investigational 
product (IP), be permitted. No prophyl ctic antiemetic, local anesthetics, or analgesic medications are 
allowed at any time. A single dose of study drug (either HTX-011, HTX-002, HTX-009, Marcaine, or 
saline, according to a randomization schedule) will be administered. Start and stop time of dosing will be 
recorded. Dosing stop time will be co sidered Time 0. 
Following the completion of surgery and immediate postoperative recovery stay, subjects will be 
transferred to the post-anesthesia care unit (PACU). Staff members in the PACU will be blinded to study 
treatment administered. Subjects will stay at the PACU for approximately 72 hours after the 
administration of study medication and will return to the study center 96 and 120 hours after the 
administration of study medication to complete additional assessments. Subjects will be scheduled to 
return on Day 10 for additional efficacy and safety assessments and Day 28 for an assessment of wound 
healing and collection of AEs and concomitant medications. Part A of the study will determine the 
optimal technique of administration of study drug. Efficacy assessments will include pain intensity 
scoring, use of rescue medication, PGA of pain control, assessments of nausea, and use of analgesia 
rescue medicine. Safety assessments will include monitoring of AEs, physical examinations, vital sign 
measurements, clinical laboratory tests, ECGs, and wound healing assessments and photographs of the 
surgical site. Blood samples will be obtained to assess meloxicam and bupivacaine pharmacokinetics. 
Subjects will also receive a phone call from the study site on Day 60 to collect follow-up information on 
postoperative pain and pain medications. 
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3.2 
Treatment and Schedule of Assessments 
Efficacy assessments will include pain intensity scoring using a numeric rating scale (NRS), use of rescue 
medication, and the PGA of pain control.  Safety assessments will include monitoring of AEs, vital sign 
measurements, clinical laboratory tests, ECGs, nausea assessments, and wound healing assessments. 
Blood samples will be obtained to assess meloxicam and bupivacaine pharmacokinetics. Dosing and 
formulation cohorts are outlined in Table 2, and the planned schedule of study procedures is outlined in 
Table 3, Table 4, and Table 5. 
Table 2: 
Cohorts for each Part  
Part A 
Cohort A (18 subjects) 200 mg (3.42 mL)  HTX-011-19 injection 
Cohort B (18 subjects) 400 mg (6.84 mL)  HTX-011-19 injection 
Cohort C (18 subjects) 200 mg (3.42 mL) HTX-011-19 instillation 
Cohort D (18 subjects) 400 mg (6.84 mL)  HTX-011-19 instillation  
Cohort E (18 subjects) 400 mg (6.84 mL)  HTX-011-19 injection and instil ation combination 
Cohort F (18 subjects) 6.84 mL saline placebo injection  
Part B 
Cohort M (15 subjects) 200 mg (6.84 mL) HTX-011-49 injection 
Cohort N (15 subjects) 400 mg (13.68 mL) HTX-011-49 injection  
Cohort O (15 subjects) 200 mg (6.84 mL) HTX-011-56 injection 
Cohort P (15 subjects) 400 mg (13.68 mL) HTX-011-56 injec ion 
 
Cohort Q (15 subjects) 6.84 mL saline placebo injection 
Cohort R (15 subjects) 13.68 mL saline placebo injecti n 
 
 
Part C 
Cohort S (15 subjects) 200 mg (6.84 mL) HTX-011-56 instillation 
Cohort T (15 subjects) 400 mg (13.68 mL) HTX-011 56 instillation 
Cohort U (15 subjects) 200 mg (6.84 mL) HTX-002 injection 
Cohort V (15 subjects) 400 mg (13.68 mL  HTX-002 injection 
Cohort X (15 subjects) 6.84 mL saline placebo injection 
Cohort Y (15 subjects) 13.68 mL saline placebo injection 
 
Cohort Z (15 subjects) 75 mg (30 mL) Marcaine injection 
Cohort W1 (15 subjects) 200 mg (6.84 mL) HTX-002 instillation 
Cohort W2 (15 subjects) 400 mg (13.68 mL) HTX-002 instillation 
Part D 
Cohort A1 (15 subjects) 400 mg (13.68 mL) HTX-011-56 injection and instillation combination + fentanyl 50 µg IV 
Cohort A2 (15 subjects) 400 mg (13.68 mL) HTX-011-56 injection and instillation combination + fentanyl 150 µg IV 
Cohort A3 (15 subjects) 400 mg (13.68 mL) HTX-011-56 injection and instillation combination  
Part E 
Cohort B1 (15 subjects) 12 mg (13.68 mL) HTX-009 injection and instillation combination 
Cohort B2 (5 subjects) 13.68 mL saline placebo injection and instillation combination 
Part F 
Cohort C1 (15 subjects) 13.68 mL saline placebo instillation + fentanyl 50 µg IV 
Cohort C2 (5 subjects) 400 mg (13.68 mL) HTX-011-56 instillation + fentanyl 50 µg IV 
Part G 
Cohort D1 (15 subjects) 300 mg (10.26 mL) of HTX-011-56 via instillation and fentanyl 50 μg IV before wound closure 
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Cohort D2 (15 subjects) 75 mg (30 mL) of 0.25% Marcaine w/o epinephrine via injection and fentanyl 50 μg IV before 
wound closure 
Cohort D3 (5 subjects) 10.26 mL of normal saline via injection and fentanyl 50 μg IV before wound closure 
Table 3: 
Screening 
Procedure 
Day -28 to Day -1 
Screening 
Informed Consent 
X 
Eligibility Assessment 
X 
Demographics and Medical History 
X 
Assessment of PONV Risk Factors 
X 
ASA Classification Assessment 
X 
Physical Examination 
X 
Pregnancy Test  
(female subjects of child bearing potential only) 
Xserum 
Urine Drug Screen 
X 
Alcohol Breath Test 
X 
Clinical Laboratory Tests a 
X 
Vital Signs b 
X 
BMI Determination 
X 
12-lead ECG 
X 
Pain Training 
X 
Prior and Concomitant Medication c 
X 
Serious Adverse Event Monitoring d 
X 
a Laboratory tests will include hematology and chemistry screenings in all subjects.  Results will determine subject eligibility 
for the study. 
b Resting vital signs (VS) will be collected at screening.  Resting VS include: resting blood pressure, resting pulse, respiratory 
rate, oral temperature and SpO2.  Resting tests must be obtained after resting (seated/reclined) for ≥ 5 minutes. 
c ConMeds taken within 30 days before dosing will be recorded. 
d SAEs will be reported if considered related to study participation. 
 
 
 
 
 
 
 
 
 
 
 
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Table 4: 
Prior to Surgery and Surgery (Day 0) 
 
Day 0 
Prior to Surgery 
Surgery 
Eligibility Assessment 
X 
 
Demographics and Medical History 
X 
 
Physical Examination c 
X 
 
Pregnancy Test  
(female subjects of child bearing potential only) 
Xurine 
 
Urine Drug Screen 
X 
 
Alcohol Breath Test 
X 
 
Clinical Laboratory Tests a 
X d 
 
Vital Signs b 
X 
 
12-lead ECG 
X  
 
Pain Training 
X 
 
Blood Draw for PK 
X d 
 
Neurologic Exam 
X 
 
Surgery Procedure 
 
X 
Study Drug Administration 
 
X 
Prior and Concomitant Medication f 
X 
 
Serious Adverse Event Monitoringg 
X 
X 
a Laboratory tests will include hematology and chemistry and will be used as baseline reference and not for determining subject 
eligibility. 
b Resting vital signs (VS) will be ollected at creening and check-in only, all other assessments will include resting VS only.  
Resting VS include: resting blood pressure, resting pulse, respiratory rate, oral temperature and SpO2.  Resting tests must be 
obtained after resting (seated/reclined) for ≥ 5 minutes.  VS will have a ± 15 minute window. 
c Physical examination will include weight only but not height or BMI. 
d Baseline laboratory samples can be collected prior to surgery. 
f ConMeds taken within 30 days before dosing will be recorded 
g SAEs that occur before study drug administration will be reported only if considered related to study participation.  After study 
drug administration, all SAEs that occur through Day 28 post-treatment must be reported. 
 
 
 
 
 
 
 
 
 
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Table 5: 
Post Study Medication Administration (Days 0-5) 
 
Day 0 to 5 
D10 
±2d) 
D28 
±2d) 
D60 
±8d) 
Post Study Drug Administration Time Points (hrs) 
0.5 
1f 
1 5 
2 
3 
4 
6 
8, 10, 12 
14 
18 
24 
30 
36 
42 
48g 
54g 
60g 
72g 
78g 
84g 
96g 
120  
Confinement 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
Physical Examination 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xg 
 
 
 
 
Xc  
 
 
Clinical Laboratory 
Tests a 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Vital Signs b 
 
X 
 
X 
 
X 
X 
X (12hr  
only) 
 
X 
X 
 
X 
 
X 
 
X 
X 
 
 
X 
 
X  
 
 
12-lead ECG 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
X  
 
 
Pain Intensity (PI) 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
PGA of Pain Control  
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
Use of Rescue 
Medication 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Xe 
Xe 
 
PK Blood Draws (±15 
min) 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
 
X 
X 
 
 
X 
X g 
 
 
 
Numerical Rating Scale 
for Nausea 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
Assessment of Wound 
Healing 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
X 
 
Photos  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
X 
 
 
Bupivacaine Toxicity 
and Neurological 
Assessment 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
AE Monitoring d 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
Phone Call h 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Abbreviations: AE, adverse event; D, day; ECG, electrocardiogram; hr(s), hour(s); min, minutes; PK, pharmacokinetics. 
a Laboratory tests will include hematology and chemistry. 
b Resting VS only.  Resting VS include: resting blood pressure, resting pulse, respiratory rate, oral temperature and SpO2.  Resting tests must be obtained after resting (seated/supine) for ≥ 5 minutes. 
c Physical examination will include weight only, but not height or BMI.  Weight not required at 72 hour exam. 
d AEs will be monitored after administration of study medication through the Day 10 study visit.  SAEs will be monitored through Day 28. 
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e Subjects may resume standard of care pain medication as advised by their surgeon after the 72 hour study visit. 
f 1 hour assessments to be completed if subject is awake and alert. 
g ± 30 minutes for 72hr Physical Exam, ± 60 minutes for the 48, 54, 60 and 72 hr assessments, and ± 4 hours for the 96 and 120 hr assessments 
h Subjects will receive a phone call from the study site on Day 60 (±8 days). Subjects will be asked if they have any current pain related to the operation. Subjects will also be asked to think about the previous 24 hours and to rate 
their pain intensity related to the operation using the NRS and to report any medication(s) taken to treat the pain (name, dose, and route). 
 
 
 
 
 
 
 
 
 
 
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4   STUDY ENDPOINTS 
4.1 
Efficacy Endpoints 
The primary efficacy endpoint is the summed pain intensity (SPI) scores over the first 24 hours (SPI0-24). 
Secondary efficacy endpoints include the following:  
1. SPI over various other time intervals (SPI0-6, SPI0-12, SPI12-24, SPI24-48, SPI0-48, SPI48-72, SPI0-72, 
SPI72-96, SPI0-96) 
2. The PGA of pain control at 24, 48, 72, and 96 hours 
3. Time to first use of rescue medication (any, and opioid) 
4. Total and average daily rescue analgesia consumpt on over 24, 48, 72, and 96 hours post-
treatment, by each analgesic, opioid and non-opioid  
5. Percentage of subjects who have not taken opioid rescue medication over time 
6. Percentage of subjects that are pain-free (NRS score < 1) over time by time point and comparisons 
at 24, 72, and 96 hours after study drug administration. 
Exploratory endpoints include the following  
1. Area under the curve (AUC) for PI scores collected over various time intervals (AUC0-24, AUC0-48, 
AUC0-72, AUC0-96, AUC0-6, AUC0-12  AUC12-24, AUC24-48, AUC48-72, and AUC72-96)  
2. Integrated Rank Difference fo  SPI0-24, SPI0-48, SPI0-72, SPI0-96, and total opioid use through 24, 48, 
72, and 96 hours post-study drug administration. 
4.2 
 Safety Endpoints 
The safety endpoints include: 
 AEs and SAEs 
 Sponsor defined opioid-related AEs 
 Mean nausea assessments at 6, 24, 48, and 72 hours 
 Vital signs abnormal values 
 Assessments of the surgical intervention area 
 Neurological examinations 
 Shift of clinical laboratory tests, including routine blood chemistry, liver function tests, and 
hematology  
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 Shift in ECG findings 
 Symptoms related to bupivacaine toxicity 
 
 Use of concomitant medications 
 
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.  
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 medication, whether or not considered 
causally associated with the use of the study medication. Any abnormal laboratory value deemed 
clinically significant by the investigator, regardless of cau al relationship, must be reported as an AE.  
All AEs, whether volunteered, elicited, or noted on physical examination and regardless of causality or 
seriousness, will be assessed and recorded in the case rep rt form (CRF) beginning after the 
administration of study medication through study completion or resolution of the AE, whichever comes 
first.  
Any medical condition or clinically significant laboratory abnormality with an onset date before the date 
of study drug administration is usually considered to be pre-existing, should be recorded as medical 
history, but should not be documented in the CRF as an AE. Any AE (i.e., a new event or an exacerbation 
of a pre-existing condition) with an onset date after study drug administration up to and including the 
designated follow-up safety visit should be recorded as an AE on the CRF. All AEs must be recorded on 
the AE CRF regardless of the severity or relationship to study drug.  
 
Nausea Assessments 
Nausea will be assessed during the study using an NRS scale. Assessments of nausea will be completed 
by subjects at the following time points: 6, 24, 48, and 72 hours, and at the time of early termination if it 
should occur, and only if the subject is discontinued prior to T96. 
 
Vital Signs 
Resting vital signs will be obtained after resting (seated/supine) for at least 5 minutes, and will include 
resting blood pressure, resting pulse, respiratory rate, oral temperature, and peripheral oxygen saturation 
(SpO2). After the administration of study medication, subjects will have resting vital signs measured and 
recorded at the following times: 1, 2, 4, 6, 8, 10, 12, 18, 24, 36, 48, 60, 72, and 96 hours and at the Day 10 
visit, or at early termination, with actual times recorded. 
 
Laboratory Parameters 
The clinical laboratory and other tests relating to safety to be performed during the study are described 
below. 
 Hematology parameters include: red blood cells, hematocrit, hemoglobin, platelets, white blood 
cells, neutrophils, lymphocytes, monocytes, eosinophils, basophils. 
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 Serum chemistry parameters include aspartate aminotransferase (AST), alanine aminotransferase 
(ALT), alkaline phosphatase (ALP), total bilirubin, direct bilirubin, gamma glutamyl transferase, 
albumin, total protein, creatinine, uric acid, urea, sodium, potassium, magnesium, chloride, 
phosphorus, calcium, glucose, bicarbonate, lactate dehydrogenase. 
In addition, serological testing will be performed for hepatitis B and hepatitis A, drug screening and 
salivary testing for alcohol will be performed. For women of childbearing potential, a serum pregnancy 
test will be performed at screening, and a urine pregnancy test will be performed on the day of admission 
prior to surgery. 
 
Electrocardiograms 
A 12-lead ECG will be performed after the subject has been supine for at least 5 minutes and will be 
completed for all subjects at screening, at check-in on Day 0, at 24, 48, 72, 96 hours post-treatment, and at 
the Day 10 visit, or at time of early discontinuation, if applicable. 
 
Wound Healing Assessments 
The surgical wound will be assessed 72 hours post-treatment, 10 days post-treatment and 28 days post-
treatment. Results are recorded as Normal or Abnormal  with verbatim descriptions of abnormalities. 
 
Bupivacaine Toxicity 
Subjects will be assessed for symptoms (peri ral tingling, strange taste, muscle twitching, ringing in ears, 
seizure, bradycardia, and cardiac arrest) related to bupivacaine toxicity at 24, 48, and 72 hours post-
treatment.  
 
Liver Function 
Subjects will be assessed for post-treatment abnormalities in liver function tests ALT, ALP, AST, and 
total bilirubin.  
 
Neurological Exams 
Neurological exams will be performed on Day 0 prior to surgery, and at hours 24, 48, and 72 post-
treatment (or early termination). Parameters assessed include mental status, motor, sensory, 
cerebellar/gait, and cranial nerve functioning.  
5 DATA QUALITY ASSURANCE 
Report summaries will be generated using validated SAS software, version 9.4 or higher, on a PC or 
server-based platform. Additional validated software may be used to generate analyses, as needed.  
All SAS programs that create outputs or supporting analysis datasets will be validated by a second 
statistical programmer or biostatistician. At a minimum, validation of programs will consist of a review of 
the program log, review of output or dataset format and structure, and independent confirmatory 
programming to verify output results or dataset content. Additionally, all outputs will undergo a review by 
a senior level team member before finalization. 
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The content of the source data will be reviewed on an ongoing basis by project statistical programmers 
and statisticians. Data will be checked for missing values, invalid records, and extreme outliers through 
defensive programming applications, analysis-based edit checks, and other programmatic testing 
procedures. All findings will be forwarded to sponsor for appropriate action and resolution.  
6 POPULATIONS DEFINED 
Intent-to-Treat (ITT) Population: The ITT population will include all subjects who are randomized to 
receive study medication. 
Efficacy Population: The efficacy population will include all subjects who are randomized to receive 
study medication and have at least one postdose, scheduled PI score. This population is noted as the 
modified Intent-to-Treat (mITT) population. 
Safety Population: The safety population will include all treated subjects and will be used for safety and 
tolerability assessments.  
6.1 
Sample Size Determination 
The sample size of approximately 453 subjects was selected empirically without a formal statistical 
assumption. 
7 STATISTICAL METHODS AND DATA CONSIDERATIONS 
7.1 
General Considerations 
Data will be analyzed by Agility Clinical biostatistics personnel. Statistical analyses will be reported with 
tables, figures and subject data listings, presented in rich text format, and using recommended 
International Conference on Harmonisation (ICH) numbering. Output specifications for all tables, listings 
and figures will be in conform nce with guidelines specified by the ICH guideline Statistical Principals 
for Clinical Trials (E9) (1999).  
Unless otherwise specified, safety tables will be summarized separately for Part A and Parts 
B/C/D/E/F/G. Summary tables will be grouped as follows: 
Part A 
 HTX-011-19 (all summary tables): 
1. Saline Placebo (6.84 mL) 
2. HTX-011-19 200 mg (3.42 mL) Injection 
3. HTX-011-19 200 mg (3.42 mL) Instillation 
4. HTX-011-19 200 mg (3.42 mL) Total  
5. HTX-011-19 400 mg (6.84 mL) Injection 
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6. HTX-011-19 400 mg (6.84 mL) Instillation 
7. HTX-011-19 400 mg (6.84 mL) Combination 
8. HTX-011-19 400 mg (6.84 mL) Total  
9. HTX-011-19 Total 
10. Total 
The last 2 Total groups will be included only on demographics, disposition, and protocol deviations. AE 
summary tables will not include the last Total group. 
Parts B/C/D/E/F/G 
Formulations (only for demographics, disposition, protocol deviations, and AE tables): 
1. Saline Placebo (6.84-13.68 mL) 
2. 75 mg (30 mL) Marcaine  
3. HTX-009 12 mg (13.68 mL) 
4. HTX-002 200-400 mg (6.84-13.68 mL)  
5. HTX-011-49 200-400 mg (6.84-13 68 mL) 
6. HTX-011-56 200-400 mg (6 84-13 68 mL) 
7. Total (not included on AE tables) 
Additionally, all Parts B/C/E summary tables except protocol deviations will be grouped as follows: 
HTX-011-49: 
1. Saline Placebo (6.84-13.68 mL) 
2. Marcaine 75 mg (30 mL) 
3. HTX-011-49 200 mg (6.84 mL) 
4. HTX-011-49 400 mg (13.68 mL) 
HTX-011 Components: 
1. HTX-009 12 mg (13.68 mL) Combination 
2. HTX-002 200 mg (6.84 mL) Injection 
3. HTX-002 200 mg (6.84 mL) Instillation 
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4. HTX-002 200 mg (6.84 mL) Total  
5. HTX-002 400 mg (13.68 mL) Injection 
6. HTX-002 400 mg (13.68 mL) Instillation 
7. HTX-002 400 mg (13.68 mL) Total  
All Parts B/C/D/E summary tables except protocol deviations will be grouped as follows: 
HTX-011-56: 
1. Saline Placebo (6.84-13.68 mL) 
2. Marcaine 75 mg (30 mL) 
3. HTX-011-56 200 mg (6.84 mL) Injection 
4. HTX-011-56 200 mg (6.84 mL) Instillation 
5. HTX-011-56 200 mg (6.84 mL) Total 
6. HTX-011-56 400 mg (13.68 mL) Injection 
7. HTX-011-56 400 mg (13.68 mL) Instillation 
8. HTX-011-56 400 mg (13 68 mL) Combination 
9. HTX-011-56 400 mg (13.68 mL) Total 
All Part D, F and G summary tables except protocol deviations will be grouped as follows: 
HTX-011-56 + Fentanyl: 
1. Saline Placebo (10.26-13.68 mL) + 50 µg Fentanyl IV 
2. Marcaine 75 mg (30 mL) + 50 µg Fentanyl IV 
3. HTX-011-56 300 mg (10.26 mL) + 50 µg Fentanyl IV 
 
4. HTX-011-56 400 mg (13.68 mL) + 50 µg Fentanyl IV 
5. HTX-011-56 400 mg (13.68 mL) + 150 µg Fentanyl IV 
6. HTX-011-56 400 mg (13.68 mL) Total 
In general, all data collected from all enrolled subjects will be presented in subject data listings. Listings 
will be ordered by site, subject number, and assessment or event date. The early termination visit is 
considered its own visit, where applicable.  
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In general, continuous variables will be summarized to indicate the population sample size (N), number of 
subjects with available data (n), mean, standard deviation (SD), median, minimum, and maximum values. 
Categorical variables will be summarized by the population size (N), number of subjects with available 
data (n), number of subjects in each category, and the percentage of subjects in each category. Unless 
otherwise noted, the denominator to determine the percentage of subjects in each category will be based 
on the number of subjects with available data. Select ordinal data may be summarized using both 
descriptive statistics and counts and percentages of subjects in each category, as appropriate. 
Non-zero percentages will be rounded to one decimal place. Rounding conventions for presentation of 
summary statistics will be based on the precision of the variable of summarization, as it is collected in its 
rawest form (i.e., on the CRF or as provided within an external file) and are outlined as follows: 
 The mean and median will be rounded to one more decimal place than the precision of the variable 
of summarization; 
 Measures of variability (e.g., SD, standard error of the mean [SEM]) will be rounded to two more 
decimal places than the precision of the variable of summarization; and 
 Minimum and maximum values will be presented using the same precision as the variable of 
summarization. 
Other statistics (e.g., confidence intervals [CIs]) will be presented using the same general rules outlined 
above, or assessed for the most appropriat  presentation based on the underlying data. 
Unless otherwise specified, 95% CIs will be calculated for point estimates, and statistical significance 
testing will be two-sided and performed using α=0.05. P-values will be reported for all statistical tests, 
rounded to four decimal places. P values less than 0.0001 will be displayed as “<0.0001”; p-values 
greater than 0.9999 will be displayed as “>0.9999”.  
Unless indicated otherwise (see Section 7.8), no imputation will be done for missing data, and no 
adjustments will be made for conducting multiple hypothesis tests. 
 
Standard Calculations 
Where appropriate, the calculated study time of each assessment or event will be presented with the 
assessment or event time on subject data listings. Study time is calculated using hours and minutes in 
HH:MM format, where hour is between 0 and 23, and minute is between 0 and 59. 
Study time will be calculated in reference to the time of completed application of study drug. Thus, a 
study event that occurs prior to the time of completed application of study drug would be associated with 
a negative time calculation, while a study event that occurs after time of completed application of study 
drug would be a positive time calculation. 
7.2 
Analysis Datasets 
ITT Analysis Population: The ITT analysis set will include all subjects who are randomized to receive 
study medication. 
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Efficacy Population: The efficacy analysis set will include all subjects who were randomized to receive 
study medication and have at least 1 postdose, scheduled PI score. This analysis set is noted as the mITT 
set. 
Safety Population: The safety analysis set will include all subjects who received study drug and will be 
used for safety and tolerability assessments.  
For the ITT and mITT analyses, subjects are assigned to a treatment group based on the randomization 
schedule, regardless of the treatment actually received. 
For the safety analysis, treatment group assignment will be based on the treatment actually received. 
7.3 
Disposition of Subjects and Protocol Violations 
A summary table of subject disposition will include the number of subjects who were randomized and 
number in each analysis population. Counts and percentages of randomized subjects who did/did not 
complete the study will be presented as described in Section 7.1, with subjects who did not complete the 
study summarized by reason for discontinuation. A separate summary table will include the number of 
subjects who failed screening. The summary will include counts and percentages of subjects by reason for 
screen failure. All major protocol violations in the Safety Population will be determined and appropriately 
categorized prior to database lock. The count and percentage of subjects with any major protocol 
violations as well as the number and percentage of subjects with violations within each category will be 
presented for the Formulations groups described in Section 7.1. A listing of subjects who were excluded 
from the efficacy analysis will be provided  
7.4 
Demographic and Other Baseline Characteristics 
The demographic summary will include descriptive statistics for age, sex, ethnicity, and race, presented as 
described in Section 7.1, with saline placebo cohorts pooled. The baseline characteristics will include 
weight, height, and body mass index (BMI). Age will be summarized using descriptive statistics. Sex, 
ethnicity, and race will be summarized with the count and percentage of subjects in each parameter 
category. 
Medical history will be summarized, with reported terms mapped to preferred term (PT) and system organ 
class (SOC) using the Medical Dictionary for Regulatory Activities (MedDRA), version 19.1. Subjects 
with multiple medical history events will be sorted by date of onset, date of resolution (if applicable), and 
SOC. Frequency counts and percentages to summarize subjects reporting medical history by SOC and PT 
will be presented. Subjects reporting > 1 event per SOC/PT will be counted only once. Medical history 
will also be provided in a subject listing. 
7.5 
Prior and Concomitant Medications 
Prior and concomitant medications will be coded using the World Health Organization (WHO) 
Anatomical Therapeutic Chemical (ATC) classification index (version September 01, 2016). Prior 
medications are those that stop prior to the start of the study drug administration. Any medication that 
stops at or after the start of study drug administration is considered concomitant medication. If it cannot 
be determined whether a medication was stopped prior to the start of study drug administration due to 
partial or missing medication dates, it will be considered a concomitant medication. Concomitant 
medications will be included in summaries. Prior medications will be included in a subject data listing. 
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The number and percentage of subjects who take concomitant medications will be summarized by ATC 
class and PT. Subjects reporting use of more than one medication at each level of summarization (any 
medication received, ATC class, and PT) will be counted only once. ATC class terms will be displayed by 
descending order of incidence, as will PT within each ATC class. Concomitant medications will be 
summarized as described in Section 7.1 and provided in a subject listing. Prior medications will be 
provided in a separate listing. A listing of subjects who received prohibited opioid rescue medications will 
be provided, to include Subject ID, drug name, indication, dose, route of administration, frequency, 
date/time of administration, date/time of stopping medication, and treatment cohort. 
7.6 
Treatment Compliance and Extent of Exposure 
Since study drug is administered intra-operatively, no formal summary of treatment compliance will be 
produced. 
Summary statistics for duration of surgery will include times of surgery start and completion, with 
duration calculated as completion time minus start time, and r ported in minutes. Results will be 
presented as described in Section 7.1. A per subject listing of duration of surgery will include start and 
stop time of study drug administration.  
7.7 
Efficacy Analysis   
The efficacy analysis will be performed using the mITT population. Part A will be analyzed separately. 
Parts B/C/D/E/F/ G will be analyzed together  For treatment comparisons using pooled data, data from 
treatment groups will be combined prior to conducting the statistical comparison. Unless otherwise 
specified, the planned comparisons to be performed will be described in a separate document. 
Figures for efficacy endpoints will be provided separately for Part A and Parts B/C/D/E/F/G. All efficacy 
figures will be structured according to the following groups: 
Part A 
 Pooled 200 mg HTX-011-19 (Cohorts A and C) 
 Pooled 400 mg HTX-011-19 (Cohorts B, D, and E) 
 Saline Placebo (Cohort F) 
Parts B/C/D/E 
 Pooled 200 mg HTX-011-56 (Cohorts O and S) 
 Pooled 400 mg HTX-011-56 (Cohorts A3, P, and T) 
 75 mg Marcaine (Cohort Z) 
 Pooled 200 mg HTX-002 (Cohorts U and W1) 
 Pooled 400 mg HTX-002 (Cohorts V and W2) 
 12 mg HTX-009 (Cohort B1) 
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 Saline Placebo (Cohorts B2, Q, R, X, and Y) 
Parts D/F/G 
 400 mg HTX-011-56 + 50 µg  or 150 µg Fentanyl (Cohorts A1, A2, and C2) 
 300 mg HTX-011-56 + 50 µg Fentanyl (Cohort D1) 
 75 mg Marcaine + 50 µg Fentanyl (Cohort D2) 
 Saline Placebo +  50 µg Fentanyl (Cohorts C1 and D3) 
 
 
Primary Efficacy Endpoint Analysis Methods  
The primary analysis set is the mITT Population. The primary efficacy endpoint is the SPI0-24, with last 
observation carried forward (LOCF) imputation of missing d ta as described in Section 7.8. A similar 
analysis will be conducted with missing data imputed by the windowed last observation carried forward 
(WLOCF) method described in Section 7.8.  
SPI:  
PI will be assessed by the subject for their current pain according to an 11-point NPRS (0-10) where 0 
equates to no pain and 10 equates to the worst pain imaginable.  PI scores will be measured two ways: on 
movement and at rest. PI scores will be assessed at the following time points: 1, 2, 4, 6, 8, 10, 12, 14, 18, 
24, 30, 36, 42, 48, 54, 60, 72, 78, 84, and 96 hours post study drug administration.  Assessments 
performed at 78 and 84 hours will be p rformed by subjects on an out subject basis.  PI assessments 
scheduled between 24:00 and 06:00 must be collected, even if subjects are asleep at the time of the 
assessment.   
Pain scores will be measured on movement (sitting up from a supine position) starting at Hour 4 and 
measured at 6, 8, 10, 12, 14, 18, 24, 30, 36, 42, 48, 54, 60, and 72 hours. Pain Scores will be measured at 
rest at 1, 2, 78, 84, and 96 hours after administration of study medication.  The pain score will be 
measured after the patient has been supine for a minimum of 5 minutes and a resting pain score has been 
obtained. There will be a ± 15 minute window allowed for the collection of each PI assessment unless 
otherwise stated. This is referenced as the per protocol method. 
PI will also be assessed within 5 minutes prior to administration of each dose of rescue analgesia and at 
time of early discontinuation (should it occur and only if the subject was discontinued prior to 96 hour). 
 The SPI endpoints will be derived by summing the PI score at the relevant time points weighted by the 
scheduled time duration since the prior PI assessment. For example, SPI0-24 will be calculated as below: 
SPI0-24= PI1+PI2+2*PI4+2*PI6+2*PI8+2*PI10+2*PI12+2*PI14+4*PI18+6*PI24; 
Where PIi denoted the pain intensity score at hour i. 
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The SPI endpoints will be analyzed for Part A using analysis of covariance (ANCOVA) with treatment as 
an effect, and PI collection method (per protocol or not per protocol, as described above) as covariate. For 
Parts B/C/D/E/F/G, SPI endpoints will be analyzed using analysis of variance (ANOVA) with treatment 
as an effect. The differences between the specified planned group comparisons will be examined and 
nominal p-values will be reported without adjustment for multiplicity. For Parts B/C/D/E/F/G efficacy 
analysis, all saline placebo cohorts are pooled and treated as a single group (except for the saline + 
fentanyl cohorts). The number of subjects in each group, group mean, SD, least-squares mean point 
estimates of group differences (LSMD) and the associated 95% CI will be presented for each comparison, 
with the associated p-value. The null hypothesis to be tested for each comparison is that there is no 
difference between groups of interest, Treatment A and Treatment B: 
H0:  A = B; 
Where A and B represent the mean values for Treatment A and Treatment B, respectively. The alternate 
hypothesis to be tested is that the treatment group means differ  
H1:  A ≠ B;  
7.7.2 
Secondary Efficacy Endpoint Analysis Me hods  
7.7.2.1     Sum of Pain Intensity 
SPI over various other time intervals (SPI0-24, SPI0-48, SPI0-72, SPI0-96, SPI0-6, SPI0-12, SPI12-24, SPI24-48, 
SPI48-72, and SPI72-96) will be analyzed by ANCOVA/ANOVA and reported as described above in Section 
7.7.1.  
Tables of summary statistics of SPI scores for SPI0-24, SPI0-48, SPI0-72, SPI0-96, SPI0-6, SPI0-12, SPI12-24, 
SPI24-48, SPI48-72, and SPI72 96 will be pr vided as described in Section 7.1, with data imputed using LOCF 
as described in Section 7.8, and separately summarized with data imputed using WLOCF. Summary 
statistics include the number of subjects in each group, group means, SD, SEM, and 95% CI, median, 
minimum, and maximum values. Mean SPI0-6, SPI0-12, SPI0-24, SPI0-48, SPI0-72, and SPI0-96 scores will be 
plotted against specified hours post-treatment as described in Section 7.7. 
Summaries of PI scores at every collection time point (1, 2, 4, 6, 8, 10, 12, 14, 18, 24, 30, 36, 42, 48, 54, 
60, 72, 78, 84, and 96 hours post-treatment) will be provided as described in Section 7.1, with data 
imputed using LOCF as described in Section 7.8 and separately summarized with data imputed using 
WLOCF. Summary statistics include the number of subjects in each group, group means, SD, SEM, 95% 
CI, median, maximum, and minimum values. Mean PI scores at will be plotted against every post-
treatment collection time point for groups as described in Section 7.7. 
The percentage of subjects in each treatment group who reported a PI score of 0 or 1 will be characterized 
as “pain-free”. Comparisons of percentage pain-free will be performed at 24 hours post-treatment, 48 
hours post-treatment, 72 hours post-treatment, and 96 hours post-treatment for Part A using the Cochran-
Mantel-Haenzel test, stratified by PI collection method. Comparisons of percentage pain-free will be 
performed at 24 hours post-treatment, 48 hours post-treatment, 72 hours post-treatment, and 96 hours 
post-treatment for Parts B/C/D/E/F/G using Fisher’s exact test. Data will be analyzed independently at 
each time point and will not be cumulative. Sample size, percentage pain-free, absolute percent-difference 
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between groups, and p-values will be provided for Part A and Parts B/C/D/E/F/G. In addition, exact 
unconditional 95% CIs for the difference between the groups based on the score statistic (Chan and 
Zhang, 1999) will be provided for the Parts B/C/D/E/F/G summaries. 
The percentage of subjects who were pain-free will be plotted over time by time point at every collection 
time point (1, 2, 4, 6, 8, 10, 12, 14, 18, 24, 30, 36, 42, 48, 54, 60, 72, 78, 84, and 96 hours post-treatment) 
for groups as described in Section 7.7. 
7.7.2.2     Patient Global Assessment  
Pain control will be measured on a scale of 0-4, with 0 indicating poor pain control and 4 indicating 
excellent pain control. The proportion of subjects rating their pain control as ‘Very Good’ (3), or 
‘Excellent’ (4) at 24 hours post-treatment, 48 hours post-treatment, 72 hours post-treatment, and 96 hours 
post-treatment will be compared between groups using Fisher’s exact test. Missing subject data per time 
point will be imputed as rated below ‘Very Good’. Data will be reported independently at each time point 
of interest and will not be cumulative. Group sample size, per entage of at least ‘Very Good’, absolute 
percent-difference between groups, and p-values from Fisher’s exact test will be provided. In addition, 
exact unconditional 95% CIs for the difference between the groups based on the score statistic (Chan and 
Zhang, 1999) will be provided. 
The percentage of subjects with at least very good pain control will be presented in bar charts at 24, 48, 
72, and 96 hours post-treatment for groups as described in Section 7.7.  
7.7.2.3     Rescue Medication  
The cumulative percentage of subjects who have not received opioid rescue medication over 24 hours, 48 
hours, 72 hours, and 96 hours post-treatment will be analyzed by treatment group in pairwise comparison 
using Fisher’s exact test. Use of opioid rescue medication will be imputed for subjects terminating 
without reported opioid use. Group sample size, percentage opioid-free, absolute percent-difference 
between groups, p-values, and xact unconditional 95% CIs for the difference between the groups based 
on the score statistic (Chan and Zhang, 1999) will be provided for summaries. 
Cumulative percentages will be plotted at 1, 2, 4, 6, 8, 10, 12, 14, 18, 24, 30, 36, 42, 48, 54, 60, 72, 78, 
84, and 96 hours post-treatment for groups as described in Section 7.7. 
Kaplan-Meier estimates of the median time to first administration of any rescue medication along with the 
95% CIs will be presented for each group. The time to administration of the first dose of rescue 
medication will be compared between groups using the generalized Wilcoxon test, and the comparison 
will be summarized with hazard ratios along with the 95% CI, and the associated p-value from the 
Wilcoxon test. If a subject does not take rescue medication but prematurely discontinues from the study 
during the 96-hour treatment phase, then the subject will be censored at the time of the last post-treatment 
collection of vital signs, or the stop time of study drug administration, whichever occurs later. If a subject 
never takes rescue medication and completes the 96-hour treatment phase, then the subject will be 
considered censored for analysis purposes at 96 hours. Kaplan-Meier curves will be presented for Part A 
and Parts B/C/D/E/F/G groups as described in Section 7.7, plotted as 1-S(t).  
The count and percentage of subjects who were administered only opioid rescue medications, and only 
non-opioid rescue medications will be summarized in tables, including counts and percentages of subjects 
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who received both types of analgesics but were administered opioid analgesics first, and received both but 
non-opioids first. 
All opioid dosages and formulations will have the morphine milligram equivalency (MME) calculated, 
with oxycodone plus acetaminophen treated as oxycodone (Opioid Morphine Equivalent Conversion 
Factors, Centers for Disease Control and Prevention, Atlanta, GA, May 2014). Opioid conversions 
include, but are not limited to, the medications in Table 6 (complete table will be provided in the CSR): 
Table 6: 
Analgesic Windows and Morphine Milligram Equivalencies 
Medication 
Route 
Window (Hours) 
MME Factor 
CODEINE 
PO 
6 
0.05 
DILAUDID 
PO 
4 
1.33 
DILAUDID 
IV 
4 
6.67 
HYDROCODONE 
PO 
6 
0 4 
MORPHINE 
IV 
4 
1 
MORPHINE 
PO 
4 
0 33 
OXYCODONE 
IV 
4 
1 
OXYCODONE 
PO 
6 
0 5 
SUFENTANIL 
PO 
2 
500 
TRAMADOL 
PO 
6 
0.04 
Note: One record listed as hydrocodone (Percocet) was trea ed as hydrocodone. 
Average daily use and total use will be calculated for each of the following periods: 0-24, 0-48, 0-72, and 
0-96 hours post study medication administration.  Subjects who did not use the specific rescue medication 
during a period will be assigned to “0“. Thus, for the summary of oxycodone use, a subject who received 
only morphine would be counted as zero for that outcome.  
Average daily use and total use data will be tabulated by treatment group with descriptive statistics to 
include SEM, and summarized separately by type of rescue medication (acetaminophen, morphine or 
oxycodone), and combined opioid use (morphine, oxycodone, sufentanil, tramadol, Percocet, and 
Dilaudid). Between groups comparisons of total opioid use for all opioids combined (morphine, 
oxycodone, sufentanil, tramadol, Percocet, and Dilaudid) will be performed for each time period using 
ANOVA, as described in Section 7.7.1. Results reported will include sample size, mean (SD), SEM, 
LSMD, 95% CI for LSMD, and p-value. The groups to be compared are listed in a separate document. 
 
 
     
 
 
  
 
 
 
 
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7.8 
Data Imputation and Adjustment 
7.8.1 
PI Assessments  
Any missing PI score for scheduled time points will be imputed using the standard LOCF method, unless 
the missing score occurs before values are available to carry over (such as the 1 hour post-treatment PI 
score). In such case, the missing score will be replaced by the worst score collected at any scheduled time 
point during the study. PI scores recorded or imputed during the analgesic window (duration of effect) of 
any taken rescue medication will not be used for analyses; instead alternate values will be calculated. The 
adjustment rules are as follows: 
Subjects who require rescue analgesia during the first 96 hours (inclusive) after treatment are expected to 
report their pain intensity immediately before taking the rescue medication; this PI is referenced as the 
pre-rescue PI. The analgesic windows for specified rescue analgesics are listed in Table 6:
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Analgesic Windows and Morphine Milligram Equivalencies. Non-opioid analgesic ibuprofen and 
acetaminophen are assigned a window of 6 hours. When the date/time of a scheduled PI is at or after the 
start time recorded for a rescue medication and within the analgesic window (inclusive) of the rescue 
medication, the scheduled PI score will be replaced by the pre-rescue PI score within the analgesic 
window (replaced with the worst pre-rescue PI if there were multiple rescue medications used within the 
analgesic window); if the scheduled PI score within the analgesic window is higher than the pre-rescue PI 
score, it will not be replaced. If the PI date/time is missing or time point is Hour 78 or 84 post T0, those 
time points will be imputed with the nominal date/time post T0. This method is referenced as the WLOCF 
method.  
PI scores reported will be displayed in data listings, with LOCF-imputed scores, and WLOCF-adjusted PI 
scores flagged. Where timing information is missing for administration of rescue medication, the record 
will be excluded from the WLOCF analysis.  
All SPI endpoints and PI outcomes except the PI/MME int grated rank difference will be analyzed using 
2 sets of data: PI scores with missing values imputed by LOCF only and PI scores adjusted for the use of 
rescue medications using WLOCF.  
7.8.2 
Other Assessments  
Any missing nausea assessment scores will be imputed using the LOCF method as described in Section 
7.8. The scheduled nausea scores will be displayed in a data listing, with LOCF imputed records clearly 
indicated. 
Missing data for the PGA of pain control will be imputed as a non-responder.  
7.9 
Safety Analysis 
Baseline values will be taken from Day 0 prior to surgery, if available, or otherwise from the most recent 
values available prior to Day 0  Safety summaries will be presented as described in Section 7.1. 
Summaries of safety data will include all scheduled visits; unscheduled visits will be included only in 
safety data listings, unless otherwise specified.  
 
Adverse Events 
Adverse events will be classified as treatment-emergent adverse events (TEAEs) if the AE has an onset 
date/time greater than or equal to the start date/time of the administration of the intra-operative study 
drug. Events reported with a partial onset date (e.g., month and year are reported but the day is missing) 
will be considered to be treatment-emergent if it cannot be confirmed that the event onset was prior to 
administration of study drug based on the available date entries. Except where noted, summary tables for 
AEs will include only TEAEs. However, all AEs will be listed and pre-treatment AEs will be flagged. 
Adverse events will be coded using MedDRA (Version 19.1) and the duration of each AE reported on 
data listings. The following AE summaries will be tabulated and provided as tables/listings: 
 An overall summary of the number of TEAEs, the number of subjects with at least one TEAE, the 
number of serious TEAEs, the number of subjects with serious TEAEs, the number of subjects 
with drug-related TEAEs, the number of subjects with severe TEAEs, the number of subjects with 
fatal TEAEs, and the number of subjects with TEAEs leading to premature discontinuation. 
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 TEAEs by SOC in internationally agreed order, PT in descending frequency according to total 
incidence (alphabetically for ties) in the highest HTX-011 dose group, and maximum severity 
 TEAEs by PT in descending frequency according to the total incidence (alphabetically for ties) in 
the highest HTX-011 dose group 
 TEAEs by SOC in internationally agreed order and PT in descending frequency according to total 
incidence (alphabetically for ties) in the highest HTX-011 dose group 
 TEAEs leading to premature study discontinuation by SOC in internationally agreed order and PT 
in descending frequency according to total incidence (alphabetically for ties) in the highest HTX-
011 dose group 
 Study drug-related TEAEs by SOC in internationally agreed order and PT in descending frequency 
according to total incidence (alphabetically for ties) in the highest HTX-011 dose group 
 Opioid-related TEAEs by SOC in internationally agreed order and PT in descending frequency 
according to total incidence (alphabetically for ties) in the highest HTX-011 dose group 
Opioid-related AEs defined by the Sponsor are AEs that code to any of the following PTs: Nausea, 
Vomiting, Constipation, Pruritus, Somnolence, Respiratory depression, or Urinary retention throughout 
the study. For a given SOC and PT, a subject will be counted once even if the subject has experienced 
multiple episodes for that particular SOC and PT. AE tables will be organized as described in Section 7.1. 
 
Nausea Assessments 
Nausea is measured on a scale of 0-10, with 0 indicating no nausea and 10 indicating the worst nausea 
imaginable. Assessments of nausea at each time point (6, 24, 48, and 72 hours post-treatment, early 
termination) will be analyzed using ANCOVA/ANOVA as described in Section 7.7.1. Results reported 
will include sample size, mean (SD), SEM, LSMD, 95% CI for LSMD, and p-value. Mean nausea scores 
over time will be plotted for the groups described in Section 7.7. 
 
Clinical Laboratory Tests 
Observed values at each time point and change from baseline (Day 0) will be summarized without formal 
statistical testing. Shift tables (i.e., low-normal-high at baseline versus low-normal-high at follow-up in a 
3-by-3 contingency table) will be provided to assess changes in laboratory values from Day 0 at baseline 
to each follow-up time point. The lowest post-baseline value, and the highest post-baseline value will be 
included in summary tables, and will incorporate data from both scheduled and unscheduled visits. The 
data listing of labs will flag values below and above the normal reference ranges.  
 
Vital Sign Measurements 
Observed values at each time point and change from baseline (Day 0) will be summarized without formal 
statistical testing. The count and percentage of subjects who meet the abnormal criteria (Table 7) at any 
post-baseline visit will be summarized, using data collected at scheduled and unscheduled visits. In 
addition, a table listing subjects with abnormal changes from baseline will be provided, over all scheduled 
and unscheduled visits. 
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Table 7: 
Criteria for Abnormal Vital Signs 
Vital Sign 
Low 
High 
Heart Rate 
≤ 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 
 
Electrocardiograms 
The count and percentage of subjects with abnormal ECG findings at each time point will be summarized 
without formal statistical testing. Shift tables (i.e., normal or abnormal-not clinically significant [NCS] at 
baseline versus normal, abnormal-NCS, or abnormal-clinically significant [CS] at follow-up) will be 
provided to assess changes in ECG status from Day 0 at baseline to each follow up time point. In addition, 
a table will be provided listing subjects with any change from normal or abnormal-NCS at baseline to CS 
abnormal after baseline. 
 
Physical Examinations 
Physical exam findings will be presented in a data listing.  
 
Wound Healing Assessments 
The count and percentage of subjects with abnormal healing of the wound site at each time point will be 
summarized without formal statistical testing.  
 
Bupivacaine Toxicity 
Assessments of symptoms associated with bupivacaine toxicity include perioral tingling, strange taste, 
muscle twitching, ringing in the ears, seizure, bradycardia, and cardiac arrest. Count and percentage of 
subjects with each symptom will be summarized. Listings by subject and by time/visit will be provided, 
with a verbatim description of any symptoms present, and a determination on the clinical significance of 
the symptom.  
 
Liver Function  
Results from liver function testing performed at any post-baseline scheduled and unscheduled visits that 
meet the criteria presented in Table 8 will be summarized with counts and percentages, and subjects with 
abnormal liver function test results will be presented in a separate listing: 
Table 8: 
Criteria for Abnormal Liver Function 
Test 
Criteria for Abnormality 
ALT (SGPT) 
> 3 times the upper limit of normal (ULN) 
AST (SGOT) 
> 3 ULN 
Total Bilirubin 
> 2 ULN 
ALP 
> 1.5 ULN 
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ALP 
> 2 ULN 
ALT and AST 
> 3 ULN 
ALT and Total Bilirubin 
ALT > 3 ULN and total bilirubin >1.5 ULN 
AST and Total Bilirubin 
AST > 3 ULN and total bilirubin > 1.5 ULN 
Hy’s Law 
(ALT or AST > 3 ULN) and ALP <2 ULN and total bilirubin > 2 ULN 
7.9.10 
Neurological Exam 
Date of exam, reason not done, if applicable, and a verbatim description of any clinically significant 
abnormalities will be provided in data listings. 
8  INTERIM ANALYSIS 
An interim analysis will be conducted when Part A is complete in order to determine the optimal 
technique of administration of study drug for Part B and P rt C. Administrative interim analyses will be 
performed in order to determine additional formulations, dosage, or administration techniques to be 
investigated. 
9 CHANGE FROM ANALYSIS PLANNED IN PROTOCOL 
SPI over 24 hours, SPI over 48 hours, SPI over 72 hours, and SPI over 96 hours will also be analyzed 
using a Wilcoxon Rank Sum test for integrated ass ssment of PI scores and rescue opioid use as an 
exploratory analysis. 
AUCs of PI scores over time were added s an exploratory endpoint and will be analyzed using ANOVA, 
1 set with LOCF imputation and another with WLOCF imputation. 
The analysis of number of times rescue medication used during the treatment phase was removed as 
multiple kinds of rescue medications were allowed for rescue. 
One subject who received HTX-011-49 by injection into surgical wound also received sufentanil from 
another trial. This subject was excluded from the mITT Population, and included in the Safety Population, 
effective 12MAY2016. 
Reporting of PONV risk factors was removed as these data were not explicitly collected. 
Method for time to first rescue medication analysis was changed to Wilcoxon test. 
Method of PI score collection stratification factor was added to Part A PI score analyses. 
Tabulation of subjects in each pain control category was replaced by a responder analysis for the 
percentage of subjects reporting ‘Very Good’ or ‘Excellent’ pain control. 
Analysis of the proportion of subjects requiring rescue medication was changed to an analysis of the 
proportion of opioid-free subjects. 
Additional collection of vital signs at time points 8 and 10 hours post-treatment included in listings. 
Nausea was changed from an efficacy outcome to a safety outcome. 
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10 REFERENCES 
International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use. Statistical principles for clinical trials (E9). International Conference on 
Harmonization; 1998. 
Chan ISF and Zhang Z. Test-based exact confidence intervals for the difference of two binomial 
proportions. Biometrics. 1999;(55):1202-1209. 
Silverman DG, O’Connor TZ, Brull SJ. Integrated assessment of pain scores and rescue morphine use 
during studies of analgesic efficacy. Anesth Analg. 1993;77:168-170. 
M2 eCTD: Electronic Common Technical Document Specification Appendix 7, provided by the 
International Conference on Harmonization. Available from: 
http://www.fda.gov/downloads/Drugs/GuidanceComplian eRegulatoryInformation/Guidances/ucm07324
0.pdf 
Data Standards: Position on Use of SI Units for Lab Tests. US Food and Drug Administration; 25 October 
2013. Available from: 
http://www.fda.gov/ForIndustry/DataStandards/StudyDataStandards/ucm372553.htm 
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