Clinical trial NCT02762929
Conditions: Postoperative Pain Bunions
Keywords: Analgesia Bunionectomy
Sponsor: Heron Therapeutics
Start date: 2016-05-01; Completion date: 2017-03-01
Enrollment: 430 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A Phase 2, Randomized, Controlled, Multicenter, Evaluation of the Efficacy and Safety of Locally Administered HTX-011 for Postoperative Analgesia Following Bunionectomy

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

Arms: arm 1: HTX-011A (bupivacaine/meloxicam), 200 mg/6 mg via injection. arm 2: HTX 011B (bupivacaine/meloxicam), 30 mg/0.9 mg via injection. arm 3: HTX-011B (bupivacaine/meloxicam) 60 mg/1.8 mg via injection or instillation. arm 4: HTX- 011B (bupivacaine/meloxicam), 120 mg/3.6 mg via injection or instillation. arm 5: HTX- 011B (bupivacaine/meloxicam), 200 mg/6 mg via injection. arm 6: Bupivacaine HCI, 50 mg via injection. arm 7: Saline placebo via injection. arm 8: HTX- 002, 60 mg via injection. arm 9: HTX-002, 120 mg via injection. arm 10: HTX-002, 200 mg via injection. arm 11: HTX-009, 3.6 mg via injection.
Interventions: intervention 1: HTX-011A intervention 2: Saline Placebo intervention 3: HTX-011B intervention 4: HTX-002 intervention 5: Bupivacaine HCl intervention 6: HTX-009
Intervention descriptions: intervention 1: HTX-011A (bupivacaine/meloxicam), via injection. intervention 2: Saline placebo via injection. intervention 3: HTX-011B (bupivacaine/meloxicam), via injection or instillation. intervention 4: HTX-002, via injection. intervention 5: Bupivacaine HCI, via injection. intervention 6: HTX-009, via injection.

Protocol documents:
Prot_000.pdf: 
Document Type:  
Study Protocol 
Official Title:  
A Phase 2, Randomized, Controlled, Multicenter, Evaluation of the 
Efficacy and Safety of Locally Administered HTX-011, HTX-002, or 
HTX-009 for Postoperative Analgesia Following Bunionectomy 
NCT Number:  
NCT02762929 
Document Date:  
23-Jan-2017 
 


Confidential Statement 
This document contains confidential information of Heron Therapeutics.  
Do not copy or distribute without written permission of the sponsor. 
 
 
CLINICAL STUDY PROTOCOL: HTX-011-C2016-208 
 
A Phase 2, Randomized, Controlled, Multicenter, Evaluation of the Efficacy and Safety 
of Locally Administered HTX-011, HTX-002, or HTX-009 for Postoperative Analgesia 
Following Bunionectomy 
 
Compound Name: 
Injectable Bupivacaine/Meloxicam (HTX-011) 
Injectable Bupivacaine (HTX-002) 
Injectable Meloxicam (HTX-009) 
IND # 
125927 
Protocol Version: 
7 
Date of Protocol:  
23 January 2017 
Previous Versions: 
Version 1.1:  
Version 2: 
Version 3: 
Version 4: 
Version 5: 
Version 6: 
24 March 2016 
09 May 2016 
08 June 2016 
24 June 2016 
28 September 2016 
20 December 2016 
 
 
 
 
 
 
 
 
 


Protocol No: HTX-011-C2016-208 
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Heron Therapeutics 
Confidential 
SPONSOR DETAILS 
Name of Company: 
Heron Therapeutics 
Address: 
4242 Campus Point Court 
Suite 200 
San Diego, CA 92121 
USA 
Telephone Number: 
1-858-251-4400 
Fax Number: 
1-858-251-4401 
 
 
Medical Monitor 
 
Name: 
 
Address: 
Heron Therapeutics, Inc. 
4242 Campus Point Court, Suite 200 
San Diego, CA 92121 
USA 
Telephone Number: 
Fax Number: 
E-Mail Address: 
 


Protocol No: HTX-011-C2016-208 
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Heron Therapeutics 
Confidential 
INVESTIGATOR AGREEMENT 
CLINICAL PROTOCOL HTX-011-C2016-208 
A Phase 2, Randomized, Controlled, Multicenter, Evaluation of the Efficacy and Safety 
of Locally Administered HTX-011, HTX-002, or HTX-009 for Postoperative Analgesia 
Following Bunionectomy 
I have read the protocol and agree that it contains all necessary details for carrying out this study. I 
am qualified by education, experience, and training to conduct this clinical research study. I will 
conduct the study as outlined 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 (ie, medical records, case report forms, and 
informed consent statements), study drug shipment and return forms, and all other information 
collected during the study in accordance with local and national Good Clinical Practice (GCP) 
regulations. 
 
Principal Investigator: 
 
Address: 
 
Signature: 
 
Date: 
 
 
 


Protocol No: HTX-011-C2016-208 
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Heron Therapeutics 
Confidential 
SYNOPSIS 
Name of Sponsor/Company:  
Heron Therapeutics, Inc. 
Protocol Number:  
HTX-011-C2016-208 
Name of Study Drug: 
• 
HTX-011-49 Injectable Bupivacaine/Meloxicam 
• 
HTX-011-56 Injectable Bupivacaine/Meloxicam 
• 
HTX-002 Injectable Bupivacaine 
• 
HTX-009 Injectable Meloxicam 
• 
Bupivacaine Hydrochloride Injection 
(Marcaine™) 
• 
Normal Saline 
Protocol Title: A Phase 2, Randomized, Controlled, 
Multicenter, Evaluation of the Efficacy and Safety of 
Locally Administered HTX-011, HTX-002, or 
HTX-009 for Postoperative Analgesia Following 
Bunionectomy 
Name of Active Ingredients: 
Bupivacaine/Meloxicam 
Bupivacaine 
Meloxicam 
Phase of Development: 2 
Study Objectives: 
Primary Objective: 
• 
To evaluate the efficacy and duration of analgesia following administration of HTX-011, HTX-002, and 
HTX-009 formulations by three different techniques. 
Secondary Objectives: 
• 
To determine the optimum study drug administration technique  
• 
To determine the safety and tolerability of HTX-011, HTX-002, and HTX-009 formulations  
• 
To evaluate the pharmacokinetic (PK) profiles of bupivacaine and meloxicam in HTX-011,the PK profile 
of bupivacaine in HTX-002, and the PK profile of meloxicam in HTX-009 over 120 hours after study drug 
administration  
• 
To evaluate the analgesic effects of HTX-011, HTX-002, and HTX-009 formulations over various intervals 
using a series of secondary efficacy endpoints for pain intensity 
• 
To assess the effects of HTX-011, HTX-002, and HTX-009 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, 9-part, multicenter, controlled, evaluation of the efficacy and 
safety of the intraoperative administration of study drug, in adult subjects undergoing simple unilateral 
bunionectomy. In Study Parts 1 and 2, 6.84 mL (200 mg bupivacaine) of HTX-011 or HTX-002, in Study 
Part 3, 4.1 mL of HTX-011-056 (120 mg bupivacaine),and Part 4, 2.05 mL HTX-011-56 (60 mg bupivacaine) 
and Part 5, 4.1 mL of HTX-002 (120 mg) or normal saline will be administered. Part 6, 1.0 mL of HTX-011-56 
or normal saline will be administered and Part 7, 4.1 mL of HTX-009 or normal saline will be administered. In 
Part 8, 2.05 mL of HTX-002 (60 mg bupivacaine), 10 mL of bupivacaine hydrochloride, or 2.05 mL of normal 
saline will be administered.  Part 9, 4.1 mL of HTX-011-056 (120 mg bupivacaine), 2.05 mL of HTX-011-056 
(60 mg bupivacaine), or 4.1 mL of normal saline will be administered.  The total duration of this study for each 
subject will be a maximum of 56 days that comprise 28-day screening period, 72 hours in-house treatment 
period, and 25 days post-treatment follow-up period. In addition, an X-ray will be obtained between Day 28 and 
Day 42 as part of the subject’s routine surgical follow-up visit. 
Part 1 
In Part 1, 90 subjects will be enrolled and studied in six randomly assigned cohorts (1:1:1:1:1:1) as follows: 


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Heron Therapeutics 
Confidential 
Name of Sponsor/Company:  
Heron Therapeutics, Inc. 
Protocol Number:  
HTX-011-C2016-208 
Name of Study Drug: 
• 
HTX-011-49 Injectable Bupivacaine/Meloxicam 
• 
HTX-011-56 Injectable Bupivacaine/Meloxicam 
• 
HTX-002 Injectable Bupivacaine 
• 
HTX-009 Injectable Meloxicam 
• 
Bupivacaine Hydrochloride Injection 
(Marcaine™) 
• 
Normal Saline 
Protocol Title: A Phase 2, Randomized, Controlled, 
Multicenter, Evaluation of the Efficacy and Safety of 
Locally Administered HTX-011, HTX-002, or 
HTX-009 for Postoperative Analgesia Following 
Bunionectomy 
Name of Active Ingredients: 
Bupivacaine/Meloxicam 
Bupivacaine 
Meloxicam 
Phase of Development: 2 
Cohort A (15 subjects) will be enrolled to evaluate the analgesic efficacy of 6.84 mL (200 mg) of HTX-011-49 
via closed wound infiltration (post-closure dosing technique) 
Cohort B (15 subjects) will be enrolled to evaluate the analgesic efficacy of 6.84 mL (200 mg) of HTX-011-49 
via open wound infiltration (pre-closure dosing technique)  
Cohort C (15 subjects) will be enrolled to evaluate the analgesic efficacy of 6.84 mL (200 mg) of HTX-011-56 
via closed wound infiltration (post-closure dosing technique) 
Cohort D (15 subjects) will be enrolled to evaluate the analgesic efficacy of 6.84 mL (200 mg) of HTX 011-56 
via open wound infiltration (pre-closure dosing technique) 
Cohort E (15 subjects) will be enrolled to evaluate the analgesic efficacy of 10 mL (50 mg) 0.5% bupivacaine 
hydrochloride injection (Marcaine) via a closed wound infiltration (post- closure dosing technique)  
Cohort F (15 subjects) will be enrolled to evaluate 6.84 mL of normal saline via a closed wound infiltration 
(post- closure dosing technique)  
Part 2 
An additional 60 subjects will be enrolled in Part 2 and randomized (1:1:1:1) as follows: 
Cohort G (15 subjects) will be enrolled to evaluate the analgesic efficacy of 6.84 mL (200 mg) of 
HTX-002-013 via closed wound infiltration (post-closure dosing technique) 
Cohort H (15 subjects) will be enrolled to evaluate the analgesic efficacy of 6.84 mL (200 mg) of 
HTX-002-013 via open wound infiltration (pre-closure dosing technique) 
Cohort I (15 subjects) will be enrolled to evaluate 6.84 mL of normal saline via a closed wound infiltration 
(post-closure dosing technique)  
Cohort J (15 subjects) will be enrolled to evaluate 6.84 mL of normal saline via open wound infiltration 
(pre-closure dosing technique) 
Part 3 
An additional 60 subjects will be enrolled and randomized (1:1:1:1) as follows: 
Cohort K (15 subjects) will be enrolled to evaluate the analgesic efficacy of 4.1 mL (120 mg) of HTX-011-56 
via closed wound infiltration (post-closure dosing technique). 
Cohort L (15 subjects) will be enrolled to evaluate the analgesic efficacy of 4.1 mL (120 mg) of HTX-011-56 
via open wound infiltration (pre-closure dosing technique). 
Cohort M (15 subjects) will be enrolled to evaluate the analgesic efficacy of 4.1 mL (120 mg) of HTX-011-56 
local administration via instillation. 
Cohort N (15 subjects) will be enrolled to evaluate the analgesic efficacy of 4.1 mL of normal saline via open 
wound infiltration (pre-closure dosing technique). 


Protocol No: HTX-011-C2016-208 
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Heron Therapeutics 
Confidential 
Name of Sponsor/Company:  
Heron Therapeutics, Inc. 
Protocol Number:  
HTX-011-C2016-208 
Name of Study Drug: 
• 
HTX-011-49 Injectable Bupivacaine/Meloxicam 
• 
HTX-011-56 Injectable Bupivacaine/Meloxicam 
• 
HTX-002 Injectable Bupivacaine 
• 
HTX-009 Injectable Meloxicam 
• 
Bupivacaine Hydrochloride Injection 
(Marcaine™) 
• 
Normal Saline 
Protocol Title: A Phase 2, Randomized, Controlled, 
Multicenter, Evaluation of the Efficacy and Safety of 
Locally Administered HTX-011, HTX-002, or 
HTX-009 for Postoperative Analgesia Following 
Bunionectomy 
Name of Active Ingredients: 
Bupivacaine/Meloxicam 
Bupivacaine 
Meloxicam 
Phase of Development: 2 
Part 4 
An additional 45 subjects will be enrolled and randomized (1:1:1) as follows: 
Cohort O (15 subjects) will be enrolled to evaluate the analgesic efficacy of 2.05 mL (60 mg) of HTX-011-56 
via closed wound infiltration (post-closure dosing technique). 
Cohort P (15 subjects) will be enrolled to evaluate the analgesic efficacy of 2.05 mL (60 mg) of HTX-011-56 
via open wound infiltration (pre-closure dosing technique). 
Cohort R (15 subjects) will be enrolled to evaluate the analgesic efficacy of 2.05 mL of normal saline via open 
wound infiltration (pre-closure dosing technique). 
Part 5 
An additional 45 subjects will be enrolled and randomized (1:1:1) as follows: 
Cohort S (15 subjects) will be enrolled to evaluate the analgesic efficacy of 4.1 mL (120 mg) of HTX-002 via 
closed wound infiltration (post-closure dosing technique) 
Cohort T (15 subjects) will be enrolled to evaluate the analgesic efficacy of a dose up to 4.1 mL (120 mg) of 
HTX-002 via open wound infiltration (pre-closure dosing technique) 
Cohort U (15 subjects) will be enrolled to evaluate a dose up to 4.1 mL of normal saline via open wound 
infiltration (pre-closure dosing technique) 
Part 6  
An additional 20 subjects will be enrolled and randomized (3:1) as follows: 
Cohort X (15 subjects) will be enrolled to evaluate the analgesic efficacy of 1.0 mL (30 mg) of HTX-011-56 
via closed wound infiltration (post-closure dosing technique) 
Cohort Y (5 subjects) will be enrolled to evaluate a dose up to 1.0 mL of normal saline via closed wound 
infiltration (post-closure dosing technique) 
Part 7 
An additional 40 subjects will be enrolled and randomized (3:3:1:1) as follows: 
Cohort Z1 (15 subjects) will be enrolled to evaluate the analgesic efficacy of 4.1  mL (3.61 mg) of HTX-009 
via closed wound infiltration (post-closure dosing technique) 
Cohort Z2 (15 subjects) will be enrolled to evaluate the analgesic efficacy of 4.1 mL (3.61 mg) of HTX-009 via 
open wound infiltration (pre-closure dosing technique) 
Cohort Z3 (5 subjects) will be enrolled to evaluate a dose up to 4.1 mL normal saline via closed wound 
infiltration (post-closure dosing technique) 
Cohort Z4 (5 subjects) will be enrolled to evaluate a dose up to 4.1 mL normal saline via open wound 
infiltration (pre-closure dosing technique) 


Protocol No: HTX-011-C2016-208 
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Heron Therapeutics 
Confidential 
Name of Sponsor/Company:  
Heron Therapeutics, Inc. 
Protocol Number:  
HTX-011-C2016-208 
Name of Study Drug: 
• 
HTX-011-49 Injectable Bupivacaine/Meloxicam 
• 
HTX-011-56 Injectable Bupivacaine/Meloxicam 
• 
HTX-002 Injectable Bupivacaine 
• 
HTX-009 Injectable Meloxicam 
• 
Bupivacaine Hydrochloride Injection 
(Marcaine™) 
• 
Normal Saline 
Protocol Title: A Phase 2, Randomized, Controlled, 
Multicenter, Evaluation of the Efficacy and Safety of 
Locally Administered HTX-011, HTX-002, or 
HTX-009 for Postoperative Analgesia Following 
Bunionectomy 
Name of Active Ingredients: 
Bupivacaine/Meloxicam 
Bupivacaine 
Meloxicam 
Phase of Development: 2 
Part 8 
An additional 35 subjects will be enrolled and randomized (2:2:1:1:1) as follows: 
Cohort Z5 (10 subjects) will be enrolled to evaluate the analgesic efficacy of 2.05 mL (60 mg) of HTX-002 via 
closed wound infiltration (post-closure dosing technique) 
Cohort Z6 (10 subjects) will be enrolled to evaluate the analgesic efficacy of a dose of 2.05 mL (60 mg) of 
HTX-002 via open wound infiltration (pre-closure dosing technique) 
Cohort Z7 (5 subjects) will be enrolled to evaluate the analgesic efficacy of 10 mL (50 mg) 0.5% bupivacaine 
hydrochloride (Marcaine) via a closed wound infiltration (post- closure dosing technique) 
Cohort Z8 (5 subjects) will be enrolled to evaluate the analgesic efficacy of 10 mL (50 mg) 0.5% bupivacaine 
hydrochloride (Marcaine) via open wound infiltration (pre- closure dosing technique) 
Cohort Z9 (5 subjects) will be enrolled to evaluate a dose of 2.05 mL of normal saline via open wound 
infiltration (pre-closure dosing technique) 
Part 9 
An additional 35 subjects will be enrolled and randomized (3:3:1) as follows: 
Cohort A1 (15 subjects) will be enrolled to evaluate the analgesic efficacy of 4.1 mL (120 mg) of HTX-011-
056 local administration via instillation 
Cohort A2 (15 subjects) will be enrolled to evaluate the analgesic efficacy of a dose of 2.05 mL (60 mg) of 
HTX-011-056 local administration via instillation 
Cohort A3 (5 subjects) will be enrolled to evaluate a dose of 4.1 mL of normal saline via open wound 
infiltration  
 
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.  


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Heron Therapeutics 
Confidential 
Name of Sponsor/Company:  
Heron Therapeutics, Inc. 
Protocol Number:  
HTX-011-C2016-208 
Name of Study Drug: 
• 
HTX-011-49 Injectable Bupivacaine/Meloxicam 
• 
HTX-011-56 Injectable Bupivacaine/Meloxicam 
• 
HTX-002 Injectable Bupivacaine 
• 
HTX-009 Injectable Meloxicam 
• 
Bupivacaine Hydrochloride Injection 
(Marcaine™) 
• 
Normal Saline 
Protocol Title: A Phase 2, Randomized, Controlled, 
Multicenter, Evaluation of the Efficacy and Safety of 
Locally Administered HTX-011, HTX-002, or 
HTX-009 for Postoperative Analgesia Following 
Bunionectomy 
Name of Active Ingredients: 
Bupivacaine/Meloxicam 
Bupivacaine 
Meloxicam 
Phase of Development: 2 
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 (±2) Hours: assessments of vital signs, ECG, collection of AEs and concomitant medications, 
photograph of the surgical intervention area, and a blood sample for PK. Efficacy assessments will include 
collection of Pain Intensity scores and Patient Global Assessment (PGA) of pain control evaluations. 
• 
120 (±2) Hours: obtain blood sample for pharmacokinetic analysis.  
Follow-Up Phase (Day 10 and Day 28): 
Subjects will return to the clinic site at Days 10 and 28: 
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. 
Routine Surgical Follow Up (Day 28 to Day 42) 
X-ray of surgical intervention area as part of routine surgical follow up visit (evaluate bone healing). 
Number of subjects to be enrolled: The study will enroll approximately 430 subjects, 90 in Part 1 and 60 each 
in Part 2 and Part 3, Part 4 will enroll 45 subjects, Part 5 may enroll up to 45 subjects and Part 6 may enroll up 
to an additional 20 subjects, Part 7 may enroll an additional 40 subjects, Part 8, up to 35 subjects may enroll and 
Part 9, up to 35 subjects may enroll. 
Number of study sites: Up to 6 total 
Study country location: United States 
Criteria for inclusion: 
Subject must meet all of the following criteria to be considered eligible to participate in the study: 
1. Be male or female 18 years of age or older 
2. Female subjects are eligible only if all of the following apply: 
a. 
Not pregnant (female subject of child bearing potential must have a negative serum pregnancy test 
at screening and negative urine pregnancy test before surgery) 
b. Not lactating 
c. 
Not planning to become pregnant while participating in the study 
d. Be surgically sterile; or be at least two years post-menopausal; or have a monogamous partner who 
is surgically sterile; or be practicing double-barrier contraception; or practicing abstinence (must 


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Heron Therapeutics 
Confidential 
Name of Sponsor/Company:  
Heron Therapeutics, Inc. 
Protocol Number:  
HTX-011-C2016-208 
Name of Study Drug: 
• 
HTX-011-49 Injectable Bupivacaine/Meloxicam 
• 
HTX-011-56 Injectable Bupivacaine/Meloxicam 
• 
HTX-002 Injectable Bupivacaine 
• 
HTX-009 Injectable Meloxicam 
• 
Bupivacaine Hydrochloride Injection 
(Marcaine™) 
• 
Normal Saline 
Protocol Title: A Phase 2, Randomized, Controlled, 
Multicenter, Evaluation of the Efficacy and Safety of 
Locally Administered HTX-011, HTX-002, or 
HTX-009 for Postoperative Analgesia Following 
Bunionectomy 
Name of Active Ingredients: 
Bupivacaine/Meloxicam 
Bupivacaine 
Meloxicam 
Phase of Development: 2 
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 
1 month 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 
3. 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 until at least 1 week after the administration of study 
medication 
4. Be scheduled to undergo a primary unilateral first metatarsal bunionectomy repair, without collateral 
procedures, under regional anesthesia (Section 5.5.1). 
5. Subject has not had a contralateral bunionectomy in the non-study foot in the past 3 months 
6. Have the ability and be willing to comply with the study procedures. 
7. Must be able to understand study procedures and give informed consent for the conduct for all study 
procedures, using an IRB approved consent form 
Criteria for Exclusion: 
1. Unwilling to sign informed consent or not willing or able to complete all study procedures 
2. Have a contraindication or be allergic to any medication to be used during the trial period  
3. Have clinically significant cardiac abnormalities that, in the opinion of the investigator, would pose a health 
risk to the subject 
4. Have American Society of Anesthesiologists (ASA) Physical Status classification system category ≥ 4 
(Appendix D) 
5. Has AST or ALT > 3 x ULN, and/or creatinine > 2 x ULN 
6. Have another pre-existing painful condition that may confound pain assessments, in the opinion of the 
Investigator 
7. Have another surgery planned within 30 days of procedure  
8. Have a known or suspected history of alcohol or drug abuse, or a positive drug screen 
9. Currently taking analgesics for a chronically painful condition, or has taken long acting opioids within 
3 days of surgery, or taken any opioids within 24 hours of scheduled surgery for this study 
10. Subjects with documented sleep apnea or are on home continuous positive airway pressure (CPAP) 
11. Subjects who are receiving oxygen therapy at the time of screening 
12. Have participated in a clinical trial within 30 days of planned surgery 
Investigational product: HTX-011 is a sterile, viscous, extended release formulation of the active entities 
bupivacaine and meloxicam to be administered via injection or instillation into the surgical site for the 
prevention of postoperative pain. The term “HTX-011” is used to represent the extended release formulations 
comprising the active ingredients. 
HTX-002 is a sterile, viscous, extended release formulation of bupivacaine only to be locally administered into 


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Heron Therapeutics 
Confidential 
Name of Sponsor/Company:  
Heron Therapeutics, Inc. 
Protocol Number:  
HTX-011-C2016-208 
Name of Study Drug: 
• 
HTX-011-49 Injectable Bupivacaine/Meloxicam 
• 
HTX-011-56 Injectable Bupivacaine/Meloxicam 
• 
HTX-002 Injectable Bupivacaine 
• 
HTX-009 Injectable Meloxicam 
• 
Bupivacaine Hydrochloride Injection 
(Marcaine™) 
• 
Normal Saline 
Protocol Title: A Phase 2, Randomized, Controlled, 
Multicenter, Evaluation of the Efficacy and Safety of 
Locally Administered HTX-011, HTX-002, or 
HTX-009 for Postoperative Analgesia Following 
Bunionectomy 
Name of Active Ingredients: 
Bupivacaine/Meloxicam 
Bupivacaine 
Meloxicam 
Phase of Development: 2 
the surgical site for the prevention of postoperative pain. 
HTX-009 is a sterile, viscous, extended release formulation of meloxicam only to be locally administered into 
the surgical site for the prevention of postoperative pain. 
The vehicle formulation for HTX-011-49, HTX-011-56, HTX-002, and HTX-009 comprises tri[ethylene glycol] 
based poly[orthoester] polymer with dimethyl sulfoxide, glycerol triacetate, and maleic acid excipients. 
This study is being conducted to evaluate the safety and analgesic efficacy of doses of HTX-011 of 200 mg or 
lower, HTX-002 of 200 mg or lower, and doses of HTX-009 of 4.1 mL or lower in subjects following unilateral 
bunionectomy. HTX-011, HTX-002 and HTX-009 formulations will be supplied by the sponsor for 
administration to subjects according to their randomization. 
For both HTX-011-49 and HTX-011-56, the content of active ingredients per volume is identical: 
4.1 mL = 119.9 mg bupivacaine and 3.59 mg of meloxicam; 6.84 mL = 200.1 mg bupivacaine and 6.0 mg of 
meloxicam. A lower volume with a corresponding lower dose of bupivacaine may be also administered. The 
two formulations of HTX-011 differ from each other in their respective quantities of the vehicle excipients. 
HTX-002 is an identical formulation as that of HTX-011-56 except that it contains only bupivacaine (at the 
same concentration) as the active pharmaceutical ingredient. 
The content of active ingredients per volume in HTX-009 is 4.1 mL of meloxicam. 
Reference therapy: Normal saline and bupivacaine hydrochloride (Marcaine). Both will be procured by sites. 
Duration of treatment: Each subject is planned to receive a single dose of study medication in divided 
aliquots. 
Overview: This study is designed to evaluate the safety and analgesic efficacy of multiple formulations of 
HTX-011, HTX-002, and HTX-009 at doses not to exceed 6.84 mL (200 mg) in subjects following unilateral 
bunionectomy. Efficacy assessments are intended to characterize the analgesic effect time curve and the 
magnitude of analgesic effect of HTX-011, HTX-002, and HTX-009 in comparison with bupivacaine 
(Marcaine) and normal saline. In addition, the study will further characterize the safety and PK profiles of 
bupivacaine and meloxicam in the HTX-011, HTX-002, HTX-009 and bupivacaine. 
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 


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Name of Sponsor/Company:  
Heron Therapeutics, Inc. 
Protocol Number:  
HTX-011-C2016-208 
Name of Study Drug: 
• 
HTX-011-49 Injectable Bupivacaine/Meloxicam 
• 
HTX-011-56 Injectable Bupivacaine/Meloxicam 
• 
HTX-002 Injectable Bupivacaine 
• 
HTX-009 Injectable Meloxicam 
• 
Bupivacaine Hydrochloride Injection 
(Marcaine™) 
• 
Normal Saline 
Protocol Title: A Phase 2, Randomized, Controlled, 
Multicenter, Evaluation of the Efficacy and Safety of 
Locally Administered HTX-011, HTX-002, or 
HTX-009 for Postoperative Analgesia Following 
Bunionectomy 
Name of Active Ingredients: 
Bupivacaine/Meloxicam 
Bupivacaine 
Meloxicam 
Phase of Development: 2 
inducing regional anesthesia 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 
(T72), after which discharge procedures will be performed. 
Efficacy analyses: 
Pain intensity (PI) scores will be assessed utilizing an 11 point (0–10) numerical pain rating scale (NPRS), at 1, 
2, 78, 84, and 96 hours after completion of administration of study medication (T0). In this NPRS scale, 
0 equates to no pain experienced and 10 equates to worst pain imaginable. 
 
PI scores will be measured two ways: in a dependent position, and, in an elevated position at rest. PI scores will 
be measured in the dependent position (ie, subject sitting on the bed with the surgically attended foot resting at 
least partially on the floor) 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 in an elevated position 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. The 
approved rescue regimen will be morphine 2 mg IV bolus doses by titration as needed in the post-anesthesia 
care area. Once effective analgesia has been reached using the morphine administered, subjects will be 
transitioned to oral oxycodone 10 mg every 4–6 hours, as needed for analgesia. Additional morphine 2 mg IV 
every 2 hours may be administered for inadequate analgesia with oxycodone. A subject who indicates a PI score 
that is ≤ 4 may be given acetaminophen 1000 mg for analgesia: however, a daily dose of acetaminophen must 
not exceed 4 grams (4000 mg). 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. 
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 12, 24, 36, 48, 60, 72, and 96 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 (ie, 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.  


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Name of Sponsor/Company:  
Heron Therapeutics, Inc. 
Protocol Number:  
HTX-011-C2016-208 
Name of Study Drug: 
• 
HTX-011-49 Injectable Bupivacaine/Meloxicam 
• 
HTX-011-56 Injectable Bupivacaine/Meloxicam 
• 
HTX-002 Injectable Bupivacaine 
• 
HTX-009 Injectable Meloxicam 
• 
Bupivacaine Hydrochloride Injection 
(Marcaine™) 
• 
Normal Saline 
Protocol Title: A Phase 2, Randomized, Controlled, 
Multicenter, Evaluation of the Efficacy and Safety of 
Locally Administered HTX-011, HTX-002, or 
HTX-009 for Postoperative Analgesia Following 
Bunionectomy 
Name of Active Ingredients: 
Bupivacaine/Meloxicam 
Bupivacaine 
Meloxicam 
Phase of Development: 2 
Each subject will have a 12-lead ECG performed at screening, at baseline (ie, Day 0, prior to anesthetic 
pre-operative procedures), and 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 nausea numerical rating 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, and at 48, 72, and 96 
hours, and at Days 10 and 28 post-T0. In parts 4, 5, 6 and 7 one of the 3 photos taken at each specific timepoint 
should be a photo of both feet together.  
An x-ray will be taken between Day 28 and Day 42 as part of routine surgical follow-up to evaluate the status of 
the bone healing process. 
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. 
Study Endpoints 
Efficacy Endpoints:  
Primary: 
Summed pain intensity score (SPI) over 24 hours (SPI0-24) 
Secondary: 
• 
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 
• 
Mean nausea assessment scores at 6, 24, 48, and 72 hours post-T0. 
• 
The percentage of subjects who remain pain free (Numerical Pain Rating Scale ≤ 1) at 72 hours and at 
96 hours after study drug administration 
Safety Endpoints:  
Safety will be evaluated by assessment of AEs, including SAEs, as described in Section 6.4.8.  


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Name of Sponsor/Company:  
Heron Therapeutics, Inc. 
Protocol Number:  
HTX-011-C2016-208 
Name of Study Drug: 
• 
HTX-011-49 Injectable Bupivacaine/Meloxicam 
• 
HTX-011-56 Injectable Bupivacaine/Meloxicam 
• 
HTX-002 Injectable Bupivacaine 
• 
HTX-009 Injectable Meloxicam 
• 
Bupivacaine Hydrochloride Injection 
(Marcaine™) 
• 
Normal Saline 
Protocol Title: A Phase 2, Randomized, Controlled, 
Multicenter, Evaluation of the Efficacy and Safety of 
Locally Administered HTX-011, HTX-002, or 
HTX-009 for Postoperative Analgesia Following 
Bunionectomy 
Name of Active Ingredients: 
Bupivacaine/Meloxicam 
Bupivacaine 
Meloxicam 
Phase of Development: 2 
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)  
• 
Use of concomitant medications  
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) 
• 
Apparent total body clearance over bioavailability (Cl/F) 
• 
Apparent total volume of distribution over bioavailability (Vz/F) 
• 
The time to reach maximum plasma concentration (Tmax) 
• 
The terminal elimination rate constant (λZ) with the respective half-life (t½) 
Statistical methods: 
Sample size determination:  
The sample size up to 430 subjects in this study was selected empirically without a formal statistical 
assumption. 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 with contrasts to test for differences 
between the cohorts or pooled cohorts and for differences between linear combinations of the cohorts or pooled 
cohorts. 
Efficacy analysis:  
A comprehensive statistical analysis plan will be developed for this study. Demographic and baseline 
characteristics will be summarized descriptively by treatment group. Efficacy endpoints will be analyzed using 
ANOVA, chi-square tests, and log-rank tests, as appropriate. 
Pharmacokinetic analysis: 
The PK parameters for bupivacaine and meloxicam will be calculated using non-compartmental analysis and 


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Name of Sponsor/Company:  
Heron Therapeutics, Inc. 
Protocol Number:  
HTX-011-C2016-208 
Name of Study Drug: 
• 
HTX-011-49 Injectable Bupivacaine/Meloxicam 
• 
HTX-011-56 Injectable Bupivacaine/Meloxicam 
• 
HTX-002 Injectable Bupivacaine 
• 
HTX-009 Injectable Meloxicam 
• 
Bupivacaine Hydrochloride Injection 
(Marcaine™) 
• 
Normal Saline 
Protocol Title: A Phase 2, Randomized, Controlled, 
Multicenter, Evaluation of the Efficacy and Safety of 
Locally Administered HTX-011, HTX-002, or 
HTX-009 for Postoperative Analgesia Following 
Bunionectomy 
Name of Active Ingredients: 
Bupivacaine/Meloxicam 
Bupivacaine 
Meloxicam 
Phase of Development: 2 
summarized for HTX 011, HTX-002 and HTX-009 formulations, in accordance with the defined PK endpoints. 
Safety analysis: 
Safety analyses will be conducted on the safety population. Treatment duration and amount of study drug 
received will be summarized by treatment group.  
All treatment-emergent adverse events and serious adverse events will be summarized for each treatment group 
using the MedDRA coding system, by system organ class, preferred term, relationship to study drug, and 
severity.  
Narratives of deaths, serious adverse events, including early withdrawals from study drug and from study due to 
adverse events, will also be provided. 
Laboratory tests including chemistry panel, complete blood count with differential, etc., will be summarized by 
study visit for each treatment group. These safety variables will also be presented over time after study drug 
administration, as appropriate. Vital signs data will be presented similarly. 
Physical and neurological examination findings and results from ECG will be listed for review. As appropriate, 
results will also be summarized descriptively for each treatment group. Concomitant medication usage for each 
subject will be listed for review. 
 


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TABLE OF CONTENTS 
SPONSOR DETAILS ................................................................................................................2 
INVESTIGATOR AGREEMENT.............................................................................................3 
SYNOPSIS .................................................................................................................................4 
TABLE OF CONTENTS .........................................................................................................15 
LIST OF APPENDICES ..........................................................................................................19 
LIST OF TABLES ...................................................................................................................20 
ABBREVIATIONS AND DEFINITIONS ..............................................................................21 
1. 
INTRODUCTION ..........................................................................................................23 
2. 
STUDY OBJECTIVES ..................................................................................................25 
2.1. 
Primary Objective ........................................................................................................25 
2.2. 
Secondary Objective ....................................................................................................25 
3. 
STUDY ENDPOINTS ...................................................................................................26 
3.1. 
Efficacy Endpoints .......................................................................................................26 
3.1.1. 
Primary Efficacy Endpoint ....................................................................................26 
3.1.2. 
Secondary Efficacy Endpoints ...............................................................................26 
3.2. 
Safety Endpoints ..........................................................................................................26 
3.3. 
Pharmacokinetic Endpoints: ........................................................................................26 
4. 
INVESTIGATIONAL PLAN ........................................................................................27 
4.1. 
Overall Study Design ...................................................................................................27 
4.1.1. 
Pretreatment Phase (Day -28 to Day -1) ................................................................30 
4.1.2. 
Treatment and Confinement Phase (Day 0 through Day 5) ...................................30 
4.1.3. 
Follow-up Phase (Day 10 ± 2 and Day 28 ± 2) .....................................................31 
4.1.4. 
Routine Surgical Follow Up (Day 28 to Day 42) ..................................................31 
4.1.5. 
Follow Up Phone Call (Day 60 ± 7) ......................................................................31 
4.2. 
Rationale for Study Design and Control Groups .........................................................31 
5. 
STUDY POPULATION ................................................................................................32 
5.1. 
Inclusion Criteria .........................................................................................................32 
5.2. 
Exclusion Criteria ........................................................................................................32 
5.3. 
Discontinuation of Subjects .........................................................................................33 
5.3.1. 
Procedures for Withdrawal ....................................................................................33 
5.3.2. 
Replacement of Subjects ........................................................................................33 
5.4. 
Lifestyle Guideline During Confinement ....................................................................34 


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5.5. 
Surgical Procedure .......................................................................................................34 
5.5.1. 
Anesthesia and Study Drug Administration ..........................................................34 
5.5.1.1. 
Anesthesia for Surgery .....................................................................................34 
5.5.1.2. 
Study Drug Administration ..............................................................................35 
5.5.2. 
Identity of Study Medication .................................................................................36 
5.5.2.1. 
HTX-011 and HTX-002 Dose Calculation ......................................................37 
5.6. 
Method of Assigning Subjects to Treatment Groups ...................................................37 
5.7. 
Selection of Doses........................................................................................................38 
5.8. 
Blinding and Unblinding of Study Medications ..........................................................38 
5.9. 
Treatment Compliance .................................................................................................38 
5.10. Drug Accountability.....................................................................................................39 
5.11. Packaging, Labeling, and Storage ................................................................................39 
5.11.1. 
Study Drug Packaging ...........................................................................................39 
5.11.2. 
Study Drug Labeling and Storage ..........................................................................39 
5.12. Prior and Concomitant Medications ............................................................................39 
5.13. Prohibited Medications ................................................................................................40 
5.14. Concomitant Interventions and Procedures .................................................................40 
5.15. Analgesia Rescue Medication ......................................................................................40 
6. 
STUDY PROCEDURES ................................................................................................42 
6.1. 
Order of Study Procedures ...........................................................................................42 
6.2. 
Demographic Assessments ..........................................................................................42 
6.2.1. 
Demographics ........................................................................................................42 
6.2.2. 
Medical History .....................................................................................................43 
6.2.3. 
Physical Examination.............................................................................................43 
6.3. 
Efficacy Assessments...................................................................................................43 
6.3.1. 
Pain Intensity (PI) ..................................................................................................43 
6.3.2. 
Patient Global Assessment (PGA) of Pain Control ...............................................44 
6.3.3. 
Analgesia Rescue Medication Usage .....................................................................44 
6.4. 
Safety Assessments ......................................................................................................44 
6.4.1. 
Clinical Laboratory Tests .......................................................................................44 
6.4.2. 
Nausea Assessment ................................................................................................45 
6.4.3. 
Vital Sign Measurements .......................................................................................45 
6.4.4. 
12-Lead Electrocardiogram (ECG) ........................................................................45 
6.4.5. 
Surgical Wound Healing Evaluation and Photographs ..........................................46 


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6.4.6. 
Neurologic Exam/Assessment ...............................................................................46 
6.4.7. 
X-Ray .....................................................................................................................46 
6.4.8. 
Assessment of Adverse Events and Prior/Concomitant Medications ....................47 
6.4.8.1. 
Blood Sampling for Bupivacaine/Meloxicam Pharmacokinetics 
Analysis............................................................................................................47 
6.4.8.2. 
Bioanalysis of Bupivacaine and Meloxicam ....................................................47 
6.5. 
Assessments by Visit ...................................................................................................47 
6.5.1. 
Screening Visit .......................................................................................................47 
6.5.2. 
Day 0 Check-in and Surgery ..................................................................................48 
6.5.3. 
Day 0 (Treatment) – Day 5 ....................................................................................48 
6.5.4. 
Day 10 ± 2 and Day 28 ± 2 (Follow-Up/End of Study Procedures) ......................49 
6.5.5. 
Day 28 through Day 42 (Routine Surgical Follow-Up Visit) ................................49 
6.5.6. 
Follow Up Phone Call (Day 60 ± 7) ......................................................................49 
6.5.7. 
Early Termination (ET) Procedures .......................................................................50 
6.5.8. 
Unscheduled Visits ................................................................................................50 
6.6. 
Appropriateness of Assessments..................................................................................50 
7. 
ADVERSE EVENTS (AEs), SERIOUS AEs, AND SERIOUS SUSPECTED 
ADVERSE REACTIONS ..............................................................................................51 
7.1. 
Definition of an Adverse Event ...................................................................................51 
7.2. 
Definition of a Serious Adverse Event ........................................................................52 
7.2.1. 
Serious Adverse Events That Occur Before Administration of Study 
Medication .............................................................................................................52 
7.2.2. 
Serious Adverse Events That Occur After Study Completion ...............................52 
7.3. 
Definition of a Suspected Adverse Reaction) ..............................................................53 
7.4. 
Definition of a Serious Suspected Adverse Reaction (SSAR).....................................53 
7.5. 
Recording and Evaluating Adverse Events and Serious Adverse Events ....................53 
7.5.1. 
Assessment of Intensity .........................................................................................53 
7.5.2. 
Assessment of Causality ........................................................................................53 
7.5.3. 
Assessment of Outcome .........................................................................................54 
7.6. 
Follow-up of Adverse Events and Serious Adverse Events ........................................55 
7.7. 
Prompt Reporting of Serious Adverse Events to the Sponsor .....................................55 
7.8. 
Regulatory Reporting Requirements ............................................................................56 
7.9. 
Precautions ...................................................................................................................56 
8. 
STATISTICAL METHODOLOGY ..............................................................................57 
8.1. 
Determination of Sample Size .....................................................................................57 
8.2. 
Study Endpoints ...........................................................................................................57 


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8.3. 
General Considerations for Statistical Analysis ..........................................................57 
8.3.1. 
Software and General Statistical Methods .............................................................57 
8.3.2. 
Analysis Datasets ...................................................................................................57 
8.3.3. 
Test Hypothesis and P Value Justification ............................................................57 
8.3.4. 
Procedures for Handling Missing Data ..................................................................58 
8.3.4.1. 
PI Score Before and After Analgesic Rescue Medication ...............................58 
8.3.4.2. 
Other Missing PI Score(s) ................................................................................58 
8.3.5. 
Derived Variables ..................................................................................................58 
8.3.5.1. 
Study Population Summaries ...........................................................................58 
8.3.6. 
Disposition .............................................................................................................59 
8.3.7. 
Demographics ........................................................................................................59 
8.3.8. 
Protocol Violations ................................................................................................59 
8.3.9. 
Treatment Compliance ...........................................................................................59 
8.3.10. 
Prior and Concomitant Medications ......................................................................59 
8.4. 
Efficacy Analysis .........................................................................................................59 
8.4.1. 
SPI and PI Analyses ...............................................................................................59 
8.4.2. 
Time to First Dose of Rescue Medication .............................................................59 
8.4.3. 
Patient Global Assessment (PGA) of Pain Control ...............................................59 
8.4.4. 
Proportion of Subjects Requiring Rescue Medication ...........................................60 
8.4.5. 
Nausea Assessments ..............................................................................................60 
8.4.6. 
Opioid Consumption and Symptoms Associated with Opioid Use .......................60 
8.4.7. 
Subgroup Analyses for Efficacy ............................................................................60 
8.5. 
Safety and Tolerability Evaluations .............................................................................60 
8.5.1. 
Adverse Events ......................................................................................................60 
8.5.2. 
Clinical Laboratory Tests .......................................................................................61 
8.5.3. 
Vital Sign Measurements .......................................................................................61 
8.5.4. 
Electrocardiograms ................................................................................................61 
8.5.5. 
Subgroup Analyses for Safety Endpoints ..............................................................61 
8.6. 
Interim Evaluation .......................................................................................................61 
9. 
STUDY ADMINISTRATION .......................................................................................62 
9.1. 
Regulatory and Ethical Considerations ........................................................................62 
9.1.1. 
Regulatory Authority Approval .............................................................................62 
9.1.2. 
Ethical Conduct of the Study and Ethics Approval ...............................................62 
9.1.2.1. 
Ethics Committees ...........................................................................................62 


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9.1.2.2. 
General Considerations ....................................................................................63 
9.1.3. 
Informed Consent...................................................................................................63 
9.1.4. 
Investigator Reporting Requirements ....................................................................64 
9.2. 
Study Monitoring .........................................................................................................64 
9.3. 
Quality Assurance ........................................................................................................64 
9.4. 
Study and Site Closure .................................................................................................64 
9.5. 
Records Retention ........................................................................................................65 
9.5.1. 
Health Insurance Portability and Accountability Act of 1996 ...............................65 
9.5.2. 
Financial Disclosure...............................................................................................65 
9.5.3. 
Access to Original Records ....................................................................................65 
9.5.4. 
Archiving of Study-Related Documents ................................................................65 
9.6. 
Provision of Study Results and Information to Investigators ......................................66 
9.7. 
Information Disclosure and Inventions ........................................................................66 
9.7.1. 
Ownership ..............................................................................................................66 
9.7.2. 
Confidentiality .......................................................................................................66 
9.7.3. 
Publication .............................................................................................................67 
9.7.4. 
Data Management ..................................................................................................67 
9.7.5. 
Data Security ..........................................................................................................67 
9.8. 
Subject Tracking ..........................................................................................................67 
10. 
REFERENCES ...............................................................................................................68 
11. 
APPENDICES ................................................................................................................69 
LIST OF APPENDICES 
Appendix A: 
OVERVIEW OF STUDY SCHEDULE ....................................................69 
Appendix B: 
INVESTIGATOR OBLIGATIONS ..........................................................73 
Appendix C: 
STUDY-SPECIFIC INFORMATION .......................................................75 
Appendix D: 
AMERICAN SOCIETY OF ANESTHESIOLOGISTS 
PHYSICAL STATUS CLASSIFICATION SYSTEM ..............................79 
Appendix E: 
WOUND SITE EVALUATION ................................................................80 
Appendix F: 
PHOTOGRAPHY INSTRUCTIONS OF THE SURGICAL FOOT 
MATERIALS .............................................................................................81 


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LIST OF TABLES 
Table 1: 
Treatment Cohorts in Part 1 .......................................................................27 
Table 2: 
Treatment Cohorts in Part 2 .......................................................................27 
Table 3: 
Treatment Cohorts in Part 3 .......................................................................28 
Table 4: 
Treatment Cohorts in Part 4 .......................................................................28 
Table 5: 
Treatment Cohorts in Part 5 .......................................................................28 
Table 6: 
Treatment Cohorts in Part 6 .......................................................................28 
Table 7:  
Treatment Cohorts in Part 7…………………………… ............…...……28 
Table 8:  
Treatment Cohorts in Part 8………………………………… ............…...29 
Table 9: 
Treatment Cohorts in Part 9 .......................................................................28 
 
Appendix A Table 1: 
Screening........................................................................................69 
Appendix A Table 2: 
Day 0 Prior To Surgery and Surgery .............................................70 
Appendix A Table 3: 
Post Study Medication Administration ..........................................71 
 
 


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ABBREVIATIONS AND DEFINITIONS 
AE 
Adverse Event 
ALT 
Alanine aminotransferase 
ANOVA 
analysis of variance 
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 
bpm 
beats per minute 
CFR 
Code of Federal Regulations  
Cmax 
Maximum Plasma Concentration 
CPAP 
Continuous positive airway pressure 
ECG 
Electrocardiogram 
eCRF 
electronic Case Report Form 
ET 
early termination 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HEENT 
head, eyes, ears, nose and throat 
HIV 
human immunodeficiency virus 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug 
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 
MAC 
minimum alveolar concentration 
MAOIs 
monoamine oxidase inhibitors 
mg 
Milligram 


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min 
Minute 
mITT 
modified Intend-to-Treat  
NNRS 
Nausea Numeric Rating Scale 
NPRS 
Numerical Pain Rating Scale 
NRS 
Numeric Rating Scale 
NSAIDS 
non-steroidal anti-inflammatory drugs 
PCP 
phencyclidine  
PGA 
Patient Global Assessment 
PI 
pain intensity 
PK 
Pharmacokinetic 
po 
By Mouth, Orally 
PONV 
postoperative nausea and vomiting  
prn 
as needed 
SAE 
Serious Adverse Event 
SAR 
Suspected Adverse Reaction 
SD 
standard deviation  
SNRIs 
serotonin-norepinephrine reuptake inhibitors  
SPI 
summed pain intensity 
SpO2 
peripheral oxygen saturation 
SSAR 
Serious Suspected Adverse Reaction 
SSRI 
Selective serotonin reuptake inhibitor 
t½  
half-life 
TCAs 
tricyclic antidepressants 
Tmax 
time to reach maximum plasma concentration 
VAS 
Visual Analog Scale 
VS 
vital signs 
WBC 
white blood cell  
WHO 
World Health Organization 
WLOCF 
Windowed Last Observation Carried Forward  
λZ 
terminal elimination rate constant 
 
 
 


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1. 
INTRODUCTION 
The use of local anesthetics has found extensive use in a vast number of patients (Renck 
1994). Medical opinion would suggest that using 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 is the limited duration of effect (6 to 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 100 mg, 200 mg, and 400 mg of 
HTX-011-19 and single doses of 100 mg and 200 mg of HTX-011-49 were administered 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 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 
because of the subcutaneous administration of the product in this healthy volunteer study. 


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A placebo-controlled Phase 2 clinical trial in the US evaluated the efficacy and safety of 
HTX-011 containing 200 mg and 400 mg of bupivacaine combined with meloxicam, 
compared with placebo, in 71 subjects undergoing bunionectomy. The primary endpoint was 
the difference, as compared to placebo, in pain intensity, as measured by the Summed Pain 
Intensity score (SPI), in the first 24 hours post-surgery. Other secondary endpoints included: 
the difference in SPI in the first 48 hours post-surgery; the difference in SPI in the first 
72 hours post-surgery; time to the first use of opioid rescue medication; and the percentage of 
subjects who received no opioid rescue medication in the first 72 hours post-surgery. No 
subject discontinued early from this study. Of the five total SAEs reported, four were 
cellulitis consisting of pain, redness, and swelling reported. These four subjects experienced 
skin infections that required hospitalization with IV antibiotics, and, subsequently, two of the 
four subjects underwent a second surgery. The fifth SAE case presented with erythematous 
vesicular reaction with noted presence of eschar on study Day 30 and was treated with oral 
antibiotics and topical cream. The sponsor conducted thorough investigations of these cases 
and concluded that, while causality by drug cannot be definitively ruled out, these events 
were likely not the result of exposure to HTX-011. 
This present study is designed to evaluate the safety and analgesic efficacy of HTX-011, 
HTX-002 and HTX-009 formulations in subjects following unilateral bunionectomy. 
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 Marcaine and 
with saline. In addition, the study will further characterize the safety and PK profiles of 
bupivacaine and meloxicam present in HTX-011 and HTX-009, and the PK profile of 
bupivacaine present in HTX-002. 
The current edition of the HTX-011/HTX-002/HTX-009 Investigator’s Brochure should be 
consulted for more detailed information on the formulations under investigation (HTX-011, 
HTX-009, and HTX-002). 


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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, HTX-002, and HTX-009 formulations by three different 
techniques and multiple doses. 
2.2. 
Secondary Objective  
The secondary objectives will be: 
• To determine the optimum study drug administration technique 
• To determine the safety and tolerability of HTX-011, HTX-002, and HTX-009 
formulations  
• To evaluate the pharmacokinetic (PK) profiles of bupivacaine and meloxicam in 
HTX-011 and the PK profile of bupivacaine in HTX-002, and the PK profile of 
meloxicam in HTX-009 over 120 hours after study drug administration  
• To evaluate the analgesic effects of HTX-011, HTX-002, and HTX-009 formulations 
over various intervals using a series of secondary efficacy endpoints for pain intensity 
• To assess the effects of HTX-011, HTX-002, and HTX-009 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. 
Efficacy Endpoints 
3.1.1. 
Primary Efficacy Endpoint 
The primary efficacy endpoint for this study will be the summed pain intensity score (SPI) 
over 24 hours (SPI0-24). 
3.1.2. 
Secondary Efficacy Endpoints 
Secondary efficacy endpoints for this study will include: 
• 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. 
• Mean nausea assessment scores at 6, 24, 48, and 72 hours post-T0. 
• The percentage of subjects who remain pain free (Numerical Pain Rating Scale ≤ 1) at 
72 hours and at 96 hours after study drug administration. 
3.2. 
Safety Endpoints 
Safety will be evaluated by assessment of AEs including SAEs as described in Section 6.4.8.  
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)  
• Use of concomitant medications 
3.3. 
Pharmacokinetic Endpoints: 
• The area under the plasma concentration-time curve from time zero to time t of the 
last measured concentration above the limit of quantification (AUC0-last) 
• The area under the plasma concentration-time curve from zero to infinity (AUC0-inf) 
• The maximum plasma concentration (Cmax) 
• Apparent total body clearance over bioavailability (Cl/F) 
• Apparent total volume of distribution over bioavailability (Vz/F) 
• The time to reach maximum plasma concentration (Tmax) 
• The terminal elimination rate constant (λZ) with the respective half-life (t½) 


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4. 
INVESTIGATIONAL PLAN 
4.1. 
Overall Study Design 
This is a Phase 2, randomized, 9-part, multicenter, controlled, evaluation of the efficacy and 
safety of the intraoperative administration of study drug in adult subjects undergoing simple 
unilateral bunionectomy. In Study Parts 1 and 2, 6.84 mL (200 mg bupivacaine) of HTX-011 
or HTX-002, in Study Part 3, 4.1 mL HTX-011-56 (120 mg bupivacaine) and Part 4, 
2.05 mL HTX-011-56 (60 mg bupivacaine), Part 5, 4.1 mL of HTX-002 (120 mg 
bupivacaine), Part 6, 1.0 mL of HTX-011-56 (30 mg bupivacaine) or normal saline will be 
administered, Part 7, 4.1 mL of HTX-009 or normal saline will be administered, Part 8, 2.05 
mL of HTX-002 (60 mg bupivacaine), bupivacaine hydrochloride, or normal saline will be 
administered and  Part 9, 4.1 mL of HTX-011-056 (120 mg bupivacaine), 2.05 mL of HTX-
011-056 (60 mg bupivacaine), or 4.1 mL of normal saline will be administered.  Up to 
34 cohorts of subjects may be enrolled for an approximate total of 430 subjects. In Part 1 
(Cohorts A through F), approximately 90 subjects will receive HTX-011-49, HTX-011-56, 
bupivacaine (Marcaine), or normal saline (Table 1). In Part 2 (Cohorts G through J), 
approximately 60 subjects will receive HTX-002 or normal saline (Table 2). Part 3 
(Cohorts K through N), approximately 60 subjects will receive HTX-011-56 or normal saline 
(Table 3). In Part 4, up to 45 additional subjects may be enrolled (Table 4), and in Part 5 up 
to an additional 45 subjects may be enrolled (Table 5). Part 6 (Cohorts X and Y) up to an 
additional 20 subjects may be enrolled to HTX-011-56 or normal saline (Table 6). Part 7 
(Cohorts Z1, Z2, Z3, and Z4) up to an additional 40 subjects may be enrolled to HTX-009 or 
normal saline (Table 7). In Part 8, Cohorts Z5, Z6, Z7, Z8, and Z9 35 subjects may be 
enrolled to HTX-002, bupivacaine hydrochloride, or normal saline (Table 8). Part 9, (Cohorts 
A1, A2 and A3) up to 35 subjects may be enrolled to HTX-011-056 (120 or 60 mg 
bupivacaine) or 4.1 mL of normal saline (Table 9).  
Table 1: 
Treatment Cohorts in Part 1 
Cohort 
Study Drug 
Administration Technique 
Number of Subjects 
Cohort A 
HTX-011-49 (200 mg) 
Closed wound infiltration 
15 
Cohort B 
HTX-011-49 (200 mg) 
Open wound infiltration 
15 
Cohort C 
HTX-011-56 (200 mg) 
Closed wound infiltration 
15 
Cohort D 
HTX-011-56 (200 mg) 
Open wound infiltration 
15 
Cohort E 
Bupivacaine (Marcaine) 
Closed wound infiltration 
15 
Cohort F 
Normal saline  
Closed wound infiltration 
15 
Table 2: 
Treatment Cohorts in Part 2 
Cohort 
Study Drug 
Administration Technique 
Number of Subjects 
Cohort G 
HTX-002 (200 mg) 
Closed wound infiltration 
15 
Cohort H 
HTX-002 (200 mg) 
Open wound infiltration 
15 
Cohort I 
Normal saline  
Closed wound infiltration 
15 


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Cohort J 
Normal saline  
Open wound infiltration 
15 
 
Table 3: 
Treatment Cohorts in Part 3 
Cohort 
Study Drug 
Administration Technique 
Number of Subjects 
Cohort K 
HTX-011-056 (120 mg) 
Closed wound infiltration 
15 
Cohort L 
HTX-011-056 (120 mg) 
Open wound infiltration 
15 
Cohort M 
HTX-011-056 (120 mg) 
Local administration via 
instillation 
15 
Cohort N 
Normal saline 
Open wound infiltration 
15 
Table 4: 
Treatment Cohorts in Part 4 
Cohort 
Study Drug 
Administration Technique 
Number of Subjects 
Cohort O 
HTX-011-056 (60 mg) 
Closed wound infiltration 
15 
Cohort P 
HTX-011-056 (60 mg) 
Open wound infiltration 
15 
Cohort R 
Normal saline 
Open wound infiltration 
15 
Table 5: 
Treatment Cohorts in Part 5 
Cohort 
Study Drug 
Administration Technique 
Number of Subjects 
Cohort S 
HTX-002 (120 mg) 
Closed wound infiltration 
15 
Cohort T 
HTX-002 (120 mg) 
Open wound infiltration 
15 
Cohort U 
Normal saline 
Open wound infiltration 
15 
Table 6: 
Treatment Cohorts in Part 6 
Cohort 
Study Drug 
Administration Technique 
Number of Subjects 
Cohort X 
HTX-011-56 (30 mg) 
Closed wound infiltration 
15 
Cohort Y 
Normal saline 
Closed wound infiltration 
5 
Table 7: 
Treatment Cohorts in Part 7 
Cohort 
Study Drug 
Administration Technique 
Number of Subjects 
Cohort Z1 
HTX-009 (3.61 mg) 
Closed wound infiltration 
15 
Cohort Z2 
HTX-009 (3.61 mg) 
Open wound infiltration 
15 
Cohort Z3 
Normal saline 
Closed wound infiltration 
5 
Cohort Z4 
Normal saline 
Open wound infiltration 
5 


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Table 8: 
Treatment Cohorts in Part 8 
Cohort 
Study Drug 
Administration Technique 
Number of Subjects 
Cohort Z5 
HTX-002 (60 mg) 
Closed wound infiltration 
10 
Cohort Z6 
HTX-002 (60 mg) 
Open wound infiltration 
10 
Cohort Z7 
Bupivacaine (Marcaine) 
Closed wound infiltration 
5 
Cohort Z8 
Bupivacaine (Marcaine) 
Open wound infiltration 
5 
Cohort Z9 
Normal Saline 
Open wound infiltration 
5 
Table 9: 
Treatment Cohorts in Part 9 
Cohort 
Study Drug 
Administration Technique 
Number of Subjects 
Cohort A1 
HTX-011-056 (120 mg) 
Local administration via 
instillation 
15 
Cohort A2 
HTX-011-056 (60 mg) 
Local administration via 
instillation 
15 
Cohort A3 
Normal saline 
Open wound infiltration 
5 
Adult subjects ≥ 18 years old undergoing elective bunionectomy will be screened for 
participation within 28 days of the scheduled surgery. 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. 
Post-operative nausea and vomiting (PONV) risk factors will be assessed, and subject will be 
trained on providing pain assessments. 
On the day of surgery (Day 0), each subject will be reassessed first for continued 
participation in the study. Subjects will undergo a primary, unilateral, first metatarsal 
bunionectomy procedure under regional anesthesia. Upon completion of the bunionectomy, a 
single dose of study drug (assigned randomly to any one of HTX-011-49, HTX-011-56, 
HTX-002, HTX-009, Marcaine or normal saline) will be administered by local infiltration. 
The operating surgeon and the attendant surgical staff will not be blinded to study medication 
because HTX-011, HTX-002, and HTX-009 are colored preparations, whereas Marcaine and 
normal saline control are not. 
Following the completion of surgery and immediate postoperative 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. Subjects will stay in the post-anesthesia care 
area for 72 hours after completion of the administration of study medication (ie, T0) prior to 
discharge from study center. Each subject will return to the study center 96 hours elapsed 
time after T0 to complete additional assessments. After completion of the 96-hour 
assessments, subjects will be scheduled to return on Days 10 and 28 for specific study 
assessments; each subject will also be asked to return to the site specifically for a PK blood 
sample draw at 120 hours. 


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Efficacy assessments will include pain intensity scoring, 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, bupivacaine toxicity, concomitant medications, 
physical examinations, neurologic assessments (including those for potential bupivacaine 
toxicity), vital sign measurements, clinical laboratory tests, ECGs, nausea assessments, and, 
wound healing assessments and photographs of the surgical intervention area.  
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. 
4.1.1. 
Pretreatment Phase (Day -28 to Day -1) 
Subjects will be consented and screened during this phase by assessments as described in 
Section 6.5. The screening period will be at any time between Day -28 and Day -1. 
4.1.2. 
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 participation in the study. Standard pre-surgery activities 
will be conducted once eligibility has been re-confirmed. 
b. Surgery (Day 0): Subjects will undergo primary unilateral first metatarsal 
bunionectomy procedure via propofol sedation and regional local anesthesia via a 
Mayo block technique utilizing 1% lidocaine without epinephrine. A standard 
anesthetic regimen will be followed for all subjects as outlined in Section 5.5.1. 
Upon completion of the bunionectomy, a single dose of study drug (ie, any one of 
HTX-011-49, HTX-011-56, HTX-002, HTX-009, Marcaine, or normal saline, 
according 
to 
random 
assignment) 
will 
be 
administered 
by 
local 
infiltration/instillation (Section 5.5.1.2). Start and stop times of dose administration 
will be recorded. Dosing stop time will be considered as T0. 
c. Postoperative Period (Days 0–5): Following surgery, subjects will be transferred to 
a post-anesthesia care area where, over the next 72 hours, they will undergo 
efficacy (see Section 6.3) and safety (see Section 6.4) assessments, and collection of 
blood samples for PK analyses (see Section 6.4.8.1). Treatments allowed during the 
postoperative period will include rescue medications for inadequately controlled 
pain symptoms (see Section 5.15). Subjects will be discharged from the clinic site 
after completion of the 72 hour assessments. Efficacy assessments scheduled at 78 
and 84 hours will be completed at home. Subjects will return to the site to complete 
the T96 efficacy and safety assessments, and they will return at T120 to allow a 
blood sample for PK analysis to be collected. 


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4.1.3. 
Follow-up Phase (Day 10 ± 2 and Day 28 ± 2) 
Subjects will return to the clinical site on Days 10 and 28 post-T0 for safety assessments (see 
Section 6.5.4). 
4.1.4. 
Routine Surgical Follow Up (Day 28 to Day 42) 
Between Days 28 and 42, an x-ray will be performed as part of routine surgical follow up to 
evaluate bone healing. 
4.1.5. 
Follow Up Phone Call (Day 60 ± 7) 
A follow up phone call will occur at Day 60 ± 7. 
4.2. 
Rationale for Study Design and Control Groups 
This study will evaluate the efficacy and safety of multiple formulations of HTX-011, 
HTX-002, and HTX-009. Previous research has demonstrated the safety and sustained 
concentrations over 96 hours of single doses of 100 mg, 200 mg, 400 mg of HTX-011 when 
administered subcutaneously to healthy subjects. 
Bunionectomy produces generally reliable and persistent pain symptoms for a period 
typically lasting over 72 hours after the surgical insult, which will allow for analysis of the 
acute analgesic effect of HTX-011, HTX-002 and HTX-009 over an extended period of time. 
Efficacy measures will be collected so as to gain a better knowledge of the analgesic effect-
time curve of HTX-011, HTX-002, and HTX-009 compared with Marcaine and with normal 
saline following a surgical procedure. In addition, the study will further characterize the 
safety and pharmacokinetic profiles of bupivacaine and meloxicam. Based on the overall PI, 
PK and safety data from the study cohorts, the optimum administration technique for HTX-
011, HTX-002, and HTX-009 will be decided: the methodology will be detailed in the 
statistical analysis plan for this study. 
Bupivacaine is one of the local anesthetics commonly administered for acute analgesic effect 
and is therefore employed in this study as a positive control, and normal saline employed as a 
negative control, for efficacy and safety evaluations. 


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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 male or female 18 years of age or older 
2. Female subjects are eligible only if all of the following apply: 
o Not pregnant (female subject of child bearing potential must have a negative 
serum pregnancy test at screening and negative urine pregnancy test before 
surgery) 
o Not lactating 
o Not planning to become pregnant while participating in the study 
o Be surgically sterile; or be at least two years post-menopausal; or have a 
monogamous partner who is surgically sterile; or be 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 1 month prior to screening visit 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 
3. Male subjects be surgically sterile (biologically or surgically) or commit to the use of a 
reliable method of birth control for the duration of the study until at least 1 week after 
the administration of study medication 
4. Be scheduled to undergo a primary unilateral first metatarsal bunionectomy repair, 
without collateral procedures, under regional anesthesia 
5. Subject has not had a contralateral bunionectomy in the non-study foot in the past 
3 months 
6. Have the ability and be willing to comply with the study procedures 
7. Must be able to understand study procedures and give informed consent for the 
conduct for all study procedures, using an IRB approved consent form 
5.2. 
Exclusion Criteria 
Subjects who meet any of the following criteria will be excluded from participating in the 
study: 
1. Unwilling to sign informed consent or not willing or able to complete all study 
procedures 


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2. Have a contraindication or be allergic to any medication to be used during the trial 
period  
3. Have clinically significant cardiac abnormalities, that in the opinion of the investigator 
would pose a health risk to the subject 
4. Have American Society of Anesthesiologists (ASA) Physical Status classification 
system category 4 or greater (Appendix D) 
5. Has AST or ALT > 3 x ULN, and/or creatinine > 2 x ULN 
6. Have another pre-existing painful condition that may confound pain assessments, in 
the opinion of the Investigator 
7. Have another surgery planned within 30 days of procedure  
8. Have a known or suspected history of alcohol or drug abuse, or a positive drug screen 
9. Currently taking analgesics for a chronically painful condition, or has taken long 
acting opioids within 3 days of surgery, or taken any opioids within 24 hours of 
scheduled surgery for this study 
10. Subjects with documented sleep apnea or are on home continuous positive airway 
pressure (CPAP) 
11. Subjects who are receiving oxygen therapy at the time of screening 
12. Have participated in a clinical trial within 30 days of planned surgery 
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 
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 drug administration. The date at 
which any subject is withdrawn, and the primary reason for the 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 between 24 and 72 hours post-treatment may be 
replaced in this study, after discussion with the investigator and at the discretion of the 
Sponsor. Subjects who discontinue after the 72-hour post-treatment timeframe will not be 
replaced in this study. 


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Any subject who is randomly assigned to study drug but who discontinues the study prior to 
the study drug administration will be replaced by the next study subject who meets the study 
entry criteria. The replacement subject will be assigned to the same study drug that was 
intended for the subject being replaced.  
5.4. 
Lifestyle Guideline During Confinement 
Bathroom privileges will be restricted during the postoperative confinement period. 
Following completion of the surgery, subjects will be restricted to use of a bedpan, bedside 
commode, or bathroom privileges via wheelchair through completion of 12-hour 
assessments; bathroom privileges may be loosened at any time at the discretion of the 
investigator. While confined at the study clinic following surgery, subjects will be required to 
remain resting in bed at least 30 minutes prior to any pain intensity assessment. Subjects will 
be encouraged to maintain the operative foot elevated at all times while in bed. Subjects will 
be allowed to ambulate according to standard postoperative care instructions. 
5.5. 
Surgical Procedure  
On the day of surgery (Day 0), subjects will undergo primary unilateral first metatarsal 
bunionectomy without collateral procedures. The surgery should be completed using the 
Austin bunion procedure with internal fixation; use of other procedures including base wedge 
procedures is not acceptable as part of this study protocol. Surgeries should be scheduled to 
accommodate induction of anesthesia so that all surgical procedures can be completed by 
approximately 5:00 pm on the day of surgery. 
5.5.1. 
Anesthesia and Study Drug Administration 
5.5.1.1. 
Anesthesia for Surgery 
The anesthetic protocol described below should be followed to minimize inter-subject 
variability owing to administration of these agents. 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. 
The surgery will be performed under regional anesthesia. Epidural or spinal anesthesia is not 
allowed. The surgical procedure should be limited to a maximum duration of 120 minutes 
with a target duration ≤ 90 minutes. The start time of surgery is defined by the time of first 
incision, and the stop time is defined by the time of last suture. A pneumatic ankle tourniquet 
inflated between 150 and 250 mmHg may be applied to achieve hemostasis. 
A single dose of fentanyl 100 μg IV and/or midazolam up to 5 mg IV may be administered, 
as part of the pre-anesthesia induction procedure, at the investigator/anesthesiologist’s 
discretion. A small dose of lidocaine (up to 5 mL of 1% lidocaine without epinephrine) may 
also be administered initially to reduce venous irritation at the propofol injection site. MAC 
sedation with propofol will be initiated utilizing propofol either as an infusion or as a slow 
injection method. An initial slow IV propofol 0.5 mg/kg bolus dose may be followed by 
either a) a maintenance IV propofol infusion at 0.025–0.075 mg/kg/min, or b) incremental IV 


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propofol bolus doses of 10–20 mg, titrated to the desired clinical effect. Administration of 
propofol infusion (if utilized) may be discontinued prior to completion of the surgery, at the 
discretion of the investigator/anesthesiologist. 
Initiation of propofol sedation will be followed by administration of lidocaine (up to 20 mL 
of 1% lidocaine without epinephrine) via the Mayo block technique (Worrell and Barbour 
1996) to facilitate the necessary regional anesthesia for the bunionectomy procedure. The 
surgical procedure itself will proceed in accordance with the standard accepted clinical 
practice and preferences of the surgical team. 
Agents for nausea prophylaxis, including 5-HT3 receptor blockers (eg, ondansetron), 
scopolamine, dexamethasone, or haloperidol, are prohibited during or upon completion of the 
surgical procedure. Anti-nausea medication will only be administered during the post-
operative period for any of the following: (1) subject records a score of ≥ 5 on the nausea 
numeric rating scale; (2) subject is actively vomiting; (3) subject requests anti-nausea 
medication. 
5.5.1.2. 
Study Drug Administration 
Before any study drug can be administered, at least 15 minutes must have elapsed after the 
lidocaine was administered for the Mayo block. The start and stop times of study drug dosing 
will be recorded in the CRF. Study drug dosing stop time will be considered as 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. 
Administration of study drug for the three techniques in this study will be as follows: 
Closed wound infiltration (Cohorts A, C, E, F, G, I, K, O, S, X, Y, Z1, Z3, Z5, and Z7): 
Following skin closure, and while maintaining a sterile environment, the study drug will be 
administered in a Mayo Block-type administration in accordance with the guidance provided 
in the study Pharmacy Manual.  
A ring of medication is injected at the proximal aspect of the first interspace, to maximal 
depth, across the dorsal metatarsal base, and along the medial aspect of the first metatarsal 
base. An injection is then placed across the plantar metatarsal base, to maximal depth, to 
complete the ring. A similar ring of study drug is then administered at the level of the first 
metatarsal phalangeal joint.  
Open wound infiltration (Cohorts B, D, H, J, L,N, P, R, T, U, Z2, Z4, Z6, Z8, and Z9): 
The study drug will be administered throughout the tissue planes to ensure equal distribution 
across the surgical field. The medication should form rings of anesthetic around both the 
proximal and distal aspects of the metatarsal. An appropriate way of doing this is as follows: 
• Start proximal to the bony incision and administer half the contents of the 3 mL 
syringe distally past the bony incision (blue arrows below)  


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• Repeat the procedure with the rest of the syringe but now start distally and inject 
proximally (red arrows below) 
• Adequate saturation of all exposed tissues in the surgical field will be ensured 
• Thereafter, skin closure will commence to complete the surgical procedure. 
Local administration via instillation (Cohort M, A1, A2, and A3) 
The study drug will be administered throughout the deep tissue planes to ensure equal 
distribution across the surgical field. The medication should form rings of anesthetic around 
both the proximal and distal aspects of the metatarsal. Care must be taken to ensure adequate 
exposure of the proximal and distal ends (ie, beyond the bony incision) of the wound to study 
drug. To ensure adequate saturation of all exposed tissues in the surgical field, it may be 
necessary to administer study drug in layers. Thereafter, skin closure will commence to 
complete the surgical procedure. 
5.5.2. 
Identity of Study Medication 
Study drug in this study is defined as the investigational drugs HTX-011 (HTX-011-49 and 
HTX-011-56), HTX-002, and HTX-009 and the comparator agents bupivacaine 
hydrochloride 0.5% (Marcaine) and normal saline. 
The excipients in the vehicle formulations for HTX-011-49, HTX-011-56, HTX-002, 
HTX-009 are tri[ethylene glycol] based poly[orthoester] polymer with dimethyl sulfoxide 
(DMSO), glycerol triacetate, and maleic acid. 


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One mL of HTX-011-49 contains 29.25 mg bupivacaine base and 0.88 mg of meloxicam. 
The proposed drug product contains 2.50% w/w bupivacaine base, 0.075% 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). HTX-011-49 will be supplied by the Sponsor. 
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-011-56 will be supplied by the Sponsor. 
One mL of HTX-002 contains 29.25 mg bupivacaine base. The proposed drug product 
contains 2.50% w/w bupivacaine base 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-002-013 will be supplied by 
the Sponsor. 
One mL of HTX-009 contains 0.88 mg of meloxicam. The proposed drug product contains 
0.075% w/w meloxicam, in 64.925% (w/w) tri(ethylene glycol) poly(orthoester) (TEG-POE), 
10.0% (w/w) dimethyl sulfoxide (DMSO) and 25% glycerol triacetate (w/w). 
HTX-011, HTX-002, and HTX-009 will be supplied by the Sponsor. 
Bupivacaine hydrochloride 0.5% Injection (Marcaine) and normal saline will be procured by 
the site and sequestered in sufficient quantities to ensure that the batch numbers for both 
agents will be respectively the same across all subjects studied at the study center.  
5.5.2.1. 
HTX-011 and HTX-002 Dose Calculation 
For both HTX-011-49 and HTX-011-56, the content of active ingredients per volume is 
identical: 4.1 mL = 119.9 mg bupivacaine and 3.59 mg of meloxicam; 6.84 mL HTX-011-49 
(or HTX-011-56) = 200.1 mg bupivacaine and 6.0 mg of meloxicam; A lower volume with a 
corresponding lower dose of bupivacaine may be also administered. 
The calculated dose for HTX-002 is such that 6.84 mL HTX-002 = 200.1 mg bupivacaine.  
Refer to the Pharmacy Manual for details on the preparation and administration of study 
medication for administration to subjects enrolled in the study. 
5.6. 
Method of Assigning Subjects to Treatment Groups 
A computer generated randomization scheme will be prepared prior to study initiation. 
Subjects in Cohorts A through F will be randomly assigned to treatment with any one of 
HTX-011-49, HTX-011-56, bupivacaine (Marcaine), or normal saline in a 1:1:1:1:1:1 
assignment. All study doses administered will be according to the original treatment 
assignment. Subjects in Cohorts G, H, I, and J will be assigned randomly on a 1:1:1:1 basis. 
Subjects in Cohorts K, L, M, and N will be assigned randomly on a 1:1:1:1 basis. Subjects in 
Cohorts O, P, and R will be assigned randomly on a 1:1:1 basis. Subjects in Cohorts S, T, 
and U will be assigned randomly on a 1:1:1 basis and subjects in Cohorts X and Y will be 
assigned randomly on a 3:1 basis. Subjects in Cohorts Z1, Z2, Z3, and Z4 will be assigned 


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randomly on a 3:3:1:1 basis. Subjects in Cohorts Z5, Z6, Z7, Z8, and Z9 will be assigned 
randomly on a 2:2:1:1:1 basis. Subjects in Cohorts A1, A2 and A3 will be assigned randomly 
on a 3:3:1 basis.  
5.7. 
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 mL of HTX-011-49 were administered 
to healthy adult volunteers. HTX-011 elicited the desired pharmacokinetic profile for both 
bupivacaine and meloxicam. Therapeutically relevant plasma bupivacaine levels were 
sustained for 2 to 3 days in the absence of large initial peak plasma concentrations that can be 
observed with commercially available formulations of the drug. The 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 because of the subcutaneous administration of the 
product in this healthy volunteer study. 
To further demonstrate analgesic efficacy and to understand better the analgesia effect-time 
curve of the two HTX-011 formulations, the bupivacaine-only formulation (HTX-002) and 
the meloxicam-only formulation (HTX-009), this study will evaluate the analgesic effects of 
multiple formulations of HTX-011, HTX-002, and HTX-009 at doses not to exceed 6.84 mL 
(200 mg) in subjects following unilateral bunionectomy. 
5.8. 
Blinding and Unblinding of Study Medications 
Because HTX-011, HTX-002, and HTX-009 formulations are colored and viscous in contrast 
to Marcaine and normal saline, 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 the subject has been transferred to the post-anesthesia 
recovery area, all site staff in the clinical unit involved in the safety and efficacy assessments 
will be blinded to the treatment assignment, and (s)he will remain masked to treatment 
assignments throughout the conduct of this study. 
The study blind may be broken only if the safety of a subject is at risk and the treatment plan 
for that subject depends on which study medication he or she received. If knowledge of the 
treatment assignment is absolutely necessary for the management of a subject’s safety, the 
investigator must contact the medical monitor for unblinding information. If 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 the premature unblinding must be clearly documented. 
5.9. 
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 


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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 syringes are completely 
emptied as part of the study drug infiltration procedure. 
5.10. Drug Accountability 
The investigator (or designee) will sign for the study medications when they are received. 
The study medication must be handled and stored as described in the pharmacy manual and 
dispensed only for those subjects formally entered and assigned randomly to 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 as per written instructions from the Sponsor. 
5.11. Packaging, Labeling, and Storage 
All study medication (HTX-011, HTX-002, and HTX-009) will be prepared (ie, packaged 
and labeled in individual doses) by the sponsor or the sponsor’s designee. All study 
medication will be dispensed by the investigator or a person under his/her supervision. 
5.11.1. 
Study Drug Packaging  
HTX-011, HTX-002, and HTX-009 will be packed and dispatched in refrigerated shipping 
containers with a temperature monitor enclosed. The lot number and a manufacturing date 
will be provided. 
5.11.2. 
Study Drug Labeling and Storage 
HTX-011, HTX-002, HTX-009 labeling will comply with federal applicable laws and 
regulations. At the minimum, the following information will be provided: 
• Study number (HTX-011-C2016-208) 
• Drug identification 
• Name, address, and telephone number of sponsor or manufacturer 
• Lot number 
• Contents of package 
• Storage conditions 
• CAUTION: New Drug – Limited by United States Law to Investigational Use Only 
All HTX-011, HTX-002, HTX-009 formulations at the study site(s) should be stored in a 
refrigerator at 2–8ºC. The refrigerator should be in a locked area with restricted access. A 
temperature log or chart should be maintained to monitor the refrigerator at the study site. 
5.12. Prior and Concomitant Medications 
All medications taken by subjects within 30 days before dosing, and administered during the 
study conduct, will be recorded in the eCRF. 


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Unless a medication has been prescribed at a stable dose for at least 30 days prior to the 
scheduled bunionectomy, it will be prohibited for administration before the surgical 
procedure within five half-lives of that specific medication, or, if half-life is unknown, within 
48 hours. 
Anti-nausea medication can only be administered during the post-operative period for any of 
the following: (1) subject records a score of ≥ 5 on the Nausea Numeric Rating Scale 
(NNRS); (2) subject is actively vomiting; (3) subject requests anti-nausea medication. 
5.13. Prohibited Medications 
The following medications are prohibited throughout the study: corticosteroids (by any 
means of administration), anticonvulsants, monoamine oxidase inhibitors (MAOIs), tricyclic 
antidepressants (TCAs), neuroleptics, or serotonin-norepinephrine reuptake inhibitors 
(SNRIs), gabapentin, and pregabalin, and administration of any of these agents, while 
participating in the study, will disqualify the subject from the efficacy evaluation. 
Selective serotonin reuptake inhibitor (SSRI) treatments are allowed if taken for at least 
30 days before the screening period of the study at an unchanged stable dose. 
Analgesic medications other than those pre-specified for post-randomization rescue use 
(Section 5.15) 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 ASA 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 
(eg, ondansetron), scopolamine, dexamethasone, or haloperidol, are prohibited during or 
upon completion of the surgical procedure.  
5.14. Concomitant Interventions and Procedures 
All interventions or procedures, whether diagnostic or therapeutic, and concomitant 
medications used for these interventions will be recorded in the eCRF, along with time, date, 
and reason for the intervention or procedure. If an intervention or procedure is implemented 
to treat an AE, the event must be recorded as an AE, along with all relevant information. 
5.15. Analgesia Rescue Medication 
Study investigators will review the HTX-011/HTX-002/HTX-009 Investigator’s Brochure so 
as to be aware of the safety related events which may be anticipated with its use. 
Investigators will be versed in the latest standard of care guidelines. A fully stocked 
emergency crash cart, oxygen, and personnel trained in emergency resuscitation will be 
available at the study center at all times during the confinement period. Pain intensity 
assessments (NPRS) must be completed prior to each dose of rescue medication. 


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Rescue analgesia (from T0 to T72) will be available to subjects with inadequately controlled 
pain symptoms. Pain intensity (PI) assessment must be completed prior to administration of 
any rescue doses administered. The approved rescue regimen will be morphine 2 mg IV 
bolus doses by titration as needed in the post-anesthesia care area. Once effective analgesia 
has been reached using the morphine administered, subjects will be transitioned to oral 
oxycodone 10 mg every 4–6 hours, as needed for analgesia. Additional morphine 2 mg IV 
every 2 hours may be administered for inadequate analgesia with oxycodone. A subject who 
indicates a PI score that is ≤ 4 may be given acetaminophen 1000 mg for analgesia: however, 
a daily dose of acetaminophen must not exceed 4 grams (4000 mg). 
Efforts should be made to encourage subjects to wait at least 60 minutes after the end of 
study drug administration prior to receiving rescue medication. Subjects do not need to have 
a qualifying pain score to receive rescue analgesia; however, whenever possible staff should 
try to ensure that rescue analgesia is administered only when the numerical pain intensity 
rating score prior to rescue is NPRS ≥ 4. 
Between T72 (ie, after discharge from the research unit) and T96, pain medication (if 
needed) will be prescribed according to the investigator’s discretion and institutional 
standard of care. 
After T96, PI scores will not be recorded: subjects may resume standard of care pain 
medication as advised by their surgeon. This may include, but is not limited to, ibuprofen, 
acetaminophen, opioids, or opiate/APAP combo medication, if still needed. The name, dose, 
reason, route and time of administration of analgesics consumed after T96 will be recorded at 
the time of Day 10 visit to the study center. 
Subjects who do not achieve adequate analgesia from the rescue regimen, or experience 
intolerable opioid-related side effects, will be discontinued from study drug efficacy 
evaluations and they can be administered the standard of care regimen of analgesics. 
However, the subject must remain in the study for all planned visits (ie, 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 all study procedures is provided in Appendix A. 
6.1. 
Order of Study Procedures 
With the exception of demographic data, medical history (including PONV risk), and height 
and weight measurements at the screening visit, all attempts will be made by assessors to 
ensure that the order of study procedures performed at any scheduled time will be as follows 
(where appropriate): 
1. Pain Intensity score (Appendix C-1) 
2. Patient Global Assessment (PGA) (Appendix C-2) 
3. Nausea assessment (Appendix C-4) 
4. Vital signs 
5. 12-Lead ECG 
6. Physical Examination (±30 minutes at 72 hours) 
7. Neurologic Exam 
8. Blood sample collection for PK and for clinical laboratory assessments 
9. Surgical Wound site assessment (Appendix E) 
10. Photograph of wound (Appendix F) 
11. Adverse events 
12. Concomitant medications 
Study procedures have a ±15 minutes window unless otherwise stated. 
6.2. 
Demographic 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), 
and height. 


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6.2.2. 
Medical History 
The investigator or designee will document each subject’s medical history (including PONV 
risk factors; Appendix C-3) during the screening visit. Medical history will be obtained 
through subject interview. The review of subject’s medical records from their primary care 
physician will not be required. Medical history will be updated on Day 0 when the subject 
reports for surgery, and the subject will be interviewed to confirm that (s)he continues 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, gastrointestinal, neurological, dermatologic, and musculoskeletal systems) during 
the screening visit, at admission (Day 0) to the study site on the day of surgery, at 72 hours 
post dosing, at Day 10 (including weight), or at early termination from the study. 
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 11 point (0–10) numerical pain rating scale (NPRS). 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 an 11-point NPRS (0-10) 
where 0 equates to no pain and 10 equates to the worst pain imaginable. PI scores will be 
measured two ways: in a dependent position, and, in an elevated position at rest. 
PI scores will be assessed in a dependent position (ie, subject sitting on the bed with the 
surgically attended foot resting at least partially on the floor) at the following time-points: 
4, 6, 8, 10, 12, 14, 18, 24, 30, 36, 42, 48, 54, 60, 72 hours post study drug administration (ie, 
post-T0). 
PI scores will be measured in an elevated position at rest at the following time-points: 1, 2, 
78, 84, and 96 (±2) hours post-T0. The assessments at 78 and 84 hours will be performed by 
subjects on an outpatient basis. 
All PI assessments scheduled between 24:00 and 06:00 must be collected, even if a subject is 
asleep at the time of the assessment. A ±15-minute window is allowed for the collection of 
each PI assessment. 
PI will also be assessed within 5 minutes prior to administration of each dose of rescue 
analgesia, and, at the time of early discontinuation in the event it occurs, and only if the 
subject is discontinued prior to T96. 


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6.3.2. 
Patient Global Assessment (PGA) of Pain Control  
Subjects will be asked to evaluate the performance of their study medication as a pain 
treatment in response to the following inquiry: “Overall, please rate how well your pain has 
been controlled during the last 24, 48, 72, and 96 hours since you received study medication? 
0-poor, 1-fair, 2-good, 3-very good, or 4-excellent.” 
The PGA of pain control will be completed at 24, 48, 72, and 96 (±2) hours after study 
medication administration (ie, T0), and, at the 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. Rescue analgesia (from T0 to T96) 
will be available to subjects with inadequately controlled pain symptoms. Between T72 and 
T96, pain medication (if needed) may be prescribed according to the PI’s discretion and 
institutional standard of care. PI assessment must be completed prior to administration of any 
rescue dose administered from T0 to T72. 
Any analgesic medication usage (name, dose, reason, route and time of administration) by 
the subject will also be recorded at the time of Day 10 visit. 
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/opioids, 
amphetamines, 
methamphetamines, 
phencyclidine (PCP), benzodiazepines, barbiturates, tricyclic antidepressant, 
methylenedioxymethamphetamine, methadone, and oxycodone. 


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• serum pregnancy testing at the screening visit, and a urine pregnancy test at check-in 
on Day 0 (female subjects of child bearing potential only). 
Screening clinical 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 the 
“baseline” reference for study analyses and not for assessing study randomization eligibility. 
Blood samples for baseline clinical laboratory assessments must be collected prior to the first 
surgical incision. 
6.4.2. 
Nausea Assessment 
Nausea will be assessed during the study using an 11-point NNRS (0-10) 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 
the 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 (ie, 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, 96 hours, and Day 10, and at the time of early discontinuation from the study. Vital signs 
will have a collection window of ±15 minutes for 1 through 72 hours and ±2 hours for 96 
hours. 
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 
(±2) hours, and, at Day 10 and at the time of early discontinuation. Data from the 12-lead 
ECG will be used to exclude a subject from participation in the study if (s)he has a clinically 
significant abnormal ECG. 
The findings (ie, classification as “normal,” “abnormal not clinically significant,” or 
“abnormal clinically significant [including heart block]”) will be recorded in the subject’s 
eCRF. A copy of the actual ECG tracings may be collected for Data Management purposes. 


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6.4.5. 
Surgical Wound Healing Evaluation and Photographs 
The wound evaluator will be a blinded investigator or other medically qualified clinical site 
person who will assess the surgical site to determine if healing is normal or abnormal at 
48 hours, 72 hours, Day 10, and Day 28 or Early Termination, and who will record the 
observations (Appendix E) on the appropriate eCRF and source document. If the institutional 
standard post-surgical recovery procedure does not facilitate this assessment to be conducted 
at 48 and at 72 hours, then is acceptable to forgo this assessment at both these timepoints. 
Normal expected post-surgical findings include but not limited to wound dry, no dehiscence, 
no erythema, no drainage, mild bruising, or mild swelling consistent with expected 
bunionectomy – none of which will be recorded as an AE. However, if a wound is assessed 
as abnormal with unexpected post-surgical finding(s), then the finding(s) will be recorded as 
an AE(s). 
Photographs of the subject’s surgical site will be taken immediately after surgery, 48, 72, and 
96 (±2) hours, Day 10, and Day 28 or early termination (Appendix F). In Parts 4, 5, 6, and 7, 
one of the 3 photos taken at each specific timepoint should be a photo of both feet together. 
6.4.6. 
Neurologic Exam/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 
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 number of different staff 
members who perform the neurologic exam for each subject should be limited to as few as 
possible 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 and assessment will be completed at the following time points: at 
Day 0 any time prior to anesthesia induction, and at 12, 24, 36, 48, 60, 72, and 96 (± 2) 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. 
6.4.7. 
X-Ray 
When subject visits the clinical study center as part of the routine surgical follow-up within 
4 to 6 weeks (ie, Day 28 to Day 42 timeframe) of the surgery, an X-ray of the intervention 
site will be obtained to evaluate the status of the cartilage and bone healing process. A copy 
of the X-ray and/or the X-ray report will be retained for the Sponsor study files. 
A report on the status of the bone healing will be provided by the investigator or in the X-ray 
report: proper healing or not. If healing is not proper, then provide one of three assessments: 
mal-union, non-union, improper healing. 


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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 or at early termination from the study. Serious AEs 
will be recorded if they occur at any time after securing the informed consent through to Day 
28 post-T0. 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. 
Blood Sampling for Bupivacaine/Meloxicam Pharmacokinetics Analysis 
Blood samples for the pharmacokinetic analysis of bupivacaine and meloxicam will be 
collected at the following times: prior to 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 72 hours and 
± 2 hours at 96 and at 120 hours). 
6.4.8.2. 
Bioanalysis of Bupivacaine and Meloxicam 
The concentrations of bupivacaine and meloxicam in plasma will be determined by 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. 
6.5. 
Assessments by Visit 
6.5.1. 
Screening Visit 
Subjects meeting the eligibility criteria listed in Section 5.1 and Section 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 (see Appendix D) 
• Review of medical history and inclusion/exclusion criteria for study eligibility 
• Measurement of resting vital signs  


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• 12-lead ECG  
• Physical examination including height and weight 
• Clinical laboratory tests 
• Urine drug screen and alcohol breath test 
• Serum pregnancy test for women of childbearing potential 
• Assessment of PONV risk factors (see Appendix C-3) 
• Training on reporting pain intensity assessments 
• Record prior and concomitant medications 
• Record SAEs after informed consent signature 
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 reporting pain intensity assessments 
• Blood draw for PK analysis of bupivacaine and meloxicam (‘baseline’ PK sample) 
• Record prior and concomitant medications 
• Record SAEs 
• Photograph of surgical intervention site (immediately after surgery end) (see 
Appendix F) 
• Study drug administration (closed wound/open wound) 
Subjects who continue to meet eligibility criteria will undergo primary unilateral 
bunionectomy. Subjects who don’t experience a clinically significant event during surgery 
(eg, excessive bleeding, hemodynamic instability) that would render the subject medically 
unstable or complicate their postsurgical 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 Day 0 – Day 5 
subsequent to the end of administration of study medication: 
• PI assessments (see Appendix C-1)  
• PGA for pain control (see Appendix C-2) 
• Assessment of NRS for nausea (see Appendix C-4) 


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• Measurement of resting vital signs  
• 12-lead ECG 
• Blood samples for PK analysis of bupivacaine and meloxicam 
• Physical examination (weight not required at the 72-hour exam) 
• Clinical laboratory tests (72-hour only) 
• Record AEs/SAEs and concomitant medications 
• Monitor and record use of analgesia rescue medication  
• Assessment of wound healing (48 and 72 hours, if the institutional standard 
post-surgical recovery procedure permits this) (see Appendix E) 
• Photograph of surgical intervention site (48, 72, and 96 hours, if the institutional 
standard post-surgical recovery procedure permits this) (see Appendix F) 
• Neurologic assessment 
One hour after administration of study medication (T1), PI assessments will be completed if 
the subject is awake and alert. 
Rescue analgesia medication will be available to subjects with inadequately controlled pain 
symptoms during the period from T0 to T72. After T72, subjects may resume standard of 
care pain medication as advised by their surgeon. 
6.5.4. 
Day 10 ± 2 and Day 28 ± 2 (Follow-Up/End of Study Procedures) 
The following end of study procedures will be conducted for all subjects during the Day 10 
and/or Day 28 visits. 
• Physical examination (Day 10 only) 
• Vital signs (Day 10 only) 
• 12-Lead ECG (Day 10 only) 
• Record analgesic medications usage 
• Record AEs/SAEs and concomitant medications 
• Assessment of wound healing (see Appendix E) 
• Photograph of surgical intervention site (see Appendix F) 
Clinically significant adverse events, examination, or test results will be followed until 
appropriate resolution can be documented. 
6.5.5. 
Day 28 through Day 42 (Routine Surgical Follow-Up Visit) 
An X-ray of the surgical intervention area will be performed for all subjects within Day 28 to 
Day 42 timeframe. 
6.5.6. 
Follow Up Phone Call (Day 60 ± 7) 
A follow up phone call will occur at Day 60 ± 7. The following questions will be asked: 
• Are you having any pain related to the operation? Yes/No 


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• 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 
• Thinking about the past 24 hours, have you taken any medication(s) to treat pain 
related to the operation? Yes/No 
• If you answered yes to Question 3, what medications (name, dose, and route) have 
you taken? 
6.5.7. 
Early Termination (ET) Procedures 
Subjects who discontinue participation or who are discontinued prior to completing study 
participation will be asked to complete ET procedures, which will include: 
• PI assessment (only if the subject discontinued prior to 96 hours) (see Appendix C-1) 
• PGA assessment (only if the subject discontinued prior to 96 hours) 
(see Appendix C-2) 
• Assessment of nausea NRS (see Appendix C-4) 
• Measurement of resting vital signs  
• 12-lead ECG 
• Physical examination, including weight only 
• Clinical laboratory tests 
• Assessment of AEs and review of concomitant medications 
• Assessment of wound healing (see Appendix E) 
• Neurologic Assessment (only if the subject discontinued prior to 72 hours) 
6.5.8. 
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 postoperative pain populations. The timing of assessments is intended to evaluate the 
time to onset of analgesia, duration of effect, and magnitude of benefit. 
Safety measures used in this study are standard for clinical trials of investigational 
medications. 


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7. 
ADVERSE EVENTS (AEs), SERIOUS AEs, 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 (SSAR) 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 (eg, abnormal physical examination 
finding) 
• signs, symptoms, or clinical sequelae of a suspected interaction 
• signs, symptoms, or clinical sequelae of a suspected overdose of the study 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 (eg, endoscopy, appendectomy), although the condition 
that leads to the procedure is an AE 
• anticipated day to day fluctuations of preexisting disease(s) or condition(s) (including 
laboratory values) present or detected at the start of the study that do not worsen 
• the disease or disorder being studied, or expected progression, signs, or symptoms of 
the disease or disorder being studied, unless they become more severe or occur with a 
greater frequency than expected for the subject’s condition 
• transient paresthesia that 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 


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administration of study medication through study completion or resolution of AE, whichever 
comes first. 
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 (ie, 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 (ie, related to study procedures or a change in existing therapy) will be 
transcribed onto the SAE reporting form and reported to the sponsor. 
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 after 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. 


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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 (SSAR) 
A SSAR is any SAR that is determined to be serious, based on the outcomes of a SAE 
described in Section 7.2; ie, 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 
outcome or on action criteria usually associated with events that pose a threat to a subject’s 
life or functioning (see Section 7.1 and 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. For this study, adverse 
events that are considered by the Investigator to have a Possible, Probable, or Definite 
relationship to the investigational product are considered to be “related” to the investigational 
product; unlikely and unrelated are considered to be “not related” to the investigational 


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product. Sponsor assessment of causality may differ from Investigator assessment in 
accordance with FDA guidance, Safety Reporting Requirements for INDs and BA/BE 
studies: 
• 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 SE 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 postoperative wound infection, or an upper respiratory tract infection. 
• Resolved with sequelae: The event has at least one secondary outcome that may result 
in permanent disability, functional limitation, or both. Such sequelae are usually 
limited to SAEs. Examples include hip replacement resulting in foot drop (foot drop 
is not the intended outcome but is a risk of surgery), stroke resulting in paralysis, or 
emboli formation after a bacterial infection resulting in a renal infarct and loss of 
renal function. 
• Not resolved: At the end of the study, a nonserious event either has not changed in 
intensity or may not have recovered to baseline values, and the outcome is unknown. 
Examples include headache, low-grade fever, or nausea. 


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• 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 and designated as ongoing and will be reviewed at 
subsequent visits or contacts. 
SAEs will be followed until the event resolves, the condition stabilizes, the event is otherwise 
explained, or the subject is lost to follow-up. The investigator will ensure that follow-up 
information provided to the sponsor includes results of any additional laboratory tests or 
investigations, histopathologic examinations, or consultations with other healthcare 
professionals that serve to clarify the nature of the event, the cause of the event, or both. 
New or updated information will be recorded on the originally completed SAE reporting 
form and entered into the eCRF pages, with all changes signed and dated by the investigator. 
The updated SAE reporting form should be resubmitted to the sponsor within the time frames 
outlined in Section 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. 
ANY SAE OR ANY OUTCOME OF DEATH DUE TO ANY CAUSE WHICH OCCURS 
DURING THE COURSE OF THIS STUDY, REGARDLESS OF RELATIONSHIP TO 
STUDY MEDICATION, MUST BE REPORTED TO THE SPONSOR IMMEDIATELY 
(within 24 hours). 
COMPLETE THE SAE DETAILS REPORTING FORM AND FORWARD BY E-MAIL 
TO THE FOLLOWING SPONSOR CONTACT: 
Medical Monitor 
 
Name: 
Gilad S. Gordon, MD, MBA 
Address: 
4242 Campus Point Court 
Suite 200 
San Diego, CA 92121 
USA 
Telephone Number: 
1-303-517-6212 
Fax Number: 
1-858-251-4401 
E-Mail Address: 
htx011safety@herontx.com 
 
 


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In the initial e-mail, the investigator must provide to the sponsor the following eCRF pages, 
completed to the greatest extent possible: 
• AE record 
• medical history 
• prior and concomitant medications 
Also, the following documents are to be forwarded: any laboratory results, diagnostic test 
results, or medical reports relevant to the SAE. 
E-mail transmission is the preferred method for notification of 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 SSARs 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 SAR 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. 
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 28 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 up to 430 subjects in this study was selected empirically without a formal 
statistical assumption. This study comprises up to 34 cohorts. Subjects will receive 
HTX-011-49, HTX-011-56, HTX-002, HTX-009, or normal saline via three different 
administration techniques or Marcaine. 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 with contrasts to test for differences between the cohorts and for 
differences between linear combinations of the cohorts. 
8.2. 
Study Endpoints 
See Section 3 for the 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 9.4 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 assigned 
randomly to receive study medication. 
Efficacy Set: The efficacy analysis set will include all subjects who are assigned randomly to 
receive study medication and who have recorded at least one PI score post study drug 
administration. This analysis set is identified 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 
This is a study designed to look at differences between the pairs of treatments or pooled 
treatments and linear combinations of the treatments or pooled treatments. The null 
hypothesis for each comparison made in this study is that there is no difference between the 


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groups being compared. The alternative hypothesis is that the treatment groups being 
compared are different. 
The primary analysis will be via an Analysis of Variance with pre-defined contrasts for all 
the comparisons. The comparisons will be made using 2-sided test at the 0.05 level of 
significance. Nominal p-value will be reported without adjustment for multiplicity. 
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 postoperative pain intensity according to the pain 
intensity schedule; those PI assessments are referenced as the scheduled PIs. Subjects who 
require rescue analgesia are expected to report their pain intensity immediately before taking 
the rescue medication; this PI is referenced as the pre-rescue PI. The duration of analgesic 
effect will be determined for the rescue medication (eg, the analgesic window for one 
oxycodone 10 mg oral is 6 hours); this analgesic duration is referenced as the analgesic 
window of this rescue medication. When the assessment of a scheduled PI is done after the 
rescue medication and the time is within the analgesic window (inclusive) of the rescue 
medication, the scheduled PI score will be replaced by the pre-rescue PI score for the purpose 
of efficacy analysis. This method is referenced as the Windowed Last Observation Carried 
Forward (WLOCF). The original scheduled PI scores will be displayed on data listing along 
with the “imputed” PI score. 
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, then 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 database 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. 


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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. 
8.3.7. 
Demographics 
The demographic summary will include descriptive statistics for age, sex, race, weight, and 
height 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 
01 June 2015. 
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. This basic analysis will be an Analysis of Variance with 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 percentage 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 


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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 between the treatment groups to require rescue 
medications during the treatment phase of the study. Proportion of subjects who used rescue 
medications at least once will be tabulated by treatment group; difference between the 
cohorts will be assessed as described in the statistical analysis plan. 
8.4.5. 
Nausea Assessments 
The mean nausea assessment scores at 6, 24, 48, and 72 hours will be calculated, and the 
analysis of the data will be described in the Statistical Analysis Plan. 
8.4.6. 
Opioid Consumption and Symptoms Associated with Opioid Use  
Average daily opioid use will be calculated for each 24-hour period post study medication 
administration. Subjects who did not use any opioid during a period will be assigned to “0.” 
Average daily opioid data will be tabulated by treatment group with descriptive statistics. All 
Adverse Events will be reviewed by the medical monitor, and opioid related AE(s) will be 
identified and summarized. 
8.4.7. 
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. 


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8.5.2. 
Clinical Laboratory Tests 
Laboratory values will be collected at screening, Day 0 during check-in, 72 hours, and Early 
Termination. Observed values at each time-point and change from baseline at the end of 
study will be summarized for the by treatment group without formal statistical testing. 
8.5.3. 
Vital Sign Measurements 
Resting vital sign values at each time point collected will be summarized by treatment 
without formal statistical testing. 
8.5.4. 
Electrocardiograms 
The number and proportion of subjects with abnormal ECG findings at each time-point 
collected will be tabulated by treatment cohort. A data listing will be provided for subjects 
with changes from normal at baseline to abnormal and clinically significant after baseline by 
treatment. 
8.5.5. 
Subgroup Analyses for Safety Endpoints 
No subgroup analysis is planned for safety endpoints. 
8.6. 
Interim Evaluation 
An interim analysis is planned after Part 1 completes the T72 evaluation to support 
formulation and technique decisions. An interim analysis will also be conducted after Part 2 
completes the T72 evaluation to support fixed combination dosing decisions, and a third 
interim analysis will be conducted after Part 3 completes the T72 evaluation to support dose 
ranging decisions and inform design of potential future studies looking at the contribution of 
the individual components. 


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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 Harmonisation (ICH) Guidance for 
Industry, E6 GCP: Consolidated Guidance; the Nuremberg Code; and, where applicable the 
principles of the Declaration of Helsinki (Recommendations guiding Medical Doctors in 
Biomedical Research Involving Human Subjects), and with the NH&MRC National 
Statement on Ethical Conduct in Human Research (2007). 
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 (eg, advertisements or information that supports or supplements the 
informed consent form) are reviewed and approved by the appropriate IRB or IEC. The 
investigator agrees to allow the IRB or IEC direct access to all relevant documents. The IRB 
or IEC must be constituted in accordance with all applicable regulatory requirements. The 
sponsor will provide the investigator with relevant documents or data needed for IRB or IEC 
review and approval of the study. Before investigational products can be shipped to the site, 
the sponsor must receive copies of the IRB or IEC approval, the approved informed consent 
form, and any other information that the IRB or IEC has approved for presentation to 
potential subjects. 
If the protocol, the informed consent form, or any other information that the IRB or IEC has 
approved for presentation to potential subjects is amended during the study, the investigator 
is responsible for ensuring that the IRB or IEC reviews and approves, where applicable, these 
amended documents. The investigator must follow all applicable regulatory requirements 
pertaining to the use of an amended informed consent form, including obtaining IRB or IEC 
approval of the amended form, before new subjects consent to take part in the study using the 
new version of the form. The investigator must promptly forward to the sponsor copies of the 
IRB or IEC approval of the amended informed consent form or other information and the 
approved amended informed consent form or other information. IRB or IEC approval of the 
consent forms must be obtained in addition to the approval given for the clinical study. 
Regulatory review and approval may be required in some countries before IRB or IEC 
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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-C2016-208. The sponsor (or its 
designee) is responsible for all of the following: 
• selecting qualified investigators 
• providing investigators with the information they need to conduct the investigation 
properly 
• ensuring proper monitoring of the investigation 
• ensuring that appropriate regulatory agencies and all participating investigators are 
properly informed of significant new information regarding AEs or risks associated 
with HTX-011, HTX-002, or HTX-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. 
Before written informed consent is obtained, the subject should be given ample time and 
opportunity to inquire about the details of the study. All questions must be answered to the 
satisfaction of the subject (or his or her legally authorized representative). 


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Before a subject undergoes procedures specific to the protocol, the informed consent form 
must be signed and dated by the subject (or his or her legally authorized representative) and 
any other signatories as required by the IRB or IEC. 
If a subject (or legally authorized representative) cannot read, a short form approved by the 
IRB or IEC may be used. Only the short form itself is to be signed by the subject or the 
representative. However, the witness shall sign both the short form and a copy of the 
summary, and the person actually obtaining the consent shall sign the copy of the summary 
in accordance with 21 CFR 50.27 (b2). 
After all required signatures have been obtained, a copy of the informed consent form should 
be provided to the subject, and the original must be kept on file at the site and made available 
for review by the sponsor. Documentation of the informed consent discussion must be noted 
in the subject’s case history. 
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. 
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 


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closed, this action may be taken after appropriate consultation between the sponsor and 
investigator. Conditions that may warrant termination of the study include, but are not 
limited to, the following: 
• discovery of an unexpected, serious, or unacceptable risk to the subjects enrolled in 
the study 
• submission of knowingly false information from the research facility to the sponsor, 
study monitor, or regulatory agencies 
• failure of the investigator to comply with GCP (eg, 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. 
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 


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contemplated marketing applications in an ICH region or until at least 2 years have elapsed 
since the formal discontinuation of clinical development of the investigational product. The 
sponsor will notify the investigator as to when these documents no longer need to be retained 
for this use. 
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. 
If a written contract is executed between Heron Therapeutics, Inc. and the study site for the 
conduct of the study and that contract includes ownership provisions inconsistent with this 
statement; that contract’s ownership provisions shall apply rather than this statement. 
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 
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 


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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 90 days to 
review the proposed publication. Proposed publications shall not include either Heron 
Therapeutics, Inc. confidential information (other than the study results) or the personal data 
(such as name or initials) of any subject. 
At Heron Therapeutics, Inc.’s request, the submission or other disclosure of a proposed 
publication will be delayed a further 90 days to allow Heron Therapeutics, Inc. to seek patent 
or similar protection of any inventions, know-how, or other intellectual or industrial property 
rights disclosed in the proposed publication. 
If a written contract is executed for the conduct of the study and that contract includes 
publication provisions inconsistent with this statement, that contract’s publication provisions 
shall apply rather than this statement. 
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 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. 
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. 
Worrell, J. B. and G. Barbour (1996). "The Mayo block: an efficacious block for hallux and 
first metatarsal surgery." AANA J 64(2): 146-152. 
 
 


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11. 
APPENDICES 
Appendix A: 
OVERVIEW OF STUDY SCHEDULE 
Appendix A 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, including weight and height 
X 
Serum Pregnancy Test  
(female subjects of child bearing potential only) 
X 
Urine Drug Screen 
X 
Alcohol Breath Test 
X 
Clinical Laboratory Tests (Hematology and Chemistry)a 
X 
Vital Signsb 
X 
12-lead ECG 
X 
Pain Training 
X 
Prior and Concomitant Medicationc 
X 
Serious Adverse Event Monitoringd 
X 
a Results will determine subject eligibility for the study. 
b Resting vital signs: blood pressure, pulse, respiration rate, oral temperature and SpO2. Resting tests must be 
obtained after resting (seated/reclined) for ≥ 5 minutes 
c Concomitant medications taken within 30 days before dosing will be recorded on the eCRF. 
d SAEs will be reported if considered related to study participation. 
 
 


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Appendix A: 
OVERVIEW OF STUDY PROCEDURES 
Appendix A Table 2: Day 0 Prior To Surgery and Surgery 
 
Day 0 
Prior to Surgery 
Surgery 
Eligibility Assessment (Inclusion/Exclusion criteria) 
X 
 
Demographics and Medical History 
X 
 
Physical Examinationc 
X 
 
Urine Pregnancy Test  
(female subjects of child bearing potential only) 
X 
 
Urine Drug Screen 
X 
 
Alcohol Breath Test 
X 
 
Clinical Laboratory Tests (Hematology and 
Chemistry)a 
Xd 
 
Vital Signsb 
X 
 
12-lead ECG 
Xe 
 
Pain Training 
X 
 
Photograph of foot undergoing surgery 
 
Xf 
Blood Draw for PK 
Xd 
 
Neurologic Exam 
X 
 
Bunionectomy Procedure 
 
X 
Study Drug Administration 
 
X 
Prior and Concomitant Medication 
X 
X 
Serious Adverse Event Monitoringg 
X 
X 
a Used as ‘baseline’ reference, and not for determining subject eligibility. 
b Resting vital signs: blood pressure, resting pulse, respiration rate, oral temperature and SpO2. Resting tests 
must be obtained after resting (seated/reclined) for ≥ 5 minutes. 
c Physical examination will include weight only but not height. 
d Blood samples must be collected prior to first surgical incision. 
e If screening 12-lead ECG was done > 7 days prior to Day 0. 
f Immediately after surgery ends. 
g SAEs that occur before study drug administration will be reported only if considered related to study 
participation. After study drug administration, all SAEs that occur through Day 28 post-treatment must be 
reported. 


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Appendix A: 
OVERVIEW OF STUDY PROCEDURES 
Appendix A Table 3: Post Study Medication Administration 
 
Day 0 to 5 
Early 
Termi-
nation 
Assess-
ments 
Post Study Drug Administration Time Points (hours) 
0.5 
1 
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 
120 
Days 10 
and 28 
(± 2) 
Days 
60  
(± 7) 
Subject confined at the study center 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
Physical Examinationc 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xg 
 
 
 
 
X (Day 
10) 
 
X 
Clinical Laboratory Testsa 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
Vital Signs (±15 min window)b 
 
X 
 
X 
 
 
X 
 
X X (12h 
only) 
 
X 
X 
 
X 
 
X 
 
X 
X 
 
 
X 
 
X (Day 
10) 
 
X 
12-lead ECG 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
X (Day 
10) 
 
X 
Pain Intensity (±15 min window) in a 
dependent position 
 
 
 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
Xi 
Pain Intensity (±15 min window) in an 
elevated position at rest 
 
Xf 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
 
 
 
Xi 
PGA of Pain Control  
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
Xi 
Use of Rescue Medication 
X 
Xf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xe 
 
Xe 
 
 
PK Blood Samples (±15 min window) 
Xj 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
 
X 
X 
 
 
X 
Xh 
 
 
 
Numerical Rating Scale for Nausea 
(±15 min window) 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
Xi 
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 
 
X 
Assessment of Wound Healing 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xn 
 
 
Xn 
 
 
 
 
X 
 
X 
Photograph of foot undergoing surgery 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xm 
 
 
Xm 
 
 
Xm 
 
X 
 
X 
Neurologic Assessment (±15 min 
window) 
 
 
 
 
 
 
 
 
 
X (12h 
only) 
 
 
X 
 
X 
 
X 
 
X 
X 
 
 
X 
 
 
 
Xk 
X-ray (surgical intervention site) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xl 
(D28-42) 
 
 
Phone Call 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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 
 
X 
 


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a Laboratory tests will include hematology and chemistry. 
b Resting vital signs: blood pressure, pulse, respiration 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. Weight not required at 72 hour exam. 
d AEs will be monitored after administration of study medication through completion of the study or resolution of AE, whichever comes first.. SAEs will be monitored through 
Day 28 post-treatment. Toxicities thought to be associated with bupivacaine will be reported as AEs. 
e Subjects may resume standard of care pain medication as advised by their surgeon after the T96 study visit. 
f 1 hour assessments to be completed if subject is awake and alert. 
g  ±30 minutes window 
h  ±2 hours window 
i  assessed only if early termination for subject is prior to T96 
j 15-minute window for sample collection not applicable to this timepoint 
k  assessed only if early termination for subject is prior to T72 
l  Day 28 to Day 42 timeframe, as part of the routine surgical follow-up. 
m If the institutional standard post-surgical recovery procedure does not warrant removal of the bandage at the specified timepoint, then it is acceptable to forgo the photograph at 
that visit. 
n If the institutional standard post-surgical recovery procedure does not facilitate this assessment to be conducted at 48 and at 72 hours, then is acceptable to forgo this assessment 
at both these timepoints. 
 
 


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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 (eg, advertisements), and any other written information to be 
provided to the subjects. You must submit the Investigator’s Brochure and any updates to the 
IRB or IEC for review. The IRB or IEC must also provide written approval of any 
amendments to the protocol that affect the conduct of the study and any changes to the 
informed consent form in advance of use. If the duration of the study is longer than 1 year, 
reapproval by the IRB or IEC must be obtained on a yearly basis (or at more frequent 
intervals if required by the IRB or IEC). All IRB or IEC approvals must be forwarded to the 
sponsor. 
You must provide reports of all SAEs from your site to the IRB or IEC. You are also 
responsible for providing the IRB or IEC with Safety Reports of any SAEs from any other 
study conducted with the study medication. The latter will be provided to you by the sponsor. 
Confidentiality and Safety of Subjects 
You are responsible for protecting the rights, safety, and welfare of subjects under your care 
and for the control of the drug(s) under investigation. 
You are responsible for keeping a record of all screened subjects, including full names and 
last known addresses. All subjects will be identified on the eCRFs by initials and subject 
numbers. Demographic information including date of birth, sex, and race will also be 
recorded on the eCRFs. Confidentiality of subject data will be maintained in accordance with 
local laws. 
In addition to your responsibilities for reporting AEs identified during the course of a 
subject’s participation in the study, you must also report any SAEs that occur within 28 days 
after the last dose of study medication (regardless of relationship to study medication) and 
any serious adverse drug reactions (SAEs for which you consider that there is a reasonable 


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possibility that the study medication caused the response) that you become aware of at any 
time (even if the event occurs more than 28 days after the subject’s last exposure to study 
medication). This obligation is in addition to any protocol-specified requirement for reporting 
AEs occurring after the last dose of study medication. Please refer to Section 7.7 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 (ie, 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. 
 
 


Protocol No: HTX-011-C2016-208 
Page 75 of 81 
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Confidential 
Appendix C: 
STUDY-SPECIFIC INFORMATION 
Appendix C-1: 
Pain Intensity Assessments 
PAIN INTENSITY- NUMERICAL PAIN RATING SCALE (NPRS) 
On a scale of 0–10, please rate your pain by marking an ‘X” in the appropriate box that 
best describes your pain NOW. 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No Pain 
 
 
 
 
 
 
 
 
 
Worst Pain 
Imaginable 
 
 
 


Pr ot oc ol N o: H T X -0 1 1 -C 2 0 1 6 -2 0 8  
P a ge 7 6  of 8 1  
Versi o n 7  
 
 
Her o n T hera pe utics  
C o nfi de ntial  
A p pe n di x  C- 2:  
P ati e nt Gl o b al Assess me nt ( P G A) of P ai n C o ntr ol  
 
C hec k o ne Ti me -p oi nt :  
 2 4 H o urs     4 8 H o urs     7 2 H o urs  
 9 6 H o urs 
 Earl y Ter mi n ati o n  
Assess me nt N ot D o n e    
 
“ O ver all, ple ase r ate h o w w ell y o ur p ai n h as bee n c o ntr olle d d uri n g t he l ast [ 2 4, 4 8, 7 2, 
9 6] h o urs si nce y o u recei ve d st u d y me dic ati o n ? ”  
 
Res p o nse t o eac h q u esti o n will be: ( C hec k ( √) o ne b o x) 
 P o or ( 0) 
 Fair ( 1)  
 G o o d ( 2) 
 Ver y G o o d ( 3) 
 E x celle nt ( 4)  
 
 


Protocol No: HTX-011-C2016-208 
Page 77 of 81 
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Heron Therapeutics 
Confidential 
Appendix C-3: 
Risk Factors for Postoperative Nausea and Vomiting 
• Past history of postoperative nausea and vomiting and/or motion sickness 
• Nonsmoking status 
• Female gender 
• Expected to receive opioid analgesia postoperatively 
 
 


Pr ot oc ol N o: H T X -0 1 1 -C 2 0 1 6 -2 0 8  
P a ge 7 8  of 8 1  
Versi o n 7  
 
 
Her o n T hera pe utics  
C o nfi de ntial  
A p pe n di x  C- 4: 
N a use a N u meric al R ati n g Sc ale  
 
C hec k o ne Ti me- p oi nt:  
 6 H o urs     2 4 H o urs     4 8 H o urs     7 2 H o urs 
 Earl y Ter mi n ati o n  
Assess me nt N ot D o n e    
 
O n a sc ale of 0 – 1 0, ple ase r ate y o ur n a use a b y m a r ki n g a n ‘ X ” i n t he a p pr o pri ate b o x 
t h at best descri bes y o ur n a use a le vel N O W. 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
1 0  
N o 
N a use a  
 
 
 
 
 
 
 
 
 
W orst 
N a use a 
I m a gi n a ble  
 
 
 


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Page 79 of 81 
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Heron Therapeutics 
Confidential 
Appendix D: 
AMERICAN SOCIETY OF ANESTHESIOLOGISTS 
PHYSICAL STATUS CLASSIFICATION SYSTEM 
I 
Normal healthy patient 
II  
Patient with mild systemic disease; no functional limitation – eg, smoker with well-
controlled hypertension 
III  
Patient with severe systemic disease; definite functional impairment – eg, diabetes 
and angina with relatively stable disease, but requiring therapy 
IV 
Patient with severe systemic disease that is a constant threat to life – eg, 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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Page 80 of 81 
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Appendix E: 
WOUND SITE EVALUATION 
Time-point: 
 48 Hours 
 72 Hours 
 Day 10 (±2 days) 
 Day 28 (±2 days) 
WOUND SITE EVALUATION NOT DONE           Early Termination  
 
Normal (Expected 
Post-Surgical 
Findings) 
*Abnormal 
*Abnormal findings are to be recorded as 
Adverse Events on the CRF 
If observations are of mild severity, then 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 
 
 
 
 
 
 
 
Investigator’s Signature 
Date 
 
 


Protocol No: HTX-011-C2016-208 
Page 81 of 81 
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Appendix F: 
PHOTOGRAPHY INSTRUCTIONS OF THE SURGICAL FOOT 
MATERIALS 
• Camera (specify type and model). 
• Identify camera settings 
• Memory card  
• Background cloth 
• ID tag: Complete for Protocol#, Subject #, Study Hour or Day, Date, Time and 
what is being photographed (ie, left foot) 
• Adhesive Backed Decal (on a roll) ruler  
 
1. Ensure the batteries in the camera are charged. If low, replace the batteries prior to 
using the camera. 
2. Place the subject’s memory card in the camera. 
3. Expose the foot 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. Apply the adhesive backed ruler decal in an area of the foot, not obscuring the wound 
area itself. 
6. Between the information entered on the ID tag and the ruler decal, ensure that 
Protocol #, Subject #, Study Hour or Day, Date, Time and what is being 
photographed (ie, left foot) is documented for reference purposes in the photograph. 
7. At each photograph timepoint, take 3 photographs with the camera looking down at 
the surgical foot and 3 photographs with a lateral view of the surgical foot, clearly 
showing the surgical incision in the hope that there will be at least one taken from 
each view that best represents the wound area. 
 



SAP_001.pdf: 
Document Type:  
Statistical Analysis Plan 
Official Title:  
A Phase 2, Randomized, Controlled, Multicenter, Evaluation of the 
Efficacy and Safety of Locally Administered HTX-011, HTX-002, or 
HTX-009 for Postoperative Analgesia Following Bunionectomy 
NCT Number:  
NCT02762929 
Document Date:  
01-Mar-2017 
 


Heron Therapeutics, Inc. 
Statistical Analysis Plan
HTX-011-C2016-208 
 
Version 2.0; 01 March 2017
 
 
Confidential 
Page 1 of 47
 
 
 
Statistical Analysis Plan 
Heron Therapeutics, Inc. 
HTX-011-C2016-208 
 
 
 
A Phase 2, Randomized, Controlled, Multicenter Evaluation of the Efficacy and Safety of 
Locally Administered HTX-011, HTX-002, or HTX-009 for Postoperative Analgesia Following 
Bunionectomy 
Protocol Version: 7.0 23 January 2017 
 
 
 
 
 
Sponsor:  
       Heron Therapeutics, Inc. 
    
                   4242 Campus Point Court 
                               Suite 200  
                               San Diego, CA 92121 
Version: 
       2.0 
Date of Creation: 07 February 2017 
 
Last Updated:      01 March 2017 
 
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HTX-011-C2016-208 
 
Version 2.0; 01 March 2017
 
 
Confidential 
Page 3 of 47
 
TABLE OF CONTENTS 
 
ABBREVIATIONS ............................................................................................................5 
 
INTRODUCTION ......................................................................................................7 
 
STUDY OBJECTIVES ..............................................................................................8 
 
STUDY DESIGN ........................................................................................................9 
3.1     Overall Study Design ...............................................................................................9 
3.2     Treatment and Schedule of Assessments .............................................................11 
 
STUDY ENDPOINTS ..............................................................................................15 
4.1 
Efficacy Endpoints ...............................................................................................15 
4.2 
Safety Endpoints ..................................................................................................15 
 
Adverse Events ...............................................
............................................16 
 
Nausea Assessments ......................................... .... ......................................16 
 
Vital Signs ......................................................... ............................................16 
 
Laboratory Parameters ............................ ....................................................17 
 
Electrocardiograms................................ ... ...... ...........................................17 
 
Wound Healing Assessments ............ ...........................................................17 
 
Liver Function ................................................................................................17 
 
Neurological Exams .................... ....... .........................................................17 
 
DATA QUALITY ASSURANCE ..... .. ...............................................................18 
 
POPULATIONS DEFINED ............. ....................................................................18 
6.1 
Sample Size Determination .... .... ......................................................................18 
 
STATISTICAL METHODS AND DATA CONSIDERATIONS.........................18 
7.1 
General Considerations .. .... ..... .....................................................................18 
 
Standard Calculations ...................................................................................21 
7.2 
Analysis Datasets . ............... .............................................................................22 
7.3 
Disposition of Subjects and Protocol Violations ...............................................22 
7.4 
Demographic and Baseline Characteristics .......................................................22 
7.5 
Prior and Concomitant Medications ..................................................................23 
7.6 
Treatment Compliance ........................................................................................23 
7.7 
Efficacy Analysis ..................................................................................................23 
 
Primary Efficacy Endpoint Analysis Methods ............................................24 
 
Secondary Efficacy Endpoint Analysis Methods ........................................25 
7.7.3 
 Exploratory Analyses....................................................................................27 
7.8 
Data Imputation and Adjustment ......................................................................28 
7.8.1 
Pain Intensity Assessments............................................................................28 
7.8.2 
Other Assessments .........................................................................................29 
7.9 
Safety Analysis .....................................................................................................29 
 
Adverse Events ...............................................................................................29 
 
Nausea Assessments .......................................................................................30 
 
Clinical Laboratory Tests..............................................................................30 
 
Vital Sign Measurements ..............................................................................30 
7.9.4 
Physical Examinations ...................................................................................31 
7.9.5 
Electrocardiograms........................................................................................31 
7.9.6 
Wound Healing Assessments ........................................................................31 
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7.9.7 
X-ray Assessment ...........................................................................................31 
7.9.8 
Liver Function ................................................................................................31 
7.9.9 
Neurological Exam .........................................................................................32 
 
INTERIM ANALYSIS .............................................................................................32 
 
CHANGE FROM ANALYSIS PLANNED IN PROTOCOL ...............................32 
9.1 
Changes within the Statistical Analysis Plan ....................................................33 
 REFERENCES .........................................................................................................33 
LIST OF TABLES, FIGURES AND DATA LISTINGS .............................................35 
List of Tables ....................................................................................................................35 
Subject Data Listings .......................................................................................................46 
 List of Tables 
Table 1 
Protocol Revision History ..........................................................................7 
Table 2 
Study Cohorts .............................................................................................9 
Table 3 
Screening ...................................................... ...........................................11 
Table 4 
Day 0 Prior to Surgery and Surgery ............... .....................................12 
Table 5 
Post Study Medication Administration ..... .... .....................................13 
Table 6 
Analgesic Windows and Morphine Milligram Equivalencies ..............27 
Table 7 
Criteria for Abnormal Vital Signs........
............................................31 
Table 8 
Criteria for Abnormal Liver Function ..................................................32 
Table 9 
Description of SAP Changes ...................................................................33 
 
 
 
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ABBREVIATIONS  
Abbreviation 
Definition 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANOVA 
analysis of variance 
ASA 
American Society of Anesthesiologists 
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 pressure 
ECG 
electrocardiogr m 
ITT 
Intent-to-Treat 
IV 
intravenous 
LOCF 
last observation carried forward 
LSMD  
least-squares mean difference 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
modified Intend-to-Treat  
MME 
morphine milligram equivalency 
NRS 
numeric rating scale 
PACU 
post anesthesia care unit 
PGA 
Patient Global Assessment 
PI 
pain intensity 
PK 
pharmacokinetic 
PT 
preferred term 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SBP 
systolic blood pressure 
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Abbreviation 
Definition 
SD 
standard deviation 
SEM 
standard error of the mean 
SOC 
system organ class 
SPI 
summed pain intensity 
SpO2 
peripheral oxygen saturation 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 
WHO 
World Health Organization 
WLOCF 
windowed last observation carried forward  
 
 
 
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 INTRODUCTION 
This statistical analysis plan (SAP) describes the planned statistical analysis and reporting of 
the clinical study HTX-011-C2016-208 titled “A Phase 2, Randomized, Controlled, 
Multicenter Evaluation of the Efficacy and Safety of Locally Administered HTX-011, HTX-002, 
or HTX-009 for Postoperative Analgesia Following Bunionectomy”. 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 1.1 
24 Mar 2016 
Original protocol submitted to FDA on 01 April 2016; 
initial IRB submission on 25 March 2016 
Protocol Version 2.0 
09 May 2016 
Added X-ray evaluation of bone healing and other 
clarifications 
Protocol Version 3.0 
08 June 2016 
Injectable bupivacaine HCL added (HTX-002) 
Protocol Version 4.0 
24 June 2016 
To evalu te lower doses of HTX-011-56; add new 
administration method: Local administration via 
instillation 
Protocol Version 5.0 
28 September 
2016 
Add Parts 5, 6 and 7 
Protocol Version 6.0 
20 December 
2016 
Add Part 8, add follow-up phone call at Day 60 
Protocol Version 7.0 
23 January 2017 
Add Part 9 
Note:  This SAP may not be revi
d with every amendment of the study protocol.  
This SAP was based on protocol version 7.0, issued 23 January 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 the SAP 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. 
The present Phase 2 study is designed to evaluate the safety, efficacy, and duration of analgesia 
following administration of HTX-011, HTX-002, or HTX-009 by three different techniques and 
various doses. There are 9 parts to this study. Part 1 will evaluate two HTX-011 formulations 
(HTX-011-49, HTX-011-56) administered in a single dose of 200 mg to the surgical site by 
closed or open wound infiltration following simple unilateral bunionectomy. Part 2 will 
evaluate the efficacy and safety of HTX-002 administered in a single 200 mg dose to the 
surgical site by closed or open wound infiltration following simple unilateral bunionectomy. 
Part 3 will evaluate HTX-011-56 administered in a single dose of 120 mg to the surgical site by 
closed or open wound infiltration, or local administration via instillation following simple 
unilateral bunionectomy. Part 4 will evaluate HTX-011-56 administered in a single dose of 
60 mg to the surgical site by closed or open wound infiltration following simple unilateral 
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bunionectomy. Part 5 will evaluate HTX-002 administered in a single dose of 120 mg to the 
surgical site by closed or open wound infiltration following simple unilateral bunionectomy. 
Part 6 will evaluate HTX-011-56 administered in a single dose of 30 mg to the surgical site by 
closed wound infiltration following simple unilateral bunionectomy. Part 7 will evaluate HTX-
009 administered in a single dose of 3.61 mg to the surgical site by closed or open wound 
infiltration following simple unilateral bunionectomy. 
Subjects enrolled in Part 8 will receive 60 mg HTX-002 or Marcaine via closed wound or open 
wound infiltration, and subjects enrolled in Part 9 will receive 60 mg or 120 mg HTX-011-56 
administered locally via instillation following simple unilateral bunionectomy.  
Saline placebo groups will be included in each part to match part-specific administration 
methods and fluid volume. 
Efficacy assessments are intended to characterize the analgesic effect-time curve and the 
magnitude of analgesic effect of HTX-011-49, HTX-011-56, HTX-002, or HTX-009 
administered via 3 techniques, in comparison with bupivacaine HCl (Marcaine™) and normal 
saline. In addition, the study will further characterize the safety and PK profiles of bupivacaine 
and/or meloxicam in HTX-011, HTX-002, HTX-009, and bupivacaine HCl. 
 STUDY OBJECTIVES 
The primary objective is to evaluate the efficacy and duration of analgesia following 
administration of HTX-011, HTX-002, and HTX-009 formulations by 3 different techniques and 
multiple doses. 
The secondary objectives to be evalua ed are as follows: 
 To determine the optimum study drug dose and administration technique. 
 To determine the safety and tolerability of HTX-011, HTX-002, and HTX-009 
formulations as evaluated by adverse events (AEs), serious AEs (SAEs), vital signs, 
clinical laboratory tests, electrocardiograms (ECGs), and indicators of surgical healing. 
 To evaluate the PK profiles of bupivacaine and meloxicam in HTX-011, the PK profile of 
bupivacaine in HTX-002, and the PK profile of meloxicam in HTX-009 over 120 hours 
after study drug administration (details provided in a separate SAP). 
 To evaluate the analgesic effects of HTX-011, HTX-002, and HTX-009 over various time 
intervals using a series of secondary efficacy endpoints for pain intensity (such as the 
patient’s global assessment of pain control, time to administration of first dose of 
rescue analgesia, and total and average daily rescue consumption). 
 To assess the effects of HTX-011, HTX-002, and HTX-009 formulations on wound 
healing at 48 hours, 72 hours, and on Days 10 and 28 post-treatment. 
 To evaluate nausea at 6, 24, 48, and 72 hours post-treatment. 
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 To evaluate the percentage of subjects who remain pain-free over various time intervals. 
 STUDY DESIGN 
3.1     Overall Study Design 
This is a Phase 2, 9-part, multicenter, randomized, controlled evaluation of the efficacy and 
safety of the intraoperative administration via closed or open wound infiltration or administration 
via local instillation of HTX-011-49, HTX-011-56, HTX-002, or HTX-009 in adult subjects 
undergoing simple unilateral bunionectomy. Marcaine is a local anesthetic commonly 
administered for acute analgesic effect and is therefore employed in this study as an active 
control, and normal saline is employed as a negative control, for efficacy and safety evaluations. 
Treatment cohorts will be enrolled for a planned total of 430 subjects (Table 2). In Part 1 
(Cohorts A through F), approximately 90 subjects will receive HTX-011-49, HTX-011-56, 
bupivacaine HCl (Marcaine), or normal saline. In Part 2 (Cohorts G through J), approximately 
60 subjects will receive HTX-002 or normal saline. In Part 3 (Cohorts K through N), 
approximately 60 subjects will receive HTX-011-56 or norm l saline. In Part 4 (Cohorts O, P, 
and R), 45 subjects will receive HTX-011-56 or normal saline. In Part 5 (Cohorts S, T and U), 45 
subjects will receive HTX-002 or normal saline. In Part 6 (Cohorts X and Y), 20 subjects will 
receive HTX-011-56 or normal saline. In Part 7 (cohorts Z1 to Z4), 40 subjects will receive 
HTX-009 or normal saline. In Part 8 (cohorts Z5 to Z9) 35 subjects will receive HTX-002 or 
Marcaine, and in Part 9 (cohorts A1 to A3) 35 subjects will receive HTX-011-56 or normal 
saline. 
Table 2 
Study Cohorts  
Part 1 
Cohort A (15 subjects) 200 mg HTX-011-49 via open wound infiltration  
Cohort B (15 subjects) 200 mg HTX 011-49 via closed wound infiltration  
Cohort C (15 subjects) 200 mg HTX-011-56 via open wound infiltration  
Cohort D (15 subjects) 200 mg HTX-011-56 via closed wound infiltration  
Cohort E (15 subjects) 50 mg bupivacaine (Marcaine) via a closed wound infiltration  
Cohort F (15 subjects) normal saline via a closed wound infiltration  
 
Part 2 
Cohort G (15 subjects) 200 mg HTX-002 via closed wound infiltration  
Cohort H (15 subjects) 200 mg HTX-002 via open wound infiltration  
Cohort I (15 subjects) 6.84 mL of normal saline via a closed wound infiltration 
Cohort J (15 subjects) 6.84 mL of normal saline via open wound infiltration 
 
Part 3 
Cohort K (15 subjects) 120 mg HTX-011-56 via closed wound infiltration 
Cohort L (15 subjects) 120 mg HTX-011-56 via open wound infiltration 
Cohort M (15 subjects) 120 mg HTX-011-56 local administration via instillation 
Cohort N (15 subjects) 4.1 mL of normal saline via open wound infiltration 
 
Part 4 
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Cohort O (15 subjects) 60 mg HTX-011-56 via closed wound infiltration 
Cohort P (15 subjects) 60 mg HTX-011-56 via open wound infiltration 
Cohort R (15 subjects) 2 mL of normal saline via open wound infiltration 
 
Part 5 
Cohort S (15 subjects) 120 mg HTX-002 via closed wound infiltration 
Cohort T (15 subjects) 120 mg HTX-002 via open wound infiltration 
Cohort U (15 subjects) 4.1 mL of normal saline via open wound infiltration 
 
Part 6 
Cohort X (15 subjects) 30 mg HTX-011-56 via closed wound infiltration 
Cohort Y (5 subjects) 1.00 mL of normal saline via closed wound infiltration 
 
Part 7 
Cohort Z1 (15 subjects) 3.61 mg HTX-009 via closed wound infiltration 
Cohort Z2 (15 subjects) 3.61 mg HTX-009 via open wound infiltration 
Cohort Z3 (5 subjects) 4.1 mL normal saline via closed wound infiltration 
Cohort Z4 (5 subjects) 4.1 mL normal saline via open wound infiltration 
 
Part 8 
Cohort Z5 (10 subjects) 60 mg HTX-002 via closed wound infiltration 
Cohort Z6 (10 subjects) 60 mg HTX-002 via open wound infiltration 
Cohort Z7 (5 subjects) 50 mg bupivacaine (Marcaine) via closed wound infiltration 
Cohort Z8 (5 subjects) 50 mg bupivacaine (Marcaine) via open wound infiltration 
Cohort Z9 (5 subjects) 2.05 mL normal saline via open wound infiltration 
 
Part 9 
Cohort A1 (15 subjects) 120 mg HTX-011-56 via instillation  
Cohort A2 (15 subjects) 60 mg HTX-011-56 via instillation  
Cohort A3 (5 subjects) 4.1 mL of normal saline via open wound infiltration  
Male and female subjects ≥ 18 years of age undergoing elective bunionectomy will be screened 
for participation within 28 days of the scheduled surgery. After signing the informed consent 
form, subjects will be assessed for American Society of Anesthesiologists (ASA) classification, 
medical history, prior/concomitant medications, vital sign measurements, physical examination, 
clinical laboratory tests, drug and alcohol screen tests, 12-lead ECG, and serum pregnancy test. 
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), each subject will be reassessed first for continued participation in 
the study. Subjects will undergo a primary, unilateral, first metatarsal bunionectomy procedure 
under regional anesthesia. Upon completion of the bunionectomy, a single dose of study drug 
will be administered by local open or closed wound infiltration or local instillation. 
Following the completion of surgery and immediate postoperative recovery, subjects will be 
transferred to the post-anesthesia care unit (PACU). Staff members in the PACU will be blinded 
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to study treatment administered. Subjects will stay in the PACU for 72 hours after completion of 
the administration of study medication (T0) prior to discharge from the study center. Each 
subject will return to the study center 96 hours elapsed time after T0 to complete additional 
assessments. After completion of the 96-hour assessments, subjects will be scheduled to return 
on Days 10 and 28 for specific study assessments. 
3.2     Treatment and Schedule of Assessments 
Efficacy assessments will include pain intensity (PI) scoring using a numeric rating scale (NRS), 
use of rescue medication, and Patient Global Assessment (PGA) of pain control. Safety 
assessments will include AEs, nausea assessments, concomitant medications, physical 
examinations, neurologic assessments (including those for potential bupivacaine toxicity), vital 
sign measurements, clinical laboratory tests, ECGs, and wound healing assessments of the 
surgical intervention area. The planned schedule of study procedures is outlined in Table 3, 
Table 4, and Table 5. 
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, including weight 
d height 
X 
Serum Pregnancy Test  
(female subjects of child bearing potential o ly) 
X 
Urine Drug Screen 
X 
Alcohol Breath Test 
X 
Clinical Laboratory Tests (Hematology and Chemistry)a 
X 
Vital Signsb 
X 
12-lead ECG 
X 
Pain Training 
X 
Prior and Concomitant Medicationc 
X 
Serious Adverse Event Monitoringd 
X 
a Results will determine subject eligibility for the study. 
b Resting vital signs: blood pressure, pulse, respiration rate, oral temperature and SpO2. Resting tests must be obtained 
after resting (seated/reclined) for ≥ 5 minutes 
c Concomitant medications taken within 30 days before dosing will be recorded on the eCRF. 
d SAEs will be reported if considered related to study participation. 
 
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Table 4 
Day 0 Prior to Surgery and Surgery  
Procedure 
Day 0 
Prior to Surgery 
Surgery 
 Eligibility Assessment (Inclusion/Exclusion criteria) 
X 
 
Demographics and Medical History 
X 
 
Physical Examinationc 
X 
 
Urine Pregnancy Test (female subjects of childbearing potential) 
X 
 
Alcohol Breath Test 
X 
 
Clinical Laboratory Tests (Hematology and Chemistry)a 
Xd 
 
Vital Signsb 
X 
 
12-lead Electrocardiogram 
X 
 
Pain Assessment Training 
X 
 
Photograph of Foot Undergoing Surgery 
 
Xf 
Blood Draw for Pharmacokinetic Analysis 
Xd 
 
Neurologic Exam 
X 
 
Bunionectomy Procedure 
 
X 
Study Drug Administration 
 
X 
Prior and Concomitant Medication 
X 
X 
Adverse Event (AE) Monitoringg 
X 
X 
a Used as ‘baseline’ reference and not to determine eligibili y  
b Resting vital signs: blood pressure, pulse, re pirati n rate, oral temperature, and SpO2. Resting tests must be obtained after resting 
(seated/reclined) for ≥ 5 minutes. 
c Physical exam will include weight only but not height  
d Blood samples must be collected prior  first surgical i cision. 
e If screening 12-lead ECG was done >7 days prio  to Day 0. 
f Immediately after surgery ends. 
g AEs that occur before study drug administration will be reported only if considered related to study participation. After study drug 
administration, all AEs that occur through Day 28 post-treatment must be reported. 
 
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Table 5 
Post Study Medication Administration 
 
 
Day 0 to 5 
 
 
Post Study Drug Administration Time Points (hours) 
0.5 
1 
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 
120 
Days 10 
and 28 
(± 2) 
60 
ET  
Subject confined at the study center 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
Physical Examinationc 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xg 
 
 
 
 
X (Day 10) 
 
X 
Clinical Laboratory Testsa 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
Vital Signs (±15 min window)b 
 
X 
 
X 
 
 
X 
 
X X (12h 
only) 
 
X 
X 
 
X 
 
X 
 
X 
X 
 
 
X 
 
X (Day 10) 
 
X 
12-lead ECG 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
X (Day 10) 
 
X 
Pain Intensity (±15 min window) in a 
dependent position 
 
 
 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
Xi 
Pain Intensity (±15 min window) in an 
elevated position at rest 
 
Xf 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
 
 
 
Xi 
PGA of Pain Control  
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
Xi 
Use of Rescue Medication 
X 
Xf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xe 
 
Xe 
 
 
PK Blood Samples (±15 min window) 
Xj 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
 
X 
X 
 
 
X 
Xh 
 
 
 
Numerical Rating Scale for Nausea 
(±15 min window) 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
Xi 
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 
 
X 
Assessment of Wound Healing 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xn 
 
 
Xn 
 
 
 
 
X 
 
X 
Photograph of foot undergoing 
surgery 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X
m 
 
 
X
m 
 
 
Xm 
 
X 
 
X 
Neurologic Assessment (±15 min 
window) 
 
 
 
 
 
 
 
 
 
X (12h 
only) 
 
 
X 
 
X 
 
X 
 
X 
X 
 
 
X 
 
 
 
Xk 
X-ray (surgical intervention site) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xl 
(D28-42) 
 
 
Phone Call 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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 
 
X 
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a Laboratory tests will include hematology and chemistry. 
b Resting vital signs: blood pressure, pulse, respiration 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. Weight not required at 72 hour exam. 
d AEs will be monitored after administration of study medication through completion of the study or resolution of AE, whichever comes first. SAEs will be monitored through Day 28 post-treatment. 
Toxicities thought to be associated with bupivacaine will be reported as AEs. 
e Subjects may resume standard of care pain medication as advised by their surgeon after the T96 study visit. 
f 1 hour assessments to be completed if subject is awake and alert. 
g  ±30 minutes window 
h  ±2 hours window 
i  Assessed only if early termination for subject is prior to T96. 
j 15-minute window for sample collection not applicable to this timepoint. 
k  Assessed only if early termination for subject is prior to T72. 
l  Day 28 to Day 42 timeframe, as part of the routine surgical follow-up. 
m If the institutional standard post-surgical recovery procedure does not warrant removal of the bandage at the specified timepoin  then it is acceptable to forgo the photograph at that visit. 
n  If the institutional standard post-surgical recovery procedure does not facilitate this assessment to be conducted at 48 nd t 72 hours, then is acceptable to forgo this assessment at both these time points. 
 
 
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 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) 
4. Total and average daily rescue analgesia consumption over 24, 48, 72, and 96 hours post-
treatment, by each analgesic, opioid and non-opioid  
5. Percentage of subjects who have not taken opioid rescue medication over time by time 
point and comparisons at 24, 72, and 96 hours 
6. Percentage of subjects who are pain free (NRS score = 0 or 1) over time by time point and 
comparisons at 24, 72, and 96 hours after study drug administration. 
Exploratory endpoints include the following: 
1. Area under the curve (AUC) for PI scores collected over various time intervals (AUC0-24, 
AUC0-48, AUC0-72, AUC0-96, AUC0-6, AUC0-12, AUC12-24, AUC24-48, AUC48-72, and 
AUC72-96)  
2. Integrated Rank Difference for SPI0-24, SPI0-48, SPI0-72, SPI0-96 and total opiate use through 
24, 48, 72, and 96 hours post-study drug administration. 
4.2 
Safety Endpoints 
The safety endpoints include: 
 AEs and SAEs 
 Opioid-related AEs 
 Mean nausea assessments at 6, 24, 48, and 72 hours 
 Vital signs abnormal values 
 Assessments of the surgical intervention area 
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 Neurological examinations 
 Shift of clinical laboratory tests, including routine blood chemistry, liver function tests, 
and hematology  
 Shift in ECG findings 
 Use of concomitant medications 
 
 
Adverse Events 
An AE is defined as any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related.  
An AE may be any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a st dy 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.  
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 th ough study completion or resolution of the AE, 
whichever comes first.  
Any medical condition or clinically significant laboratory abnormality with an onset date before 
the first date of study drug administration is usually considered to be pre-existing, should be 
recorded as medical history, but should not be documented in the CRF as an AE. Any AE (i.e., a 
new event or an exacerbation of a pre existing condition) with an onset date after study drug 
administration up to and including the designated follow-up safety visit should be recorded as an 
AE on the CRF. All AEs must be recorded on the AE CRF regardless of the severity or 
relationship to study drug.  
 
Nausea Assessments 
Nausea is measured on a scale of 0-10, with 0 indicating no nausea and 10 indicating the worst 
nausea imaginable. Assessments of nausea will be performed at 6, 24, 48, and 72 hours post 
study medication administration. 
 
Vital Signs 
Vital signs will be obtained after resting (seated/supine) for at least 5 minutes, and will include 
resting blood pressure, resting pulse, respiratory rate, oral temperature, and peripheral oxygen 
saturation (SpO2). After the administration of study medication, subjects will have resting vital 
signs measured and recorded at the following times: 1, 2, 4, 6, 10, 12, 18, 24, 36, 48, 60, 72, and 
96 hours and at the Day 10 visit, or at early termination, with actual times recorded for all events. 
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Laboratory Parameters 
The clinical laboratory and other tests relating to safety to be performed during the study are 
described below:  
 Hematology parameters include: red blood cells, hematocrit, hemoglobin, platelets, white 
blood cells, neutrophils, lymphocytes, monocytes, eosinophils, basophils. 
 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 salivary testing for alcohol will be performed. For women 
of childbearing potential, a serum pregnancy test will be performed at screening, and a urine 
pregnancy test will be performed on the day of admission prior to surgery. 
 
Electrocardiograms 
A 12-lead ECG will be performed after the subject has been supine for at least 5 minutes and will 
be completed for all subjects at screening, at check in on Day 0, at 24, 48, 72, 96 hours post-
treatment, and at the Day 10 visit, or at the tim  of early termination, if applicable. 
 
Wound Healing Assessments 
The surgical wound will be assessed 48 and 72 hours post-treatment, and on Days 10 and 28 
post-treatment, or early terminati n, if applicable. Results are recorded as Normal or Abnormal, 
with a verbatim description of any ab ormalities. Specific indications of wound healing will be 
assessed and results for each indi
tion recorded. A photograph of the surgical intervention area 
will be taken immediately after surgery, and at 48, 72, and 96 hours, and on Days 10 and 28 
post-T0, and an X-ray assessm nt will be performed between Day 28 and Day 42 to evaluate the 
status of the cartilage and bone healing process. 
 
Liver Function 
Subjects will be assessed for post-treatment abnormalities in liver function tests ALT, ALP, 
AST, and total bilirubin.  
 
Neurological Exams 
Neurological exams will be performed on Day 0 prior to surgery, and at hours 12, 24, 36, 48, 60, 
72, and 96 post-treatment (or early termination). Parameters assessed include mental status, 
motor, sensory, cerebellar/gait, and cranial nerve function.  
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 DATA QUALITY ASSURANCE 
Report summaries will be generated using validated SAS software, version 9.4 or higher, on a 
PC or server-based platform. Additional validated software may be used to generate analyses, as 
needed.  
All SAS programs that create outputs or supporting analysis datasets will be validated by a 
second statistical programmer or biostatistician. At a minimum, validation of programs will 
consist of a review of the program log, review of output or dataset format and structure, and 
independent confirmatory programming to verify output results or dataset content. Additionally, 
all outputs will undergo a review by a senior level team member before finalization. 
The content of the source data will be reviewed on an ongoing basis by project statistical 
programmers and statisticians. Data will be checked for missing values, invalid records, and 
extreme outliers through defensive programming applications  analysis-based edit checks, and 
other programmatic testing procedures. All findings will be forwarded to sponsor for appropriate 
action and resolution.  
 POPULATIONS DEFINED 
Intent-to-Treat (ITT) Population: The ITT analysis set will include all subjects who are 
randomized to receive study medication. 
Efficacy Population: The efficacy analysis set will include all subjects who are randomized to 
receive study medication and have at least one post dose, scheduled PI score. This analysis set is 
noted as the modified Intent-to-Treat (mITT) population. 
Safety Population: The safety analysis set will include all treated subjects and will be used for 
safety and tolerability asses ments.  
6.1 
Sample Size Determination 
The sample size of approximately 430 subjects was selected empirically without a formal 
statistical assumption. This study comprises 34 treatment cohorts in 9 parts, with between 5 and 
15 subjects per cohort.  
 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 Harmonistation (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).  
Subject Disposition, Demographics, Protocol Deviations, and AE summary tables will be 
grouped as follows: 
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 Formulations 
1. 
Saline Placebo (1.00-6.84 mL) 
2. 
Marcaine 50 mg (10 mL)  
3. 
HTX-009 3.61 mg (4.1 mL) 
4. 
HTX-002 60-200 mg (2.05-6.84 mL) 
5. 
HTX-011-49 200 mg (6.84 mL) 
6. 
HTX-011-56 30-200 mg (1.00-6.84 mL) 
7. 
Total (not included on AE tables) 
In addition, all summary tables except Protocol Deviations will be grouped as follows: 
 HTX-011-49: 
1. 
Saline Placebo (1.00-6.84 mL)  
2. 
Marcaine 50 mg (10 mL) 
3. 
HTX-011-49 200 mg (6.84 mL) Closed Wound 
4. 
HTX-011-49 200 mg (6.84 mL) Open Wound 
5. 
HTX-011-49 200 mg (6.84 mL) Total 
 HTX-002: 
1. 
HTX-002 60 mg (2.05 mL) Closed Wound 
2. 
HTX-002 60 mg (2.05 mL) Open Wound 
3. 
HTX-002 60 mg (2.05 mL) Total  
4. 
HTX-002 120 mg (4.1 mL) Closed Wound 
5. 
HTX-002 120 mg (4.1 mL) Open Wound 
6. 
HTX-002 120 mg (4.1 mL) Total  
7. 
HTX-002 200 mg (6.84 mL) Closed Wound 
8. 
HTX-002 200 mg (6.84 mL) Open Wound 
9. 
HTX-002 200 mg (6.84 mL) Total 
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 HTX-009: 
1. 
HTX-009 3.61 mg (4.1 mL) Closed Wound 
2. 
HTX-009 3.61 mg (4.1 mL) Open Wound 
3. 
HTX-009 3.61 mg (4.1 mL) Total  
 HTX-011-56 200 mg: 
1. 
Saline Placebo (1.00-6.84 mL) 
2. 
Marcaine 50 mg (10 mL)  
3. 
HTX-011-56 200 mg (6.84 mL) Closed Wound 
4. 
HTX-011-56 200 mg (6.84 mL) Open Wound 
5. 
HTX-011-56 200 mg (6.84 mL) Total  
 HTX-011-56 120 mg 
1. 
Saline Placebo (1.00-6.84 mL) 
2. 
Marcaine 50 mg (10 mL)  
3. 
HTX-011-56 120 mg (4.1 mL) Closed Wound 
4. 
HTX-011-56 120 mg (4.1 mL) Open Wound 
5. 
HTX-011-56 120 mg (4.1 mL) Instillation 
6. 
HTX-011-56 120 mg (4.1 mL) Total 
 HTX-011-56 30-60 mg: 
1. 
Saline Placebo (1.00-6.84 mL) 
2. 
Marcaine 50 mg (10 mL)  
3. 
HTX-011-56 30 mg (1.00 mL) Closed Wound 
4. 
HTX-011-56 60 mg (2.05 mL) Closed Wound 
5. 
HTX-011-56 60 mg (2.05 mL) Open Wound 
6. 
HTX-011-56 60 mg (2.05 mL) Instillation 
7. 
HTX-011-56 60 mg (2.05 mL) Total 
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In general, all data collected from all enrolled subjects will be presented in subject data listings. 
Listings will be ordered by site, subject number, and assessment or event date. The early 
termination visit is considered its own visit, where applicable. 
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 mor  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 
2 more decimal places than the precision of the variable of summarization; and 
 Minimum and maximum values will be presented using the same precision as the variable 
of summarization. 
Other statistics (e.g., confidence intervals [CIs]) will be presented using the same general rules 
outlined above, or assessed for the most 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 4 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. 
 
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. 
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7.2 
Analysis Datasets 
ITT Analysis Population: The ITT analysis set 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 1 post dose, scheduled PI score. This analysis set is 
noted as the mITT set. 
Safety Population: The safety analysis set will include all subjects who received study drug and 
will be used for safety and tolerability assessments.  
For the ITT and mITT analyses, subjects are assigned to a treatment group based on the 
randomization schedule, regardless of the treatment actually received. 
For the safety analysis, treatment group assignment will be based on the treatment actually 
received. 
7.3 
Disposition of Subjects and Protocol Violations 
A summary table of subject disposition will include the number of subjects who were 
randomized and number in each analysis population. Counts and percentages of randomized 
subjects who did/did not complete the study will b  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 eason for screen failure. All major protocol 
violations in the Safety Population will be determined and appropriately categorized prior to 
database lock. The count and percentage of subjects with any major protocol violations as well as 
the number and percentage of subjects with violations within each category will be presented for 
the Formulations groups described in Section 7.1. A listing of subjects who were excluded from 
the efficacy analysis will be provided. 
7.4 
Demographic and 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. Subjects with multiple medical history events will be sorted by date of onset, date 
of resolution (if applicable), and SOC. Frequency counts and percentages to summarize subjects 
reporting medical history by SOC and PT will be presented. Subjects reporting > 1 event per 
SOC/PT will be counted only once. Medical history will also be provided in a subject listing. 
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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 those that stop prior to the start of the study drug administration. Any medication 
that stops at or after the start of study drug administration is considered concomitant medication. 
If it cannot be determined whether a medication was stopped prior to the start of study drug 
administration due to partial or missing medication dates, it will be considered a concomitant 
medication. Concomitant medications will be included in summaries. Prior medications will be 
included in a subject data listing. 
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 sep rate listing. A listing of subjects 
who received prohibited opioid rescue medications will be provided, to include Subject ID, drug 
name, indication, dose, route of administration, frequency, date/time of administration, date/time 
of stopping medication, and treatment cohort. 
7.6 
Treatment Compliance 
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 minutes. Results 
will be presented as described in Section 7.1. A per subject listing of duration of surgery will 
include start and stop time of study drug administration.  
7.7 
Efficacy Analysis   
The efficacy analysis will be performed using the mITT population. Parts 1 through 9 will be 
analyzed as described in a separate comparisons document. 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: 
 Pooled 200 mg HTX-011-56 (Cohorts C and D) 
 
 Pooled 120 mg HTX-011-56 (Cohorts K, L, M, and A1) 
 
 Pooled 60 mg HTX-011-56 (Cohorts O, P, and A2) 
 
 30 mg HTX-011-56 (Cohort X) 
 
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 Pooled 200 mg HTX-002 (Cohorts G and H) 
 
 Pooled 120 mg HTX-002 (Cohorts S and T) 
 
 Pooled 60 mg HTX-002 (Cohorts Z5 and Z6) 
 
 Saline Placebo (Cohorts F, I, J, N, R, U, Y, Z3, Z4, Z9, and A3) 
 
 50 mg Marcaine (Cohorts E, Z7, and Z8) 
 
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. 
SPI 
PI will be assessed by the subject for their current pain according to an 11-point NRS (0-10) 
where 0 equates to no pain and 10 equates to the worst pain imaginable. PI scores will be 
measured 2 ways: in a dependent position and in an elevated position at rest. PI scores will be 
assessed in a dependent position (i.e., subject sitting on the bed with the surgically attended foot 
resting at least partially on the floor) at the foll wing time points: 4, 6, 8, 10, 12, 14, 18, 24, 30, 
36, 42, 48, 54, 60, 72 hours post study drug administration (i.e., post-T0). PI scores will be 
measured in an elevated position at rest at he following time points: 1, 2, 78, 84, and 96 (±2) 
hours post-T0. The assessments at 78 and 84 hours will be performed by subjects on an 
outpatient basis. All PI assessments scheduled between 24:00 and 06:00 must be collected, even 
if a subject is asleep at the time of the assessment. A ±15-minute window is allowed for the 
collection of each PI assessment. PI w ll also be assessed within 5 minutes prior to 
administration of each dose of rescue analgesia, and, at the time of early discontinuation 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 PI score at hour i. 
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: A = B; 
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Where A and B 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: A ≠ B; 
 
Secondary Efficacy Endpoint Analysis Methods  
7.7.2.1     Sum of Pain Intensity 
SPI over various other time intervals (SPI0-24, SPI0-48, SPI0-72, SPI0-96, SPI0-6, SPI0-12, SPI12-24, 
SPI24-48, SPI48-72, and SPI72-96) will be analyzed by 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 windowed last observation carried forward (WLOCF)  Summary statistics include the 
number of subjects in each group, group means, SD, SEM, and 95% CI, median, minimum, and 
maximum values. Mean SPI0-6, SPI0-12, SPI0-24, SPI0-48, SPI -72, and SPI0-96 scores will be plotted 
against specified hours post-treatment as described in Section 7.7. 
Summaries of PI scores at every collection time point (1, 2, 4, 6, 8, 10, 12, 14, 18, 24, 30, 36, 42, 
48, 54, 60, 72, 78, 84, and 96 hours post-treatment) will be provided as described in Section 7.1, 
with data imputed using LOCF as described in Section 7.8, and separately summarized with data 
imputed using WLOCF. Summary statistics include the number of subjects in each group, group 
means, SD, SEM, 95% CI, median, maximum, and minimum values. Mean PI scores at will be 
plotted against every post-treatment collection time point for groups as described in Section 7.7. 
The percentage of subjects in each tre tment group who reported a PI score no greater than 1 will 
be characterized as “pain-free”. Comparisons of percentage pain-free will be performed at 
24 hours post-treatment, 48 hours post-treatment, and 72 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. 
The percentage of subjects who were pain-free will be plotted over time by time point at every 
collection time point (1, 2, 4, 6, 8, 10, 12, 14, 18, 24, 30, 36, 42, 48, 54, 60, 72, 78, 84, and 96 
hours post-treatment) for groups as described in Section 7.7. 
7.7.2.2     Patient Global Assessment  
Pain control will be measured on a scale of 0-4, with 0 indicating poor pain control and 
4 indicating excellent pain control. The proportion of subjects rating their pain control as ‘Very 
Good’ (3), or ‘Excellent’ (4) at 24 hours post-treatment, 48 hours post-treatment, 72 hours post-
treatment, and 96 hours post-treatment will be compared between groups using Fisher’s exact 
test. Missing subject data per time point will be imputed as rated below ‘Very Good’. Data will 
be reported independently at each time point of interest and will not be cumulative. Group 
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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.  
7.7.2.3     Rescue Medication  
The cumulative percentage of subjects who have not received opioid rescue medication over 
24 hours, 48 hours, 72 hours, and 96 hours post-treatment will be analyzed by treatment group in 
pairwise comparison using Fisher’s exact test. Use of opioid rescue medication will be imputed 
for subjects terminating without reported opioid use. Group sample size, percentage opioid-free, 
absolute percent-difference between groups, p-values, and exact unconditional 95% CIs for the 
difference between the groups based on the score statistic (Chan and Zhang, 1999) will be 
provided for summaries. 
Cumulative percentages will be plotted at 1, 2, 4, 6, 8, 10  12, 14, 18, 24, 30, 36, 42, 48, 54, 60, 
72, 78, 84, and 96 hours post-treatment for groups as described in Section 7.7. 
Kaplan-Meier estimates of the median time to first administration of any rescue medication 
along with 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 ime of the last post-treatment collection of vital signs, or the 
stop time of study drug administration, whichever occurs later. If a subject never takes rescue 
medication and completes the 96-hour treatment phase of the study, then the subject will be 
considered censored for analysis purposes at 96 hours. Time to administration of first opioid 
rescue medication will be analyzed in the same manner as time to first administration of any 
rescue medication. Kaplan-Meier curves will be presented for groups as described in Section 7.7, 
plotted as 1-S(t).  
The count and percentage of subjects who were administered only opioid rescue medications, 
and only non-opioid rescue medications will be summarized in tables, including counts and 
percentages of those who received both types of analgesics but were administered opioid 
analgesics first, and received both but non-opioids first.  
All opioid dosages and formulations will have the morphine milligram equivalency (MME) 
calculated, with oxycodone plus acetaminophen treated as oxycodone (Opioid Morphine 
Equivalent Conversion Factors, Centers for Disease Control and Prevention, Atlanta, GA, May 
2014). Opioid conversions include, but are not limited to, the medications in Table 6 (complete 
table will be provided in the CSR): 
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Table 6 
Analgesic Windows and Morphine Milligram Equivalencies 
Medication 
Route 
Window (Hours) 
MME Factor 
MORPHINE 
IV 
4 
1 
MORPHINE 
PO 
4 
0.33 
OXYCODONE 
IV 
4 
1 
OXYCODONE 
PO 
6 
0.5 
TRAMADOL 
PO 
6 
0.04 
HYDROCODONE 
PO 
6 
0.4 
Average daily use and total use of rescue medications will be calculated for each of the following 
periods: 0 to 24, 0 to 48, 0 to 72, and 0 to 96 hours post study medication administration. 
Subjects who did not use the specific rescue medication during a period will be assigned to “0”. 
Thus, for the summary of oxycodone use, a subject who received only morphine would be 
counted as zero for that outcome.  
Average daily use and total use data will be tabulated and summarized with descriptive statistics 
to include SE, and summarized separately by type of rescue medication (acetaminophen, 
morphine, or oxycodone), and combined opioid use (morphine and oxycodone). Between group 
comparisons of total opioid use for all opioids combined (morphine and oxycodone) will be 
performed for each time period using ANOVA, a  described in Section 7.7.1. Groups to be 
compared are listed in the separate comparisons document. Results reported will include sample 
size, mean (SD), SEM, LSMD, 95% CI for LSMD, and p-value.  
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7.8 
Data Imputation and Adjustment 
7.8.1 
Pain Intensity Assessments  
Any missing PI score for scheduled time points will be imputed using the standard LOCF 
method, unless the missing score occurs before values are available to carry over (such as the 1 
hour post-treatment PI score). In such case, the missing score will be replaced by the worst score 
collected at any scheduled time p int during the study. PI scores recorded or imputed during the 
analgesic window (duration of effect) of any taken rescue medication will not be used for 
analyses; instead alternate values will be calculated. The adjustment rules are as follows: 
PI scores recorded or imputed during the analgesic window (duration of effect) of any taken 
rescue medication will not be used for WLOCF analysis; instead alternate values will be 
calculated. The adjustment rules are as follows: All subjects are expected to assess their post-
operative pain intensity according to the pain intensity schedule; this PI is referenced to as the 
scheduled PIs. Subjects who require rescue analgesia during the first 96 hours (inclusive) after 
treatment are expected to report their pain intensity immediately before taking the rescue 
medication; this PI is referenced as the pre-rescue PI.  The analgesic windows for specified 
opioid rescue analgesics are listed in Table 6 Analgesic Windows and Morphine Milligram 
EquivalenciesNon-opioid analgesics ibuprofen and acetaminophen are assigned a window of 6 
hours. When the date/time of a scheduled PI is at or after the start time recorded for a rescue 
medication and within the analgesic window (inclusive) of the rescue medication, the scheduled 
PI score will be replaced by the pre-rescue PI score within the analgesic window (replaced with 
the worst pre-rescue PI if there were multiple rescue medications used within the analgesic 
window); if the scheduled PI score within the analgesic window is higher than the pre-rescue PI 
score, it will not be replaced. If the PI date/time is missing or time point is Hour 78 or 84 post 
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T0, those time points will be imputed with the nominal date/time post T0. This method is 
referenced as the WLOCF method.  
PI scores reported will be displayed in data listings, with LOCF-imputed scores, and WLOCF-
adjusted PI scores flagged. Where timing information is missing for administration of rescue 
medication, the record will be excluded from the WLOCF analysis.  
All SPI endpoints and PI outcomes except the PI/MME integrated rank difference will be 
analyzed using 2 sets of data: PI scores with missing values imputed by LOCF only and PI 
scores adjusted for the use of rescue medications using WLOCF.  
7.8.2 
Other Assessments  
Any missing nausea assessment scores will be imputed using the LOCF method as described in 
Section 7.8. The scheduled nausea scores will be displayed in a data listing, with LOCF imputed 
records clearly indicated. 
Missing data for the PGA of pain control will be imputed as a non-responder.  
7.9 
Safety Analysis 
Baseline values will be taken from Day 0 prior to surgery, if available, or otherwise from the 
most recent values available prior to Day 0. Safety summaries will be presented as described in 
Section 7.1. Summaries of safety data will include all scheduled visits; unscheduled visits will be 
included only in safety data listings, unl
s otherwise specified.  
 
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 intra-operative 
study drug. Events reported with a partial onset date (e.g., month and year are reported but the 
day is missing) will be considered to be treatment emergent if it cannot be confirmed that the 
event onset was prior to administration of study drug based on the available date entries. Except 
where noted, summary tables for AEs will include only TEAEs. However, all AEs will be listed 
and pre-treatment AEs will be flagged. AEs will be coded using the MedDRA dictionary 
(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 for of the number of TEAEs, the number of subjects with at least 
1 TEAE, the number of serious treatment-emergent SAEs, the number of subjects with 
serious treatment-emergent AEs, the number of subjects with study drug-related TEAEs, 
the number of subjects with severe TEAEs, the number of subjects with fatal TEAEs, and 
the number of subjects with TEAEs leading to premature discontinuation 
 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 
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 TEAEs by PT in descending frequency according to the total incidence (alphabetically for 
ties) in the highest HTX-011 dose group 
 TEAEs by SOC in internationally agreed order and PT according to total incidence 
(alphabetically for ties) in the highest HTX-011 dose group 
 TEAEs leading to premature study discontinuation by SOC in internationally agreed order 
and PT according to total incidence (alphabetically for ties) in the highest HTX-011 dose 
group 
 Study drug-related TEAEs by SOC in internationally agreed order and PT according to 
total incidence (alphabetically for ties) in the highest HTX-011 dose group 
 Opioid-related TEAEs (defined by the Sponsor) 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 defined by the Sponsor are AEs that code to any of the following PTs: 
Nausea, Vomiting, Constipation, Pruritus, Somnolence, R spiratory depression, or Urinary 
retention throughout the study. For a given SOC and PT, a subject will be counted once even if 
the subject has experienced multiple episodes for that particular SOC and PT. AE tables will be 
organized as described in Section 7.1. 
 
Nausea Assessments 
Nausea is measured on a scale of 0-10, with 0 indicating no nausea and 10 indicating the worst 
nausea imaginable. Assessments of nausea at each time point (6, 24, 48, and 72 hours post-
treatment) will be analyzed using ANOVA as described in Section 7.7.1. Groups to be compared 
are listed in the separate comparisons document. Results reported will include sample size, mean 
(SD), SEM, LSMD, 95% CI for LSMD, and p-value. Mean nausea scores over time will be 
plotted for the groups described in Section 7.7. 
 
Clinical Laboratory Tests 
Observed values at each time point and change from baseline (Day 0) will be summarized 
without formal statistical testing. Shift tables (i.e., low-normal-high at baseline versus low-
normal-high at follow-up in a 3-by-3 contingency table) will be provided to assess changes in 
laboratory values from Day 0 at baseline to each follow-up time point. The lowest post-baseline 
value, and the highest post-baseline value will be included in summary tables, and will 
incorporate data from both scheduled and unscheduled visits. The data listing of labs will flag 
values below and above the normal reference ranges.  
 
Vital Sign Measurements 
Observed values at each time point and change from baseline (Day 0) will be summarized 
without formal statistical testing. The count and percentage of subjects who meet the abnormal 
criteria (Table 7) at any post-baseline visit will be summarized, using data collected at scheduled 
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and unscheduled visits. In addition, a table listing subjects with abnormal changes from baseline 
will be provided, over all scheduled and unscheduled visits. 
Table 7 
Criteria for Abnormal Vital Signs 
Vital Sign 
Low 
High 
Heart Rate 
≤50 bpm and ≥15 bpm decrease from 
baseline 
≥120 bpm and ≥15 bpm increase from 
baseline 
SBP 
≤90 mmHg and ≥20 mmHg decrease from 
baseline 
≥160 mmHg and ≥20 mmHg increase from 
baseline 
DBP 
≤50 mmHg and ≥15 mmHg decrease from 
baseline 
≥100 mmHg and ≥15 mmHg increase from 
baseline 
7.9.4 
Physical Examinations 
Physical exam findings will be presented in a data listing.  
7.9.5 
Electrocardiograms 
The count and percentage of subjects with abnormal ECG findings at each time point will be 
summarized without formal statistical testing. Shift tables (i.e., normal or abnormal-not clinically 
significant [NCS] at baseline versus normal, abnormal-NCS, or abnormal-clinically significant 
[CS] at follow-up) will be provided to assess changes in ECG status from Day 0 at baseline to 
each follow up time point. In addition, a table will be provided listing subjects with any change 
from normal or abnormal-NCS at baseline to CS abnormal after baseline. 
7.9.6 
Wound Healing Assessm nts 
The count and percentage of subjects with abnormal healing of the wound site at each time point 
will be summarized without form l 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 subject listing will be 
provided for photographs taken at time points 48, 72, and 96 hours, and on Days 10 and 28 post-
T0 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. 
7.9.7 
X-ray Assessment 
X-rays will be performed between Day 28 and Day 42, and results reported in a subject listing. 
Parameters include date of scan, and an assessment of whether or not appropriate healing 
occurred. Inappropriate healing is characterized as mal-union, non-union, or improper healing. 
7.9.8 
Liver Function  
Results from liver function testing performed at any post-baseline scheduled and unscheduled 
visits that meet the criteria presented in Table 8 will be summarized with counts and percentages. 
Subjects with abnormal liver function test results will be presented in a separate listing. 
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Table 8 
Criteria for Abnormal Liver Function 
Test 
Criteria for Abnormality 
ALT  
> 3 ULN 
AST  
> 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 ner e function 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 Not Done. Results will be summarized without formal statistical tests for 
each parameter and assessment time point, and will in lude the count and percentage of subjects 
within each category. The subject listing will also include a verbatim description of any 
abnormalities. 
 INTERIM ANALYSIS 
Interim analyses are planned after Part 1 completes the 72 hour evaluation to support formulation 
and technique decisions; after Part 2 completes the 72 hour evaluation to support fixed 
combination dosing decisions; nd after Part 3 completes the 72 hour evaluation to support dose 
ranging decisions and inform design of potential future studies looking at the contribution of the 
individual components. 
 CHANGE FROM ANALYSIS PLANNED IN PROTOCOL 
SPI over 24 hours, SPI over 48 hours, and SPI over 72 hours will also be analyzed using a 
Wilcoxon Rank Sum test for integrated assessment of PI scores and rescue opioid use as an 
exploratory analysis. 
AUCs of PI scores over time were added as an exploratory endpoint and will be analyzed using 
ANOVA, 1 set with LOCF imputation and another with WLOCF imputation. 
Linear combinations of cohorts will not be tested, only pairwise comparisons from ANOVA. 
Analysis of time to first opioid was added. 
Analysis of percentage of subjects with no opioid use was added. 
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In Part 1, Cohort codes A and B were switched to B and A (C and D were switched to D and C) 
in the randomization file and caused inconsistent cohort codes between the analysis plan and the 
protocol.  
Hour 24 added to analysis of percentage of subjects who were pain-free. 
Time-to-event analysis will use the Wilcoxon test, rather than the log-rank test, to analyze 
between group differences. 
A mistake was made in the randomization file description in Part 1 for Cohort E (50 mg 
bupivacaine via a closed wound infiltration), the randomization file showed open wound 
infiltration instead. Twelve of the 15 subjects randomized to receive bupivacaine via closed 
wound infiltration actually received drug via open wound infiltration, this cohort will be 
analyzed as open wound infiltration. 
9.1 
Changes within the Statistical Analysis Plan  
Changes to the SAP between Version 1.0 and Version 2.0 are detailed in Table 9. 
Table 9 
Description of SAP Changes 
SAP Revision Chronology: 
04NOV2016 
MedDRA version updated to 19.1  and ATC version updated to September, 2016. 
24JAN2017 
Table layouts and efficacy figu s were updated to reflect added cohorts. 
26JAN2017 
The description of the WLOCF method of imputation was expanded to include rules for missing 
date/time. 
31JAN2017 
Tramadol and hydrocodone were added to the MME table. 
09FEB2017 
Nausea was changed from an efficacy outcome to a safety outcome. 
23FEB2017 
Screening table added, -019, -056 and -049 changed to -19, -56 and -49. 
01MAR2017 
Window timing for ibuprofen and acetaminophen added to text. 
 REFERENCES 
International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use. Statistical principles for clinical trials (E9). International 
Conference on Harmonization; 1998. 
Chan ISF and Zhang Z. Test-based exact confidence intervals for the difference of two binomial 
proportions. Biometrics. 1999;(55):1202-1209. 
Silverman DG, O’Connor TZ, Brull SJ. Integrated assessment of pain scores and rescue 
morphine use during studies of analgesic efficacy. Anesth Analg. 1993;77:168-170. 
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M2 eCTD: Electronic Common Technical Document Specification Appendix 7, provided by the 
International Conference on Harmonization. Available from: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/u
cm073240.pdf 
Data Standards: Position on Use of SI Units for Lab Tests. U.S Food and Drug Administration; 
25 October 2013. Available from: 
http://www.fda.gov/ForIndustry/DataStandards/StudyDataStandards/ucm372553.htm  
 
 
 
 
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LIST OF TABLES, FIGURES AND DATA LISTINGS 
List of Tables  
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Heron Therapeutics, Inc.  
Statistical Analysis Plan
HTX-011-C2016-208 
 
Version 2.0; 01 March 2017
 
Confidential 
Page 39 of 47
 
Statistical Analysis Plan V2 HTX-011-208 01Mar2017 | VV-TMF-05111 | 1.0
Downloaded by System  on 11/17/2017


Heron Therapeutics, Inc.  
Statistical Analysis Plan
HTX-011-C2016-208 
 
Version 2.0; 01 March 2017
 
Confidential 
Page 40 of 47
 
Statistical Analysis Plan V2 HTX-011-208 01Mar2017 | VV-TMF-05111 | 1.0
Downloaded by System  on 11/17/2017


Heron Therapeutics, Inc.  
Statistical Analysis Plan
HTX-011-C2016-208 
 
Version 2.0; 01 March 2017
 
Confidential 
Page 41 of 47
 
Statistical Analysis Plan V2 HTX-011-208 01Mar2017 | VV-TMF-05111 | 1.0
Downloaded by System  on 11/17/2017


Heron Therapeutics, Inc.  
Statistical Analysis Plan
HTX-011-C2016-208 
 
Version 2.0; 01 March 2017
 
Confidential 
Page 42 of 47
 
Statistical Analysis Plan V2 HTX-011-208 01Mar2017 | VV-TMF-05111 | 1.0
Downloaded by System  on 11/17/2017


Heron Therapeutics, Inc.  
Statistical Analysis Plan
HTX-011-C2016-208 
 
Version 2.0; 01 March 2017
 
Confidential 
Page 43 of 47
 
Statistical Analysis Plan V2 HTX-011-208 01Mar2017 | VV-TMF-05111 | 1.0
Downloaded by System  on 11/17/2017


Heron Therapeutics, Inc.  
Statistical Analysis Plan
HTX-011-C2016-208 
 
Version 2.0; 01 March 2017
 
Confidential 
Page 44 of 47
 
Statistical Analysis Plan V2 HTX-011-208 01Mar2017 | VV-TMF-05111 | 1.0
Downloaded by System  on 11/17/2017


Heron Therapeutics, Inc.  
Statistical Analysis Plan
HTX-011-C2016-208 
 
Version 2.0; 01 March 2017
 
 
Confidential 
Page 45 of 47
 
List of Figures  
Statistical Analysis Plan V2 HTX-011-208 01Mar2017 | VV-TMF-05111 | 1.0
Downloaded by System  on 11/17/2017


Heron Therapeutics, Inc.  
Statistical Analysis Plan
HTX-011-C2016-208 
 
Version 2.0; 01 March 2017
 
 
Confidential 
Page 46 of 47
 
Subject Data Listings  
Statistical Analysis Plan V2 HTX-011-208 01Mar2017 | VV-TMF-05111 | 1.0
Downloaded by System  on 11/17/2017


Heron Therapeutics, Inc.  
Statistical Analysis Plan
HTX-011-C2016-208 
 
Version 2.0; 01 March 2017
 
Confidential 
Page 47 of 47
 
 
Statistical Analysis Plan V2 HTX-011-208 01Mar2017 | VV-TMF-05111 | 1.0
Approv
Downloaded by System  on 11/17/2017