Clinical trial NCT02689258
Conditions: Postoperative Pain
Sponsor: Heron Therapeutics
Start date: 2016-02-23; Completion date: 2017-04-01
Enrollment: 277 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A Phase 2, Randomized, Controlled Evaluation of the Efficacy and Safety of HTX-011 or HTX-002 for Post-Operative Analgesia Following Abdominoplasty Surgery

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 the bupivacaine component. 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 was evaluated.

Arms: arm 1: HTX- 011A (bupivacaine/meloxicam), 200 mg/6 mg via injection arm 2: Saline placebo via injection arm 3: HTX- 011B (bupivacaine/meloxicam), 200 mg/6 mg via injection arm 4: HTX- 011B (bupivacaine/meloxicam), 400 mg/12 mg via injection arm 5: HTX- 011B (bupivacaine/meloxicam), 400 mg/12 mg via combination arm 6: HTX- 011B (bupivacaine/meloxicam), 600 mg/18 mg via injection arm 7: HTX-002, 400 mg via combination arm 8: HTX-011B (bupivacaine/meloxicam), 400 mg/12 mg via instillation arm 9: HTX-011B (bupivacaine/meloxicam), 400 mg/12 mg via combination arm 10: HTX-011B (bupivacaine/meloxicam), 300 mg/9 mg via combination arm 11: Bupivacaine HCl, 100 mg via injection arm 12: Saline placebo via injection
Interventions: intervention 1: HTX-011B intervention 2: Placebo intervention 3: HTX-011A intervention 4: HTX-002 intervention 5: Bupivicaine HCl
Intervention descriptions: intervention 1: HTX- 011B (bupivacaine/meloxicam) via injection intervention 2: Saline placebo via injection intervention 3: HTX- 011A (bupivacaine/meloxicam) via injection intervention 4: HTX-002 via combination intervention 5: Bupivacaine HCl via injection

Protocol documents:
Prot_000.pdf: 
Document Type:  
Study Protocol 
Official Title:  
A Phase 2, Randomized, Controlled Evaluation of the Efficacy and 
Safety of HTX-011 or HTX-002 for Post-Operative Analgesia Following 
Abdominoplasty Surgery 
NCT Number:  
NCT02689258 
Document Date:  
06-Feb-2017 
 


 
CLINICAL STUDY PROTOCOL 
PROTOCOL NUMBER HTX-011-C2015-203 
(PRT-0048) 
A Phase 2, Randomized, Controlled Evaluation of the Efficacy and Safety of HTX-011 
or HTX-002 for Post-Operative Analgesia Following Abdominoplasty Surgery 
U.S. IND Number: 125927 
 
Compound Name: 
HTX-011 (extended-release 2.5% bupivacaine and 0.075% 
meloxicam) 
HTX-002 (extended-release 2.5% bupivacaine) 
Protocol Version: 
12 
Date of Protocol: 
06 February 2017 
Previous Versions: 
Version 1: 04 December 2015 
Version 2: 08 January 2016 
Version 3: 21 January 2016 
Version 4: 30 March 2016 
Version 5: 29 April 2016 
Version 6: 08 June 2016 
Version 7: 08 August 2016 
Version 8: 28 September 2016 
Version 9: 30 November 2016 
Version 10: 10 January 2017 
Version 11: 18 January 2017 
 
Confidentiality Statement 
This document contains confidential information of Heron Therapeutics, Inc. 
Do not copy or distribute without written permission of the Sponsor. 
Any authorized use, reproduction, publication, or dissemination is strictly prohibited. 




Protocol HTX-011-C2015-203, Version 12 
Page 3 of 87 
Heron Therapeutics 
Confidential 
INVESTIGATOR AGREEMENT 
CLINICAL PROTOCOL HTX-011-C2015-203 
A Phase 2, Randomized, Controlled Evaluation of the Efficacy and Safety of HTX-011 
or HTX-002 for Post-Operative Analgesia Following Abdominoplasty Surgery  
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-C2015-203, Version 12 
Page 4 of 87 
Heron Therapeutics 
Confidential 
SYNOPSIS 
Name of Sponsor/Company:  
Heron Therapeutics, Inc. 
Protocol Number:   
HTX-011-C2015-203 
Name of Investigational Product:  
HTX-011 (extended-release 2.5% bupivacaine and 
0.075% meloxicam)  
• 
HTX-011-49  
• 
HTX-011-56  
HTX-002 (extended-release 2.5% bupivacaine) 
Protocol Title:   
A Phase 2, Randomized, Controlled Evaluation of the 
Efficacy and Safety of HTX-011 or HTX-002 for 
Post-Operative Analgesia Following Abdominoplasty 
Surgery  
Name of Active Ingredients:  
Bupivacaine and Meloxicam (HTX-011) 
Bupivacaine (HTX-002) 
Phase of Development:   
2 
Objective: 
The primary objective is to evaluate the efficacy and duration of analgesia following administration of 
HTX-011 or HTX-002 formulations. 
The secondary objectives will be: 
• 
To determine the safety and tolerability of HTX-011 and HTX-002 formulations  
• 
To determine the optimum study drug administration technique 
• 
To evaluate the pharmacokinetic (PK) profiles of bupivacaine and meloxicam in HTX-011 formulations 
and the PK profile of bupivacaine in HTX-002 over 120 hours after study drug administration  
• 
To evaluate the analgesic effects of HTX-011 and HTX-002 formulations over various intervals using a 
series of secondary efficacy endpoints for pain intensity 
• 
To assess the effects of HTX-011 and HTX-002 formulations on wound healing at 48 hours, 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 remain pain free over time 
Methodology: This is a Phase 2, randomized, controlled evaluation of the efficacy and safety of HTX-011 and 
HTX-002 for post-operative analgesia following abdominoplasty surgery in adult subjects undergoing 
abdominoplasty.  The total duration of this study for each subject will be a maximum of 88 days that comprise 
28-day screening period, 72 hours in-house treatment period, and 25 days post-treatment period involving 
4 post-treatment visits to the clinic.  Subjects will also receive a phone call from the study site on Day 60. 
Up to approximately 523 subjects will be enrolled and studied as follows: 
Part A 
Part A of the study is the dose-escalation phase of the study.  The primary objective of Part A will be to 
evaluate the efficacy and duration of analgesia following administration of two HTX-011 formulations 
(HTX-011-49 and HTX-011-56).  An optimal formulation/dose will be selected from Part A, and the identified 
formulation/dose will be utilized for subjects who will be enrolled into Part B.  In Part A of the study, the 
surgical procedure will be restricted to a mini-abdominoplasty, i.e., it will exclude liposuction and/or 
repositioning of the umbilicus. 
Subjects enrolling into Part A will be randomized into each cohort at a ratio of 2:1 to either active or saline.  
Enrollment of HTX-011-49 and HTX-011-56 cohorts may occur in parallel.  
Approximately 90 subjects will be enrolled into Cohorts 1–6 with approximately 15 subjects per Cohort. 
• 
Cohort 1 will be to evaluate the analgesic efficacy of 6.84 mL (200 mg) of HTX-011-49 compared to saline 
• 
Cohort 2 will be to evaluate the analgesic efficacy of 13.68 mL (400 mg) of HTX-011-49 compared to 
saline 


Protocol HTX-011-C2015-203, Version 12 
Page 5 of 87 
Heron Therapeutics 
Confidential 
Name of Sponsor/Company:  
Heron Therapeutics, Inc. 
Protocol Number:   
HTX-011-C2015-203 
Name of Investigational Product:  
HTX-011 (extended-release 2.5% bupivacaine and 
0.075% meloxicam)  
• 
HTX-011-49  
• 
HTX-011-56  
HTX-002 (extended-release 2.5% bupivacaine) 
Protocol Title:   
A Phase 2, Randomized, Controlled Evaluation of the 
Efficacy and Safety of HTX-011 or HTX-002 for 
Post-Operative Analgesia Following Abdominoplasty 
Surgery  
Name of Active Ingredients:  
Bupivacaine and Meloxicam (HTX-011) 
Bupivacaine (HTX-002) 
Phase of Development:   
2 
• 
Cohort 3 will be to evaluate the analgesic efficacy of 20.52 mL (600 mg) of HTX-011-49 compared to 
saline 
• 
Cohort 4 will be to evaluate the analgesic efficacy of 6.84 mL (200 mg) of HTX-011-56 compared to saline 
• 
Cohort 5 will be to evaluate the analgesic efficacy of 13.68 mL (400 mg) of HTX-011-56 compared to 
saline 
• 
Cohort 6 will be to evaluate the analgesic efficacy of 20.52 mL (600 mg) of HTX-011-56 compared to 
saline 
Note: Dose-escalation to the next cohort will not proceed if any of the following are observed: 
• 
3 or more subjects experience an SAE reported by the investigator and confirmed by sponsor to be at least 
possibly related to active study medication. 
• 
3 or more subjects experience a neurological AE reported by the investigator and confirmed by sponsor to 
be at least possibly related to active study medication (excluding minor neurologic findings that are not 
clinically significant, e.g., headache, paresthesia). 
• 
3 or more subjects experience clinically significant ECG findings reported by the investigator and 
confirmed by sponsor to be at least possibly related to active study medication. 
• 
2 or more subjects have PK levels of bupivacaine levels with a Cmax of ≥ 1,000 ng/mL 
If any one or more of the dose-escalation rules are triggered in the study of Cohorts 1 or 4, then additional 
subjects may be enrolled in the affected Cohort to further confirm the tolerability profile of the 200 mg dose.  
If any one or more of the dose-escalation rules are triggered in the study of any one of Cohorts 2, 3, 5, or 6, then 
additional subjects may be enrolled in the affected Cohort to further confirm the tolerability profile of the dose 
being studied in the affected Cohort. 
Specifically, with respect to the rule on PK levels, the dose of Cohort 3 or Cohort 6 can be modified according 
to the following:  
• 
If 2 or more subjects in Cohort 2 or Cohort 5 have plasma levels of bupivacaine with a Cmax of 
≥ 1,000 ng/mL, then an additional 15 subjects will be dosed at 17.10 mL (500 mg) in Cohort 3A or 
Cohort 6A. 
• 
If 2 or more subjects in Cohort 3 or Cohort 6 who are dosing with 20.52 mL have plasma bupivacaine 
levels with a Cmax of ≥ 1,000 ng/mL, an additional 15 subjects will be randomly assigned to Cohort 3A to 
administer 17.10 mL (500 mg) of HTX-011-49 or to Cohort 6A to administer 17.10 mL (500 mg) of 
HTX-011-56 (10 subjects) or saline (5 subjects). 
Part B 
Enrollment in Part B will be initiated following the completion of enrollment in Part A and will evaluate 
HTX-011 compared with HTX-002 or saline. In this part of the study, the surgical procedure allowed will be 
broadened to accommodate an abdominoplasty that can include liposuction and/or repositioning of the 
umbilicus.  
Part B comprises 3 cohorts enrolling a total of approximately 120 subjects. Subjects will be randomized (1:1; 


Protocol HTX-011-C2015-203, Version 12 
Page 6 of 87 
Heron Therapeutics 
Confidential 
Name of Sponsor/Company:  
Heron Therapeutics, Inc. 
Protocol Number:   
HTX-011-C2015-203 
Name of Investigational Product:  
HTX-011 (extended-release 2.5% bupivacaine and 
0.075% meloxicam)  
• 
HTX-011-49  
• 
HTX-011-56  
HTX-002 (extended-release 2.5% bupivacaine) 
Protocol Title:   
A Phase 2, Randomized, Controlled Evaluation of the 
Efficacy and Safety of HTX-011 or HTX-002 for 
Post-Operative Analgesia Following Abdominoplasty 
Surgery  
Name of Active Ingredients:  
Bupivacaine and Meloxicam (HTX-011) 
Bupivacaine (HTX-002) 
Phase of Development:   
2 
active: saline) into each cohort as follows: 
• HTX-011-56 13.68 mL (400 mg) via a combination of injection and instillation compared with saline 13.68 
mL via injection (mini abdominoplasty)  
• HTX-011-002 13.68 mL (400 mg) via a combination of injection and instillation compared with saline 
13.68 mL via injection (mini abdominoplasty)  
• HTX-011-56 13.68 mL (400 mg) via a combination of injection and instillation compared with saline 13.68 
mL via injection (complete abdominoplasty) 
Part C 
Part C will include subjects undergoing complete abdominoplasty without liposuction. Approximately 
30 subjects will be randomized to 1 of the following 2 cohorts in a 1:1 ratio:  
• HTX-011-56 13.68 mL (400 mg) via instillation (15 subjects) 
• Bupivacaine HCl 0.25% 100 mg (40 mL) via injection (15 subjects) 
Part D (Optional) 
Part D will include subjects undergoing complete abdominoplasty with liposuction. Approximately 50 subjects 
will be randomized to 1 of up to 4 cohorts in a 3:3:3:1 ratio:  
• HTX-011-56 400 mg (13.68 mL) via instillation and/or injection (as determined by the Sponsor) 
(15 subjects) 
• HTX-011-56 300 mg (10.26 mL) via instillation and/or injection (as determined by the Sponsor) 
(15 subjects) 
• HTX-011-56 200 mg (6.84 mL) via instillation and/or injection (as determined by the Sponsor) 
(15 subjects)  
• Saline (13.68 mL) via injection (5 subjects) 
Part E (Optional) 
Part E will include subjects undergoing complete abdominoplasty without liposuction. Approximately 
48 subjects will be randomized to 1 of up to 5 cohorts in a 2:2:2:1:1 ratio: 
• HTX-011-56 400 mg (13.68 mL) via instillation and/or injection (as determined by the Sponsor) and 
fentanyl 50 µg IV before wound closure (12 subjects) 
• HTX-011-56 300 mg (10.26 mL) via instillation and/or injection (as determined by the Sponsor) and 
fentanyl 50 µg IV before wound closure (12 subjects) 
• HTX-011-56 200 mg (6.84 mL) via instillation and/or injection (as determined by the Sponsor) and fentanyl 
50 µg IV before wound closure (12 subjects) 
• Saline (13.68 mL) via injection and fentanyl 50 µg IV before wound closure (6 subjects) 
• Bupivacaine HCl 0.25% 100 mg (40 mL) via injection and fentanyl 50 µg IV before wound closure 
(6 subjects)  


Protocol HTX-011-C2015-203, Version 12 
Page 7 of 87 
Heron Therapeutics 
Confidential 
Name of Sponsor/Company:  
Heron Therapeutics, Inc. 
Protocol Number:   
HTX-011-C2015-203 
Name of Investigational Product:  
HTX-011 (extended-release 2.5% bupivacaine and 
0.075% meloxicam)  
• 
HTX-011-49  
• 
HTX-011-56  
HTX-002 (extended-release 2.5% bupivacaine) 
Protocol Title:   
A Phase 2, Randomized, Controlled Evaluation of the 
Efficacy and Safety of HTX-011 or HTX-002 for 
Post-Operative Analgesia Following Abdominoplasty 
Surgery  
Name of Active Ingredients:  
Bupivacaine and Meloxicam (HTX-011) 
Bupivacaine (HTX-002) 
Phase of Development:   
2 
Part F (Optional) 
Part F will include subjects undergoing complete abdominoplasty without liposuction. Approximately 
50 subjects will be randomized to 1 of up to 4 cohorts in a 3:3:3:1 ratio: 
• HTX-011-56 400 mg (13.68 mL) via instillation and/or injection (as determined by the Sponsor), fentanyl 
50 µg IV, and acetaminophen IV (1000 mg) before wound closure (15 subjects) 
• HTX-011-56 300 mg (10.26 mL) via instillation and/or injection (as determined by the Sponsor), fentanyl 
50 µg IV, and acetaminophen IV (1000 mg) before wound closure (15 subjects) 
• HTX-011-56 200 mg (6.84 mL) via instillation and/or injection (as determined by the Sponsor), fentanyl 
50 µg IV, and acetaminophen IV (1000 mg) before wound closure (15 subjects) 
• Saline (13.68 mL) via injection, fentanyl 50 µg IV, and acetaminophen IV (1000 mg) before wound closure 
(5 subjects) 
Part G (Optional) 
Part G will include subjects undergoing complete abdominoplasty with liposuction. Approximately 50 subjects 
will be randomized to 1 of up to 4 cohorts in a 3:3:3:1 ratio: 
• HTX-011-56 400 mg (13.68 mL) via instillation and/or injection (as determined by the Sponsor) and 
fentanyl 50 µg IV before wound closure (15 subjects) 
• HTX-011-56 300 mg (10.26 mL) via instillation and/or injection (as determined by the Sponsor) and 
fentanyl 50 µg IV before wound closure (15 subjects) 
• HTX-011-56 200 mg (6.84 mL) via instillation and/or injection (as determined by the Sponsor) and fentanyl 
50 µg IV before wound closure (15 subjects) 
• Saline (13.68 mL) via injection and fentanyl 50 µg IV before wound closure (5 subjects) 
Part H (Optional) 
Part H will include subjects undergoing complete abdominoplasty with liposuction. Approximately 50 subjects 
will be randomized to 1 of up to 4 cohorts in a 3:3:3:1 ratio: 
• HTX-011-56 400 mg (13.68 mL) via instillation and/or injection (as determined by the Sponsor), fentanyl 
50 µg IV, and acetaminophen IV (1000 mg) before wound closure (15 subjects) 
• HTX-011-56 300 mg (10.26 mL) via instillation and/or injection (as determined by the Sponsor), fentanyl 
50 µg IV, and acetaminophen IV (1000 mg) before wound closure (15 subjects) 
• HTX-011-56 200 mg (6.84 mL) via instillation and/or injection (as determined by the Sponsor), fentanyl 
50 µg IV, and acetaminophen IV (1000 mg) before wound closure (15 subjects) 
• Saline (13.68 mL) via injection, fentanyl 50 µg IV, and acetaminophen IV (1000 mg) before wound closure 
(5 subjects) 
Part I (Optional) 
Part I will include subjects undergoing complete abdominoplasty without liposuction. Up to approximately 


Protocol HTX-011-C2015-203, Version 12 
Page 8 of 87 
Heron Therapeutics 
Confidential 
Name of Sponsor/Company:  
Heron Therapeutics, Inc. 
Protocol Number:   
HTX-011-C2015-203 
Name of Investigational Product:  
HTX-011 (extended-release 2.5% bupivacaine and 
0.075% meloxicam)  
• 
HTX-011-49  
• 
HTX-011-56  
HTX-002 (extended-release 2.5% bupivacaine) 
Protocol Title:   
A Phase 2, Randomized, Controlled Evaluation of the 
Efficacy and Safety of HTX-011 or HTX-002 for 
Post-Operative Analgesia Following Abdominoplasty 
Surgery  
Name of Active Ingredients:  
Bupivacaine and Meloxicam (HTX-011) 
Bupivacaine (HTX-002) 
Phase of Development:   
2 
35 subjects will be randomized to 1 of the following 2 cohorts in a 6:1 ratio: 
• HTX-011-56 300 mg (10.26 mL) via instillation and/or injection (as determined by the Sponsor) 
(30 subjects) 
• Saline (10.26 mL) via injection (5 subjects) 
Pretreatment Phase (Day -28 to Day -1): 
Subjects will be consented and screened. 
Treatment and Confinement Phase (Day 0 to Day 5): 
Subjects will be re-assessed on Day 0 for eligibility to continue in this study, and will be confined from Day 0 
to 72 hours after receiving study medication. 
Efficacy evaluations will include collection of Pain Intensity scores and Patient Global Assessment of pain 
control at pre-defined time intervals throughout the study. 
Subject safety will be monitored by regular assessments of vital signs, electrocardiographs (ECGs), physical 
examination, neurologic exams, clinical laboratory tests, wound healing, and by collection of AEs and 
concomitant medications.  
Blood samples will be obtained to evaluate pharmacokinetic (PK) profiles of bupivacaine and meloxicam. 
Subjects will return to the clinic site at 96 and 120 hours post-administration of study drug for safety and 
efficacy evaluations, as follows: 
• 96 Hours: assessments of vital signs, ECG, collection of AEs and concomitant medications, and a blood 
sample for PK.  Efficacy assessments will include collection of Pain Intensity scores and Patient Global 
Assessment (PGA) evaluations. 
• 120 Hours: obtain blood sample for pharmacokinetic analysis, collection of AEs and concomitant 
medications.  
Follow-Up Phase (Days 10, 28, and 60): 
Day 10: physical examination, vital signs, ECG, photograph of the surgical intervention area, and assessments 
of wound healing, AEs, and concomitant medications. 
Day 28: assessment of AEs, concomitant medications, wound healing, and photograph of the surgical 
intervention area. 
Day 60: subjects will receive a phone call from the study site to collect follow-up information on post-operative 
pain and pain medications. 
Number of subjects to be enrolled: Up to approximately 523 subjects will be enrolled in this study: 90 in 
Part A, 120 in Part B, 30 in Part C, 50 in Part D, 48 in Part E, 50 in Part F, 50 in Part G, 50 in Part H, and 35 in 
Part I. Parts D through I are optional. 
Number of study sites:  Up to 8 
Study country location: United States  


Protocol HTX-011-C2015-203, Version 12 
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Heron Therapeutics 
Confidential 
Name of Sponsor/Company:  
Heron Therapeutics, Inc. 
Protocol Number:   
HTX-011-C2015-203 
Name of Investigational Product:  
HTX-011 (extended-release 2.5% bupivacaine and 
0.075% meloxicam)  
• 
HTX-011-49  
• 
HTX-011-56  
HTX-002 (extended-release 2.5% bupivacaine) 
Protocol Title:   
A Phase 2, Randomized, Controlled Evaluation of the 
Efficacy and Safety of HTX-011 or HTX-002 for 
Post-Operative Analgesia Following Abdominoplasty 
Surgery  
Name of Active Ingredients:  
Bupivacaine and Meloxicam (HTX-011) 
Bupivacaine (HTX-002) 
Phase of Development:   
2 
Criteria for inclusion: 
Subjects must meet all of the following criteria to be considered eligible to participate in the study: 
1. Be scheduled to undergo abdominoplasty surgery that is amenable to treatment with a long acting local 
anesthetic as per the anesthesia protocol in Section 5.5.1 
2. Be American Society of Anesthesiology (ASA) physical Class I or II 
3. Subjects 18 years of age or older 
4. Have clinical laboratory values that are within normal limits (WNL) or if abnormal, not clinically 
significant; subjects with AST/ALT < 3 x ULN, and/or creatinine < 2 x ULN are acceptable. 
5. Have a body mass index ≤ 30 kg/m2 
6. Female subjects are eligible only if all of the following apply: 
• 
Not pregnant (female subject of child bearing potential must have a negative serum pregnancy tests at 
screening and negative urine pregnancy test before surgery) 
• 
Not lactating 
• 
Not planning to become pregnant during the study 
• 
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 
7. Male subjects 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 
8. Does NOT have, as determined by the investigator or the study’s medical monitor, a history or clinical 
manifestations of significant renal, hepatic, cardiovascular, metabolic, neurologic, psychiatric, or other 
condition that would preclude participation in the study 
9. Must be able to understand study procedures and be willing to comply and give informed consent for the 
conduct of all study procedures, using an IRB approved consent 
Criteria for Exclusion: 
Subjects who meet any of the following criteria will be excluded from participating in the study: 
1. Have a contraindication or be allergic to any medication to be used during the trial period  
2. Have another painful physical condition that, in the opinion of the investigator, may confound the 
assessments of post-operative pain 
3. Have a history of migraine or frequent headaches, seizures, or are currently taking anticonvulsants 
4. 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 
5. Previous abdominal surgery, as determined by the investigator, that would preclude participation in the 


Protocol HTX-011-C2015-203, Version 12 
Page 10 of 87 
Heron Therapeutics 
Confidential 
Name of Sponsor/Company:  
Heron Therapeutics, Inc. 
Protocol Number:   
HTX-011-C2015-203 
Name of Investigational Product:  
HTX-011 (extended-release 2.5% bupivacaine and 
0.075% meloxicam)  
• 
HTX-011-49  
• 
HTX-011-56  
HTX-002 (extended-release 2.5% bupivacaine) 
Protocol Title:   
A Phase 2, Randomized, Controlled Evaluation of the 
Efficacy and Safety of HTX-011 or HTX-002 for 
Post-Operative Analgesia Following Abdominoplasty 
Surgery  
Name of Active Ingredients:  
Bupivacaine and Meloxicam (HTX-011) 
Bupivacaine (HTX-002) 
Phase of Development:   
2 
study 
6. Subjects that require liposuction as part of the abdominoplasty procedure in Part A, C, E, F, or I of the 
protocol 
7. Subjects that are to have ancillary procedures performed during the abdominoplasty surgery that are 
unrelated to the abdominal area (breast reduction, breast augmentation, etc.) 
8. Subjects unable to discontinue medications that have not been at a stable dose for at least 14 days prior to 
the scheduled abdominoplasty procedure and before dosing with investigational product 
9. Subjects taking the following medications; anticonvulsants, sedatives (including benzodiazepines) 
corticosteroids (by any means of administration), nonsteroidal anti-inflammatory drugs (NSAIDS) within 
24 hours of study drug dosing, morphine, monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants 
(TCAs), neuroleptics, or serotonin-norepinephrine reuptake inhibitors (SNRIs). Gabapentin and pregabalin 
are not permitted 
10. Have a known or suspected history of alcohol or drug abuse  
11. Have positive results on the alcohol breath test indicative of alcohol abuse or urine drug screen indicative 
of  illicit drug use (unless results can be explained by a current prescription or acceptable over-the-counter 
medication at screening as determined by the investigator).  The urine drug screen prior to surgery must be 
negative 
12. Have evidence of a clinically significant 12-lead ECG abnormality according to the judgment of the 
investigator 
13. Have received any investigational product within 30 days before start of study 
14. Have previously received HTX-011 in clinical trials 
15. Experiences a clinically significant event during surgery prior to the administration of the investigational 
product (e.g., excessive bleeding, hemodynamic instability) that would render the subject medically 
unstable, complicate their post-surgical course, or significantly increase the risk of study drug 
administration as per the judgment of the investigator.  This will result in the subject being reported as 
randomized, not treated. 
16. Subjects with sleep apnea or are on home continuous positive airway pressure (CPAP) 
17. Subjects who are receiving oxygen therapy at the time of screening 
Investigational product: HTX-011 is a sterile, viscous, extended-release fixed-ratio combination of 
bupivacaine and meloxicam.  The term “HTX-011” is used to represent the formulations HTX-011-49 and 
HTX-011-56.  HTX-002 is a sterile, viscous, extended-release formulation identical to HTX-011-56 except that 
it contains only bupivacaine (at the same concentration) as the active pharmaceutical ingredient.  All 
3 formulations are to be locally administered into the surgical site for the prevention of post-operative pain. 
The vehicle formulation for HTX-011-49, HTX-011-56, and HTX-002 comprises tri[ethylene glycol] based 
poly[orthoester] polymer with dimethyl sulfoxide, glycerol triacetate, and maleic acid excipients. 
The HTX-011 and HTX-002 formulations will be supplied by the sponsor. 


Protocol HTX-011-C2015-203, Version 12 
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Confidential 
Name of Sponsor/Company:  
Heron Therapeutics, Inc. 
Protocol Number:   
HTX-011-C2015-203 
Name of Investigational Product:  
HTX-011 (extended-release 2.5% bupivacaine and 
0.075% meloxicam)  
• 
HTX-011-49  
• 
HTX-011-56  
HTX-002 (extended-release 2.5% bupivacaine) 
Protocol Title:   
A Phase 2, Randomized, Controlled Evaluation of the 
Efficacy and Safety of HTX-011 or HTX-002 for 
Post-Operative Analgesia Following Abdominoplasty 
Surgery  
Name of Active Ingredients:  
Bupivacaine and Meloxicam (HTX-011) 
Bupivacaine (HTX-002) 
Phase of Development:   
2 
Reference therapy: Normal saline and bupivacaine HCl 0.25%.  Reference therapy will be sourced and 
supplied by sites. 
Duration of treatment: Each subject is planned to receive a single dose of study medication. 
Overview: This study is designed to evaluate the safety and analgesic efficacy of up to four dose levels of two 
HTX-011 formulations and HTX-002 in subjects following abdominoplasty surgery.  The study will also 
evaluate different local administration techniques (injection, instillation, and a combination of the 2 techniques) 
as well as the effects of a fentanyl and acetaminophen administration at the end of surgery and before wound 
closure on the analgesic efficacy of HTX-011.  Efficacy assessments are intended to characterize the analgesic 
effect time curve and the magnitude of analgesic effect of HTX-011 and HTX-002 in comparison with saline or 
bupivacaine HCl.  In addition, the study will further characterize the safety and PK profiles of bupivacaine and 
meloxicam in the HTX-011 formulations and the PK profile of bupivacaine in the HTX-002 formulation. 
Subjects will participate in the screening visit within 28 days of the scheduled surgery.  ASA classification and 
inclusion/exclusion criteria for eligibility to participate in the study will be assessed.  Medical history, vital 
signs, physical examination, clinical laboratory tests, drug and alcohol screening, 12-lead ECG, collection of 
prior/concomitant medications, and a serum pregnancy test will be performed.  PONV risk factors will be 
assessed, and subject will be trained on providing pain intensity assessments. 
On the day of surgery, Day 0, subjects will be reassessed for eligibility.  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 for 
inducing general anesthesia or as detailed in the protocol. 
Subjects will be assigned randomly to a cohort and dosed as described above.  Start and stop time of dosing will 
be recorded.  Dosing stop time will be considered Time 0 (T0). 
Subjects will be transferred to the post-anesthesia care area and observed according to institutional standards.  
While in the post-anesthesia care area, subjects may receive morphine iv rescue medication for pain control, as 
needed, as per local practice. 
Each subject will be sequestered in the post-anesthesia care area at each study center for 72 hours post-Time 0, 
after which discharge procedures will be performed. 
Efficacy analyses: 
Pain intensity (PI) scores will be assessed by the subject for their pain according to the Visual Analog Scale 
(VAS), at 1, 2, 78, 84, and 96 hours after completion of administration of study medication (T0).  For the VAS, 
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 measured on movement (i.e., subject 
sitting up from a supine position) at the following time-points: 4, 6, 8, 10, 12, 14, 18, 24, 30, 36, 42, 48, 54, 60, 
and 72 hours post-T0. 
PI scores at rest will be measured at 1, 2, 78, 84, and 96 hours post-T0. 
Rescue analgesia (from T0 to T72) will be available to subjects with inadequately controlled pain symptoms. 
Pain intensity assessment must be completed prior to administration of any rescue dose administered.  


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Name of Sponsor/Company:  
Heron Therapeutics, Inc. 
Protocol Number:   
HTX-011-C2015-203 
Name of Investigational Product:  
HTX-011 (extended-release 2.5% bupivacaine and 
0.075% meloxicam)  
• 
HTX-011-49  
• 
HTX-011-56  
HTX-002 (extended-release 2.5% bupivacaine) 
Protocol Title:   
A Phase 2, Randomized, Controlled Evaluation of the 
Efficacy and Safety of HTX-011 or HTX-002 for 
Post-Operative Analgesia Following Abdominoplasty 
Surgery  
Name of Active Ingredients:  
Bupivacaine and Meloxicam (HTX-011) 
Bupivacaine (HTX-002) 
Phase of Development:   
2 
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 2 hours, as needed for analgesia.  Additional morphine up to 10 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).  Between T72 and T96, pain medication 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 for inadequately controlled pain, as advised by their 
surgeon. 
Each subject’s PGA of pain control will be obtained at 24, 48, 72, and 96 hours post-T0. 
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. 
Safety analyses: 
A neurologic exam and assessment will be completed at the following time points: at Day 0 any time prior to 
anesthesia induction, and at 24, 48, and 72 hours post-T0.  The exam will include awareness and assessment for 
signs and symptoms of potential bupivacaine toxicity. 
Vital signs will be measured at screening, at Baseline (i.e., Day 0, prior to anesthetic pre-operative procedures), 
and at 1, 2, 4, 6, 12, 18, 24, 36, 48, 60, 72, and 96 hours, and at Day 10 after T0. 
Each subject will have a 12-lead ECG performed at screening; at baseline (i.e., Day 0, prior to anesthetic 
pre-operative procedures); at 1, 2, 3, 4, 5, 6 hours (Parts B through I); at 24, 48, 72, and 96 hours; and at Day 10 
post-T0. 
Blood samples for clinical laboratory tests will be obtained at screening visit, at Baseline, and at 72 hours 
post-T0. 
Each subject will be assessed for nausea 6, 24, 48, and 72 hours post-T0 using a visual analog scale. 
Each subject will be assessed for wound healing at 48 and 72 hours and at Days 10 and 28 post-T0. 
A photograph of the surgical intervention area will be taken immediately after surgery, at 48, 72 hours, and at 
Days 10 and 28 post-T0. 
Subjects will be assessed for adverse events and concomitant medications throughout the study. 
Pharmacokinetics analyses: 
Blood samples for PK analyses will be drawn prior to administration of the investigational product (IP) and at 
0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 18, 24, 30, 36, 48, 60, 72, 96, and 120 hours post-T0. 
Efficacy Endpoints: 
Summed pain intensity score (SPI) over the first 24 hours (SPI0-24) 
Secondary:  


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Name of Sponsor/Company:  
Heron Therapeutics, Inc. 
Protocol Number:   
HTX-011-C2015-203 
Name of Investigational Product:  
HTX-011 (extended-release 2.5% bupivacaine and 
0.075% meloxicam)  
• 
HTX-011-49  
• 
HTX-011-56  
HTX-002 (extended-release 2.5% bupivacaine) 
Protocol Title:   
A Phase 2, Randomized, Controlled Evaluation of the 
Efficacy and Safety of HTX-011 or HTX-002 for 
Post-Operative Analgesia Following Abdominoplasty 
Surgery  
Name of Active Ingredients:  
Bupivacaine and Meloxicam (HTX-011) 
Bupivacaine (HTX-002) 
Phase of Development:   
2 
• 
SPI at other time points: SPI0-6, SPI0-12, SPI12-24, SPI24-48, SPI0-48, SPI48-72, SPI0-72, SPI72-96, and SPI0-96 
• 
The PGA of pain control at 24, 48, 72, and 96 hours post-T0 
• 
Time to administration of first dose of rescue analgesia 
• 
Total and average daily rescue consumption over 24, 48, 72, and 96 hours post-T0 
• 
The percentage of subjects who remain pain free (VAS score ≤ 1) at 72 hours and at 96 hours after study 
drug administration 
Safety Endpoints: 
Safety will be evaluated by assessment of AEs, including SAEs.  Additional safety endpoints include the 
following parameters: 
• 
Nausea assessments 
• 
Wound assessments of the surgical intervention area 
• 
Vital signs  
• 
Neurological examinations  
• 
Clinical laboratory tests (serum chemistry, hematology)  
• 
Electrocardiograms (ECGs) 
Pharmacokinetic Endpoints: 
• 
The area under the plasma concentration-time curve from time zero to time t of the last measured 
concentration above the limit of quantification (AUC0-last) 
• 
The area under the plasma concentration-time curve from zero to infinity (AUC0-inf) 
• 
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) 
Statistical Methodology 
The primary efficacy endpoint for this study is the summed pain intensity scores over the first 24 hours 
(SPI0-24).  The primary analysis will be via an analysis of variance for pairwise or pooled group comparisons. 
The sample size in this study was selected empirically without a formal statistical assumption.   
 
 


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TABLE OF CONTENTS 
SPONSOR DETAILS ................................................................................................................2 
INVESTIGATOR AGREEMENT.............................................................................................3 
SYNOPSIS .................................................................................................................................4 
LIST OF TABLES ...................................................................................................................18 
LIST OF APPENDICES ..........................................................................................................18 
ABBREVIATIONS AND DEFINITIONS ..............................................................................19 
1. 
INTRODUCTION ..........................................................................................................21 
2. 
STUDY OBJECTIVES ..................................................................................................23 
2.1. 
Primary Objective ........................................................................................................23 
2.2. 
Secondary Objectives...................................................................................................23 
3. 
STUDY ENDPOINTS ...................................................................................................24 
3.1. 
Primary Efficacy Endpoint: .........................................................................................24 
3.2. 
Secondary Efficacy Endpoints: ....................................................................................24 
3.3. 
Safety Endpoints: .........................................................................................................24 
3.4. 
Pharmacokinetic Endpoints: ........................................................................................24 
4. 
INVESTIGATIONAL PLAN ........................................................................................26 
4.1. 
Overall Study Design ...................................................................................................26 
4.1.1. 
Dose Escalation and Dose Modification Rules for Study Part A ..........................30 
4.1.2. 
Pretreatment Phase (Day -28 to Day -1) ................................................................31 
4.1.3. 
Treatment and Confinement Phase (Day 0 Through Day 5) .................................31 
4.1.4. 
Follow-Up (Day 10 ± 2, Day 28 ± 2, and Day 60 ± 7) ..........................................32 
4.2. 
Rationale for Study Design and Control Groups .........................................................32 
5. 
STUDY POPULATION ................................................................................................33 
5.1. 
Inclusion Criteria .........................................................................................................33 
5.2. 
Exclusion Criteria ........................................................................................................33 
5.3. 
Discontinuation of Subjects .........................................................................................34 
5.3.1. 
Procedures for Withdrawal ....................................................................................34 
5.3.2. 
Replacement of Subjects ........................................................................................35 
5.4. 
Lifestyle Guidelines During Confinement ...................................................................35 
5.4.1. 
Diet .........................................................................................................................35 
5.5. 
Surgical Procedure .......................................................................................................36 
5.5.1. 
Anesthesia Protocol and Administration of Study Medication ..............................36 


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5.5.1.1. 
Anesthesia for Surgery .....................................................................................36 
5.5.1.2. 
Study Drug Administration ..............................................................................36 
5.6. 
Identity of Study Medication .......................................................................................39 
5.7. 
Method of Assigning Subjects to Treatment Groups ...................................................40 
5.8. 
Selection of Doses........................................................................................................41 
5.9. 
Blinding and Unblinding of Study Medications ..........................................................41 
5.10. Treatment Compliance .................................................................................................41 
5.11. Drug Accountability.....................................................................................................42 
5.12. Packaging, Labeling, and Storage ................................................................................42 
5.12.1. 
Study Drug Packaging ...........................................................................................42 
5.12.2. 
Study Drug Labeling and Storage ..........................................................................42 
5.13. Prior and Concomitant Medications ............................................................................43 
5.14. Prohibited Medications ................................................................................................43 
5.15. Concomitant Interventions and Procedures .................................................................43 
5.16. Analgesia Rescue Medication ......................................................................................43 
6. 
STUDY PROCEDURES ................................................................................................45 
6.1. 
Order of Study Procedures ...........................................................................................45 
6.2. 
Demographic and Efficacy Assessments .....................................................................45 
6.2.1. 
Demographics ........................................................................................................45 
6.2.2. 
Medical History .....................................................................................................45 
6.2.3. 
Physical Examination.............................................................................................45 
6.3. 
Efficacy Assessments...................................................................................................46 
6.3.1. 
Pain Intensity (PI) ..................................................................................................46 
6.3.2. 
Patient Global Assessment of Pain Control (PGA) ...............................................46 
6.3.3. 
Analgesia Rescue Medication Usage .....................................................................47 
6.4. 
Safety Assessments ......................................................................................................47 
6.4.1. 
Clinical Laboratory Tests .......................................................................................47 
6.4.2. 
Nausea Assessment ................................................................................................48 
6.4.3. 
Vital Sign Measurements .......................................................................................48 
6.4.4. 
12-Lead Electrocardiogram (ECG) ........................................................................48 
6.4.5. 
Surgical Wound Healing Evaluation and Photographs ..........................................48 
6.4.6. 
Blood Sampling for Bupivacaine/Meloxicam Pharmacokinetics Analysis ...........49 
6.4.6.1. 
Bioanalysis of Bupivacaine and Meloxicam ....................................................49 
6.4.7. 
Neurologic Exam and Assessment.........................................................................49 
6.4.8. 
Assessment of Adverse Events and Prior/Concomitant Medications ....................49 


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6.4.8.1. 
Treatment of Bradycardia, Hypotension, and Low Oxygen Saturation...........50 
6.5. 
Assessments by Visit ...................................................................................................50 
6.5.1. 
Screening Visit .......................................................................................................50 
6.5.2. 
Day 0 Check-In and Surgery..................................................................................51 
6.5.3. 
Day 0 (Treatment) – Day 5 ....................................................................................52 
6.5.4. 
Day 10 ± 2 and Day 28 ± 2 (Follow-Up Procedures) ............................................53 
6.5.5. 
Day 60 Follow-Up Phone Call (±7 days) ..............................................................53 
6.5.6. 
Early Termination (ET) Procedures .......................................................................53 
6.5.7. 
Unscheduled Visits ................................................................................................54 
6.6. 
Appropriateness of Assessments..................................................................................54 
7. 
ADVERSE EVENTS, SERIOUS ADVERSE EVENTS, AND SERIOUS 
SUSPECTED ADVERSE REACTIONS .......................................................................55 
7.1. 
Definition of an Adverse Event ...................................................................................55 
7.2. 
Definition of a Serious Adverse Event ........................................................................56 
7.2.1. 
Serious Adverse Events That Occur Before Administration of Study 
Medication .............................................................................................................56 
7.2.2. 
Serious Adverse Events That Occur After Study Completion ...............................57 
7.3. 
Definition of a Suspected Adverse Reaction ...............................................................57 
7.4. 
Definition of a Serious Suspected Adverse Reaction ..................................................57 
7.5. 
Recording and Evaluating Adverse Events and Serious Adverse Events ....................57 
7.5.1. 
Assessment of Intensity .........................................................................................57 
7.5.2. 
Assessment of Causality ........................................................................................58 
7.5.3. 
Assessment of Outcome .........................................................................................58 
7.6. 
Follow-Up of Adverse Events and Serious Adverse Events .......................................59 
7.7. 
Prompt Reporting of Serious Adverse Events to the Sponsor .....................................59 
7.8. 
Regulatory Reporting Requirements ............................................................................60 
7.9. 
Precautions ...................................................................................................................61 
8. 
STATISTICAL METHODOLOGY ..............................................................................62 
8.1. 
Determination of Sample Size .....................................................................................62 
8.2. 
Study Endpoints ...........................................................................................................62 
8.3. 
General Considerations for Statistical Analysis ..........................................................62 
8.3.1. 
Software and General Statistical Methods .............................................................62 
8.3.2. 
Analysis Datasets ...................................................................................................62 
8.3.3. 
Test Hypothesis and P Value Justification ............................................................62 
8.3.4. 
Procedures for Handling Missing Data ..................................................................63 


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8.3.4.1. 
PI Score Before and After Analgesic Rescue Medication ...............................63 
8.3.4.2. 
Other Missing PI Score(s) ................................................................................63 
8.3.5. 
Derived Variables ..................................................................................................63 
8.3.5.1. 
Study Population Summaries ...........................................................................63 
8.3.6. 
Disposition .............................................................................................................63 
8.3.7. 
Demographics ........................................................................................................64 
8.3.8. 
Protocol Violations ................................................................................................64 
8.3.9. 
Treatment Compliance ...........................................................................................64 
8.3.10. 
Prior and Concomitant Medications ......................................................................64 
8.4. 
Efficacy Analysis .........................................................................................................64 
8.4.1. 
SPI and PI Analyses ...............................................................................................64 
8.4.2. 
Time to First Dose of Rescue Medication .............................................................64 
8.4.3. 
Patient Global Assessment (PGA) of Pain Control ...............................................64 
8.4.4. 
Proportion of Subjects Requiring Rescue Medication ...........................................64 
8.4.5. 
Opioid Consumption and Symptoms Associated With Opioid Use ......................65 
8.4.6. 
Subgroup Analyses for Efficacy ............................................................................65 
8.5. 
Safety and Tolerability Evaluations .............................................................................65 
8.5.1. 
Adverse Events ......................................................................................................65 
8.5.2. 
Nausea Assessments ..............................................................................................65 
8.5.3. 
Clinical Laboratory Tests .......................................................................................65 
8.5.4. 
Vital Sign Measurements .......................................................................................65 
8.5.5. 
Electrocardiograms ................................................................................................65 
8.5.6. 
Subgroup Analyses for Safety Endpoints ..............................................................66 
8.6. 
Interim Evaluation .......................................................................................................66 
9. 
STUDY ADMINISTRATION .......................................................................................67 
9.1. 
Regulatory and Ethical Considerations ........................................................................67 
9.1.1. 
Regulatory Authority Approval .............................................................................67 
9.1.2. 
Ethical Conduct of the Study and Ethics Approval ...............................................67 
9.1.2.1. 
Ethics Committees ...........................................................................................67 
9.1.2.2. 
General Considerations ....................................................................................68 
9.1.3. 
Informed Consent...................................................................................................68 
9.1.4. 
Investigator Reporting Requirements ....................................................................69 
9.2. 
Study Monitoring .........................................................................................................69 
9.3. 
Quality Assurance ........................................................................................................69 


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9.4. 
Study and Site Closure .................................................................................................70 
9.5. 
Records Retention ........................................................................................................70 
9.5.1. 
Health Insurance Portability and Accountability Act of 1996 ...............................70 
9.5.2. 
Financial Disclosure...............................................................................................70 
9.5.3. 
Access to Original Records ....................................................................................71 
9.5.4. 
Archiving of Study-Related Documents ................................................................71 
9.6. 
Provision of Study Results and Information to Investigators ......................................71 
9.7. 
Information Disclosure and Inventions ........................................................................71 
9.7.1. 
Ownership ..............................................................................................................71 
9.7.2. 
Confidentiality .......................................................................................................71 
9.7.3. 
Publication .............................................................................................................72 
9.7.4. 
Data Management ..................................................................................................72 
9.7.5. 
Data Security ..........................................................................................................73 
9.8. 
Subject Tracking ..........................................................................................................73 
10. 
REFERENCES ...............................................................................................................74 
11. 
APPENDICES ................................................................................................................75 
LIST OF TABLES 
Table 1: 
SCREENING .............................................................................................75 
Table 2: 
DAY 0 PRIOR TO SURGERY AND SURGERY ....................................76 
Table 3: 
POST STUDY MEDICATION ADMINISTRATION (DAYS 0 – 
5) ................................................................................................................77 
Table 4: 
POST STUDY MEDICATION ADMINISTRATION (FOLLOW-
UP) .............................................................................................................78 
LIST OF APPENDICES 
Appendix A: 
OVERVIEW OF STUDY SCHEDULE ....................................................75 
Appendix B: 
INVESTIGATOR OBLIGATIONS ..........................................................79 
Appendix C: 
STUDY-SPECIFIC INFORMATION .......................................................81 
Appendix D: 
BMI CALCULATION...............................................................................83 
Appendix E: 
AMERICAN SOCIETY OF ANESTHESIOLOGISTS 
PHYSICAL STATUS CLASSIFICATION SYSTEM ..............................84 
Appendix F: 
WOUND ASSESSMENT ..........................................................................85 
Appendix G: 
PHOTOGRAPHY INSTRUCTIONS ........................................................86 
Appendix H: 
DAY 60 FOLLOW-UP PHONE CALL ....................................................87 
 


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ABBREVIATIONS AND DEFINITIONS 
AE 
Adverse Event 
ALT 
alanine aminotransferase 
APAP 
acetyl-para-aminophenol (Acetaminophen) 
API 
active pharmaceutical ingredient 
ASA 
American Society of Anesthesiology 
AST 
aspartate aminotransferase 
AUC 
area under the plasma concentration-time curve 
BMI 
body mass index 
BP 
blood pressure 
bpm 
beats per minute 
CFR 
Code of Federal Regulations  
Cmax 
Maximum Plasma Concentration 
CPAP 
continuous positive airway pressure  
DMSO 
dimethyl sulfoxide 
ECG 
Electrocardiogram 
eCRF 
electronic Case Report Form 
ET 
early termination 
GCP 
Good Clinical Practice 
FDA 
Food and Drug Administration 
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 
LOCF 
last observation carried forward 
MAOIs 
monoamine oxidase inhibitors  
Mg 
Milligram 


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Min 
Minute 
mITT 
modified Intend-to-Treat  
NNRS 
Nausea Numeric Rating Scale 
NRS 
Numeric Rating Scale 
NSAIDS 
non-steroidal anti-inflammatory drugs 
PCP 
phencyclidine  
PGA 
Patient Global Assessment 
PI 
pain intensity 
PK 
pharmacokinetic 
PONV 
post-operative nausea and vomiting  
PRN 
as needed 
SAE 
serious adverse event 
SD 
standard deviation  
SNRIs 
serotonin-norepinephrine reuptake inhibitors  
SPI 
summed pain intensity 
SpO2 
peripheral oxygen saturation 
SSRI 
Selective serotonin reuptake inhibitor 
t½  
half-life 
TCAs 
tricyclic antidepressants 
Tmax 
time to reach maximum plasma concentration 
ULN 
Upper Limit of Normal 
VAS 
Visual Analog Scale 
VS 
Vital signs 
WBC 
white blood cell  
WHO 
World Health Organization 
WLOCF 
Windowed Last Observation Carried Forward  
WNL 
Within Normal Limits 
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 would suggest 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 two sustained release formulations 
(HTX-011-49 and HTX-011-56), intended for the management of post-operative pain via 
wound infiltration, that have demonstrated positive results in a non-clinical model of post-
surgical pain.  These formulations have been selected for further clinical investigation.  Both 
HTX-011-49 and HTX-011-56 contain bupivacaine and meloxicam as active ingredients and 
both have vehicle formulations comprising tri[ethylene glycol] based poly[orthoester] 
polymer with dimethyl sulfoxide (DMSO), glycerol triacetate, and maleic acid.  The two 
formulations differ from each other in their respective quantities of the vehicle excipients. 
The Sponsor has also developed a formulation, HTX-002, which is identical in 
pharmaceutical composition to HTX-011-56 except that it contains only bupivacaine as the 
active pharmaceutical ingredient (API).  Therefore, the HTX-002 formulation is a 
bupivacaine-only comparator to the HTX-011-56 formulation.  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 pharmacokinetic (PK) characteristics of HTX-002 are similar to that of HTX-011-56.  
Both the active ingredient (bupivacaine) and the identical biochronomer polymer vehicle 
have been studied in humans whereas HTX-002 has not yet been studied. 
In a placebo-controlled Phase 1 clinical trial, single doses of 1.71 mL, 3.42 mL, and 6.88 mL 
of HTX-011 were administered subcutaneously to healthy volunteers.  HTX-011 achieved 
the desired PK profile for both bupivacaine and meloxicam.  Therapeutically relevant plasma 
bupivacaine levels were sustained for 2 to 3 days in the absence of the large initial peak 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 three 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 subcutaneous injection sites in this healthy volunteer 
study. 




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2. 
STUDY OBJECTIVES 
2.1. 
Primary Objective 
The primary objective is to evaluate the efficacy and duration of analgesia following 
administration of HTX-011 or HTX-002 formulations. 
2.2. 
Secondary Objectives 
The secondary objectives will be: 
• To determine the safety and tolerability of HTX-011 and HTX-002 formulations  
• To determine the optimum study drug administration technique 
• To evaluate the pharmacokinetic (PK) profiles of bupivacaine and meloxicam in 
HTX-011 formulations and the PK profile of bupivacaine in HTX-002 over 120 hours 
after study drug administration 
• To evaluate the analgesic effects of HTX-011 and HTX-002 formulations over 
various intervals using a series of secondary efficacy endpoints for pain intensity 
• To assess the effects of HTX-011 and HTX-002 formulations on wound healing at 48 
hours, 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 remain pain free over time 


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3. 
STUDY ENDPOINTS 
3.1. 
Primary Efficacy Endpoint: 
Summed pain intensity score (SPI) over the first 24 hours (SPI0-24) 
3.2. 
Secondary Efficacy Endpoints: 
• SPI at other time points: SPI0-6, SPI0-12, SPI12-24, SPI24-48, SPI0-48, SPI48-72, SPI0-72, 
SPI72-96, and SPI0-96 
• The PGA of pain control at 24, 48, 72, and 96 hours post-T0 
• Time to administration of first dose of rescue analgesia 
• Total and average daily rescue consumption over 24, 48, 72, and 96 hours post-T0 
• The percentage of subjects who remain pain free (Visual Analog Scale [VAS] score 
≤ 1) at 72 hours and at 96 hours after study drug administration 
3.3. 
Safety Endpoints: 
Safety will be evaluated by assessment of AEs, including SAEs.  Additional safety endpoints 
include the following parameters: 
• Nausea assessments 
• Wound assessments of the surgical intervention area 
• Vital signs 
• Neurological examinations 
• Clinical laboratory tests (serum chemistry, hematology) 
• Electrocardiograms (ECGs) 
3.4. 
Pharmacokinetic Endpoints: 
• The area under the plasma concentration-time curve from time zero to time t of the 
last measured concentration above the limit of quantification (AUC0-last) 
• The area under the plasma concentration-time curve from zero to infinity (AUC0-inf) 
• The maximum plasma concentration (Cmax) 
• The time to reach maximum plasma concentration (Tmax) 


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• The terminal elimination rate constant (λZ) with the respective half-life (t½) 


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4. 
INVESTIGATIONAL PLAN 
4.1. 
Overall Study Design 
This is an exploratory Phase 2, randomized, multicenter, observer-blind, controlled, 
evaluation of the efficacy and safety of HTX-011 in adult subjects undergoing 
abdominoplasty surgery.  The study is planned to be conducted in up to 9 parts and to enroll 
up to approximately 523 subjects total: approximately 90 in Part A, 120 in Part B, 30 in 
Part C, 50 in Part D, 48 in Part E, 50 in Part F, 50 in Part G, 50 in Part H, and 35 subjects in 
Part I. Parts D through I are optional.  Additional subjects may be added for reasons defined 
in Section 5.3.2. 
The design of each study part is as follows: 
Part A 
Study Part A comprises 6 study cohorts enrolling approximately 90 subjects (approximately 
15 subjects per cohort).  Subjects enrolling into Part A will be randomized (2:1; active: 
saline) into each cohort to receive any one of HTX-011-49, HTX-011-56, or normal saline.  
For study Part A, the surgical procedure will be restricted to a mini-abdominoplasty, i.e., it 
will exclude liposuction and/or repositioning of the umbilicus. 
Enrollment to the separate HTX-011-49 and HTX-011-56 cohorts may occur in parallel; 
however, escalation from one cohort to the next for each respective formulation is subject to 
meeting certain safety criteria as described further below in Section 4.1.1. 
Cohorts 1 to 6 in study Part A will be as follows: 
• Cohort 1 will evaluate the analgesic efficacy of 6.84 mL (200 mg) of HTX-011-49 
compared to saline 
• Cohort 2 will evaluate the analgesic efficacy of 13.68 mL (400 mg) of HTX-011-49 
compared to saline 
• Cohort 3 will evaluate the analgesic efficacy of 20.52 mL (600 mg) of HTX-011-49 
compared to saline 
• Cohort 4 will evaluate the analgesic efficacy of 6.84 mL (200 mg) of HTX-011-56 
compared to saline 
• Cohort 5 will be to evaluate the analgesic efficacy of 13.68 mL (400 mg) of 
HTX-011-56 compared to saline 
• Cohort 6 will be to evaluate the analgesic efficacy of 20.52 mL (600 mg) of 
HTX-011-56 compared to saline 


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Part B 
Enrollment in Part B will be initiated following completion of enrollment in Part A and will 
evaluate HTX-011 compared with HTX-002 or saline. The surgical procedure allowed will 
be broadened to accommodate an abdominoplasty that can include liposuction and/or 
repositioning of the umbilicus. 
Part B comprises 3 cohorts enrolling a total of approximately 120 subjects. Subjects will be 
randomized (1:1; active: saline) into each cohort as follows: 
• HTX-011-56 13.68 mL (400 mg) via a combination of injection and instillation 
compared with saline 13.68 mL via injection (mini-abdominoplasty) 
• 
HTX-011-002 13.68 mL (400 mg) via a combination of injection and instillation 
compared with saline 13.68 mL via injection (mini-abdominoplasty)  
• HTX-011-56 13.68 mL (400 mg) via a combination of injection and instillation 
compared with saline 13.68 mL via injection (complete abdominoplasty)  
Part C 
Part C will include subjects undergoing complete abdominoplasty without liposuction. 
Approximately 30 subjects will be randomized to 1 of the following 2 cohorts in a 1:1 ratio:  
• HTX-011-56 13.68 mL (400 mg) via instillation (15 subjects) 
• Bupivacaine HCl 0.25% 100 mg (40 mL) via injection (15 subjects) 
Part D (Optional) 
Part D will include subjects undergoing complete abdominoplasty with liposuction. 
Approximately 50 subjects will be randomized to 1 of up to 4 cohorts in a 3:3:3:1 ratio:  
• HTX-011-56 400 mg (13.68 mL) via instillation and/or injection (as determined by 
the Sponsor) (15 subjects) 
• HTX-011-56 300 mg (10.26 mL) via instillation and/or injection (as determined by 
the Sponsor) (15 subjects) 
• HTX-011-56 200 mg (6.84 mL) via instillation and/or injection (as determined by the 
Sponsor) (15 subjects) 
• Saline (13.68 mL) via injection (5 subjects) 
Part E (Optional) 
Part E will include subjects undergoing complete abdominoplasty without liposuction. 
Approximately 48 subjects will be randomized to 1 of up to 5 cohorts in a 2:2:2:1:1 ratio: 


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• HTX-011-56 400 mg (13.68 mL) via instillation and/or injection (as determined by 
the Sponsor) and fentanyl 50 µg IV before wound closure (12 subjects) 
• HTX-011-56 300 mg (10.26 mL) via instillation and/or injection (as determined by 
the Sponsor) and fentanyl 50 µg IV before wound closure (12 subjects) 
• HTX-011-56 200 mg (6.84 mL) via instillation and/or injection (as determined by the 
Sponsor) and fentanyl 50 µg IV before wound closure (12 subjects) 
• Saline (13.68 mL) via injection and fentanyl 50 µg IV before wound closure 
(6 subjects) 
• Bupivacaine HCl 0.25% 100 mg (40 mL) via injection and fentanyl 50 µg IV before 
wound closure (6 subjects) 
Part F (Optional) 
Part F will include subjects undergoing complete abdominoplasty without liposuction. 
Approximately 50 subjects will be randomized to 1 of up to 4 cohorts in a 3:3:3:1 ratio: 
• HTX-011-56 400 mg (13.68 mL) via instillation and/or injection (as determined by 
the Sponsor), fentanyl 50 µg IV, and acetaminophen IV (1000 mg) before wound 
closure (15 subjects) 
• HTX-011-56 300 mg (10.26 mL) via instillation and/or injection (as determined by 
the Sponsor), fentanyl 50 µg IV, and acetaminophen IV (1000 mg) before wound 
closure (15 subjects) 
• HTX-011-56 200 mg (6.84 mL) via instillation and/or injection (as determined by the 
Sponsor), fentanyl 50 µg IV, and acetaminophen IV (1000 mg) before wound closure 
(15 subjects) 
• Saline (13.68 mL) via injection, fentanyl 50 µg IV, and acetaminophen IV (1000 mg) 
before wound closure (5 subjects) 
Part G (Optional) 
Part G will include subjects undergoing complete abdominoplasty with liposuction. 
Approximately 50 subjects will be randomized to 1 of up to 4 cohorts in a 3:3:3:1 ratio: 
• HTX-011-56 400 mg (13.68 mL) via instillation and/or injection(as determined by the 
Sponsor)  and fentanyl 50 µg IV before wound closure (15 subjects) 
• HTX-011-56 300 mg (10.26 mL) via instillation and/or injection (as determined by 
the Sponsor) and fentanyl 50 µg IV before wound closure (15 subjects) 
• HTX-011-56 200 mg (6.84 mL) via instillation and/or injection (as determined by the 
Sponsor) and fentanyl 50 µg IV before wound closure (15 subjects) 


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• Saline (13.68 mL) via injection and fentanyl 50 µg IV before wound closure 
(5 subjects) 
Part H (Optional) 
Part H will include subjects undergoing complete abdominoplasty with liposuction. 
Approximately 50 subjects will be randomized to 1 of up to 4 cohorts in a 3:3:3:1 ratio: 
• HTX-011-56 400 mg (13.68 mL) via instillation and/or injection (as determined by 
the Sponsor), fentanyl 50 µg IV, and acetaminophen IV (1000 mg) before wound 
closure (15 subjects) 
• HTX-011-56 300 mg (10.26 mL) via instillation and/or injection (as determined by 
the Sponsor), fentanyl 50 µg IV, and acetaminophen IV (1000 mg) before wound 
closure (15 subjects) 
• HTX-011-56 200 mg (6.84 mL) via instillation and/or injection (as determined by the 
Sponsor), fentanyl 50 µg IV, and acetaminophen IV (1000 mg) before wound closure 
(15 subjects) 
• Saline (13.68 mL) via injection, fentanyl 50 µg IV, and acetaminophen IV (1000 mg) 
before wound closure (5 subjects) 
Part I (Optional) 
Part I will include subjects undergoing complete abdominoplasty without liposuction. 
Approximately 35 subjects will be randomized to 1 of the following 2 cohorts in a 6:1 ratio: 
• HTX-011-56 300 mg (10.26 mL) via instillation and/or injection (as determined by 
the Sponsor) (30 subjects) 
• Saline (10.26 mL) via injection (5 subjects) 
Adult subjects ≥ 18 years old who require abdominoplasty will be screened for participation 
at the study sites within 28 days before surgery.  During the screening visit, after signing the 
informed consent, subjects will be assessed for ASA classification, medical history and 
prior/concomitant medications, vital sign measurements, physical examination, clinical 
laboratory tests, drug and alcohol screen tests, 12-lead electrocardiogram (ECG), serum 
pregnancy test (as appropriate).  Post-operative nausea and vomiting (PONV) risk factors 
will be assessed, and subjects will be trained on providing pain assessments. 
On the day of surgery (Day 0), subjects will undergo abdominoplasty under a standardized 
general anesthesia regimen.  The abdominoplasty procedure types will be documented on the 
eCRF. 
A single dose of the study drug (i.e., either HTX-011-49, HTX-011-56, HTX-002, saline, or 
bupivacaine HCl, according to a randomization schedule) will be administered 
intra-operatively (as detailed in the Pharmacy Manual).  The operating surgeon and the 


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attendant surgical staff will not be blinded to the study medication because HTX-011 and 
HTX-002 are colored preparations, whereas normal saline and bupivacaine HCl are not. 
Following the completion of surgery and immediate post-operative recovery, subjects will be 
transferred to the post-anesthesia care area.  Staff members in the post-anesthesia care area 
will be blinded to study treatment administered, as well as the investigator assessing the AEs.  
Subjects will stay in the post-anesthesia care area for 72 hours after completion of the 
administration of study medication (i.e., T0), prior to discharge from the study center.  Each 
subject will return to the study center 96 hours elapsed time (T96) after T0 to complete 
additional assessments.  After completion of the 96-hour assessments, subjects will be 
scheduled to return to the study center on Days 10 and 28 for study specific assessments; 
each subject will be asked to return to the study center specifically for a PK blood sample 
draw at 120 hours (T120) post-T0. Subjects will also receive a phone call from the study site 
on Day 60 to collect follow-up information on post-operative pain and pain medications. 
Efficacy assessments will include pain intensity scoring using the Visual Analog Scale 
(VAS), use of rescue medication, and Patient Global Assessment (PGA) of pain control. 
Blood samples will be obtained to assess meloxicam and bupivacaine pharmacokinetics out 
to 120 hours post-T0. 
Safety assessments will include AEs, concomitant medications, physical examinations, 
neurologic assessments (including neurological/cardiovascular assessments for potential 
bupivacaine toxicity), vital sign measurements, clinical laboratory tests, ECGs, nausea 
assessments (using a VAS for nausea), and wound healing assessments and photographs of 
the surgical invention area. 
4.1.1. 
Dose Escalation and Dose Modification Rules for Study Part A 
Enrollment to the next cohort in each of the parallel formulation study cohorts will not 
proceed if any of the following are observed: 
• 3 or more subjects experience an SAE reported by the investigator and confirmed by 
sponsor to be at least possibly related to active study medication 
• 3 or more subjects experience a neurological AE reported by the investigator and 
confirmed by the sponsor to be at least possibly related to active study medication 
(excluding minor neurologic findings that are not clinically significant, 
e.g., headache, paresthesia). 
• 3 or more subjects experience clinically significant ECG changes reported by the 
investigator confirmed by the sponsor to be at least possibly related to study 
medication  
• 2 or more subjects have  plasma bupivacaine levels with a Cmax of ≥ 1,000 ng/mL 


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If any one or more of the dose escalation rules are triggered in the study of Cohorts 1 or 4, 
then additional subjects may be enrolled in the affected Cohort to further confirm the 
tolerability profile of the 200 mg dose. 
If any one or more of the dose escalation rules are triggered in the study of any one of 
Cohorts 2, 3, 5 or 6, then additional subjects may be enrolled in the affected Cohort to further 
confirm the tolerability profile of the dose being studied in the affected Cohort. Specifically, 
with respect to the rule on PK levels, the dose of Cohort 3 or Cohort 6 can be modified 
according to the following: 
• If 2 or more subjects in Cohort 2 or Cohort 5 have plasma levels of bupivacaine with 
a Cmax of ≥ 1,000 ng/mL, then an additional 15 subjects will be dosed at 17.10 
(500 mg) mL in Cohort 3A or Cohort 6A. 
• If 2 or more subjects in Cohort 3 or Cohort 6 who are dosed with 20.52 mL have 
plasma bupivacaine levels with a Cmax of ≥ 1,000 ng/mL, an additional 15 subjects 
will be randomly assigned to 17.10 mL (500 mg) of HTX-011-49 or 17.10 mL 
(500 mg) of HTX-011-56 (10 subjects) or saline (5 subjects) – these subjects will be 
designated as Cohorts 3A and 6A, respectively, if applicable. 
The following sections summarize the three phases of activities for this study: 
1) Pretreatment Phase, 2) Treatment and Confinement Phase, and 3) Follow-up Phase. 
4.1.2. 
Pretreatment Phase (Day -28 to Day -1) 
Subjects will be consented and screened during this phase by assessments as described in 
Section 6.5.1.  The screening period will be at any time between Day -28 and Day -1. 
4.1.3. 
Treatment and Confinement Phase (Day 0 Through Day 5) 
a. Pre-surgery (Day 0): Subjects will be admitted to the surgical unit and reassessed 
for eligibility to continue participating in the study.  Standard pre-surgery 
activities will be conducted once eligibility has been re-confirmed. 
b. Surgery (Day 0): Subjects will undergo an abdominal surgical procedure under 
general anesthesia.  A standard anesthetic regimen will be followed for all 
subjects as outlined in the anesthesia protocol (Section 5.5.1).  A single dose of 
the study drug (either HTX-011-49, HTX-011-56, HTX-002, saline, or 
bupivacaine HCl, according to a randomization schedule) will be administered by 
local infiltration intra-operatively and/or by instillation, and upon completion of 
the surgery, in accordance with instructions provided in the Pharmacy Manual.  
Start and stop times of dose administration will be recorded.  Dosing stop time 
will be considered T0. 
c. Post-operative Period (Days 0–5): Following surgery, subjects will be transferred 
to the post-anesthesia care area where, over the next 72 hours, they will undergo 
efficacy (see Section 3.1) and safety (see Section 3.3) assessments, and collection 
of blood samples for PK analyses (see Section 6.4.6).  Treatments allowed during 




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5. 
STUDY POPULATION 
5.1. 
Inclusion Criteria 
Subjects must meet all of the following criteria to be considered eligible to participate in the 
study: 
1. Be scheduled to undergo abdominoplasty surgery that is amenable to treatment with a 
long acting local anesthetic as per the anesthesia protocol in Section 5.5.1 
2. Be American Society of Anesthesiology (ASA) physical Class I or II 
3. Subjects 18 years of age or older 
4. Have clinical laboratory values that are within normal limits (WNL) or if abnormal, 
not clinically significant; subjects with AST/ALT < 3 x ULN and/or creatinine 
< 2 x ULN are acceptable. 
5. Have a body mass index ≤ 30 kg/m2  
6. 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 a negative urine pregnancy test before 
surgery) 
o Not lactating 
o Not planning to become pregnant while participating 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 
7. Male subjects 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 
8. Does NOT have, as determined by the investigator or the study’s medical monitor, a 
history or clinical manifestations of significant renal, hepatic, cardiovascular, 
metabolic, neurologic, psychiatric, or other condition that would preclude 
participation in the study 
9. Must be able to understand and agree to comply with all study procedures and 
voluntarily provide written informed consent to participate in the study. 
5.2. 
Exclusion Criteria 
Subjects who meet any of the following criteria will be excluded from participating in 
the study: 
1. Have a contraindication or be allergic to any medication to be used during the trial 
period 


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2. Have another painful physical condition that, in the opinion of the investigator, may 
confound the assessments of post-operative pain 
3. Have a history of migraine or frequent headaches, seizures, or are currently taking 
anticonvulsants 
4. 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 
5. Previous abdominal surgery, as determined by the investigator, that would preclude 
participation in the study 
6. Subjects that require liposuction as part of the abdominoplasty procedure in Part A, 
C, E, F, or I of the protocol 
7. Subjects that are to have ancillary procedures performed during the abdominoplasty 
surgery that are unrelated to the abdominal area (breast reduction, breast 
augmentation, etc.) 
8. Subjects unable to discontinue medications that have not been at a stable dose for at 
least 14 days prior to the abdominoplasty surgery procedure and before dosing with 
investigational product 
9. Subjects taking the following medications; anticonvulsants, sedatives (including 
benzodiazepines) corticosteroids (by any means of administration), nonsteroidal 
anti-inflammatory drugs (NSAIDS) within 24 hours of study drug dosing, morphine, 
monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants (TCAs), 
neuroleptics, or serotonin-norepinephrine reuptake inhibitors (SNRIs).  Gabapentin 
and pregabalin are not permitted 
10. Have a known or suspected history of alcohol or drug abuse  
11. Have positive results on the alcohol breath test indicative of alcohol abuse or urine 
drug screen indicative of illicit drug use (unless results can be explained by a current 
prescription or acceptable over-the-counter medication at screening as determined by 
the investigator).  The urine drug screen prior to surgery must be negative 
12. Have evidence of a clinically significant 12-lead ECG abnormality according to the 
judgment of the investigator 
13. Have received any investigational product within 30 days before start of study 
14. Have previously received HTX-011 in clinical trials 
15. Experiences a clinically significant event during surgery prior to the administration of 
the investigational product (e.g., excessive bleeding, hemodynamic instability) that 
would render the subject medically unstable, complicate their post-surgical course, or 
significantly increase the risk of study drug administration as per the judgment of the 
investigator.  This will result in the subject being reported as randomized, not treated 
16. Subjects with sleep apnea or are on home continuous positive airway pressure 
(CPAP) 
17. Subjects who are receiving oxygen therapy at the time of screening 
5.3. 
Discontinuation of Subjects 
5.3.1. 
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.  Any 


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subject who withdraws consent to continue treatment or who is discontinued from the study 
before completing the protocol specified duration of treatment should be encouraged to 
complete the early termination assessments.  All subjects will be encouraged to agree to be 
followed for up to 28 ± 2 days after completion of study medication administration.  The date 
at which the subject is withdrawn, and the primary reason for discontinuation, will be 
recorded in the subject’s electronic case report form (eCRF). 
5.3.2. 
Replacement of Subjects 
Subjects who discontinue from this study up to 96 hours post-T0 may be replaced in this 
study, after discussion with the investigator and at the discretion of the Sponsor. 
Protocol violations or subjects not administered with study drug according to protocol, or any 
other inadvertent events, that lead to a subject not completing the study as planned may result 
in a replacement subject being enrolled, at the discretion of the Sponsor. 
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. 
Additional subjects may also be added to a cohort for any one of the following reasons, but 
not limited to: 
• Better define drug administration techniques 
• Better characterize PK profile 
• Better characterize potential safety signals 
5.4. 
Lifestyle Guidelines During Confinement 
Bathroom privileges will be restricted during the post-operative 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 
in the post-anesthesia care area following surgery, subjects will be required to remain resting 
in bed at least 30 minutes prior to any pain intensity assessment.  Subjects will be encouraged 
to maintain a semi-recumbent position while in bed.  Subjects will be allowed to ambulate 
according to standard post-operative care instructions. 
5.4.1. 
Diet 
While confined at the research unit, subjects may receive the diet normally provided by the 
institution for post-operative patients. 


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5.5. 
Surgical Procedure 
On the day of surgery (Day 0), subjects will undergo an abdominoplasty surgical procedure.  
Surgery should be scheduled to accommodate induction of anesthesia so that all surgical 
procedures to be completed by approximately 5:00 pm on the day of surgery. 
5.5.1. 
Anesthesia Protocol and Administration of Study Medication 
5.5.1.1. 
Anesthesia for Surgery 
The anesthetic protocol described 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 to ensure that necessary measures are undertaken to preserve 
subject safety. 
Subjects will undergo an abdominal procedure under general anesthesia.  Epidural or spinal 
anesthesia is also not allowed.  Midazolam up to 5 mg IV may be administered 
pre-operatively for anxiolysis.  Propofol induction may include a small dose of lidocaine (up 
to 5 mL of 1% lidocaine without epinephrine) to minimize injection discomfort.  In 
mini-abdominoplasty, up to 100 μg IV of fentanyl may be administered during surgery, and 
general anesthesia will be maintained with a volatile anesthetic agent. In complete 
abdominoplasty, the use of fentanyl and the maintenance of gaseous general anesthesia shall 
be in accordance with the institutional practice.  In addition, subjects in Parts E, F, G and H 
will be administered 50 μg IV of fentanyl at the end of the surgery and before wound closure. 
Subjects in Part F and H will also receive 1000 mg IV acetaminophen at the end of surgery 
and before wound closure. Should intubation be required, rocuronium should be used for 
muscle relaxation.  Muscle relaxation to be reversed per standard dosing.  Succinylcholine to 
be avoided if possible.  One dose of ondansetron may be administered with induction. 
Agents for nausea prophylaxis, including other 5-HT3 receptor blockers (e.g., ondansetron), 
scopolamine, dexamethasone, or haloperidol are not allowed 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 Visual 
Analog Scale for Nausea; (2) subject is actively vomiting; (3) subject requests anti-nausea 
medication. 
5.5.1.2. 
Study Drug Administration 
For all study drug administration techniques, 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. 
Infiltration Dosing Technique for Mini-Abdominoplasty 
Study medication will be administered intra-operatively by infiltration in equally divided 
volumes for injection. 


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• After the plication is completed, approximately one third of the total volume will be 
administered to the plication area of the posterior rectus sheath via approximately 
5 injections. 
• Another one-third of the study drug volume will be administered just above and 
below the external fascial layers of the rectus and external oblique muscles via 
approximately 10 injections at a 45-degree angle in two tracks parallel on either side 
of the central midline of the abdomen (i.e., the semilunaris).  The trajectory of the 
needle should be visualized throughout the entire length by the translucency of the 
fascia, to avoid inadvertent injection deep in the abdomen or in the muscle itself. 
• Lastly, prior to skin closure, the remaining third of study drug will be administered 
via injections into the upper third of the subcutaneous tissue along the upper and 
lower abdominal incision within the bikini line. 
Combined Infiltration and Instillation Dosing Technique for Mini-Abdominoplasty 
Study medication will be administered in equally divided volumes. 
• After the plication is completed, approximately one third of the total volume will be 
administered via infiltration to the plication area of the posterior rectus sheath via 
approximately 5 injections. 
• Another one-third of the study drug volume will be administered via infiltration just 
above and below the external fascial layers of the rectus and external oblique muscles 
via approximately 10 injections at a 45-degree angle in two tracks parallel on either 
side of the central midline of the abdomen (i.e., the semilunaris).  The trajectory of 
the needle should be visualized throughout the entire length by the translucency of the 
fascia to avoid inadvertent injection deep in the abdomen or in the muscle itself. 
• Lastly, prior to skin closure, the remaining third of study drug will be administered 
via instillation along the upper and lower abdominal incision within the bikini line 
where the subcutaneous fascia emerges from the deeper tissue. 
Combined Infiltration and Instillation Dosing Technique for Complete Abdominoplasty 
• After plication is completed, approximately 1/3 of the total study drug volume will be 
administered via infiltration to the entire plication area of the posterior rectus sheath 
via approximately 8 injections. 
• Another 1/3 will be administered via infiltration just above and below the external 
fascial layers of the rectus and external oblique muscles via approximately 
12 injections at a 45 degree angle in two tracks parallel on each side of the central 
midline of the abdomen (ie, the semilunaris). The trajectory of the needle should be 
visualized throughout the entire length by the translucency of the fascia, to avoid 
inadvertent injection deep in the abdomen or in the muscle itself. 


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• If the procedure involved relocation of the umbilicus, a small amount of study drug is 
to be administered via infiltration around the pedicle of the relocated tissue. 
• Prior to skin closure, the remaining 1/3 of study drug will be administered via 
instillation, after removing the needle from the syringe into the subcutaneous tissue 
along the upper and lower abdominal incision within the bikini line where the 
subcutaneous fascia emerges from the deeper tissue. 
Instillation Only Dosing Technique for Complete Abdominoplasty 
• Approximately 1/3 of the total study drug volume will be administered via instillation 
(i.e., without a needle on the syringe) to the entire plication area of the posterior 
rectus sheath; it is critical that the agent be applied to the posterior sheath rather than 
just the anterior sheath. Note that an acceptable way of administering the product to 
the posterior sheath on either side of the linea alba would be prior to the plication. 
• Another 1/3 will be administered via instillation just above and below the external 
fascial layers of the rectus and external oblique muscles at a 45 degree angle in two 
tracks parallel on each side of the central midline of the abdomen (i.e., the 
semilunaris).  
• If the procedure involved relocation of the umbilicus, a small amount of study drug is 
to be instilled around the pedicle of the relocated tissue. 
• Lastly, prior to skin closure, the remaining 1/3 of study drug will be administered via 
instillation to the subcutaneous tissue along the upper and lower abdominal incision 
within the bikini line where the subcutaneous fascia emerges from the deeper tissue. 
Dosing Technique for Administering Saline and Bupivacaine HCl Controls in Complete 
Abdominoplasty 
Administer saline and bupivacaine HCl 0.25% intra-operatively by infiltration in equally 
divided volumes for injection. 
• After the plication is completed, administer approximately one third of the total 
volume of study drug to the plication area of the posterior rectus sheath via 
approximately 5 injections. 
• Administer another one-third of the study drug volume just above and below the 
external fascial layers of the rectus and external oblique muscles via approximately 
10 injections at a 45-degree angle in two tracks parallel on either side of the central 
midline of the abdomen (i.e., the semilunaris).  The trajectory of the needle should be 
visualized throughout the entire length by the translucency of the fascia, to avoid 
inadvertent injection deep in the abdomen or in the muscle itself. 
• If the procedure involved relocation of the umbilicus, a small amount of study drug is 
to be administered around the pedicle of the relocated tissue. 


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• Lastly, prior to skin closure, administer the remaining third of study drug via 
injections into the upper third of the subcutaneous tissue along the upper and lower 
abdominal incision within the bikini line. 
Fentanyl IV Administration for Part E, F, G, and H 
For Part E, F, G, and H a dose of 50 μg fentanyl IV will be administered at the conclusion of 
surgery and before wound closure. Fentanyl will be administered per the product label 
instructions. 
Acetaminophen IV Administration for Part F and H 
For Part F and H, a dose of 1000 mg acetaminophen IV will be administered at the 
conclusion of surgery and before wound closure. Acetaminophen IV will be administered per 
the product label instructions. 
5.6. 
Identity of Study Medication 
Study drug in this study is defined as HTX-011 (an extended-release, fixed-ratio combination 
of bupivacaine and meloxicam), HTX-002 (an extended-release bupivacaine formulation), 
normal saline, or bupivacaine HCl.  The HTX-011 formulations that will be used for this 
study are HTX-011-49 and HTX-011-56.  HTX-011 and HTX-002 are sterile viscous 
injectable formulations to be administered intraoperatively by local infiltration for the 
prevention of postoperative pain.  HTX-011 and HTX-002 are colored preparations, whereas 
the controls (normal saline and bupivacaine HCl) are not. 
The excipients in the vehicle formulation for HTX-011-49, HTX-011-56, and HTX-002 are 
tri[ethylene glycol] based poly[orthoester] polymer with dimethyl sulfoxide (DMSO), 
glycerol triacetate, and maleic acid. 
Each 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, 0.15% w/w maleic acid, 8.00% w/w DMSO, and 35% w/w glycerol 
triacetate (or triacetin). 
One mL of HTX-011-56 contains 29.25 mg bupivacaine base and 0.88 mg of meloxicam.  
The proposed drug product contains 2.50% w/w bupivacaine base and 0.075% w/w 
meloxicam in 62.375% w/w AP135, 0.05% w/w maleic acid, 10.00% w/w DMSO, and 
25.00% w/w glycerol triacetate. 
HTX-002 is an identical formulation as that of HTX-011-56 except that it contains only 
bupivacaine as the API. 
HTX-011-49, HTX-011-56, and HTX-002 will be supplied by the sponsor.  Normal saline, 
bupivacaine HCl 0.25%, fentanyl and acetaminophen will be sourced and supplied by the 
site. 


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5.7. 
Method of Assigning Subjects to Treatment Groups 
A computer generated randomization scheme for each part of the study will be prepared prior 
to study initiation.  Subjects will be identified by a 7 digit number, ABC-DEFG: ABC-Site 
number, DEFG-sequential subject number starting at 0001 (e.g. 001-0001). 
For Part A of the study, subjects will be randomly assigned to treatment with any one of 
HTX-011-49, HTX-011-56, or saline in a 2:1 ratio (active:saline) according to the 
randomization scheme. 
For Part B of the study, subjects will be randomly assigned to treatment with HTX-011-56 or 
saline in a 1:1 ratio (active:saline) according to the randomization scheme. 
For Part C of the study, subjects will be randomly assigned to treatment with HTX-011-56 or 
bupivacaine HCl in a 1:1 ratio (active:active control) according to the randomization scheme. 
For Part D of the study, subjects will be randomly assigned to treatment with HTX-011-56 or 
saline in a 3:3:3:1 ratio (active:saline) according to the randomization scheme. 
For Part E of the study, subjects undergoing complete abdominoplasty without liposuction 
will be randomly assigned to treatment with HTX-011-56 and fentanyl 50 µg IV before 
wound closure, saline and fentanyl 50 µg IV before wound closure, or bupivacaine HCl and 
fentanyl 50 µg IV before wound closure in a 2:2:2:1:1 ratio (active:saline or active control) 
according to randomization scheme. 
For Part F of the study, subjects undergoing complete abdominoplasty without liposuction 
will be randomly assigned to treatment with HTX-011-56, fentanyl 50 µg IV, and 1000 mg 
acetaminophen IV before wound closure or saline, fentanyl 50 µg IV, and 1000 mg 
acetaminophen IV before wound closure in a 3:3:3:1 ratio (active:saline) according to 
randomization scheme. 
For Part G of the study, subjects undergoing complete abdominoplasty with liposuction will 
be randomly assigned to treatment with HTX-011-56 and fentanyl 50 µg IV before wound 
closure or saline and fentanyl 50 µg IV before wound closure in a 3:3:3:1 ratio (active:saline) 
according to randomization scheme. 
For Part H of the study, subjects undergoing complete abdominoplasty with liposuction will 
be randomly assigned to treatment with HTX-011-56, fentanyl 50 µg IV, and 1000 mg 
acetaminophen IV before wound closure or saline, fentanyl 50 µg IV, and 1000 mg 
acetaminophen IV before wound closure in a 3:3:3:1 ratio (active:saline) according to 
randomization scheme. 
For Part I of the study, subjects undergoing complete abdominoplasty without liposuction 
will be randomly assigned to treatment with HTX-011-56 or saline in a 6:1 ratio 
(active:saline) according to randomization scheme. 
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 treatment. 


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5.8. 
Selection of Doses 
In a placebo-controlled Phase 1 clinical trial, single doses of 100 mg, 200 mg, and 400 mg of 
HTX-011-19 (another different formulation of the HTX-011 combination of bupivacaine and 
meloxicam), and single doses of 100 mg and 200 mg 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 analgesic 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. 
To further demonstrate analgesic efficacy and to better understand the analgesic effect-time 
curve of the two HTX-011 formulations, this study will evaluate the analgesic effects of 
HTX-011 and HTX-002 in subjects with acute pain following abdominoplasty surgery. 
5.9. 
Blinding and Unblinding of Study Medications 
Because HTX-011 and HTX-002 formulations are colored and viscous in contrast to normal 
saline and bupivacaine HCl, 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 post-anesthesia care 
area, all site staff in the post-anesthesia care area as well as study center staff involved in the 
assessment of safety and efficacy will be blinded to the treatment assignment and (s)he will 
remained masked to treatment assignments throughout the conduct of the 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, then 
the investigator must contact the medical monitor for unblinding information.  If a subject’s 
treatment assignment is 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 leading to a premature unblinding must be clearly documented. 
5.10. Treatment Compliance 
Because the study medication is being administered as a component of the surgical 
procedure, a lack of treatment compliance is not expected.  The exact date, start and stop 
time, and dose of study medication administration will be recorded in the subject’s eCRF.  It 
is important that all study medication is administered and that the dosing syringes are 
completely emptied as part of the study drug infiltration procedure. 


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5.11. Drug Accountability 
The investigator (or designee) will sign for the study medications when they are received at 
the site.  The study medication must be handled and stored as described in the pharmacy 
manual and dispensed only to those subjects formally entered and assigned randomly into a 
study cohort. 
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. 
5.12. Packaging, Labeling, and Storage 
All active HTX-011 and HTX-002 study medication will be prepared (i.e., packaged and 
labeled in individual doses) by the sponsor or the sponsor’s designee.  Normal saline, 
bupivacaine HCl, fentanyl and acetaminophen will be sourced and supplied by the study site.  
All study medication will be dispensed and administered by the unblinded staff. 
5.12.1. 
Study Drug Packaging 
HTX-011 and HTX-002 will be packed and dispatched in refrigerated shipping containers 
with a temperature monitor enclosed.  The lot number and a manufacturing date will be 
provided.  
5.12.2. 
Study Drug Labeling and Storage 
HTX-011 and HTX-002 labeling will comply with the applicable laws and regulations.  At 
the minimum, the following information will be provided: 
• Study number (HTX-011-C2015-203) 
• Drug identification 
• Name, address, and telephone number of sponsor or manufacturer 
• Lot number 
• Content of package 
• Storage conditions 
• CAUTION: New Drug – Limited by United States Law to Investigational Use Only 
All HTX-011 and HTX-002 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 daily 
temperature log or chart should be maintained to monitor the refrigerator temperature at the 
study site. 


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Please refer to the study Pharmacy Manual for complete storage, preparation, and 
administration instruction. 
5.13. Prior and Concomitant Medications 
All medications taken by subjects within 14 days before dosing and administered during the 
study conduct will be recorded in the eCRF. 
Unless a medication has been prescribed at a stable dose for at least 30 days prior to the 
scheduled abdominoplasty, it will be prohibited for administration before the surgical 
procedure within 5 half-lives of that specific medication, or, if half-life is unknown, within 
48 hours. 
5.14. Prohibited Medications 
The following medications are prohibited throughout the study: anticonvulsants, 
corticosteroids (by any means of administration), monoamine oxidase inhibitors (MAOIs), 
tricyclic antidepressants (TCAs), neuroleptics or 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 5.16) are prohibited during the period from T0 to T72, and the prohibited 
medications include, but are not limited to: hydrocodone, codeine, fentanyl, meperidine, 
tramadol, opioid combinations and NSAIDS.  Aspirin (acetylsalicylic acid) is also prohibited 
excluding low dose aspirin for cardiac prophylaxis. 
Sedatives (including benzodiazepines) used as minor tranquilizers or hypnotics are not 
allowed unless approved by the investigator and the Sponsor 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. 
5.15. Concomitant Interventions and Procedures 
All interventions or procedures that occur in a study subject, whether diagnostic or 
therapeutic, 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, 
then the event must be recorded as an AE, along with all relevant information. 
5.16. Analgesia 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 


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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 post-
anesthesia care area at all times during the confinement period. 
Rescue analgesia (from T0 to T72) will be available to subjects with inadequately controlled 
pain symptoms.  Pain intensity (PI) assessments must be completed prior to administration of 
any rescue analgesia dose.  The approved rescue regimen will be morphine 2 mg iv bolus 
doses by titration as needed in the post-anesthesia recovery area.  Once effective analgesia 
has been reached using the morphine administered, subjects will be transitioned to oral 
oxycodone 10 mg every 2 hours, as needed for analgesia.  Additional morphine up to 10 mg 
IV every 2 hours as needed 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).  For 
subjects in Parts F or H, the fact that they received 1000 mg IV acetaminophen in the 
operating room must be accounted for so their daily consumption of acetaminophen on Day 0 
must not exceed an additional 3000 mg in the 24 hours following surgery. 
Efforts should be made to encourage subjects to wait at least 60 minutes after the end of 
surgery to receive rescue medication.  Pain intensity assessment must be completed prior 
to administration of any rescue dose administered.  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 PI prior to rescue is a Visual 
Analog Scale for Pain of ≥ 4.0 cm.  Pain Intensity will also be assessed within 5 minutes 
prior to administration of each dose of rescue analgesia. 
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.  The name, dose, reason, route, and time of administration of analgesics 
consumed after T72 will be recorded in a subject diary and presented at the time of the T96 
visit to the study center. 
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, 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 receive adequate analgesia from the rescue regimen or experience 
intolerable opioid related side effects can be administered the standard of care analgesics.  
The subjects will not be evaluable for efficacy; 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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6. 
STUDY PROCEDURES 
A schedule of study procedures for overall study assessments and day-of-dosing assessments 
is provided in Appendix A. 
6.1. 
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 Score 
2. Patient Global Assessment 
3. Nausea assessment 
4. Vital signs 
5. 12-Lead ECG 
6. Physical Examination (± 30 minutes at 72 hours) 
7. Neurologic Exam 
8. Blood draw for PK and clinical laboratory assessments 
9. Surgical Wound site assessment (Appendix F) 
10. Photography of wound 
11. Adverse events 
12. Concomitant medications 
Study procedures have a ± 15 minutes window unless otherwise stated. 
6.2. 
Demographic and Efficacy Assessments 
6.2.1. 
Demographics 
Demographic information will be collected during screening visit including age, sex, 
ethnicity, race, weight, (also measured at Day 0 and at any early termination from the study) 
height, and BMI (see Appendix D). 
6.2.2. 
Medical History 
The investigator or designee will document each subject’s medical history (including PONV 
risk factors; Appendix C-2) during the screening visit.  Medical history will be obtained 
through subject interview.  The review of 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. 
6.2.3. 
Physical Examination 
The investigator or designee will perform a physical examination (HEENT, cardiovascular, 
respiratory, abdominal, gastrointestinal, neurological, dermatologic, and musculoskeletal 
systems) during the screening visit, at admission (Day 0) to the study site on the day of 


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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.  Weight does 
not need to be measured at 72 hours after administration of study medication. 
The study investigator may 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 medical history or condition. 
6.3. 
Efficacy Assessments 
At screening visit, each subject will be trained with how to provide pain intensity 
assessments as determined by the VAS.  A refresher training will be provided when subject 
returns to study center on Day 0 prior to surgery. 
6.3.1. 
Pain Intensity (PI) 
PI will be assessed by the subject for their current pain according to the Visual Analog Scale 
for Pain 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.  A ± 15 minute window allowed for 
the collection of each PI assessment.  PI assessments must be collected, even if subjects are 
asleep at the time of the assessment. 
PI scores will be solicited 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.  The level of pain 
experienced will be measured in two ways: when subject is at rest, and when subject makes a 
deliberate movement.  Assessments performed at 78 and 84 hours will be performed by 
subjects at home using a patient diary. 
PI scores will be measured at rest at the following time-points after time T0: 1, 2, 78, 84, and 
96 hours after the administration of study medication. 
Pain scores will be measured on movement (i.e., sitting up from a supine position) at the 
following time-points after time T0: 4, 6, 8, 10, 12, 14, 18, 24, 30, 36, 42, 48, 54, 60, and 
72 hours.  A PI assessment will first be obtained at rest.  Then a second PI assessment will be 
obtained after the subject sits up. 
PI will also be assessed within 5 minutes prior to administration of each dose of rescue 
analgesia, and at time of early discontinuation in the event it occurs, and only if the subject is 
discontinued prior to T96. 
6.3.2. 
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, 96) hours since you received study medication: 
0-poor, 1-fair, 2-good, 3-very good, or 4-excellent.” 


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The PGA of pain control will be completed at 24, 48, 72, and 96 hours after study medication 
(i.e., T0) administration, and at time of early discontinuation if it should occur and only if the 
subject is discontinued prior to T96. 
6.3.3. 
Analgesia Rescue Medication Usage 
All subjects will be monitored for analgesia rescue medication administration/usage 
beginning at T0 and ending at T96.  The medication name, dose, reason, route, and time of 
administration will be recorded in the subject’s eCRF. 
The total and average daily rescue analgesic consumption over 24, 48, 72, and 96 hours 
post-T0 will be calculated for each subject. 
6.4. 
Safety Assessments 
6.4.1. 
Clinical Laboratory Tests 
During the screening visit, on Day 0 during check-in, and at 72 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, 
amphetamines, 
methamphetamines, 
phencyclidine (PCP), benzodiazepines, barbiturates, tricyclic antidepressant, 
methylenedioxymethamphetamine, methadone, and oxycodone. 
• serum pregnancy testing at the screening visit, and urine pregnancy testing at check-
in on Day 0 (female subjects of child bearing potential only). 
Screening laboratory results will be used for assessing eligibility for study randomization.  
Clinical laboratory test data from Day 0 prior to surgery will be used as “baseline” reference 
for study analysis and not for assessing study randomization eligibility.  Blood samples for 
baseline laboratory samples must be collected prior to the first surgical incision. 


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6.4.2. 
Nausea Assessment 
Nausea will be assessed during the study using the Visual Analog Scale for Nausea 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 and at the time of early discontinuation, if it should occur and only if a 
subject is discontinued prior to T96. 
6.4.3. 
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 (i.e. post-T0), 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, and at time of early discontinuation, if any.  Vital 
signs will have a collection window of ± 15 minutes for 1 through 72 hours and ± 2 hours for 
96 hours and for Day 10 (± 2 days). 
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. 
6.4.4. 
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 (if screening ECG was 
done > 7 days prior to Day 0), and at the following post-T0 time-points: 24, 48, 72, and 
96 hours, and at the Day 10 visit and at time of early discontinuation.  ECG intervals, notably 
qTC, will be analyzed in the context of time matching to peak PK values. 
For subjects enrolled in Parts B through I, additional ECGs will be performed post–T0 
timepoint at 1, 2, 3, 4, 5, and 6 hours.  Data from the 12-lead ECG will be used to exclude a 
subject from participation in the study at screening or Day 0 if (s)he has 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.  ECGs that are “abnormal clinically significant” may be collected; otherwise a copy of 
actual ECG tracings will not be collected for Data Management purposes. 
6.4.5. 
Surgical Wound Healing Evaluation and Photographs 
The wound evaluator will be a blinded investigator, or other medically qualified clinical site 
personnel, who will assess the surgical site to determine if healing is normal or abnormal at 
48 hours, 72 hours, Day 10, Day 28, and at time of early discontinuation (if applicable), and 
who will record observations (Appendix F) on the appropriate source document and eCRF.  


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If a wound is assessed as abnormal and unexpected post-surgical finding(s), then the 
finding(s) will be recorded as an AE. 
Photographs of the subject’s abdomen/surgical intervention site will be taken immediately 
after surgery and at following time-points after T0: 72 hours, Day 10, Day 28, and at time of 
early discontinuation (if applicable) (Appendix G). 
6.4.6. 
Blood Sampling for Bupivacaine/Meloxicam Pharmacokinetics Analysis 
Blood samples for the pharmacokinetic analysis of bupivacaine and meloxicam 
concentrations will be collected at the following times: prior to anesthesia induction for 
surgery, and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 18, 24, 30, 36, 48, 60, 72, 96, and at 
120 hours after study medication administration (± 15 minutes for all draws from 1 hour 
through 36 hours, ± 1 hour for 48 hours through 72 hour draws, and ± 4 hours at 96 and 
120 hours).  Please refer to the PK lab manual for the procedures for blood sample collection 
and handling. 
6.4.6.1. 
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. 
6.4.7. 
Neurologic Exam and Assessment 
The neurologic examination includes a mental status exam and evaluation of cranial nerve, 
motor, sensory, and cerebellar function.  The potential for bupivacaine toxicity will be 
assessed during the neurologic exam and may include (but not necessarily limited to) any of 
the following: perioral tingling, strange taste, muscle twitching, ringing in ears, seizure, 
bradycardia and cardiac arrest. 
Neurologic examinations should be completed by a physician or other health professional 
qualified to perform such examinations, and, if possible, the same individual should perform 
the neurologic exam throughout the study.  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 neurologic exam/assessment will be completed at the following time points: at Day 0 
any time prior to anesthesia induction, and at 24, 48, and 72 hours post-T0 within a 
± 15 minute window.  A neurologic exam and assessment will also be completed at early 
termination from the study if it occurs at ≤ T72. 
6.4.8. 
Assessment of Adverse Events and Prior/Concomitant Medications 
Prior/concomitant medications and AE assessments will be conducted throughout the study 
conduct after Day 0 until Day 28 post-T0 from the study.  Serious AEs will be recorded if 


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they occur at any time after study drug administration through to Day 28 post-T0.  SAEs that 
occur before study drug administration will be reported only if considered related to study 
participation.  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 associated with AEs will be documented in the eCRF. 
6.4.8.1. 
Treatment of Bradycardia, Hypotension, and Low Oxygen Saturation 
If a subject’s heart rate drops < 50 beats/minutes, with symptoms of bradycardia present, then 
interventions can be made in accordance with the investigator’s discretion and following 
standard of care guidelines. 
If a subject’s systolic blood pressure drops < 90 mm Hg or has a symptomatic decrease from 
baseline (pre T0 value), then interventions can be made in accordance with the investigator’s 
discretion and following standard of care guidelines. 
If a subject’s peripheral oxygen saturation drops to ≤ 90% for ≥ 1 minute, then treatment 
with oxygen via nasal cannula can be initiated at the discretion of the investigator, with a 
target saturation of 95% or a return to baseline levels. 
All interventions should be recorded in the subject’s eCRF. 
6.5. 
Assessments by Visit 
6.5.1. 
Screening Visit 
Subjects meeting the eligibility criteria listed in Sections 5.1 and 5.2 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 
• ASA classification 
• Review of medical history and the inclusion/exclusion for study eligibility 
• Measurement of resting vital signs 


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• 12-lead ECG  
• Physical examination including height, weight, and BMI  
• Clinical laboratory tests  
• Urine drug screen and alcohol breath test  
• Serum pregnancy test for women of childbearing potential 
• Assessment of PONV risk factors 
• Training on reporting pain intensity assessments 
• Record prior and concomitant medications 
• Record SAEs after informed consent signature (only if considered related to study 
participation) 
6.5.2. 
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 (if screening ECG was > 7 days prior to Day 0) 
• Physical examination, including weight only 
• Neurologic Exam 
• Clinical laboratory tests  
• Urine drug screen and alcohol breath test  
• Urine pregnancy test for women of childbearing potential 
• Training reminders on pain assessments and placebo response 
• Blood draw for PK analysis of bupivacaine and meloxicam (‘baseline’ PK sample) 
• Record prior and concomitant medications 


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• Record SAEs 
• Study drug administration 
Subjects who continue to meet eligibility criteria will undergo an abdominoplasty surgical 
procedure.  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 complicate their post-surgical course will be administered study medication 
according to the randomization scheme. 
6.5.3. 
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 for pain control 
• Assessment of VAS for nausea 
• Measurement of resting vital signs 
• 12-lead ECG 
• Blood samples for PK analysis of bupivacaine and meloxicam (through 120 hours) 
• Physical examination (72 hour only) 
• Clinical laboratory tests (72 hour only) 
• Record AEs/SAEs and concomitant medications 
• Monitor and record use of analgesia rescue medication  
• Wound Healing Assessment (48 hour and 72 hour) 
• Photograph of surgical intervention site (Day 0 immediately post surgery, 48 hour 
and 72 hour) 
• Neurologic assessment (24, 48, 72 hours) 
One hour after administration of study medication (T1) 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 – T72.  After T72, subjects may resume standard of 
care pain medication as advised by their surgeon. 


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6.5.4. 
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) 
• Vital signs (Day 10 only) 
• Record analgesic medications usage 
• Record AEs/SAEs and concomitant medications  
• Assessment of wound healing  
• Photograph of surgical intervention site  
Clinically significant adverse events, examination, or test results will be followed until 
appropriate resolution can be documented. 
6.5.5. 
Day 60 Follow-Up Phone Call (±7 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 H for details on the 
information to be collected. The results will be recorded in source documents. 
6.5.6. 
Early Termination (ET) Procedures 
Subjects who discontinue participation or who are discontinued prior to completing the 
Day 28 visit will be asked to complete ET procedures, which will include: 
• Pain intensity 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 VAS (only if the subject was discontinued prior to 96 hour) 
• Measurement of resting vital signs  
• 12-lead ECG 
• Physical examination, including weight only 
• Clinical laboratory tests 


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• Assessment of AEs and review of concomitant medications 
• Assessment wound healing  
• Photograph of abdominal wound 
• Neurologic assessment (only if subject was discontinued prior to 72 hours)  
6.5.7. 
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. 
6.6. 
Appropriateness of Assessments 
The efficacy measures utilized in this study are commonly used in clinical studies performed 
in acute post-operative 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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7. 
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. 
7.1. 
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 


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• transient paresthesia’s 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 28 study visit. 
7.2. 
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. 
7.2.1. 
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. 


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7.2.2. 
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 
30 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 7.7. 
7.3. 
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 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. 
7.4. 
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 7.2; 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. 
7.5. 
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. 
7.5.1. 
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 


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outcome or on action criteria usually associated with events that pose a threat to a subject’s 
life or functioning (see Section 7.2). 
7.5.2. 
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.  The investigator will 
assess the relationship to the study medication by using the following criteria: 
• 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. 
• Unlikely Related: An AE does not follow a temporal relationship to study drug.  The 
AE can be explained due to study factors. 
• 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. 
7.5.3. 
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 post-operative wound infection, or an upper respiratory tract infection. 


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• 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 
7.6. 
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 are 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 7.7. 
7.7. 
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 of being informed about the event. 
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). 


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COMPLETE THE SAE DETAILS REPORTING FORM AND FORWARD BY E-MAIL 
TO THE FOLLOWING SPONSOR CONTACT: 
Htx011safety@herontx.com 
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, photographs, 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. 
7.8. 
Regulatory Reporting Requirements 
The investigator must promptly report all SAEs to the sponsor in accordance with the 
procedures detailed in Section 7.7, “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 reactions that are either 
unexpected or observed with increasing occurrence be reported and legal obligations and 
ethical responsibilities regarding the safety of other subjects are met. 
Investigator letters are prepared according to sponsor policy and are forwarded to the 
investigators as necessary.  An investigator letter is prepared for any suspected adverse 
reaction that is attributable to study 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. 


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7.9. 
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 30 days after receiving study 
medication.  The sponsor must be notified of all pregnancies reported to the investigator (see 
Section 7.7 for contact information). 


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8. 
STATISTICAL METHODOLOGY 
8.1. 
Determination of Sample Size 
The sample size in this study was selected empirically without a formal statistical 
assumption. 
8.2. 
Study Endpoints 
See Section 3 for efficacy, safety, and PK endpoints. 
8.3. 
General Considerations for Statistical Analysis 
8.3.1. 
Software and General Statistical Methods 
Data processing, tabulation of descriptive statistics, calculation of inferential statistics, and 
graphical representations will be performed primarily using SAS (release 9.2 or higher) for 
Windows.  If the use of other software is warranted, the final statistical methodology report 
will detail what software was used for what purposes. 
For continuous variables, summary statistics including number of subjects with data, mean, 
standard deviation (SD), median, minimum, and maximum will be provided.  For categorical 
variables, the number of subjects and percentage for each category will be presented. 
8.3.2. 
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. 
8.3.3. 
Test Hypothesis and P Value Justification 
The null hypothesis is that there is no difference between each comparison (pairwise or 
pooled group comparisons).  The alternative hypothesis is that 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. 


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8.3.4. 
Procedures for Handling Missing Data 
Unless indicated otherwise (see Section 8.3.4.1 and 8.3.4.2), no imputation will be done for 
missing data. 
8.3.4.1. 
PI Score Before and After Analgesic Rescue Medication 
All subjects are expected to assess their post-operative 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 Q2 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. 
8.3.4.2. 
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 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. 
8.3.5. 
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. 
8.3.5.1. 
Study Population Summaries 
Population summaries will be provided for the safety analysis set included in this study. 
8.3.6. 
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. 


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8.3.7. 
Demographics 
The demographic summary will include descriptive statistics for age, sex, race, weight, 
height, and BMI for the overall and by treatment group. 
8.3.8. 
Protocol Violations 
All protocol violations and deviations will be identified.  Tabulation may be provided if data 
are warranted. 
8.3.9. 
Treatment Compliance 
Since study medication is administered intra-operatively, no formal summary of treatment 
compliance will be produced. 
8.3.10. 
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. 
8.4. 
Efficacy Analysis 
8.4.1. 
SPI and PI Analyses 
The analyses of the primary and all secondary endpoints will be described in the statistical 
analysis plan.  The basic analysis plan will be an Analysis of Variance with the contrasts to 
test for differences between the cohorts. 
8.4.2. 
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. 
8.4.3. 
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. 
8.4.4. 
Proportion of Subjects Requiring Rescue Medication 
The analysis will evaluate the relative risk (HTX-011 or HTX-002 vs. saline or bupivacaine 
HCl) 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; 
difference between HTX-011, HTX-002, saline, and bupivacaine HCl will be assessed as 
described in the statistical analysis plan. 


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8.4.5. 
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. 
8.4.6. 
Subgroup Analyses for Efficacy 
No subgroup analysis for efficacy endpoints is planned. 
8.5. 
Safety and Tolerability Evaluations 
8.5.1. 
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. 
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. 
8.5.2. 
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.   
8.5.3. 
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. 
8.5.4. 
Vital Sign Measurements 
Resting vital sign values at each time point collected will be summarized by treatment 
without formal statistical testing. 
8.5.5. 
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 


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with changes from normal at baseline to abnormal and clinically significant after baseline by 
treatment. 
8.5.6. 
Subgroup Analyses for Safety Endpoints 
No subgroup analysis is planned for safety endpoints. 
8.6. 
Interim Evaluation 
An evaluation of the data in Part A will be used to determine the optimal HTX-011 
formulation(s) and dose(s) for Part B. 


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9. 
STUDY ADMINISTRATION 
9.1. 
Regulatory and Ethical Considerations 
9.1.1. 
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. 
9.1.2. 
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 Harmonization (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). 
9.1.2.1. 
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.  The study agreement must also be fully executed. 
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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9.1.2.2. 
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-C2015-203.  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 or HTX-002. 
9.1.3. 
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. 


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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). 
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. 
9.1.4. 
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. 
9.2. 
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. 
9.3. 
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. 


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9.4. 
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 
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 
9.5. 
Records Retention 
9.5.1. 
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. 
9.5.2. 
Financial Disclosure 
Financial disclosure is required for this study. 


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9.5.3. 
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 9.1.4) 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. 
9.5.4. 
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 
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. 
9.6. 
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. 
9.7. 
Information Disclosure and Inventions 
9.7.1. 
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. 
9.7.2. 
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 


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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 9.7.3.  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. 
9.7.3. 
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 9.7.1. 
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 120 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. 
9.7.4. 
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 clinical and PK 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. 


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9.7.5. 
Data Security 
Access to the data will be strictly controlled. 
9.8. 
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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10. 
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, et al. (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, et al. (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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11. 
APPENDICES 
Appendix A: 
OVERVIEW OF STUDY SCHEDULE 
Table 1: 
SCREENING 
Procedure 
Day -28 to -1 
Screening 
Informed Consent 
X 
Eligibility Assessment 
X 
Demographics and Medical History 
X 
Assessment of PONV Risk Factors 
X 
Physical Examination e  
X 
Serum Pregnancy Test 
(female subjects of child bearing potential only) 
X 
Urine Drug Screen 
X 
Alcohol Breath Test 
X 
Clinical Laboratory Tests a 
X 
Vital Signs b 
X 
BMI Determination 
X 
12-lead ECG 
X 
Subject Pain Training 
X 
Prior and Concomitant Medication c 
X 
Serious Adverse Event Monitoring d 
X 
a Laboratory tests will include hematology and chemistry.  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  Concomitant medications taken within 14 days before dosing will be recorded on the eCRF. 
d SAEs will be reported if considered related to study participation. 
e PE will include weight, height, and BMI. 
 
 


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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 
 
Urine Pregnancy Test 
(female subjects of child bearing potential only) 
X 
 
Urine Drug Screen 
X 
 
Alcohol Breath Test 
X 
 
Clinical Laboratory Tests a 
X d 
 
Vital Signs b 
X 
 
12-lead ECG 
X e 
 
Subject Pain Training 
X 
 
Blood Draw for PK 
X d 
 
Neurologic Exam 
X 
 
Abdominoplasty Procedure 
 
X 
Study Drug Administration 
 
X 
Prior and Concomitant Medication 
X 
X 
Serious Adverse Event Monitoring f 
X 
X 
Post-surgical Photograph of Abdominal Wound 
 
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. 
e If screening 12-lead ECG was done > 7 days prior to Day 0. 
f 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 must be reported. 
 


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Appendix A: 
OVERVIEW OF STUDY SCHEDULE 
Table 3: 
POST STUDY MEDICATION ADMINISTRATION (DAYS 0 – 5) 
 
 
Day 0 to 5 
 
Post Study Drug Administration Time Points (hrs) 
0.5 
1f 
1.5 
2 
2.5 
3 
4 
5 
6 
8, 10, 12 
14 
18 
24 
30 
36 
42 
48 
54 
60 
72 
78 
84 
96h 
120h 
Confinement 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Physical Examination c 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
Xg 
 
 
 
 
Clinical Laboratory Tests a 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Vital Signs b 
 
X 
 
X 
 
 
X 
 
X 
X (hr 12 
only) 
 
X 
X 
 
X 
 
X 
 
X 
X 
 
 
X 
 
12-lead ECG 
 
Xi 
 
Xi 
 
Xi 
Xi 
Xi 
Xi 
 
 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
Pain Intensity (PI) At Rest 
 
X 
 
X 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Pain Intensity (PI) on Movement 
 
 
 
 
 
 
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 
Xe 
 
 
Xe 
 
PK Blood Draws (± 15 min 1 hr 
through 36 hr, ± 1 hr 48-72 hrs, ± 4 
hrs 96 + 120 hrs) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
 
X 
X 
 
 
X 
X 
Nausea Assessment 
 
 
 
 
 
 
 
 
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 
X 
Assessment of Wound Healing 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
Abdominal Photographs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
Neurologic Exam and Assessment 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
X 
 
 
 
 
Adverse Event 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 
X 
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 28 study visit.  SAEs will be monitored from screening 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. 
h  ± 4 hours, except for vital signs, which will be measured at ± 2 hours. 
i Parts B, C, D, E, F, G, H, and I. 


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Table 4: 
POST STUDY MEDICATION ADMINISTRATION (FOLLOW-UP) 
 
Post Study Drug Administration Time Points 
Early Termination 
Day 10 (± 2 days) 
Day 28 (± 2 days) 
Day 60 (± 7 days) 
Physical Examination 
Xc  
 
 
X 
Clinical Laboratory Tests a 
 
 
 
X 
Vital Signs b 
X 
 
 
X 
12-lead ECG 
X 
 
 
X 
Pain Intensity (PI) 
 
 
 
Xe 
PGA of Pain Control  
 
 
 
Xe 
Nausea Assessment 
 
 
 
Xe 
Concomitant Medications 
X 
X 
 
X 
Assessment of Wound Healing 
X 
X 
 
X 
Abdominal Photographs 
X 
X 
 
X 
Neurologic Exam and Assessment 
 
 
 
Xf 
Adverse Event Monitoring d 
X 
X 
 
X 
Phone Call g 
 
 
X 
 
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.   
d AEs will be monitored after administration of study medication through the Day 28 study visit.  SAEs will be monitored through from screening to Day 28. 
e PI, PGA, and nausea assessments are only required at the Early Termination Visit if the subject discontinues before T96. 
f Neurologic examination and assessment is only required at the Early Termination Visit if the subject discontinues before T72. 
g Subjects will receive a phone call from the study site on Day 60 (±7 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) 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 30 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 30 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 7.7 
and 7.8 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: 
Patient Global Assessment (PGA) of Pain Control  
The following question will be answered by the patient 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-2: 
Risk Factors for Post-Operative Nausea and Vomiting 
• Past history of post-operative nausea and vomiting and/or motion sickness 
• Habitual nonsmoking status 
• Female gender 
• Expected to receive opioid analgesia post-operatively 
 


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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 patient 
II  
Patient with mild systemic disease; no functional limitation – e.g. smoker with well-
controlled hypertension 
III  
Patient with severe systemic disease; definite functional impairment – e.g. diabetes 
and angina with relatively stable disease, but requiring therapy 
IV 
Patient with severe systemic disease that is a constant threat to life – e.g. diabetes and 
angina and congestive heart failure; patients with dyspnea on mild exertion and chest 
pain 
V 
Unstable moribund patient who is not expected to survive 24 hours with or without 
operation 
VI 
Brain dead patient 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 ASSESSMENT 
WOUND SITE EVALUATION 
Timepoint:  Post-Surgical  48 Hour 
 72 Hour  
 Day 10 
 Day 28 
WOUND SITE EVALUATION NOT DONE   
 
Normal (Expected 
Post-Surgical 
Findings) 
*Abnormal 
*Abnormal findings which are to 
be recorded on the CRF as Adverse 
Events 
If observations are mild they should 
not be recorded on the CRF as 
Adverse Events.  Please describe 
below any other wound abnormalities 
that are not listed in boxes below. 
 
 
 
 
Wound Site: 
 
 
Other, specify in the boxes below: 
 
 
 
Wound Description 
Normal 
*Abnormal 
Not present 
Wet 
  
  
 
Dehiscence 
  
  
 
Erythema 
  
  
 
Drainage 
 Blood 
 Serous 
 Purulent 
 Other (specify) 
____________________________ 
  
  
 
Bruising 
 
  
 
Swelling 
 
 
 
 


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Appendix G: 
PHOTOGRAPHY INSTRUCTIONS 
INSTRUCTIONS FOR TAKING PHOTOGRAPHS OF  
ABDOMINOPLASTY SURGICAL WOUND 
Materials 
• Camera (type and model to be specified) Identify camera settings 
• Memory card 
• Background cloth 
• ID tag: Complete for Protocol #, Subject #, Study Hour or Day, Date, Time, and 
what is being photographed (i.e., abdomen) 
 
1. Ensure the batteries in the camera are charged.  If low, replace the batteries prior to 
using the camera. 
2. Place the memory card in the camera. 
3. Expose the entire abdomen to be photographed and place the background cloth under 
the area to be photographed. 
4. Remove any dressing and place the completed ID tag adjacent to the area to be 
photographed taking care not to obscure any area of the wound itself to be 
photographed. 
5. Ensure that Protocol #, Subject #, Study Hour or Day, Date, Time, and what is 
being photographed (i.e., abdomen) is documented for reference purposes in the 
photograph. 
6. At each photograph timepoint take 3 photographs with the camera looking down at 
the abdomen so that the abdominal area fills the camera window, clearly showing the 
entire surgical abdominal incision.  This is done to ensure that there will be at least 
one photograph taken that best represents the abdominal incision area. 
 
 


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Appendix H: 
DAY 60 FOLLOW-UP PHONE CALL  
Subjects will receive a follow-up phone call from the site on Day 60 (±7 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:  
A Phase 2, Randomized, Controlled Evaluation of the Efficacy and 
Safety of HTX-011 or HTX-002 for Post-Operative Analgesia Following 
Abdominoplasty Surgery 
NCT Number:  
NCT02689258 
Document Date:  
23-Aug-2017 
 


Heron Therapeutics, Inc. 
Statistical Analysis Plan
HTX-011-C2015-203 
Version 2.0; 23AUG2017
Statistical Analysis Plan 
Heron Therapeutics, Inc. 
HTX-011-C2015-203 
A Phase 2, Randomized, Controlled Evaluation of the Efficacy and Safety of HTX-
011 or HTX-002 for Post-Operative Analgesia Following Abdominoplasty Surgery 
Protocol Version: 12 06 February 2017 
Sponsor: 
       Heron Therapeutics, Inc. 
4242 Campus Point Court, Suite 200 
San Diego, CA 92121 
Version: 
       2 0 
Date of Creation: 25 July 2017 
Last Updated:      23 August 2017 
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Statistical Analysis Plan
Statistical Analysis Plan: Study HTX-011-C2015-203 
Version 2.0; 23AUG2017
TABLE OF CONTENTS 
ABBREVIATIONS ............................................................................................................5 
1 
INTRODUCTION ......................................................................................................7 
2 
STUDY OBJECTIVES ..............................................................................................8 
3 
STUDY DESIGN ........................................................................................................8 
3.1     Overall Study Design ...............................................................................................8 
3.2     Treatment and Schedule of Assessments ...............................................................9 
4 
STUDY ENDPOINTS ..............................................................................................14 
4.1 
Efficacy Endpoints ...............................................................................................14 
4.2 
Safety Endpoints ..................................................................................................15 
4.2.1 
Adverse Events ...............................................................................................15 
4.2.2 
Nausea Assessments .......................................................................................16 
4.2.3 
Vital Signs .......................................................... ...........................................16 
4.2.4 
Laboratory Parameters .......................................... .....................................16 
4.2.5 
ECG .................................................................... ..... .....................................16 
4.2.6 
Wound Healing Assessments ................... ........ ...........................................17 
4.2.7 
Neurological Exams ............................... ....
............................................17 
5 
DATA QUALITY ASSURANCE ................ ..... ....................................................17 
6 
POPULATIONS DEFINED ....................................................................................17 
6.1 
Sample Size Determination .............. ........ .........................................................18 
7 
STATISTICAL METHODS AND DATA CONSIDERATIONS ........................18 
7.1 
General Considerations .................. ...................................................................18 
7.1.1 
Standard Calculations ..... ...... .....................................................................20 
7.2 
Analysis Datasets ..................... ..........................................................................20 
7.3 
Disposition of Subjects and Protocol Violations ...............................................20 
7.4 
Demographic and Baseline Characteristics .......................................................21 
7.5 
Prior and Concomitant Medications ..................................................................21 
7.6 
Treatment Compliance .... ...................................................................................21 
7.7 
Efficacy Analysis ...... ...........................................................................................22 
7.7.1 
Primary Efficacy Endpoint Analysis Methods ............................................22 
7.7.2 
Secondary Efficacy Endpoint Analysis Methods ........................................24 
 
 
7.8 
Data Imputation and Adjustment ......................................................................27 
7.8.1 
Pain Intensity Assessments ............................................................................27 
7.8.2 
Other Assessments .........................................................................................28 
7.9 
Safety Analysis .....................................................................................................28 
7.9.1 
Adverse Events ...............................................................................................28 
7.9.2 
Nausea Assessments .......................................................................................29 
7.9.3 
Clinical Laboratory Tests..............................................................................29 
7.9.4 
Vital Sign Measurements ..............................................................................29 
7.9.5 
Physical Examinations ...................................................................................30 
7.9.6 
Electrocardiograms........................................................................................30 
7.9.7 
Wound Healing Assessments ........................................................................30 
7.9.8 
Liver Function ................................................................................................30 
7.9.9 
Neurological Exam .........................................................................................30 
8 
INTERIM ANALYSIS .............................................................................................31 
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9 
CHANGE FROM ANALYSIS PLANNED IN PROTOCOL ...............................31 
9.1 
Changes in the SAP from Version 1.0 to Version 2.0 .......................................31 
10 REFERENCES .........................................................................................................32 
List of tables, figures and data listings ...........................................................................33 
List of Tables ....................................................................................................................33 
Subject Data Listings .......................................................................................................41 
 
 
List of Tables 
Table 1: 
Protocol Revision History..........................................................................7 
Table 2: 
Cohorts for Each Part .............................................................................10 
Table 3: 
Screening ...................................................................................................11 
Table 4: 
Day 0 Prior to Surgery and Surgery ......................................................12 
Table 5: 
Post Study Medication Administration (Days 0-5) ...............................13 
Table 6: 
Post Study Medication Administration (Follow-Up) ............................14 
Table 7: 
Analgesic Windows and Morphine Milligram Equivalencies ..............26 
Table 8: 
Criteria for Abnormal Vital Signs..........................................................29 
Table 9: 
Criteria for Abnormal Liver Function ...... ...........................................30 
 
 
 
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ABBREVIATIONS  
Abbreviation 
Definition 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANOVA 
analysis of variance 
AST 
aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
AUC 
area under the curve 
BMI 
body mass index 
BPM 
beats per minute 
CRF 
case report form 
CSR 
clinical study report 
DBP 
diastolic blood pressur  
ECG 
electrocardiogram 
HIV 
human immunodeficiency virus 
ITT 
Intent-to-Treat 
IV 
intravenous 
LOCF 
last observ tion carried forward 
LSMD  
least squares mean difference 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
modified Intend-to-Treat  
PGA 
Patient Global Assessment 
PI 
pain intensity 
PK 
pharmacokinetic 
PT 
preferred term 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SBP 
systolic blood pressure 
SD 
standard deviation 
SE 
standard error  
SOC 
System Organ Class 
 
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Abbreviation 
Definition 
SPI 
summed pain intensity 
SpO2 
peripheral oxygen saturation 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 
VAS 
Visual Analog Scale 
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-C2015-203 titled “A Phase 2, Randomized, Controlled Evaluation of the Efficacy and 
Safety of HTX-011 or HTX-002 for Post-Operative Analgesia Following Abdominoplasty Surgery”. 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 
04 Dec 2015 
Original protocol submitted to FDA 
Protocol Version 2 
08 Jan 2016 
Original protocol submitted to IRB and submitted to sites for study 
initiation visits on 13 January 2016 
Protocol Version 3 
21 Jan 2016 
Protocol revised to address FDA reviewer comments. 
Protocol Version 4 
30 Mar 2016 
Added HTX-011 56 formulation doses; removed HIV, hepatitis B 
and hepatitis C testing for inclusion criteria; added option of 
offering subjects acetaminophen 1000 mg for PI scores that are ≤ 4 
Protocol Version 5 
29 Apr 2016 
Added the option to the protocol that additional subjects may be 
enrolled to further confirm the tolerability profile of a given 
Cohort.     
Protocol Version 6 
08 Jun 2016 
Added more optional cohorts in Part B. Study drug administration 
instructions were clarified and a PK blood draw was added to 
determine bupivacaine levels if there was an AE associated with 
neurologic or cardiac symptoms. 
Protocol Version 7 
08 Aug 2016 
Added hourly ECGs from 1 hour to 6 hours post surgery in Part B, 
and clarified combined infiltration and instillation dosing technique 
for mini-abdominoplasty. 
Protocol Version 8 
28 Sep 2016 
Study drug administration instructions added for combination 
infiltration and instillation in subjects undergoing complete 
abdominoplasty. 
Protocol Version 9 
30 Nov 2016 
Part C added to evaluate HTX-011-56 compared with bupivacaine 
HCl in subjects undergoing complete abdominoplasty without 
liposuction. Optional Part D added to evaluate HTX-011-56 
compared with normal saline in subjects undergoing complete 
abdominoplasty with liposuction. 
Protocol version 10 
10 Jan 2017 
Optional parts E through H added. 
Protocol Version 11 
18 Jan 2017 
Optional Parts E through H updated, optional Part I added.  
Protocol Version 12 
06 Feb 2017 
Added option of administering HTX-011-56 via instillation, 
injection, or a combination of injection and instillation, in Parts D 
through I; added bupivacaine HCl cohort to optional Part E; 
removed HTX-56 200mg and bupivacaine HCl cohorts from 
optional Part I; revised sample sizes for Parts B, E, and I. 
Note:  This SAP may not be revised with every amendment of the study protocol.  
 
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Heron Therapeutics  
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Statistical Analysis Plan: Study HTX-011-C2015-203 
 
Version 2.0; 23AUG2017
 
This SAP was based on protocol version 12, issued 06 February 2017 and was prepared prior to database 
lock to provide full details to be included in the clinical study report (CSR). Revisions can be made to this 
SAP while the study is ongoing, but it must be finalized before the database is locked. Any changes 
between the statistical section 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. 
This is a Phase 2, randomized, controlled evaluation of the efficacy and safety of up to four dose levels of 
two HTX-011 formulations and one dose level of HTX-002 in subjects following abdominoplasty 
surgery. The study will also evaluate different local administration techniques (injection, instillation, and 
a combination of the 2 techniques) on the analgesic efficacy of HTX-011. Efficacy assessments are 
intended to characterize the analgesic effect time curve and the magnitude of analgesic effect of HTX-011 
in comparison with saline or HTX-002 or bupivacaine HCl. In addition, the study will further characterize 
the safety and PK profiles of bupivacaine and meloxicam in the HTX-011 formulations and the PK profile 
of bupivacaine in the HTX-002 formulation.  
2 STUDY OBJECTIVES 
The primary objective is to evaluate the efficacy and duration of analgesia following administration of 
HTX-011 or HTX-002 formulations.  
The secondary objectives are as follows: 
• To determine the safety and tolerability of HTX-011 and HTX-002 formulations. 
• To determine the optimum study drug administration technique.  
• To evaluate the PK profiles of bupivacaine and meloxicam in HTX-011 formulations and the PK 
profile of  bupivacaine in HTX-002 over 120 hours after study drug administration (a separate 
SAP). 
• To evaluate the analgesic effects of HTX-011 and HTX-002 formulations over various intervals 
using a series of secondary efficacy endpoints for pain intensity. 
• To assess the effects of HTX-011 and HTX-002 formulations on wound healing at 48 hours, 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 remain pain free over time. 
3 STUDY DESIGN 
3.1     Overall Study Design 
This is a Phase 2, randomized, multicenter, observer-blind, controlled evaluation of the efficacy and 
safety of HTX-011 and HTX-002 for post-operative analgesia following abdominoplasty surgery in 
approximately 275 adult subjects undergoing abdominoplasty. The total duration of this study for each 
 
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subject will be a maximum of 88 days that comprise a 28-day screening period, 72 hours in-house 
treatment period, and 25 days post-treatment period involving 4 post-treatment visits to the clinic.  
Subjects will also receive a phone call from the study site on Day 60.  Subjects at least 18 years of age 
requiring abdominoplasty 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 
American Society of Anesthesiologists classification, medical history and prior/concomitant medications, 
vital sign measurements, physical examination, clinical laboratory tests, drug and alcohol screen tests, 
neurologic exam, 12-lead electrocardiogram (ECG), and serum pregnancy test (as appropriate). Post-
operative nausea and vomiting (PONV) risk factors will be assessed, and subjects will be trained on 
providing pain assessments.  
Part A of the study is the dose-escalation phase of the study. Subjects enrolling into Part A will be 
randomized (2:1; active:saline) into each cohort to receive any one of HTX-011-49, HTX-011-56, or 
normal saline. For study Part A, the surgical procedure will be restricted to a mini-abdominoplasty, i.e., it 
will exclude liposuction and/or repositioning of the umbilicus. The primary objective of Part A will be to 
evaluate the efficacy and duration of analgesia following administration of two HTX-011 formulations 
(HTX-011-49 and HTX-011-56) in a range of doses. An optimal formulation/dose will be selected from 
Part A, and the identified formulation/dose will be utilized for subjects who will be enrolled into Part B. 
Part B will evaluate HTX-011 compared with HTX-002 or saline. The surgical procedure allowed will be 
broadened to accommodate an abdominoplasty that can include liposuction and/or repositioning of the 
umbilicus. Part C will include subjects undergoing complete abdominoplasty without liposuction. 
Approximately 30 subjects will be randomized to 1 of 2 cohorts in a 1:1 ratio (active HTX-011-
56:Bupivacaine HCl).  Part I will include subje ts undergoing complete abdominoplasty without 
liposuction. Approximately 35 subjects will be randomized to 1 of 2 cohorts in a 6:1 ratio (active:saline). 
On the day of surgery (Day 0), after having been reassessed for eligibility, subjects will undergo 
abdominoplasty under a standardized general anesthesia regimen.  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.  A single dose of study drug (HTX-011-49, HTX-011-56, HTX-002, 
Bupivacaine HCl, or saline placebo, according to a randomization schedule) will be administered intra-
operatively by local infiltration, instillation, or combined infiltration and instillation.  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 post-anesthesia care unit and, when appropriate, to the clinic floor. Subjects will stay in 
the post-anesthesia care unit for 72 hours after completion of the administration of study medication (i.e., 
T0), prior to discharge from the study center. Each subject will return to the study center 96 hours elapsed 
time (T96) after T0 to complete additional assessments. After completion of the 96-hour assessments, 
subjects will be scheduled to return to the study center on Days 10 and 28 for study specific assessments; 
each subject will be asked to return to the study center specifically for a PK blood sample draw at 120 
hours (T120) post-T0. Subjects will also receive a phone call from the study site on Day 60 to collect 
follow-up information on post operative pain and whether any pain medications were used. 
3.2     Treatment and Schedule of Assessments 
Efficacy assessments will include pain intensity (PI) scoring using the Visual Analog Scale (VAS), use of 
rescue medication, and Patient Global Assessment (PGA) of pain control. Blood samples will be obtained 
 
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to assess meloxicam and bupivacaine pharmacokinetics out to 120 hours post-administration of study 
drug. Safety assessments will include adverse events (AEs), concomitant medications, physical 
examinations, neurologic assessments (including neurological/cardiovascular assessments for potential 
bupivacaine toxicity), vital sign measurements, clinical laboratory tests, ECGs, nausea assessments (using 
a VAS for nausea), and wound healing assessments and photographs of the surgical invention area. 
Dosing and formulation cohorts are outlined in Table 2, and the planned schedule of study procedures is 
outline in Table 3, Table 4, Table 5 and Table 6. 
Table 2: 
Cohorts for Each Part 
 Part A: (mini-abdominoplasty) 
Cohort A: 200 mg (6.84 mL)  HTX-011-49 via injection administration / 6.84 mL saline (2:1)  
Cohort E: 200 mg  (6.84 mL) HTX-011-56 via injection administration / 6.84 mL saline (2:1) 
Cohort F: 400 mg (13.68 mL) HTX-011-56 via injection administration / 13.68 mL saline (2:1)  
Cohort G: 600 mg (20.52 mL) HTX-011-56 via injection administration / 20.52 mL saline (2:1)  
Cohort H: Saline solution injection 
 
Part B 
 
Cohort D: 13.68 mL saline solution via injection administration  
Cohort I: 400 mg  (13.68 mL) HTX-011-56 via instillation and i jection combination administration (mini-abdominoplasty)  
Cohort J: 400 mg (13.68 mL) HTX-002 via instillation and injection combination administration (mini-abdominoplasty) 
Cohort K: 13.68 mL saline solution via injection adm nistration (mini-abdominoplasty) 
Cohort L: 400 mg (13.68 mL) HTX-011-56 via instillati
 and injection combination administration for complete 
abdominoplasty  
Cohort M: 13.68 mL saline solution via injection dministration for complete abdominoplasty 
 
Part C 
Cohort N: 400 mg (13.68 mL) HTX-011-56 via instillation for complete abdominoplasty without liposuction 
Cohort O: 40 mL 0.25% Bupivacaine H l via injection for complete abdominoplasty without liposuction 
 
Part I 
Cohort U1: 300 mg HTX-011-56 via instillation and injection combination for complete abdominoplasty without liposuction 
Cohort U2: 10.26 mL saline solution via injection for complete abdominoplasty without liposuction 
 
 
 
 
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Table 3: 
Screening 
Procedure 
Day -28 to -1 
Screening 
Informed Consent 
X 
Eligibility Assessment 
X 
Demographics and Medical History 
X 
Assessment of PONV Risk Factors 
X 
Physical Examination e  
X 
Serum Pregnancy Test 
(female subjects of child bearing potential only) 
X 
Urine Drug Screen 
X 
Alcohol Breath Test 
X 
Clinical Laboratory Tests a 
X 
Vital Signs b 
X 
BMI Determination 
X 
12-lead ECG 
X 
Subject Pain Training 
X 
Prior and Concomitant Medication c 
X 
Serious Adverse Event Monitoring d 
X 
a Laboratory tests will include hematology and hemistry.  Results will determine subject eligibility for the study. 
b Resting vital signs (VS) will be collected a  scre ning.  Resting VS include: resting blood pressure, resting pulse, respiratory 
rate, oral temperature and SpO2.  Rest g test  must be obtained after resting (seated/reclined) for ≥ 5 minutes. 
c  Concomitant medications taken within 14 days before dosing will be recorded on the eCRF. 
d SAEs will be reported if considered elated to tudy participation. 
e  PE will include weight, height, and BMI. 
 
 
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Table 4: 
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 
 
Urine Pregnancy Test 
(female subjects of child bearing potential only) 
X 
 
Urine Drug Screen 
X 
 
Alcohol Breath Test 
X 
 
Clinical Laboratory Tests a 
X d 
 
Vital Signs b 
X 
 
12-lead ECG 
X e 
 
Subject Pain Training 
X 
 
Blood Draw for PK 
X d 
 
Neurologic Exam 
X 
 
Abdominoplasty Procedure 
 
X 
Study Drug Administration 
 
X 
Prior and Concomitant Medication 
X 
X 
Serious Adverse Event Monitoring f 
X 
X 
Post-surgical Photograph of Abdominal Wound 
 
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. 
e If screening 12-lead ECG was done > 7 days prior to Day 0. 
f 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 must be reported. 
 
 
 
 
 
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Table 5: 
Post Study Medication Administration (Days 0-5) 
 
 
Day 0 to 5 
 
Post Study Drug Administration Time Points (hrs) 
0.5 
1f 
1.5 
2 
2
.
5 
3 
4 
5 
6 
8, 10, 
12 
1
4 
1
8 
24 
3
0 
3
6 
4
2 
4
8 
5
4 
6
0 
7
2 
7
8 
8
4 
9
6
h 
12
0h 
Confinement 
X 
X 
X 
X 
X 
X X 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Physical Examination c 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
X
g 
 
 
 
 
Clinical Laboratory Tests a 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Vital Signs b 
 
X 
 
X 
 
 
X 
 
X 
X (hr 
12 
only) 
 
X 
X 
 
X 
 
X 
 
X 
X 
 
 
X 
 
12-lead ECG 
 
Xi 
 
Xi 
 
Xi Xi 
X
i 
Xi 
 
 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
Pain Intensity (PI) At Rest 
 
X 
 
X 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Pain Intensity (PI) on 
Movement 
 
 
 
 
 
 
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
e 
 
 
X
e 
 
PK Blood Draws (± 15 min 
1 hr through 36 hr, ± 1 hr 
48-72 hrs, ± 4 hrs 96 + 120 
hrs) 
X 
X 
X 
X 
X 
X X 
X X 
X 
 
X 
X 
X 
X 
 
X 
 
X 
X 
 
 
X 
X 
Nausea Assessment 
 
 
 
 
 
 
 
 
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 
X 
Assessment of Wound 
Healing 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
Abdominal Photographs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
Neurologic Exam and 
Assessment 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
X 
 
 
 
 
Adverse Event 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 
X 
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 28 study visit.  SAEs will be monitored from screening 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. 
h  ± 4 hours, except for vital signs, which will be measured at ± 2 hours. 
i Parts B, C, D, E, F, G, H, and I. 
 
 
 
 
 
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Table 6: 
Post Study Medication Administration (Follow-Up) 
 
 
Post Study Drug Administration Time Points 
Early 
Termination 
Day 10 (± 2 days) 
Day 28 (± 2 days) 
Day 60 (± 7 days) 
Physical Examination 
Xc  
 
 
Xe 
Clinical Laboratory Tests a 
 
 
 
X 
Vital Signs b 
X 
 
 
X 
12-lead ECG 
X 
 
 
X 
Pain Intensity (PI) 
 
 
 
Xe 
PGA of Pain Control  
 
 
 
Xe 
Nausea Assessment 
 
 
 
Xe 
Concomitant Medications 
X 
X 
 
X 
Assessment of Wound Healing 
X 
X 
 
X 
Abdominal Photographs 
X 
X 
 
X 
Neurologic Exam and Assessment 
 
 
 
Xf 
Adverse Event Monitoring d 
X 
X 
 
X 
Phone Call g 
 
 
X 
 
a Laboratory tests will include hematology and chemist y. 
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 (se ted/supine) for ≥ 5 minutes. 
c Physical examination will include weight only, bu  not height or BMI.  Weight not required at 72 hour exam. 
d AEs will be monitored after administrat on of study medication through the Day 10 study visit.  SAEs will be monitored through 
Day 28. 
e PI, PGA, and nausea assessments are nly required at the Early Termination Visit if the subject discontinues before T96. 
f Neurologic examination and assessment is only required at the Early Termination Visit if the subject discontinues before T72. 
g Subjects will receive a phone call from the study site on Day 60 (±7 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) to treat the pain (name, dose, and route). 
4 STUDY ENDPOINTS 
4.1 
Efficacy Endpoints 
The primary efficacy endpoint is the summed pain intensity (SPI) score 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) 
 
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All AEs, whether volunteered, elicited, or noted on physical examination and regardless of causality or 
seriousness, will be assessed and recorded in the case report 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.  
4.2.2 
Nausea Assessments 
Nausea will be assessed during the study using the VAS for Nausea. Assessment of nausea will be 
completed by subjects at the following time points: 6, 24, 48, nd 72 hours within a ± 15 minute window 
and at the time of early discontinuation, if it should occur and only if a subject is discontinued prior to 
T96. 
4.2.3 
Vital Signs 
Vital signs will be obtained after resting (seated/s pine) 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, 12, 18  24, 36  48, 60, 72, and 96 hours and at the Day 10 visit, and at 
the time of early termination, with actual times recorded. 
4.2.4 
Laboratory Parameters 
The clinical laboratory and oth r 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. 
• 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,  
phosphate, calcium, glucose, bicarbonate, lactate dehydrogenase  
In addition, urine drug screening and breath 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. 
4.2.5 
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 (if screening ECG was done > 7 days prior to 
 
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Day 0), at 24, 48, 72, 96 hours post-treatment, and at the Day 10 visit, and at the time of early 
termination, if applicable. 
For subjects enrolled in Parts B through I, additional ECGs will be performed post-T0 time point at 1, 2, 
3, 4, 5, and 6 hours. Data from the 12-lead ECG will be used to exclude a subject from participation in the 
study at screening or Day 0 if (s)he has a clinically significant abnormal ECG. 
ECG intervals, notably QTc, will be analyzed in the context of time matching to peak PK values. The 
vendor (Biomedical Systems) will provide a separate SAP in ECG and PK exposure for Part B, C and I 
subjects. 
4.2.6 
Wound Healing Assessments 
The surgical wound will be assessed 48 and 72 hours post-treatment, on Days 10 and 28 post-treatment 
and at time of early termination (if applicable). Results are recorded as Normal or Abnormal, with a 
verbatim description of any abnormalities. Specific indications of wound healing (wet[ness], dehiscence, 
erythema, presence of drainage, type of drainage, bruising, and swelling) will be assessed and results for 
each indication recorded. A photograph of the surgical in ervention area will be taken immediately after 
surgery, and at 72 hours, Days 10 and 28 and at time of early termination (if applicable).  
4.2.7 
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 Base 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. 
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 the sponsor for appropriate action and resolution.  
6 POPULATIONS DEFINED 
Intent-to-Treat (ITT) Dataset: The ITT dataset will include all subjects who are randomized to receive 
study medication. 
 
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Efficacy Dataset: The efficacy dataset will include all subjects who are randomized to receive study 
medication and have recorded at least one scheduled post dosing PI score.  This dataset is noted as the 
modified Intend-to-Treat (mITT) set. 
Safety Dataset: The safety dataset will include all treated subjects and will be used for safety and 
tolerability assessments.  
6.1 
Sample Size Determination 
Sample sizes for this study were 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 conformance with guidelines specified by the ICH guideline Statistical Principals 
for Clinical Trials (E9) (1999).  
Summary tables will be organized by surgical procedure, with mini-abdominoplasty summarized 
separately from complete abdominoplasty (without liposuction). Part A, Part B Step 1, and Part B Step 2 
will be summarized together (mini abdominoplasty). Part B Step 3, and Parts C and I will be summarized 
together (complete abdominoplasty).  Disposition, demographics, protocol deviation, and AE summary 
tables will be grouped as follows: 
• Mini Abdominoplasty (only for disposition, demographics, protocol deviations, and AE tables) 
1. Saline Placebo 6 84 20.52 mL) 
2. HTX-002 400 mg (13.68 mL) 
3. HTX-011-49 200 mg (6.84 mL) 
4. HTX-011-56 200 mg (6.84 mL) 
5. HTX-011-56 400 mg (13.68 mL) 
6. HTX-011-56 600 mg (20.52 mL) 
7. HTX-011-56 Total  
8. Total (not included on AE tables) 
• Mini Abdominoplasty (all tables except protocol deviations) 
1. Saline Placebo (6.84-20.52 mL) 
2. HTX-002 400 mg Combination (13.68 mL) 
 
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3. HTX-011-49 200 mg Injection (6.84 mL) 
4. HTX-011-56 200 mg Injection (6.84 mL) 
5. HTX-011-56 400 mg Injection (13.68 mL) 
6. HTX-011-56 400 mg Combination (13.68 mL) 
7. HTX-011-56 400 mg Total (13.68 mL) 
8. HTX-011-56 600 mg Injection (20.52 mL) 
• Complete Abdominoplasty (all tables) 
1. Saline Placebo (10.26-13.68 mL) 
2. Bupivacaine HCl 100 mg (40 mL) 
3. HTX-011-56 300 mg (10.26 mL) Combination 
4. HTX-011-56 400 mg (13.68 mL) Combination 
5. HTX-011-56 400 mg (13.68 mL) Installation  
6. HTX-011-56 400 mg (13.68 mL) Total 
7. Total (only included on disposition, demographics, and protocol deviation tables) 
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 pplicable.  
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 sample 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). Rounding conventions are described 
below. 
• 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 
 
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• 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 appropriate 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 7.8.1), no imputation will be conducted for missing data, and no 
adjustments will be made for conducting multiple hypothesis tests. 
7.1.1 
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 which occurs prior to the time of completed application of study drug would be associated 
with a negative time calculation, while a study event which occurs after time of completed application of 
study drug would be a positive time calculation. 
7.2 
Analysis Datasets 
ITT Analysis Population: The ITT dataset will include all subjects who are randomized. 
Efficacy Population: The efficacy analysis set will include all subjects who were randomized to receive 
study medication and have at least one scheduled post dosing PI score.  This analysis set is noted as the 
mITT set. 
Safety Population: The safety set will include all treated subjects 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 protocol violations in the Safety Population will be determined and appropriately 
 
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categorized prior to database lock. The count and percentage of subjects by category will be presented for 
the groups described in Section 7.1. A listing of subjects who were excluded from the efficacy analysis 
will be provided. 
7.4 
Demographic and 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. A listing of PONV risk factors for each subject (obtained at Screening) will be provided. 
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. Frequency 
counts and percentages to summarize subjects reporting m dical history by SOC and PT will be 
presented. Subjects reporting more than one 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 1, 2016). Prior 
medications are defined as medications with a stop date occurring before Day 0 (surgery date).  
Concomitant medications are defined as medications that are ongoing on Day 0 or with a start date 
occurring on or after Day 0.  Medications with start and stop dates which bracket Day 0, or for which 
missing start and/or stop dates make it impossible to determine the prior or concomitant status, will be 
summarized as concomitant medications. 
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 concomitant medications 
within 72 hours (T0-T72) 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 
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 reported in hours. 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.  
 
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7.7 
Efficacy Analysis   
The efficacy analysis will be performed using the mITT population. Part A, Part B Step 1 and Part B Step 
2 will be analyzed separately from Part B Step 3, Part C, and Part I. For treatment comparisons using 
pooled data, data from treatment groups will be combined prior to conducting the statistical comparison.  
All efficacy figures will be structured according to the following groups: 
Mini Abdominoplasty- 
• HTX-011-56 200 mg  (Cohort E) 
• Pooled HTX-011-56 400mg (Cohorts F and I) 
• HTX-011-56 600 mg (Cohort G) 
• HTX-002 400 mg (Cohort J) 
• Saline Placebo (Cohorts D, H, and K) 
Complete Abdominoplasty- 
• Saline Placebo (Cohorts M and U2) 
• Bupivacaine 100 mg (Cohort O) 
• HTX-011-56 300 mg (U1) 
• Pooled HTX-011-56 400 mg (Cohorts L and N) 
7.7.1 
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 data 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. The following comparisons will be made for all efficacy 
endpoints: 
Mini Abdominoplasty- 
• HTX-011-49 200 mg (6.84 mL) injection vs. Saline Placebo (6.84-20.52 mL) 
• HTX-011-56 200 mg (6.84 mL) injection vs. Saline Placebo (6.84-20.52 mL) 
• HTX-011-56 400 mg (13.68 mL) injection vs. Saline Placebo (6.84-20.52 mL) 
• HTX-011-56 400 mg (13.68 mL) injection vs. HTX-002 400 mg (13.68 mL) 
• HTX-011-56 400 mg (13.68 mL) combo vs. Saline Placebo (6.84-20.52 mL) 
 
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• HTX-011-56 400 mg (13.68 mL) combo vs. HTX-002 400 mg (13.68 mL) 
• HTX-011-56 400 mg (13.68 mL) pooled vs. Saline Placebo (6.84-20.52 mL) 
• HTX-011-56 400 mg (13.68 mL) pooled vs. HTX-002 400 mg (13.68 mL) 
• HTX-011-56 600 mg (20.56 mL) injection vs. Saline Placebo (6.84-20.52 mL) 
Complete Abdominoplasty- 
• HTX-011-56 300 mg (10.26 mL) Instillation vs. Saline Placebo (10.26-13.68 mL) 
• HTX-011-56 300 mg (10.26 mL) Instillation vs. Bupivacaine HCl 100 mg (40 mL) 
• HTX-011-56 400 mg (13.68 mL) combo vs. Saline Placebo (10.26-13.68 mL) 
• HTX-011-56 400 mg (13.68 mL) combo vs. Bupivacaine HCl 100 mg (40 mL) 
• HTX-011-56 400 mg (13.68 mL) Instillation vs  Saline Placebo (10.26-13.68 mL) 
• HTX-011-56 400 mg (13.68 mL) Instillation vs  Bupivacaine HCl 100 mg (40 mL) 
• HTX-011-56 400 mg (13.68 mL) pooled vs. Saline Placebo (10.26-13.68 mL) 
• HTX-011-56 400 mg (13.68 mL) pooled vs. Bupivacaine HCl 100 mg (40 mL) 
SPI: 
PI will be assessed by the subject for their current pain according to VAS where 0 equates to no pain and 
10 equates to the worst pain imaginable  PI scores will be measured in two ways: on movement and at 
rest. There will be a ± 15 minute window allowed for the collection of each PI assessment. 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 
performed by subjects at home using a patient diary.  
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. A PI assessment will first be 
obtained at rest. A second PI assessment will be obtained after the subject sits up. 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. This is referenced as the per protocol method. PI will also be assessed within 5 minutes 
prior to administration of rescue analgesia, and at the time of early termination in the event it occurs, and 
only if the subject is discontinued prior to T96. 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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At movement PI scores from hours 4-72 will be used for analysis, the at rest PI scores for these time 
points will only be listed. The 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.  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:  µA = µB; 
Where µA and µB represent the mean values for Treatment A and Treatment B, respectively.  The 
alternative hypothesis to be tested is that the treatment group means differ: 
H1:  µA ≠ µB; 
7.7.2 
Secondary Efficacy Endpoint Analysis Methods  
7.7.2.1     Sum of Pain Intensity 
SPI over various other time intervals (SPI0-48, SPI0-72, SPI0-96, SPI0-6, SPI0-12, SPI12-24, SPI24-48, SPI48-72, 
and SPI72-96) will be analyzed by 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 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, SE, 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. 
7.7.2.2     Pain Intensity 
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, SE, 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 VAS score less than or equal to 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 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 between groups, p-values, and exact unconditional 
95% CIs for the difference between the groups based on the score statistic (Chan and Zhang, 1999) will 
be provided for summaries. 
 
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The percentage of subjects 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. 
7.7.2.3     Patient Global Assessment  
Pain control is 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 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, percentage 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.  
7.7.2.4     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 exact u conditional 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 
their 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 their 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 of the study, 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 phase of the study, then the 
subject will be considered censored at 96 hours. Kaplan-Meier curves will be presented for groups as 
described in Section 7.7, plotted as 1-S(t). Time to administration of first opioid rescue medication will be 
analyzed in the same manner as time to first administration of any rescue medication. 
The count and percentage of subjects in the following categories will be summarized in tables: 
1. Those who received only opioid rescue medications 
2. Those who received only non-opioid rescue medications  
 
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rescue PI score within the window (replace 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 worst PI score, it is not replaced. 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 date/time information is missing for a PI score, scheduled hours from 
dose end time will determine timing. 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 Integrated Rank Difference will be analyzed 
using two 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 on 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 are 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.  
7.9.1 
Adverse Events 
AEs 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 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 application 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. AEs 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 study drug-related TEAEs, TEAE by severity and serious TEAE by severity, and the number 
of subjects with TEAEs leading to premature discontinuation 
• 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 
 
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• Study drug-related TEAEs by SOC in internationally agreed order and PT 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 according to total incidence 
(alphabetically for ties) in the highest HTX-011 dose group 
Opioid related AEs are AEs that code to any of the following PTs: Nausea, Vomiting, Constipation, 
Pruritus, Somnolence, Respiratory depression, or Urinary retention. 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. 
7.9.2 
Nausea Assessments 
Nausea is measured on a VAS 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 ANOVA as described in Section 7.7.1. Results reported will include 
sample size, mean (SD), LSMD, 95% CI for LSMD, and p value. Mean nausea scores over time will be 
plotted for the groups described in Section 7.7. 
7.9.3 
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 change from baseline to the lowest post-baseline value, and the change 
from baseline to the highest post-baseline value will be included on summary tables, and will incorporate 
data from both scheduled and unscheduled visits. The data listing of laboratory values will flag values 
below and above the normal rang s.  
7.9.4 
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 8) 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. 
Table 8: 
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 
 
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7.9.5 
Physical Examinations 
Physical exam data will be presented in a data listing.  
7.9.6 
Electrocardiograms 
The count and percentage of subjects with abnormal ECG findings at each time point will be summarized 
without formal statistical testing. Shift tables (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 
clinically significant abnormal after baseline. Subject in Parts B, C, and I will have additional ECGs 
performed at 1, 2, 3, 4, 5, and 6 hours after administration of study medication. 
7.9.7 
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. Assessments of symptoms associated with wound healing 
include wet(ness), dehiscence, erythema, presence of drainage, type of drainage, bruising, and swelling. 
Findings from wound healing assessments will be listed per subject, per time point, and will include 
descriptions of any abnormalities found. A per subject listing will be provided for photographs taken at 
time points 48, 72, and 96 hours, and at Days 10 and 28 to visually document wound healing. Records 
include date and time of photograph, whether or not photographs were uploaded, location of the surgical 
site, and reason why photographs were not taken, if applicable. 
7.9.8 
Liver Function  
Results from liver function tests performed at any post-baseline scheduled and unscheduled visits that 
meet the criteria presented in Table 9 will be summarized with counts and percentages, and subjects with 
abnormal liver function tes  re ults will be presented in a separate listing. 
Table 9: 
Criteria for Abnormal Liver Function 
Test 
Criteria for Abnormality 
ALT (SGPT) 
> 3 ULN 
AST (SGOT) 
> 3 ULN 
Total Bilirubin 
> 2 ULN 
ALP 
> 1.5 ULN 
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 
7.9.9 
Neurological Exam 
Mental status, motor, sensory, cerebellar/gait, and cranial nerve functioning will be assessed as Normal, 
Abnormal or Not Done. Abnormal results will be noted as NCS or CS. Change in overall neurological 
assessment from the previous assessment will be characterized as Better, Same or Unchanged, Worse, or 
 
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10 REFERENCES 
Chan, I. S. F. and Zhang, Z. (1999), “Test-Based Exact Confidence Intervals for the Difference of Two 
Binomial Proportions,” Biometrics, 55, 1202–1209. 
David G. Silverman, MD, Theresa Z. O’Connor, MPH, and Sorin J. Brull, MD (1993), “Integrated 
Assessment of Pain Scores and Rescue Morphine Use During Studies of Analgesic Efficacy,” Anesth 
Analg 1993;77:168-70. 
 
 
 
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LIST OF TABLES, FIGURES AND DATA LISTINGS 
List of Tables  
 
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List of Figures  
 
 
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Subject Data Listings  
 
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