Conditions: Post Operative Pain
Keywords: Post-operative pain non-opioid analgesic opioid reduction laparoscopic cholecystectomy laparoscopic surgery bupivacaine extended release locally acting analgesic
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 399
Healthy volunteers: no

Brief summary:
This is a research study of SABER® -Bupivacaine, an experimental medication designed to reduce pain for up to 3 days after surgery. Given once by the surgeon at the end of surgery, SABER® - Bupivacaine delivers a locally-acting pain reliever directly to the surgical wound.

The purpose of this study is to measure how well it works in reducing pain after laparoscopic cholecystectomy (surgery to remove the gall bladder) and to investigate the safety of SABER®-Bupivacaine (its side effects).

Detailed description:

Arms:
arm 1: SABER-Bupivacaine and Saline Placebo arm 2: SABER-Bupivacaine and Bupivacaine HCl

Interventions: intervention 1: SABER-Bupivacaine (Part 1) intervention 2: SABER-Bupivacaine (Part 2) intervention 3: Saline Placebo intervention 4: Bupivacaine HCl
Intervention descriptions: intervention 1: 5 ml once at end of surgery intervention 2: 5 ml once at end of surgery intervention 3: 5 ml once at end of surgery intervention 4: 0.5%, 15 ml, once at end of surgery

Protocol document:
Prot_SAP_000.pdf: 
A Placebo-controlled (Part 1) or Active-controlled (Part 2) 
trial of SABER®-Bupivacaine for the management of 
poStoperatIve pain following laparoScopic cholecysTectomy 
(PERSIST)
Unique Protocol ID: 
NCT Number: 
Date of Protocol: 
C803-028 
NCT02574520 
08 March 2017 


PROTOCOL TITLE:  A Placebo-controlled (Part 1) or Active-controlled (Part 2) 
trial of SABER®-Bupivacaine for the management of 
poStoperatIve pain following laparoScopic 
cholecysTectomy (PERSIST) 
NCT Number:  NCT02574520 
Date of Document:  08 March 2017 


DURECT Corporation 
Protocol # C803-028, Amendment 05 
 
Protocol Amendment Date: 08 March 2017   
CONFIDENTIAL 
Page 1 of 126 
 
CLINICAL PROTOCOL 
Protocol No. 
C803-028 
Title: 
A Placebo-controlled (Part 1) or Active-controlled (Part 2) trial of 
SABER
Phase 
®-Bupivacaine for the management of poStoperatIve pain following 
laparoScopic cholecysTectomy (PERSIST) 
3 
IND: 
66086 
Version: 
Original:  26 August 2015 
Amendment 01:  06 October 2015 
Amendment 02:  22 February 2016 
Amendment 03:  02 June 2016 
Amendment 04:  09 January 2017 
Amendment 05:  08 March 2017 
 
Sponsor: 
DURECT Corporation  
10260 Bubb Road 
Cupertino, CA  95014, USA 
TEL: 
 
FAX: 
 
GCP Statement: The trial will be conducted in accordance with the principles of Good Clinical 
Practice (GCP) set forth in the International Conference on Harmonization (ICH) 
Good Clinical Practice, the US Code of Federal Regulations (CFR Title 21), the 
Health Insurance Portability and Accountability Act of 1996 (HIPAA) and any 
local requirements. 
Lead Principal Investigator:  
 
 
 
 
 
 
CONFIDENTIAL 
This document contains proprietary and confidential information of DURECT Corporation (hereafter, 
DURECT) Acceptance of this document constitutes agreement by the recipient that no previously 
unpublished information contained herein will be published or disclosed without the prior written approval 
of DURECT with the exception that this document may be disclosed to trial personnel under your 
supervision who need to know the contents for conducting the trial and appropriate Institutional Review 
Boards (IRBs)/Ethics Committees (EC) under the condition that the personnel have agreed to keep this 
information confidential. The foregoing shall not apply to disclosure required by governmental regulations 
or laws; however, DURECT shall be promptly notified of any such disclosure. 
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Protocol# C803-028, Amendment 05 
Protocol Amendment Date: 08 March 2017 
INVESTIGATOR AGREEMENT PAGE 
DURECT Corporation 
C803-028 
Amendment 05: 08 March 2017 
I have read and understood the information in this protocol and agree to conduct the trial 
according to the protocol (subject to any amendments), in accordance with the principles of 
Good Clinical Practice, the Investigator responsibilities stated in this protocol, and in 
compliance with all federal, state and local regulations, as well as with the requirements of 
the appropriate IRB/IEC and any other institutional requirements. Any changes in procedure 
will only be made if necessary to protect the safety, rights or welfare of patients. 
I agree to conduct in person or to supervise the trial. I will provide copies of the protocol, 
any subsequent protocol amendments, and access to all information provided by the Sponsor 
to the trial personnel under my supervision. I will discuss this material with them to ensure 
that they are fully informed about the test drug, the trial protocol, are aware of their 
obligations, are qualified to perform the tasks required, and are trained in any trial specific 
procedures 
Principal Investigator: 
Printed Name: 
Date 
Institution: 
Address: 
Date 
 
This document contains proprietary and confidential information ofDURECT Corporation (hereafter, 
DURECT) Acceptance of this document constitutes agreement by the recipient that no previously unpublished 
information contained herein will be published or disclosed without the prior written approval ofDURECT with 
the exception that this document may be disclosed to trial personnel under your supervision who need to know 
the contents for conducting the trial and appropriate Institutional Review Boards (IRBs)/Ethics Committees 
(EC) under the condition that the personnel have agreed to keep this information confidential. The foregoing 
shall not apply to disclosure required by governmental regulations or laws; however, DURECT shall be 
promptly notified of any such disclosure 
CONFIDENTIAL 
Page 2 of 126 
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Protocol # C803-028, Amendment 05 
 
Protocol Amendment Date: 08 March 2017   
CONFIDENTIAL 
Page 3 of 126 
Sponsor Contacts 
 
DURECT Corporation 
10260 Bubb Road 
Cupertino, CA  95014 
USA 
 
Medical Monitor  
 
  
 
TEL: 
 
CELL: 
 
FAX: 
 
EMAIL:  
 
 
Biostatistician 
 
 
 
TEL:    
 
FAX:     
 
EMAIL: 
 
 
 
Clinical Team Leader 
 
 
 
TEL: 
 
FAX:  
 
EMAIL: 
 
 
 
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CONFIDENTIAL 
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1.0 
TABLE OF CONTENTS 
CLINICAL PROTOCOL ..............................................................................................................1 
INVESTIGATOR AGREEMENT PAGE ...................................................................................2 
1.0 
TABLE OF CONTENTS ..................................................................................................4 
2.0 
TRIAL SYNOPSIS ............................................................................................................9 
3.0 
LIST OF ABBREVIATIONS .........................................................................................16 
 
 
 
 
 
 
 
 
5.0 
CURRENT TRIAL ..........................................................................................................23 
5.1 
Trial Objective .......................................................................................................23 
 
 
 
 
 
 
5.3 
Population ..............................................................................................................26 
5.3.1 
Inclusion Criteria ...................................................................................26 
5.3.2 
Screening Exclusion Criteria.................................................................27 
5.3.3 
Post-randomization (i.e. Intra-operative) Exclusion Criteria ................28 
5.4 
Trial Design ............................................................................................................28 
5.4.1 
Dose ......................................................................................................29 
5.4.2 
Primary and Secondary Endpoints ........................................................30 
5.5 
Anesthesia Requirements .......................................................................................31 
5.6 
Surgical Requirements ...........................................................................................32 
5.7 
Rescue Analgesia for Postoperative Pain Management.........................................33 
5.7.1 
PACU Rescue Medication Regimen .....................................................33 
5.7.2 
Oral Rescue Medication Regimen for Home Use .................................34 
6.0 
TRIAL CONDUCT ..........................................................................................................35 
6.1 
Investigative Sites ..................................................................................................35 
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6.2 
Sponsor Obligations of Trial Conduct ...................................................................35 
6.3 
Duration .................................................................................................................36 
6.4 
Discontinuation of Trial .........................................................................................36 
7.0 
TRIAL PROCEDURES ..................................................................................................36 
7.1 
Patient Randomization ...........................................................................................37 
7.2 
Maintenance of the Blind .......................................................................................39 
7.3 
Trial Test Drug .......................................................................................................39 
7.3.1 
Test Drug Administration Instructions for SABER®-
Bupivacaine and Saline Placebo ...........................................................39 
7.3.2 
Test Drug Administration Instructions for Bupivacaine HCl 
(Part 2) ...................................................................................................41 
7.3.3 
Packaging and Labeling of Test Drug ...................................................41 
7.3.4 
Storage of Test Drug .............................................................................42 
7.3.5 
Preparation of Test Drug .......................................................................42 
7.3.6 
Drug Accountability ..............................................................................42 
7.4 
Trial Visits and Follow-Up Phone Calls ................................................................43 
7.4.1 
Visit 1 (Screening) ................................................................................43 
7.4.2 
Visit 2 (Day of Surgery/Study Day 1)...................................................44 
7.4.3 
Follow-up Calls (Study Day 2 and 3) ...................................................47 
7.4.4 
Patient Completed Evaluations (Study Days 2, 3, and 4) .....................47 
7.4.5 
Visit 3 (Study Day 4) ............................................................................48 
7.4.6 
Patient Completed Evaluations (Study Day 5 to 8) ..............................48 
7.4.7 
Visit 4 (Study Day 8 ± 1 day) ...............................................................49 
7.4.8 
Visit 5 (Study Day 15 ± 2 days) ............................................................49 
7.4.9 
Visit 6  (Study Day 29 ± 3 days) ...........................................................50 
7.4.10 
Visit 7 (Study Day 60 ± 3 days) ............................................................51 
7.4.11 
Early Termination Visit.........................................................................51 
7.5 
Electronic Diary (LogPad) .....................................................................................52 
7.6 
Medication other than Test Drug ...........................................................................53 
7.6.1 
Prohibited Concomitant Medications ....................................................53 
7.6.2 
Anesthesia .............................................................................................54 
7.6.3 
Rescue Analgesia for Postoperative Pain Management ........................54 
8.0 
ASSESSMENT OF EFFICACY .....................................................................................56 
8.1 
Efficacy Assessments.............................................................................................56 
8.2 
Method and Rationale for Assessments .................................................................58 
8.2.1 
Pain Intensity Endpoints .......................................................................58 
8.2.2 
Rescue Opioid Endpoints ......................................................................58 


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8.2.3 
Modified Post-Anesthesia Discharge Scoring System 
(mPADSS) ............................................................................................59 
9.0 
ASSESSMENT OF SAFETY ..........................................................................................60 
9.1 
Safety Assessments: Patient Visits and Follow-Up Phone Calls ...........................60 
9.2 
Method and Timing of Assessments ......................................................................60 
9.2.1 
Adverse Event Recording .....................................................................60 
9.2.2 
12-Lead ECGs .......................................................................................61 
9.2.3 
Laboratory Tests....................................................................................61 
9.2.4 
Vital Signs .............................................................................................62 
9.2.5 
Physical Examination ............................................................................63 
9.2.6 
Surgical Site Examination and Assessment of Surgical Site AEs ........63 
9.3 
Adverse Events ......................................................................................................64 
9.3.1 
Definitions .............................................................................................64 
9.3.2 
Adverse Event Reporting ......................................................................67 
9.3.3 
Reporting of Serious Adverse Events ...................................................68 
9.3.4 
Serious Adverse Events of Special Interest ..........................................69 
9.3.5 
Cardiac or Neurological Serious Adverse Events .................................69 
9.3.6 
Adverse Event Follow-up .....................................................................69 
9.4 
Pregnancy ...............................................................................................................70 
10.0 
PHARMACOKINETICS ................................................................................................70 
11.0 
STATISTICAL METHODS AND DATA ANALYSIS ................................................70 
11.1 
Trial Design Considerations ..................................................................................70 
11.2 
Sample Size Determination....................................................................................71 
11.3 
Patient Randomization ...........................................................................................72 
11.4 
Definition of Analysis Population .........................................................................73 
11.5 
General Statistical Analysis Considerations ..........................................................73 
11.6 
Methodology for Dropouts and/or Missing Data ...................................................74 
11.7 
Demographic and Baseline Characteristics ...........................................................74 
11.8 
Statistical Analyses of Efficacy Endpoints ............................................................75 
11.8.1 
Primary Efficacy Endpoint ....................................................................75 
11.8.2 
Secondary Efficacy Endpoints ..............................................................76 
 
11.8.4 
Adjustment for Multiple Hypotheses Testing .......................................78 
11.8.5 
Subgroup Analysis ................................................................................78 
11.8.6 
Analyses Strategy for Pooling Trial Centers .........................................79 
11.9 
Interim Analyses and Data Monitoring..................................................................79 
11.9.1 
Study-Stopping Criteria ........................................................................79 
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11.10 Statistical Analysis of Safety Endpoints ................................................................80 
11.10.1 
Safety Variables and Summaries ..........................................................80 
11.11 Changes and Deviations to the Statistical Analysis Plan .......................................82 
12.0 
ACCESS TO SOURCE DATA/DOCUMENTATION .................................................82 
12.1 
Confidentiality .......................................................................................................82 
12.2 
Data Identification .................................................................................................83 
13.0 
QUALITY CONTROL AND QUALITY ASSURANCE .............................................83 
13.1 
Monitoring .............................................................................................................83 
13.2 
Protocol Deviations ................................................................................................83 
13.3 
Case Report Forms .................................................................................................84 
13.4 
Coding ....................................................................................................................84 
13.5 
Data Safety Monitoring Committee .......................................................................84 
13.6 
Safety Assessment Committee ...............................................................................84 
14.0 
ETHICAL CONSIDERATIONS ....................................................................................84 
14.1 
Institutional Review Board / Ethics Committee ....................................................85 
14.2 
Regulatory Compliance .........................................................................................85 
14.3 
Regulatory Status ...................................................................................................85 
14.4 
Patient Information and Informed Consent............................................................85 
14.4.1 
Patient Withdrawal ................................................................................85 
15.0 
DATA HANDLING AND RECORD RETENTION ....................................................86 
15.1 
Data Ownership .....................................................................................................86 
15.2 
Retention of Trial Records .....................................................................................86 
16.0 
FINANCE AND INSURANCE .......................................................................................87 
17.0 
PUBLICATION PLAN ...................................................................................................87 
17.1 
Confidentiality .......................................................................................................87 
17.2 
Clinical Trial Report ..............................................................................................87 
17.3 
Publications ............................................................................................................87 
18.0 
REFERENCES .................................................................................................................89 
19.0 
APPENDICES ..................................................................................................................93 
 
 
 
 
Appendix 5: CDC/NHSN Surgical Site Infection Definitions and Diagnostic Criteria ..............100 
Appendix 6: Investigator Responsibilities ...................................................................................103 
Appendix 7: Sponsor’s Responsibilities ......................................................................................105 
 
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List of Tables 
Table 1: Schedule of Events ..........................................................................................................13 
Table 2: Patient LogPad Schedule of Events .................................................................................15 
Table 3: Test Drug Distribution in Laparoscopic Ports .................................................................41 
Table 4: Safety Laboratory Tests ...................................................................................................62 
 
 
 


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2.0 
Trial Synopsis 
Title of Trial: 
A Placebo-controlled (Part 1) or Active-controlled (Part 2) trial of 
SABER
Sponsor: 
®-Bupivacaine for the management of poSt-operatIve pain 
following laparoScopic cholecysTectomy (PERSIST) 
DURECT Corporation 
Phase of 
Development: 
 
Phase 3 
Objective: 
To evaluate the safety and efficacy of SABER®-Bupivacaine for 
alleviating postoperative pain on-movement compared with 
bupivacaine HCl in patients undergoing laparoscopic 
cholecystectomy. 
 
Efficacy Endpoints: 
• Pain intensity on movement measured at scheduled time points 
from 0-48 hours following test drug administration, adjusted for 
prior rescue medication use and analyzed by a mixed effect 
ANOVA model of repeated measures (MMRM).  
Primary Efficacy Endpoint: 
 
• Pain intensity on movement measured at scheduled time points 
from 0-72 hours following test drug administration, adjusted for 
prior rescue medication use and analyzed by a mixed effect 
ANOVA model of repeated measures (MMRM). 
Key Secondary Efficacy Endpoint: 
• Total IV morphine-equivalent dose of rescue opioids used during 
0-72 hours following test drug administration 
Additional Secondary Efficacy Endpoints: 
• Composite endpoint of Silverman’s Integrated Analgesic (SIA) 
assessment score over 0-72 hours following test drug 
administration 
• Proportion of patients taking no opioid rescue medication from 
PACU discharge until 72 hours after test drug administration 
• Time to first opioid rescue medication use after discharge from the 
PACU 
• Time to PACU discharge eligibility as assessed by modified Post-
Anesthesia Discharge Scoring System (mPADSS)  
 
 
 


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Safety Assessments: 
• Adverse Events (both spontaneous and a solicited subset of AEs)  
• Standard 12-lead ECG  
• Safety Laboratory Tests  
• Vital Signs and pulse oximetry 
•  Physical Examination  
• Surgical site examination for bruising, bleeding or drainage from 
the incision(s), hematoma, dehiscence, infection and healing  
Trial Design: 
C803-028 is a randomized, parallel-group, double-blind, 
placebo-controlled ( Part 1) and active-controlled (Part 2) multi-
center  trial evaluating the safety and efficacy of SABER®-
Bupivacaine 5 mL in patients undergoing elective outpatient 
laparoscopic cholecystectomy. Randomization will be stratified by 
sex (See Sections 7.1, 11.3). 
For Part 1 of the trial, the planned enrollment of approximately 320 
eligible patients will be stopped early due to the transition to an 
active control in Part 2 of the trial.  Approximately 90 patients will 
be enrolled in Part 1of the trial, before transition to Part 2.  All data 
from these patients will remain blinded until completion of Part 2. 
For Part 2 of the trial, 132 evaluable patients per treatment arm will 
provide at least 90% power (See Section 11.2) to meet the primary 
efficacy endpoint.  Approximately 274 eligible patients will be 
randomized (See Section 5.3) in a 1:1 ratio to receive one of two 
treatments: 5 mL of SABER®-Bupivacaine instilled directly into the 
laparoscopic ports at the close of surgery or 15 mL of 0.5% 
bupivacaine HCl infiltrated into the port incisions at the close of 
surgery. 
Five postoperative outpatient clinic visits will be scheduled for 
assessment of safety parameters including AEs and surgical site 
examinations and for collection of rescue medication usage data.  
All AEs, of whatever etiology and location, occurring after 
informed consent will be recorded on the eCRF.  All AEs will be 
followed until resolution unless the patient is lost to follow up. 
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Pain intensity 
Measurements: 
During the first 72 hours after test drug administration (i.e., 
through Study Day 4/Postoperative Day [POD] 3; See Table 1) 
pain intensity, 
 on movement (defined as sitting 
up, or attempting to do so, from a supine position), will be 
recorded by the patient.  Patients will use an 11-point (0-10) 
numerical pain rating scale (NPRS) displayed by an electronic 
diary (LogPad®) to record their pain scores at specified times after 
administration of the test drug (see Table 2: Patient LogPad 
Schedule of Events).  Pain intensity 
 on movement will 
also be recorded (1) prior to each IV fentanyl administration 
requested by the patient in the PACU, and (2) at home before the 
patient self-administers either one of two possible rescue 
medications (acetaminophen or oxycodone).  
 
  Patients should then record their pain-on-movement 
score by sitting up, or attempting to do so, from a supine position 
and recording the worst pain experienced during the sit up. If the 
patient is unable to sit up completely due to severe pain, 
weakness, or lack of recovery from anesthesia, the patient should 
be instructed to make his or her best attempt, and that pain score 
will be recorded. 
Trial Population: 
The trial population will consist of adult patients (males and 
females, 18 years of age and older) undergoing elective outpatient 
laparoscopic cholecystectomy under general anesthesia.  For 
Part 1, approximately 90 patients will be randomized.  For Part 2, 
approximately 274 eligible patients will be randomized in order to 
obtain 264 evaluable patients (i.e., patients who received any test 
drug). It has been estimated that 4% of randomized patients may 
not receive any test drug due to unforeseeable intra-operative 
exclusion (see Section 5.3). 
Test drug, dosage  
and mode of 
administration:  
SABER®-Bupivacaine 5 mL (660 mg bupivacaine base) will be 
instilled with a blunt-tipped applicator directly into the four 
laparoscopic ports just prior to closure. The 5 mL dose of test 
drug should be divided among the multiple ports to provide 
coverage of all surgical incisions.  A sterile 5cc syringe with an 
attached 14G x 1¼ inch
IV catheter will be used to 
instill the test drug. Refer to Section 7.3.1 for detailed 
instructions. 
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Comparator, dosage 
and mode of 
administration: 
 
 
For Part 1 of the study, 5 mL of 0.9% sterile normal saline will be 
instilled into the four laparoscopic ports in exactly the same way 
as SABER®-Bupivacaine. For Part 2 of the study, bupivacaine 
HCl, 15 mL of 0.5% solution (75 mg) without epinephrine, will 
be infiltrated into the four laparoscopic ports using a sterile 10 cc 
syringe and a 22 G x 1½ inch hypodermic needle.  The dose 
should be divided between the four ports according to incision 
size in the same distribution proportion as for SABER®-
Bupivacaine. Refer to Section 7.3.1 for detailed instructions. 
Each site will have a site specific Blinding Plan in place to 
describe the steps taken to ensure the blind is maintained as well 
as indicating which study staff will be blinded or un-blinded. 
Power Calculations: 
For Part 2 of the study, 132 subjects enrolled in each treatment 
group of the study will result in 90% power (assuming 
type 1 error rate of 5%) to detect a difference between 5 mL of 
SABER®-Bupivacaine and 15mL of bupivacaine HCl of
 (the average 
pain on movement score during 48-hours post-dose). The sample-
size estimate was based on an estimated effect size of
 
 
see Section 11.2).  
Schedule of Events: 
Refer to Table 1: Schedule of Events below. 
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Table 1: Schedule of Events 
 
Visit 1 
Visit 2 
Follow-up 
Call 1 
Follow-up 
Call 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
 
Visit 7 
 
Trial Procedures 
Screening 
≥ 5 days  
(starts ≤ 30d 
and ≥ 5d 
pre-op) 
Day of  
Surgery 
(Study  
Day 1) 
Study  
Day 2 
Study  
Day 3 
Study  
Day 4 
Study  
Day 8 
(±1 day) 
Study  
Day 15 
(±2 days) 
Study  
Day 29  
(+ 3 days) 
Study  
Day 60  
(±3 days) 
 
POD 1 
POD 2 
POD 3 
POD 7  
(±1 day) 
POD 14 
(±2 days) 
POD 28 
(+ 3 days) 
POD 59 
(± 3 days) 
Informed Consent (prior to any trial procedures)  
√ 
 
 
 
 
 
 
 
 
Demographics and Medical & Surgical History 
√ 
 
 
 
 
 
 
 
 
Physical Examination (including height and weight) 
√ 
 
 
 
 
 
 
√1 
√1 
Inclusion / Exclusion Criteria  
√ 
√2 
 
 
 
 
 
 
 
Safety Labs (Chemistry, Hematology, Urinalysis)  
√3 
 
 
 
√ 
 
 
√ 
√ 
Pregnancy Test 
√4 
√5 
 
 
 
 
 
 
 
12-lead ECG 
√ 
 
 
 
 
 
 
√ 
√ 
Vital Signs6 (BP, HR, RR, T) and SpO27) 
√ 
√7 
 
 
√ 
√ 
√ 
√ 
√ 
Dispense LogPad and Train in Use 
√ 
 
 
 
 
 
 
 
 
√9 
√ 
 
 
 
 
 
 
 
Adverse Events10,11 
 
 
Prior and Concomitant Medications 
 
 
IWRS Randomization 
 
√12 
 
 
 
 
 
 
 
 
√ 
 
 
 
 
 
 
 
Surgery 
 
√ 
 
 
 
 
 
 
 
Dosing of Test Drug 
 
√ 
 
 
 
 
 
 
 
 
√ 
 
 
 
 
 
 
 
mPADSS and PACU time of discharge13 
 
√ 
 
 
 
 
 
 
 
√ 
 
 
 
 
Rescue Medication and Pain Scores15 
 
 
 
 
 
Surgical Site Exam and Assessment of Surgical Site AEs 
 
√16 
 
 
√ 
√ 
√ 
√ 
√ 
Discharge from hospital/surgcenter
 
√ 
 
 
 
 
 
 
 
Rescue Medication Reconciliation/Pill Count 
 
√17 
 
 
√ 
√ 
√ 
√ 
* 
Surgical Complications Questionnaire 
 
 
√ 
√ 
 
 
 
 
 
Level of Activity (ambulation, sleeping, eating, and surgical 
wound pain18) 
 
 
√ 
√ 
√ 
√18 
√18 
√18 
* 
Medical Resource Utilization Assessment 
 
 
√ 
√ 
√ 
√ 
√ 
√ 
* 
Review LogPad data 
 
√ 
√ 
√ 
√ 
√ 
 
 
 
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1. Weight only 
Footnotes for Schedule of Events Table: 
2. Review Inclusion/Exclusion Criteria to confirm patient is still eligible 
3. In addition to safety labs, a urine drug screen for opiates, oxycodone, cannabinoids, amphetamines, 
cocaine, and methadone will be performed. Allow 3-7 days for central safety laboratory to process and 
provide results 
4. Serum pregnancy test for females of childbearing potential 
5. Urine pregnancy test for females of childbearing potential 
6. Vital Signs measured after 5 minute rest (supine or sitting) 
7. Vital signs and pulse oxygen saturation (SpO2) will be measured on Visit 2 pre- and post-surgery. The 
vital signs (BP, HR, RR, temperature) and SpO2 will be recorded on the eCRF at 15 minute intervals 
for a period of at least 2 hours after surgery. 
8. 
 
 
9. 
 
10. AE collection starts from the time the patient signs the consent form and continues through final 
visit/early termination. All AEs will be followed until resolution. Resolution means no further changes 
in the event are expected, i.e., the point at which a subject experiencing such an AE is appropriately 
treated and stabilized even though they may continue to experience lingering sequelae that may never 
resolve.  
11. Follow-up on both the pre-specified patient-reported AEs (including dizziness, somnolence, 
constipation, nausea, vomiting, pruritus, headache, dysgeusia, hypoesthesia, and paresthesia) solicited 
on the LogPad through POD 3, as well as spontaneous AEs. 
12. If all Screening (i.e. pre-operative) Inclusion/Exclusion criteria are met randomization can be done up 
to 
 day prior to surgery. 
13. Eligibility for PACU discharge will be assessed by mPADSS.  The mPADSS will be administered 
starting at 30 minutes after admission to the PACU and will be repeated at 15 minute intervals until a 
score of 9 or greater has been reached, indicating discharge eligibility. 
14. 
  
Patients should then record their pain-on-movement score by sitting up, or attempting to do so, from a 
supine position and recording the worst pain experienced during the sit up. If the patient is unable to sit 
up all the way due to severe pain, weakness, or lack of recovery from anesthesia, the patient should be 
instructed to make his or her best attempt, and that score will be recorded. Patients will complete 
assessments per the schedule detailed in Table 2: Patient LogPad Schedule of Events.   
15. See Rescue Medication Regimen. Pre-rescue pain on movement score for oral rescue is recorded in the 
LogPad through Study Day 4. The site records IV rescue medication taken and corresponding pain 
score in the patient’s chart and eCRF. The subject records oral opioid and acetaminophen rescue 
medication taken on the LogPad until Study Day 8. After Study Day 8 all rescue medication will be 
recorded in the investigative site source documents and Concomitant Medication (CM) eCRF.  
NSAIDs are not
16. On the day of surgery, Surgical Site Examination done at time of discharge to home (or hospital 
admission) 
 allowed until after Study Day 8. 
17. Record details of opioid prescription and acetaminophen dispensed for home use (identity, dose, 
amount dispensed, and dosing instructions) and if permitted, retain a copy of the opioid prescription in 
the source documents. 
18. The site will ask the patient to rate their current surgical wound pain at Visit 4, 5 and 6.  
 
*  To be done only if completed as part of an Early Termination Visit.
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Table 2: Patient LogPad Schedule of Events   
Trial Procedures 
Screening 
Day of Surgery  
(Study Day 1) 
Study Day 2-4 
(Postoperative Day 1 to 3) 
Study Day 5-8 
(Postop Day 4 to 7) 
Target time 
Hours post-dose  
Target time (± 1 hour) 
till Visit 4 (POD 7) 
20:00 (±1h) 
1 
4 
6 
8 
10 
08:00 
12:00 
16:00 
20:00 
 
+1 hour 
(±30 minutes) 
Scheduled Pain Intensity
on Movement1  
√2 
(5-7 days for 
training) 
√3 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 
Solicited AE Checklist4 
 
 
 
√ 
 
√ 
 
 
 
√ 
 
Pain 
 on Movement Score 
prior to Oral Recue1,5 
 
Oral med pain scores recorded on LogPad through POD 3 
 
IV med pain scores recorded on chart 
 
Oral Rescue Analgesia5 
 
 
Subject records oral rescue medication on LogPad  
Site records IV rescue medication on chart 
1 
  Patients should then record their 
pain-on-movement score by sitting up, or attempting to do so, from a supine position and recording the worst pain experienced during the sit up. If 
the patient is unable to sit up all the way due to severe pain, weakness, or lack of recovery from anesthesia, the patient should be instructed to make 
his or her best attempt, and that score will be recorded.   
2 
 
 
3 
Investigative site personnel enter the time of test drug dosing into the LogPad prior to the subject awakening from anesthesia.  
  
4 
At each point of contact with the patient, investigative site personnel will follow-up with the patient regarding severity, frequency, duration and 
action taken of any AEs (including dizziness, somnolence, constipation, nausea, vomiting, pruritus, headache, dysgeusia, hypoesthesia, and 
paresthesia) reported on the LogPad. 
5 
Only oral rescue medication is recorded in the LogPad. IV rescue medication and corresponding pain 
 on movement scores are recorded 
by the site in the patient’s chart and eCRF. 
 
I I I 
-
-
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3.0 
List of Abbreviations 
Abbreviation or Term 
Definition/Explanation 
AE 
Adverse event 
ALT (SGPT) 
Alanine amino transferase (Serum Glutamic Pyruvic Transaminase) 
ANOVA 
Analysis of variance 
AR 
Adverse reaction 
AST (SGOT) 
Aspartate amino transferase (Serum Glutamic Oxaloacetic 
Transaminase) 
AUC 
Area under the curve 
BA 
Benzyl alcohol 
BOCF 
Baseline Observation Carried Forward 
BP 
Blood pressure 
BSV 
Between-subject-variability  
BUN 
Blood Urea Nitrogen 
CDC/NHSN 
Centers for Disease Control National Healthcare Safety Network 
Cmax 
Maximum concentration 
CFR 
Code of Federal Regulations  
CL/F 
Apparent clearance  
CM 
Concomitant medication 
CNS 
Central nervous system 
CRF 
Case report form 
CK 
Creatine kinase 
CRO 
Contract research organization 
CRU 
Clinical Research Unit 
CVS 
Cardiovascular system 
DEA 
Drug Enforcement Administration  
DSMB 
Data and Safety Monitoring Board 
DVT 
Deep Vein Thrombosis 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
ER 
Extended Release 
ES 
Effect Size 
FAERS 
FDA Adverse Event Reporting System 
FDA 
Food and Drug Administration  
GCP 
Good Clinical Practice 


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Abbreviation or Term 
Definition/Explanation 
HIPAA 
Health Insurance Portability and Accountability Act 
HR 
Heart rate  
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug  
IR 
Immediate Release 
IRB 
Institutional Review Board 
IUD 
Intrauterine device 
IWRS 
Interactive Web Response System  
ITT 
Intent to Treat 
LC 
Laparoscopic cholecystectomy 
LDH 
Lactate dehydrogenase 
LogPad® 
Electronic Diary 
LS 
Least square 
MAP 
Mean Arterial Pressure 
MedDRA 
Medical Dictionary for Regulatory Activities 
MCMC 
Markov Chain Monte Carlo method 
mPADSS 
Modified Post-Anesthesia Discharge Scoring System 
MRI 
Magnetic Resonance Imaging 
nAUC 
Normalized Area Under the Curve 
NOTES 
Natural Orifice Transluminal Endoscopic Surgery 
NPRS 
Numeric Pain Rating Scale 
NRS 
Numeric Rating Scale 
NSAIDs 
Nonsteroidal Anti-Inflammatory Drugs 
PACU 
Post-Anesthesia Care Unit 
PCA 
Patient-Controlled Analgesia 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
POD 
Postoperative Day 
PONV 
Postoperative Nausea and Vomiting 
PR 
Duration from onset of atrial depolarization until onset of ventricular 
depolarization, measured from the beginning of the P wave to the 
beginning of the QRS complex 
QRS 
Part of electrocardiographic wave representing ventricular 
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Abbreviation or Term 
Definition/Explanation 
QT 
Duration of ventricular depolarization and subsequent repolarization, 
measured from the beginning of the QRS complex to the end of the 
T wave 
QTc 
Corrected QT interval 
RBC 
Red blood cell 
ROA 
Route of administration  
RR 
Respiratory rate 
SABER® 
Sucrose acetate isobutyrate extended release 
SAE 
Serious adverse event 
SAIB 
Sucrose acetate isobutyrate 
SAP 
Statistical analysis plan 
SGOT 
Serum glutamic oxaloacetic transaminase 
SGPT 
Serum glutamate pyruvate transaminase 
SIA 
Silverman’s Integrated Analgesic assessment score 
SUSAR 
Suspected unexpected serious adverse reaction 
T1/2  
Half-life 
WBC 
White blood cell 
WHO 
World Health Organization  
WOCF 
Worst Observation Carried Forward 
 
 
 


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5.0 
Current trial 
5.1 
Trial Objective 
To evaluate the safety and efficacy of SABER®-Bupivacaine for alleviating postoperative pain 
on-movement compared with bupivacaine HCl in patients undergoing laparoscopic 
cholecystectomy. 
 
 
 
 
 
   
 
 
  
 
 
 
 
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5.3 
Population 
The trial population will consist of adult patients (males and females, 18 years of age and older) 
undergoing elective outpatient laparoscopic cholecystectomy under general anesthesia.  In Part 1, 
approximately 90 patients will be randomized. In Part 2, approximately 274 eligible patients will 
be randomized in order to obtain 264 evaluable patients (i.e., patients who received test drug). It 
has been estimated that 4% of randomized patients may not receive any test drug due to 
unforeseeable intra-operative exclusion criteria such as need to convert to open laparotomy or 
need for a fifth port and trocar. 
5.3.1 
Inclusion Criteria 
1. Patients scheduled for elective outpatient laparoscopic cholecystectomy using a conventional 
4-port laparoscopic procedure. 
2. Must be able and willing to provide written informed consent, complete trial-related 
procedures, and communicate with the trial staff. 
3. Males and females 18 years of age or older. 
4. ASA Class I, II, or III. 
5. Patients of child-bearing potential must agree to use a medically acceptable method of 
contraception to prevent pregnancy for the duration of their participation in the trial.  
Medically acceptable methods of contraception that may be used by the patient and/or the 
partner include: oral contraception or patches (consistently for 3 months prior to trial dosing), 
NuvaRing (etonogestrel/ethinyl estradiol vaginal ring), diaphragm with vaginal spermicide, 
IUD (coil), condom and vaginal spermicide, surgical sterilization (6 months post-surgery), 
post-menopausal patient (not experienced a menstrual period for a minimum of two years), 
and progestin implant or injection (used consistently for 3 months prior to trial dosing). 
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6. Must be living close enough to the investigative site to attend the four scheduled follow-up 
clinic visits.  
5.3.2 
Screening Exclusion Criteria 
1. Pregnant or nursing females. 
2. Patients with absolute or relative contraindications to laparoscopic cholecystectomy. These 
include, but are not limited to: generalized peritonitis, septic shock from cholangitis, severe 
acute pancreatitis, untreated coagulopathy, previous abdominal operations which prevent safe 
abdominal access or progression of the procedure, advanced cirrhosis with failure of hepatic 
function, and suspected gallbladder cancer (SAGES Guidelines, 2010). 
3. Patients with prior midline abdominal surgery who are at risk for adhesions that may 
complicate laparoscopic cholecystectomy and/or accurate pain assessments.  
4. Patients requiring emergency surgery or urgent surgery (fewer than 5 days between screening 
and surgery). Patients that require the preoperative placement of a cholecystostomy tube for 
the management of acute cholecystitis are also excluded. 
5. Patients with a pre-planned overnight stay or pre-planned hospital admission.  
6. Patients scheduled for single incision, mini trocars, natural orifice transluminal endoscopic 
surgery (NOTES), robotic laparoscopic procedures, or any procedure (other than 
cholangiograms and minimal adhesiolysis) in addition to laparoscopic cholecystectomy. 
7. Patients with known hypersensitivity to amide local anesthetics such as bupivacaine. 
8. Patients with acute pain that is not due to cholecystitis. 
9. Patients with a history of chronic pain unrelated to gallbladder disease. 
10. Patients with ongoing depression or psychosis. 
11. Patients undergoing long-term treatment with opioids or other analgesics, including 
acetaminophen, NSAIDs, anticonvulsants (gabapentin or pregabalin), and antidepressants 
(SSRIs, SNRIs, and tricyclics), but not
7.6.1
 including daily low-dose aspirin (see full list of 
excluded medications in Section 
). 
12. Patients who are being treated chronically with systemic corticosteroids or who will require 
peri-operative corticosteroids because of adrenal insufficiency (inhalational or topical 
corticosteroids are permitted). 
13. Patients who may be unsuitable for opioid administration (such as sensitivity [e.g., history of 
severe nausea and vomiting] hypersensitivity, known history of abuse or addiction, or 
unwillingness to take prescribed rescue opioids). 
14. Use of long-acting anticoagulants and antiplatelet drugs (with the exception of low dose 
aspirin [81 mg]) in the 1-week prior to surgery.  (Short-acting new oral anticoagulants should 
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15. Patients who are incapable of operating the electronic diary (LogPad) and/or miss more than 
1 of the practice diary assessments (i.e., are less than 80% compliant) during screening 
should not be randomized. Compliance with the LogPad assessments is essential to the study. 
16. Patients who self-report an alcohol dehydrogenase deficiency. 
17. Patients participating in any other trial with an investigational drug or device concurrently or 
less than 30 days prior to surgery for this trial.  
18. Patients who, in the Investigator’s opinion, should not participate in the trial or may not be 
capable of following the trial procedures for any reason. 
5.3.3 
Post-randomization (i.e. Intra-operative) Exclusion Criteria 
19. Patients who have been converted to an open cholecystectomy or who experience other 
serious, unexpected intra-operative complications should not
20. Patients who undergo unplanned additional surgical procedures (other than cholangiograms 
and minimal adhesiolysis) in addition to laparoscopic cholecystectomy should 
 be treated with test drug. 
not
21. Patients who require intra-operative doses of fentanyl that are higher than permitted per 
protocol should 
 be treated 
with test drug. 
not
22. Patients who require the placement of a fifth laparoscopic port or percutaneous surgical drain 
should 
 be treated with the test drug. 
not
Patients excluded from test drug administration because of one of the above intra-operative 
exclusions (18-21) will be listed as “randomized, but not treated”, and will be terminated from 
the trial. 
 be treated with test drug. 
5.4 
Trial Design 
C803-028 is a randomized, parallel-group, double-blind, placebo-controlled (Part 1) and 
active-controlled (Part 2), multi-center trial evaluating the safety and efficacy of 
SABER®-Bupivacaine 5 mL in patients undergoing elective outpatient laparoscopic 
cholecystectomy.   
The randomization will be stratified by sex (See Section 11.3). For Part 1, it was planned to 
enroll approximately 320 eligible patients (See Section 5.3) in a 1:1 ratio to receive one of two 
treatments: SABER®-Bupivacaine 5 mL; or sterile normal saline 5 mL (placebo) instilled 
directly into the laparoscopic ports at the close of surgery.  The 5 mL of test drug is divided 
between the multiple ports to provide coverage of all surgical incisions (see Section 7.3.1).
 
  The data from Part 1 
patients will continue to be blinded until the completion of Part 2 of the trial. 
For Part 2 of the trial, 132 evaluable patients per treatment arm will provide at least 90% power 
(See Section 11.2) to meet the primary efficacy endpoint. In order to obtain 264 evaluable 
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patients, approximately 274 eligible patients (assuming 4% of patients may not be dosed due to 
unforeseeable intra-operative exclusion) will be randomized in a 1:1 ratio to receive one of two 
treatments: 5 mL of SABER®-Bupivacaine instilled directly into the laparoscopic ports or 15 mL 
of 0.5% bupivacaine HCl infiltrated into the port incisions at the close of surgery. 
Five postoperative outpatient clinic visits will be scheduled for assessment of safety parameters 
including AEs and surgical site examinations and for collection of rescue medication usage data. 
All AEs, of whatever etiology and location, occurring after informed consent will be recorded on 
the eCRF. All AEs will be followed until resolution unless the patient is lost to follow up. 
Resolution means no further changes in the event would be expected, i.e., the point at which a 
subject experiencing such an AE is appropriately treated and stabilized even though they may 
continue to experience lingering sequelae that may never resolve. 
 
5.4.1 
Dose 
Test drug for the trial consists of a single administration of one of two treatments based on a 
computer-generated randomization schedule prepared before the study:  
Part 1 
• Treatment Group 1: SABER®-Bupivacaine 5 mL (POSIMIR®)(132 mg/mL, 660 mg 
bupivacaine base) 
• Treatment Group 2: Sterile normal saline 5 mL (0.9% sodium chloride injection, USP) 
(placebo) 
Part 2 
• Treatment Group 3: SABER®-Bupivacaine 5 mL (POSIMIR®)(132 mg/mL, 660 mg 
bupivacaine base) 
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• Treatment Group 4: Bupivacaine HCl without epinephrine, 15 mL of 0.5% solution 
(75 mg) 
5.4.2 
Primary and Secondary Endpoints 
The primary efficacy endpoint is:  
• Pain intensity on movement measured at scheduled time points from 0-48 hours 
following test drug administration, adjusted for prior rescue medication use and analyzed 
by a mixed effect ANOVA model of repeated measures (MMRM).  
To account for the impact of rescue medication use on the scheduled pain scores, the half-life 
substitution method will be used. Specifically, if the scheduled pain score has been assessed 
within one plasma half-life after the use of rescue medication (IV or oral opioid or oral 
acetaminophen), and if the pre-rescue medication pain score is higher than the scheduled one, 
then the pain score recorded at the time of rescue medication administration will be 
substituted for the scheduled pain score (FDA, 2014).  If a rescue medication pain score is 
missing, then the worst pain score up to that point will be substituted instead. 
The key secondary efficacy endpoint is: 
Pain intensity on movement measured at scheduled time points from 0-72 hours following test 
drug administration, adjusted for prior rescue medication use and analyzed by a mixed effect 
ANOVA model of repeated measures (MMRM). Additional secondary endpoints are: 
• Total IV morphine-equivalent dose of rescue opioids used during 0-72 hours following 
test drug administration (standard conversion factors are used to convert different opioids 
to IV morphine-equivalents; 
 
• Composite endpoint of Silverman’s Integrated Analgesic (SIA) assessment score 
(Dai et al, 2013 and Silverman et al, 1993) over 0-72 hours following test drug 
administration 
• Proportion of patients taking no opioid rescue medication from PACU discharge until 
72 hours after test drug administration 
• Time to first opioid rescue medication use after discharge from PACU 
• Time to PACU discharge eligibility as assessed by mPADSS (Chung, 1995; Awad and 
Chung, 2006)  
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5.5 
Anesthesia Requirements  
Operative anesthetic choices may have a significant bearing on postoperative pain. Investigators 
should therefore observe the following anesthesia requirements, the objectives of which are 
threefold: (1) to reduce variability in the baseline (pre-dose) state of the trial patients, (2) to limit 
the obscuring effect of excessive intra-operative opioid analgesia on the postoperative pain 
signal, and (3) to ensure that potential confounders, such as the use of local or regional 
anesthesia, can be avoided.  
The anesthesia requirements are: 
• General endotracheal anesthesia 
• Midazolam, up to 2 mg, may be given pre-operatively 
• Propofol induction   
• Maintenance with inhalational anesthesia (sevoflurane or desflurane) and an oxygen/air 
mixture. 
o No isoflurane or nitrous oxide 
o No total intravenous anesthesia (TIVA) 
• Intra-operative opioid analgesia will be limited to IV fentanyl, with a maximum dose of 
2.5 mcg/kg (including the induction dose) during the first hour the patient is anesthetized. 
If necessary, additional fentanyl may be given starting in the second hour, with a 
maximum dose of 1.0 mcg/kg during each subsequent 30 minute interval.  
 
o Subjects requiring higher doses should not be treated with test drug, even if 
previously randomized. 
 
o Any fentanyl given per patient complaint of pain after emergence from anesthesia 
will be considered rescue medication and will be limited to doses of 12.5 mcg or 
25 mcg at minimum 5 minute intervals, as described in Section 5.7.1. 
• A single IV dose of a 5-HT3 antagonist (ondansetron 4 mg, granisetron 1 mg, or 
dolasetron 12.5 mg) should be administered at the close of surgery to all patients for 
prophylaxis of post-operative nausea and vomiting (PONV).  
o No Aloxi® (palonosetron HCl) should be administered. 
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• No use of local anesthetics will be permitted for neuraxial analgesia, regional nerve 
block, intra-abdominal administration, and wound infiltration (other than test drug).  
o However, IV lidocaine may be used to ameliorate propofol injection pain; 
maximum dose of 40 mg. 
• No peri-operative oral or IV acetaminophen or NSAIDs (including Toradol® [ketorolac] 
Injection, Caldolor® [ibuprofen] Injection, and Ofirmev® [acetaminophen] Injection), or 
any other agent with potential analgesic properties (e.g., ketamine, dexmedetomidine, 
other alpha-2 agonists) will be permitted. 
• No dexamethasone or other corticosteroids will be permitted.  
5.6 
Surgical Requirements 
• Patients must be scheduled for elective outpatient laparoscopic cholecystectomy.  The 
surgery should be scheduled before noon to allow for completion of the 10 hour 
post-dose pain assessment at home.  
o Emergency or urgent cases will not
o Patients who require the pre-operative placement of a cholecystostomy tube for 
the management of acute cholecystitis are 
 be eligible.  
not
o Patients with a pre-planned overnight stay or pre-planned hospital admission are 
 eligible 
not
o No combination procedures (other than cholangiograms and minimal 
adhesiolysis) should be contemplated pre-operatively. Patients who undergo 
additional surgical procedures intra-operatively should 
 eligible. 
not
o If during surgery, significant adhesions are encountered that, in the opinion of the 
investigator would complicate surgery and increase postoperative pain, that 
patient should 
 be treated with test 
drug. 
not
o Patients who require the placement of a fifth laparoscopic port or percutaneous 
surgical drain should 
 be treated with test drug. 
not
• A conventional 4-port laparoscopic procedure using a combination of 5 mm and 
10-12 mm port incisions to afford instrument access (
 be treated with test drug. 
Baron et al, 2015; SAGES 
Guidelines, 2010) will be required to allow standardization of test drug administration.   
o If more than 4 ports are required, the patient should not
o 
 be treated with test drug.  
No
o 
 single incision, NOTES, or robotic laparoscopic cholecystectomy will be 
permitted.  
No
• Prophylactic antibiotics should be used as per institutional standards. 
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• For the larger 10-12 mm incisions, the fascia should be closed with interrupted 
absorbable sutures.  The skin layer should be closed with absorbable subcuticular sutures, 
followed by application of Steri-Strips, Dermabond or equivalent skin adhesive.   
o If gauze or other opaque dressing is used, it must be lifted during the surgical site 
examination to permit visualization of the wound. 
• Patients at high risk for conversion to open surgery are not
o Patients who have been converted to an open cholecystectomy or who experience 
other serious, unexpected intra-operative complications that would increase 
postoperative pain or risks should 
 suitable for randomization. 
not
• Thromboprophylaxis for DVT prevention should be provided, as needed, per institutional 
standards.  
 be treated with test drug. 
• Long-acting anticoagulants, such as warfarin, and long-acting antiplatelet drugs, such as 
clopidogrel, should be discontinued one week prior to surgery. Short-acting newer oral 
anticoagulants should be discontinued prior to surgery according to the labeled 
instructions.  Low dose aspirin (81 mg) may be continued throughout surgery (Joseph, et 
al., 2015).  The anticoagulants and antiplatelet agents may be restarted after surgery when 
hemostasis is assured and there are no bleeding complications from surgery 
5.7 
Rescue Analgesia for Postoperative Pain Management 
• IV fentanyl 12.5 or 25 mcg bolus doses given at no less than 5-minute intervals 
PACU 
• Oxycodone IR 5 mg tablets 
Home Use 
• Acetaminophen 500 mg tablets 
5.7.1 
PACU Rescue Medication Regimen 
In the PACU, pain may be treated with rescue analgesia (IV fentanyl in 12.5 or 25 mcg doses 
given at no less than 5-minute intervals).  IV fentanyl should be given only as necessary to 
control pain, only at the patient’s request, and not as a scheduled or prophylactic dose.  The 
patient’s pain score 
 on movement (defined as sitting up, or attempting to do so, from a 
supine position) should be assessed immediately before giving each rescue dose of IV fentanyl.  
If the patient is unable to sit up all the way due to severe pain, weakness, or lack of recovery 
from anesthesia, the patient should be instructed to make his or her best attempt, and that pain 
score will be recorded.  The dose and time of administration of IV fentanyl and associated pain 
scores must be recorded on the patient’s chart and on the eCRF.  No IV acetaminophen, IV 
NSAIDs, or any analgesic drug (including Toradol® [ketorolac] Injection, Caldolor® [ibuprofen] 
Injection, and Ofirmev® [acetaminophen] Injection) other than IV fentanyl should be given 
during the PACU stay.  However, the following exception will apply: at sites where patients are 
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transferred prior to discharge to a Phase 2 recovery unit (or step down unit), then oral oxycodone 
or oral acetaminophen may be given according to the instructions described in Section 5.7.2 for 
the use of oral rescue medication. 
5.7.2 
Oral Rescue Medication Regimen for Home Use  
Patients will be provided written instructions regarding rescue medication usage prior to 
discharge. Prior to rescue dosing, the patient must record pain intensity 
 
on movement. Each dose of rescue medication will be recorded by the patient on the 
LogPad. 
From PACU discharge through Study Day 8 (POD 7), analgesic rescue medications are 
limited to oxycodone IR 5 mg tablets, prescribed by the surgeon (or surgeon's delegate), 
and acetaminophen 500 mg tablets, supplied by the Sponsor. 
Patients must be instructed to not take both oxycodone and acetaminophen within 4 hours 
of each other.  Generally, oxycodone should be taken for moderate to severe pain and 
acetaminophen should be taken for mild to moderate pain and the two drugs should not
No Combination products (e.g., Percocet, Vicodin, Vicoprofen, Zydone, and Percodan) or 
extended release opioid products (e.g., Oxycontin, Opana ER, Kadian, and Ultram ER) will be 
permitted from screening to trial completion (Study Day 60). 
 be taken 
together. 
Patients will be instructed that they must bring any unused rescue medication (oxycodone IR and 
acetaminophen) with them to the clinic visits (through Visit 6 or early termination) for 
reconciliation purposes. The number of tablets dispensed will be recorded and the number of 
remaining tablets will be counted at each clinic visit.   
5.7.2.1 
Rescue Oral Opioids 
For the treatment of moderate to severe pain, patients will be prescribed oxycodone IR 5 mg 
tablets.  Exactly 24 tablets should be prescribed.  One or two tablets may be taken every 4 hours 
for moderate to severe pain.  Each dose of oxycodone will be recorded by the patient on their 
LogPad.  
5.7.2.2 
Rescue Oral Acetaminophen  
For the treatment of mild to moderate pain, patients will be supplied by the sponsor with 
acetaminophen 500 mg tablets (one bottle of 24 tablets).  One or two tablets may be taken every 
4 hours as required for pain.  No more than 8 tablets (4000 mg) may be taken in any 24 hour 
period.  Each dose of acetaminophen will be recorded by the patient on their LogPad.  A screen 
will display an alert that they have reached the maximum allowed dose when a patient takes an 
8th tablet (4000 mg total) in any 24 hour period. 
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5.7.2.3 
No Concomitant Use of Oxycodone and Acetaminophen 
Oxycodone and acetaminophen may not be taken concomitantly within the same four hour 
interval. 
 
6.0 
Trial Conduct 
6.1 
Investigative Sites 
The trial will be conducted at a minimum of 5 and up to 25 investigative sites in the United 
States.  
Investigative sites will be selected based on experience in conducting analgesic studies and 
access to the selected patient population through either general surgery practices or hospitals 
where a general surgeon qualified by training or experience is available to perform or oversee 
procedures required by the protocol.   
Each Investigator participating in this trial will meet the following criteria: 
• Appropriate qualifications including current medical license, applicable certificates or 
personnel/sub-investigators with certificates (e.g. Drug Enforcement Administration 
[DEA] documentation regarding prescribing of Schedule II and higher drugs), and 
adequate GCP knowledge 
• Availability of accessible, interested, and well organized support staff  
• Availability of diagnostic facilities to support trial data requirements  
• Adequate test drug storage facilities 
• Availability of physician emergency response at all times 
A full description of the Investigator responsibilities has been included in Appendix 6.  
If a given investigative site approaches randomization of 20% of the total number of evaluable 
subjects (264) into Part 2 of the trial, the Sponsor will assess the appropriateness of allowing the 
center to continue randomizing additional subjects into the trial based upon factors such as 
monitored site performance including documentation and protocol compliance. 
6.2 
Sponsor Obligations of Trial Conduct 
Sponsor responsibilities such as data management (including electronic case report forms), site 
management, site monitoring, and central safety laboratory services will be transferred to one or 
more contract research organizations (CRO). 
The safety profile of bupivacaine is well established.  SABER®-Bupivacaine treatment is not 
intended to prolong life or reduce risk of a major adverse health outcome or major morbidity.  
Therefore, a Data Safety Monitoring Board has not been planned for this trial, which involves a 


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single dose administration and short trial duration.  However, periodic reviews of blinded safety 
data will be performed by the DURECT Medical Monitor according to the Safety Monitoring 
Plan (see Section 11.9).  If pre-specified serious adverse events of interest (see Section 9.3.1) 
reach a specified threshold incidence, an independent Safety Assessment Committee will review 
unblinded safety data for the affected patients (see Section 9.3.4). 
6.3 
Duration 
Patient participation will last for up to 93 days, consisting of:  
• Up to 30 day screening period (minimum of 5 days, with at least 7 days recommended)  
• Surgery (Study Day 1) and the administration of the single dose of test drug with 
discharge to home (or hospital admission, if necessary) on the day of surgery per local 
practice or ≥ 2 hours post-surgery, whichever is later. 
• Follow-up phone calls on POD 1 and 2/Study Days 2 and 3  
• Follow-up outpatient clinic visits on:  
o Study Day 4/POD 3,  
o Study Day 8/POD 7 ± 1 day,  
o Study Day 15/POD 14 ± 2 day,  
o Study Day 29/POD 28 ± 3 days, 
o A final clinic visit on Study Day 60/POD 59 ± 3 days.  
Outpatient clinic visits will be done for assessment of AEs, surgical site examinations, and 
rescue medication usage.  
All AEs, of whatever etiology and location, occurring after informed consent should be recorded 
on the eCRF as an AE.  All AEs will be followed until resolution unless the patient is lost to 
follow up. Resolution means no further changes in the event are expected, i.e., the point at which 
a subject experiencing such an AE is appropriately treated and stabilized even though they may 
continue to experience lingering sequelae that may never resolve.   
6.4 
Discontinuation of Trial 
DURECT Corporation reserves the right to terminate the trial at any time.  
 
7.0 
Trial Procedures 
Surgery will be performed under general anesthesia as described in Section 5.5 at a hospital or 
ambulatory surgical center.  Discharge will occur on the day of surgery per local practice. If 
conversion to open surgery is necessary, or more than 4 ports have been deemed necessary 
during the trial, then the patient is not to be dosed with test drug.    


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Operating room (OR) personnel will be un-blinded due to inherent differences between 
SABER®-Bupivacaine and Placebo saline or bupivacaine HCl in viscosity and color.  
Assessment of study endpoints, adverse events and surgical site examinations, must be done by 
blinded personnel. Patients must remain blinded throughout the study.  Investigators will be 
asked to sign a form for each patient that appropriate personnel have remained blinded to patient 
group assignment. 
During the first 72 hours after test drug administration (i.e., through 
 Day 4/Postoperative 
Day [POD] 3) pain intensity, both 
 on movement (defined as sitting up, or attempting 
to do so, from a supine position), will be recorded by the subject using a 11-point (0-10) 
numerical pain rating scale (NPRS) on an electronic diary (LogPad®) at specified times after 
recovery from anesthesia (see Table 2: Patient LogPad Schedule of Events).   
Pain intensity 
 on movement will also be recorded (1) prior to each IV fentanyl 
administration requested by the patient in the PACU, and (2) at home before the patient self-
administers either rescue medication.  
 
  Patients should then record their pain-on-movement 
score by sitting up, or attempting to do so, from a supine position and recording the worst pain 
experienced during the sit up. If the patient is unable to sit up all the way due to severe pain, 
weakness, or lack of recovery from anesthesia, the patient should be instructed to make his or her 
best attempt, and that score will be recorded. 
If a patient is admitted to the hospital following test drug administration, pain assessments and 
rescue medication should follow the same instructions as for home use, to the extent possible.   
7.1 
Patient Randomization 
It was planned that approximately 320 eligible patients would be randomized, in order to obtain 
306 evaluable patients (i.e., patients who received any test drug and have at least one post-
surgical pain intensity score).  It had been estimated that 4% of randomized patients may not 
receive any test drug due to unforeseeable intra-operative exclusion.  Patients would be 
randomized in a 1:1 ratio to receive one of two treatments based on a computer-generated 
randomization schedule prepared before the study:  
Part 1 
• Treatment Group 1: SABER®-Bupivacaine 5 mL (POSIMIR®)(132 mg/mL, 660 mg 
bupivacaine base) 
• Treatment Group 2: Sterile normal saline 5 mL (0.9% sodium chloride injection, USP) 
(placebo) 
Due to the early administrative stopping, only approximately 90 subjects will be enrolled and 
randomized in Part 1. 
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Approximately 274 eligible patients will be randomized, in order to obtain 264 evaluable patients 
(i.e., patients who received any test drug).  It has been estimated that 4% of randomized patients 
may not receive any test drug due to unforeseeable intra-operative exclusion such as conversion 
to open cholecystectomy or need for a fifth port.  Patients will be randomized in a 1:1 ratio to 
receive one of two treatments based on a computer-generated randomization schedule prepared 
before the study:  
Part 2 
• Treatment Group 3: SABER®-Bupivacaine 5 mL (POSIMIR®)(132 mg/mL, 660 mg 
bupivacaine base) 
• Treatment Group 4: Bupivacaine HCl without epinephrine, 15 mL of 0.5% solution (75 mg)  
 
 
 
 
 
Following screening and confirmation of eligibility, an interactive web response system (IWRS) 
will be used to assign patients to a treatment group.  The IWRS will confirm randomization via 
automatic notification to the investigative site.  
If all Screening (i.e. pre-operative) Inclusion/Exclusion criteria have been met, randomization 
can be done up to 1 business day prior to surgery. In the event that a randomized patient does not 
have the surgical procedure for unforeseen circumstances (see Section 5.3.3) or does not receive 
any test drug, replacement of the patient has been planned. The IWRS system will be 
algorithmically instructed to issue the appropriate randomization replacement and to ensure the 
balance of treatment as planned. Precise details on the IWRS algorithm have been described in 
the IWRS specifications.   
 
 
 
 
If a given study center approaches randomization of 20% of the total number of evaluable 
subjects (264) into Part 2 of the trial the Sponsor will assess the appropriateness of allowing the 
center to continue randomizing additional subjects into the trial based upon factors such as 
monitored site performance including documentation and protocol compliance. 
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7.2 
Maintenance of the Blind 
For the best chance of achieving a valid and reliable test of efficacy, the blind must be 
maintained despite the fact that several members of the site staff (pharmacist, operating room 
staff) will necessarily be un-blinded by the difference in color and viscosity between 
SABER®-Bupivacaine and comparator (saline placebo [Part 1] or bupivacaine HCl [Part 2]) test 
drugs. 
Nonetheless, un-blinded trial staff must not
Vial cartons will carry identical labels and vials will be packaged in individual cartons to avoid 
any side-by-side comparisons of the vial carton contents. Each vial carton and the boxes 
containing multiple vial cartons will have tamper-evident seals.  
 disclose which test drug the patient received, or bias 
the patient or blinded staff by discussing the group assignments with them.  Surgeons and other 
operating room personnel should take care not to include any potentially unblinding information 
(e.g., volume or method of test drug administration) in their operative notes or other routinely 
collected surgical records).  Assessment of study endpoints, such as adverse events and surgical 
site examinations, must be done by blinded personnel. During any routine postoperative clinical 
examinations, the un-blinded surgeon must take care not to inadvertently un-blind the patient.  
Any clinical examinations done by the operating surgeon will be done for standard of care only 
and must not be used for any of the trial-related surgical site examinations.  Each site will have a 
site specific Blinding Plan in place to describe the steps taken to ensure the blind is maintained 
as well as indicating which study staff will be blinded or un-blinded.  Included in this Blinding 
Plan will be a form that must be signed by the principal investigator stipulating that un-blinded 
staff have not discussed group assignment with blinded staff, and that all protocol related 
evaluations have been performed only by the latter. 
If in a medical emergency knowledge as to whether SABER®-Bupivacaine or saline Placebo 
(Part 1) or bupivacaine HCl (Part 2) has been administered is critical for the supportive therapy 
of the patient or will influence further medical treatment of the patient, the Investigator or 
designee should obtain the patient’s test drug treatment assignment from the IWRS system.  If a 
patient is un-blinded by the investigative site, the IWRS system will send an alert to the Sponsor 
and their designee, and the site must contact the sponsor directly within 24 hours of the incident. 
The date, time, reasons for breaking the blind and person doing so must be documented in the 
source record as it will be reviewed by Sponsor representatives.  Unless medically indicated, the 
treatment should not be disseminated further or shared with the patient to prevent introduction of 
bias.  Before a blind is broken, the Sponsor should be contacted if possible.   
7.3 
Trial Test Drug  
7.3.1 
Test Drug Administration Instructions for SABER®-Bupivacaine and Saline 
Placebo 
Using sterile technique, the test drug (either SABER®-Bupivacaine 5 mL [Part 1 and Part 2] or 
sterile normal saline 5 mL [Part 1 only]) will be drawn up into a 5 mL Norm-Ject® syringe using 


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a 16 G hypodermic needle, both of which will be supplied by the Sponsor.  A small excess of test 
drug (approximately 5.5 mL) should be drawn up into the syringe to allow for dead space in the 
catheter used for administration. The 16 G needle will be removed and replaced with a plastic 
14G x 1¼ inch
IV catheter (supplied by Sponsor) to aid in the administration of the test 
drug into all of the port incisions.  Once the catheter has been attached to the syringe, the excess 
contents will be expelled through the catheter (along with any air) to bring the total quantity in 
the syringe to 5 mL. The test drug may be drawn up into the syringe up to one hour before 
dosing. 
After removal of the trocars, desufflation of the abdomen, and closure of the fascial layer 
associated with the larger ports, the test drug will be administered sequentially into each of the 
port incisions. Each incision will be closed with a running subcuticular suture. Prior to tying the 
final knot, the plastic syringe-tip applicator (IV catheter) will be inserted into the wound and 
directed down to the level of the fascia. While pulling mildly upward on the free ends of the 
suture to create a virtual intra-incisional space, the prescribed quantity of test drug will be 
instilled into the incision via the syringe-tip applicator. The applicator should be gradually 
withdrawn while instilling test drug to ensure even distribution throughout the wound, and mild 
upward tension on the suture ends should be maintained to ensure the test drug remains entirely 
within the wound.  The final knot will then be tied to complete closure of the incision. The 
patient number, drug vial number, date and time of drug administration (defined as the time of 
completion of administration), and the volume of test drug administered into each laparoscopic 
port will be recorded.    
The 5 mL dose of test drug should be divided among the multiple ports to provide coverage of all 
surgical incisions.  In this clinical trial, a conventional 4-port laparoscopic procedure has been 
required to allow standardization of test drug administration.  If more than 4 ports are required 
the patient should not
After subcuticular closure, any excess test drug remaining on the skin should be grossly removed 
with a sterile sponge or gauze pad. If a film of test drug remains on the skin, it should be wiped 
clean with one or more isopropyl alcohol wipes before application of Steri-Strips, Dermabond, or 
equivalent skin adhesive. 
 be treated with the test drug. The test drug should be distributed according 
to the length of the port incisions and the function of the port.  The 10-12 mm ports—and 
especially the port used for extraction of the gall bladder—should receive proportionally more of 
the test drug than the smaller 5 mm ports.     
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One of the two following test drug distribution patterns is recommended for typical laparoscopic 
ports:   
Table 3: Test Drug Distribution in Laparoscopic Ports  
Port size* 
SABER®-Bupivacaine 5mL 
Bupivacaine HCl 15mL 
4 ports 
Target  
Volume 
Percentage of  
Total 
Target  
Volume 
Percentage of 
Total 
5 mm 
5 mm 
10-12 mm 
10-12 mm 
0.5 mL 
0.5 mL 
2.0 mL 
2.0 mL 
10% 
10% 
40% 
40% 
1.5 mL 
1.5 mL 
6.0 mL 
6.0 mL 
10% 
10% 
40% 
40% 
5 mm 
5 mm 
5 mm 
10-12 mm 
0.8 mL 
0.8 mL 
0.8 mL 
2.6 mL 
16% 
16% 
16% 
52% 
2.4 mL 
2.4 mL 
2.4 mL 
7.8 mL 
16% 
16% 
16% 
52% 
* This refers to the trocar diameter.  The actual incision length will be longer and may vary 
depending on the method of abdominal entry. 
NOTE: For Part 2, amount administered to each port must be recorded in the source and eCRF as 
a percentage rather than a millimeter amount to avoid inadvertent unblinding due to differences 
in the volume administered between the 2 treatment groups.  
7.3.2 
Test Drug Administration Instructions for Bupivacaine HCl (Part 2) 
After completion of the laparoscopic cholecystectomy, desufflation of the abdomen, removal of 
the trocars, and closure of the fascial layer for the larger ports, bupivacaine HCl, 15 mL of 0.5% 
solution will be infiltrated into the margins of the incisions according to the distribution in 
Table 3.  The infiltration should be done according to usual practice, using the supplied 10 cc 
syringes and the 22GA x 1½̎  hypodermic needles.  After infiltration of a total of 15 mL of 
bupivacaine HCl distributed among the four ports according to Table 3, the incisions are closed 
with subcuticular sutures and Steri-Strips, Dermabond, or equivalent skin adhesive. 
7.3.3 
Packaging and Labeling of Test Drug 
The Sponsor will provide SABER®-Bupivacaine (POSIMIR®) to the investigative site in single-
use 10 mL glass vials with rubber stoppers (containing 6.2 ± 0.5 mL of SABER®-Bupivacaine) 
and vials containing 10 mL of commercial, sterile normal saline placebo (0.9% sodium chloride 
injection, USP). 
Part 1 
The vial (i.e. kit) and/or carton label will contain a description of contents, trial identification, lot 
number, kit number, manufacture date (or retest date), relevant caution statements, storage 
conditions, and Sponsor information. 


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SABER®-Bupivacaine (POSIMIR®)132 mg/mL, 660 mg bupivacaine base) and commercial, 
sterile normal saline placebo (0.9% sodium chloride injection, USP) vial cartons will carry 
identical labels and will be packaged in individual cartons to avoid any side-by-side comparisons 
of the vial content.  Each vial carton and the boxes containing multiple vial cartons will have 
tamper-evident seals.  The vials containing SABER®-Bupivacaine (POSIMIR®) and commercial, 
sterile normal saline placebo will be labeled with their contents. 
The Sponsor will provide SABER®-Bupivacaine (POSIMIR®) to the investigative site in single-
use 10 mL glass vials with rubber stoppers (containing 6.2 ± 0.5 mL of SABER®-Bupivacaine) 
and vials containing 30 mL of commercial, 0.5% bupivacaine HCl without epinephrine.  
Part 2 
The vial (i.e. kit) and/or carton label will contain a description of contents, trial identification, lot 
number, kit number, manufacture date (or retest date), relevant caution statements, storage 
conditions, and Sponsor information. 
SABER®-Bupivacaine (POSIMIR®)132 mg/mL, 660 mg bupivacaine base) and commercial, 
0.5% bupivacaine HCl without epinephrine vial cartons will carry identical labels and will be 
packaged in individual cartons to avoid any side-by-side comparisons of the vial content.  Each 
vial carton and the boxes containing multiple vial cartons will have tamper-evident seals.  The 
vials containing SABER®-Bupivacaine (POSIMIR®) and commercial, 0.5% bupivacaine HCl 
without epinephrine will be labeled with their contents. 
7.3.4 
Storage of Test Drug 
SABER®-Bupivacaine (POSIMIR®), commercial, sterile normal saline placebo and bupivacaine 
HCl will be stored at 20°C to 25°C (with temperature excursions allowed between 15 to 30° C) 
in a secure area with restricted access. 
7.3.5 
Preparation of Test Drug 
The test drug requires no reconstitution or additional preparation prior to administration.   
7.3.6 
Drug Accountability 
SABER®-Bupivacaine, saline placebo (Part 1) and bupivacaine HCl (Part 2) will be accounted 
for by the investigative site and recorded on the drug accountability log.   
Test Drug  
The test drug will be administered to the patient by the un-blinded surgeon; therefore no patient 
compliance measures with regard to the test drug are necessary.  Additionally, specific test drug 
dosing information will be recorded on the appropriate source document and electronic case 
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All used syringes and needles will be disposed as per local health and safety standard operating 
procedures.   
All used and unused test drug (SABER-Bupivacaine, saline placebo [Part 1], and bupivacaine 
HCl [Part 2]) vials will be kept at the investigative site until test drug reconciliation by the un-
blinded monitor and must be available for verification during monitoring visits. 
After monitoring, a final reconciliation of drug accountability records, and authorization by 
DURECT, all used and unused vials of test drug will be returned to DURECT or properly 
disposed of at the investigative site, if permitted per local SOPs and regulations. Documentation 
of disposition of all test drug will be provided to DURECT. 
Sponsor supplied acetaminophen will be accounted for by the investigative site and recorded on 
the drug accountability log.  The number of tablets dispensed will be recorded and the number of 
remaining tablets will be counted at each clinic visit and recorded on the appropriate source 
document and eCRF.  
Sponsor Supplied Rescue Medication:  Acetaminophen 
After monitoring, a final reconciliation of drug accountability records, and authorization by 
DURECT, all used and unused Sponsor supplied acetaminophen will be returned to DURECT or 
properly disposed of at the investigative site, if permitted per local SOPs and regulations. 
Documentation of disposition of Sponsor supplied acetaminophen will be provided to DURECT. 
For the prescribed rescue opioid analgesia, the number of tablets dispensed will be recorded and 
the number of remaining tablets will be counted at each clinic visit (through Visit 6 or early 
termination) and recorded on the appropriate source document and eCRF. If a patient does not 
fill their prescription for rescue opioid analgesia, this fact will be written in the eCRF.  Following 
this reconciliation the rescue opioid analgesia will be returned to the patient.  
Rescue Medication:  Oxycodone 
7.4 
Trial Visits and Follow-Up Phone Calls 
Refer to Table 1 for Schedule of Events by Visit and Table 2 for the LogPad Schedule of Events. 
7.4.1 
Visit 1 (Screening)  
All screening procedures will be performed after obtaining informed consent no more than 
30 days prior to day of surgery. A minimum screening duration of 5 days (with 7 days being 
recommended) will be required for completion of the screening procedures. After obtaining 
informed consent, patients will be assigned a patient number and screening procedures will be 
performed.  For the patient number, patients will be numbered consecutively within each site in 
the order of their consent into the trial.  Only their assigned patient number and date of birth will 
identify patients to the Sponsor in order to maintain anonymity.   


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Screening procedures include completion of:  
• Demographic information including employment status.  
• Medical and surgical history. 
• Physical examination (including height and weight).  
• Vital signs (BP, HR, respiratory rate, temperature).  
• Review of inclusion / exclusion criteria. 
• Safety laboratory tests (chemistry, hematology, urinalysis).  
• Urine drug screen for opiates, oxycodone, cannabinoids, amphetamines, cocaine, and 
methadone 
• Serum pregnancy test (females of childbearing potential). Childbearing potential is 
considered present until menopause has lasted for more than 2 years prior to screening or if 
surgical sterilization (e.g. hysterectomy, tubal ligation) has occurred at least 6 months prior to 
screening.   
• 12-lead ECG.  
• Record prior and concomitant medications (taken within 30 days of screening). 
• Assign LogPad and train in use. Patient completes Log Pad evaluations. Remind patients that 
enrollment is dependent upon their compliance with preoperative LogPad training (must 
complete a minimum of 80% of preoperative practice assessments). Refer to Section 7.5. 
• 
 
   
Patients who meet inclusion / exclusion criteria (See Section 5.3.1 and 5.3.2, respectively) will 
return to the investigative site for the scheduled surgery.  Surgery must occur within 30 days of 
the screening visit.   
7.4.2 
Visit 2 (Day of Surgery/Study Day 1) 
Patients will arrive at the investigative site and will be prepared for their scheduled surgery as 
per the site’s standard practice.  The surgery should be scheduled before noon to allow for 
patient completion of the 10 hour post-dose pain assessment. 
• Urine pregnancy test for female patients of childbearing potential 
Pre-surgery trial procedures:  
• Review and document adverse events reported and concomitant medications taken since 
the screening visit 
• Review inclusion / exclusion criteria again to confirm patient remains eligible 
• Re-review LogPad instructions (refer to Section 7.5) 
• Patient re-watches the training video (refer to Section 8.2.1) 
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• Randomization to one of two treatment groups    
o Randomization may be done on the business day prior to surgery as long as the 
patient meets the Screening (i.e. pre-operative) inclusion/exclusion criteria at the 
time of randomization 
• Vital Signs:  Subjects will remain in rest (supine or sitting) for at least 5 minutes prior to 
vital signs (BP, HR, RR, T) and pulse oxygen saturation measurements 
The surgery will be performed under general endotracheal anesthesia. Epidural or spinal 
analgesia, regional nerve blocks, intra-abdominal application of local anesthetics, and 
peri-incisional injection of local anesthetics other than the test drug have been prohibited. If 
conversion to open surgery occurs, the patient should 
Surgery trial procedures: 
not
5.5
 be treated with the test drug.  This 
surgery must occur within 30 days of the screening visit. See Sections 
 (Anesthesia 
Requirements) and 5.6 (Surgical Requirements) for additional detail.   
• Record anesthesia and intra-operative medications 
• Administer study drug as described in Section 7.3.1.  Record the time of test drug 
administration which has been defined as completion of drug deposition into the surgical 
incisions.   
• Record the length and anatomical placement of surgical incisions in the source and 
surgery eCRF. 
• Record the time of arrival in PACU. 
• The test drug administration time will be entered by the clinical trial staff into the 
patient’s LogPad within one hour post-dose. 
Post-surgery trial procedures: 
o The LogPad will be re-dispensed to the patient upon awakening.   
• PACU discharge eligibility will be assessed by blinded personnel per the site specific 
Blinding Plan with the mPADSS, starting at 30 minutes after arrival in the PACU.  The 
mPADSS will be repeated at 15 minute intervals (±5 minutes) until the patient is eligible 
for discharge (i.e. an mPADSS score of 9 or greater).  
• Vital signs including pulse oximetry will be measured and recorded on the Vitals eCRF 
upon arrival in the PACU and continuing every 15 minutes (±5 minutes) for a period of at 
least two hours after surgery 
o All clinically significant abnormalities will also be documented in the appropriate 
source document and AE eCRF. 
• All adverse events will be recorded as noted in Section 9.3.   
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• Postoperative pain will be treated according to the Rescue Analgesia instructions in 
Section 7.6.3.   
o In the PACU, the patient’s pain score 
 on movement (defined as sitting 
up, or attempting to do so, from a supine position) should be assessed 
immediately before giving each rescue dose of IV fentanyl.  If the patient is 
unable to sit up all the way due to severe pain, weakness, or lack of recovery from 
anesthesia, the patient should be instructed to make his or her best attempt, and 
that pain score will be recorded.  The dose and time of administration of IV 
fentanyl and associated pain scores must be recorded on the patient’s chart and on 
the eCRF.   
• All other concomitant medications will be recorded as noted in Section 7.6.   
• Prior to discharge to home, patients will be provided sponsor supplied acetaminophen, 
500 mg and a prescription for oxycodone IR, 5 mg, including dosing instructions 
(see Section 7.6.3). If permitted, retain a copy of the opioid prescription in the source 
documents. 
• Just prior to discharge, a blinded Investigator (e.g., not
9.2.6
 the operating surgeon or operating 
room personnel) will complete a baseline surgical site examination (see Section 
 for 
details).  
• Discharge to home should occur ≥2 hours post-surgery. 
Patients will be given written discharge instructions, including routine post-surgical instructions, 
reminder of LogPad requirements, rescue medication instructions, and follow-up call and clinic 
visit schedule. 
Patient Instructions: 
7.4.2.1 
Patient Completed Postoperative Evaluations  
(Day of Surgery/Study Day 1)  
Patients will evaluate their pain intensity 
 on movement (defined as sitting up, or 
attempting to do so, from supine position) using the LogPad.  The scheduled pain intensity 
evaluations will be done at 1, 4, 6, 8, and 10 hours post-dose on the day of surgery (see 
Section 7.5) initially in the PACU, then later after the patient has been discharged to home.   
Pain intensity evaluations prior to rescue medication (pain intensity 
 on movement) 
must also be completed (1) prior to each IV fentanyl administration requested by the patient in 
the PACU, and (2) at home before the patient self-administers either oral rescue medication.  
  
Patients should then record their pain-on-movement score by sitting up, or attempting to do so, 
from a supine position and recording the worst pain experienced during the sit up. If the patient 
is unable to sit up all the way due to severe pain, weakness, or lack of recovery from anesthesia, 
the patient should be instructed to make his or her best attempt, and that score will be recorded. 
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Postoperative pain will be treated according to the Rescue Analgesia instructions in 
Section 7.6.3.  For all oral rescue medication, the pre-rescue pain scores 
 on 
movement, plus the time, name, and number of pills taken will be recorded in the LogPad. 
Patients will also complete a solicited AE checklist (which includes dizziness, somnolence, 
constipation, nausea, vomiting, pruritus, headache, dysgeusia, hypoesthesia, and paresthesia) on 
the LogPad at 6 and 10 hours post-dose (see Sections 7.5).  
7.4.3 
Follow-up Calls (Study Day 2 and 3) 
Postoperative Day 1 and 2 
Blinded site personnel will complete the following evaluations during the follow-up calls:  
• Review completeness of Log Pad assessments and reminder of importance of 
completion of all LogPad assessments in a timely manner. 
• Review of Adverse Events (including details of any patient-reported AEs recorded on 
the LogPad) – All reported AEs will be documented as noted in Section 9.3 
• Inquire about Surgical Site AEs – 
 
• Review of Rescue Analgesia and Concomitant Medications – All other reported 
concomitant medications must be documented as noted in Section 7.6 
• Inquire about Level of Activity including ambulation, sleeping, and eating -
 
• Medical Resource Utilization Assessment – including any hospital admissions, 
Emergency Department visits, or calls to their physician or surgeon with complaint of 
unmanageable pain, nausea/vomiting, or refills of rescue opioid prescription –
 
7.4.4 
Patient Completed Evaluations (Study Days 2, 3, and 4) 
Postoperative Day 1 to 3  
Patients will complete the following evaluations: 
• Pain Intensity Evaluations- Pain assessments 
 on movement (defined as sitting 
up, or attempting to do so, from supine position) should be performed on the LogPad at 
the scheduled times noted in Table 2: Patient LogPad Schedule of Events.  
• Rescue Medication – Postoperative pain will be treated according to the Rescue 
Analgesia instructions in Section 7.6.3.  For all oral rescue medication, the pre-rescue 
pain scores 
 on movement, plus the time, name, and number of pills taken will 
be recorded in the LogPad.   
• Solicited AE Checklist (which includes dizziness, somnolence, constipation, nausea, 
vomiting, pruritus, headache, dysgeusia, hypoesthesia, and paresthesia) – assessed on the 
LogPad each evening at 20:00 ± 1 hour (clock time). 
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o If the patient reports an AE on the LogPad, an email alert will be sent to the 
investigative site personnel.  
7.4.5 
Visit 3 (Study Day 4) 
Postoperative Day 3 
A clinic visit will be conducted for assessment of AEs, surgical site examination, and rescue 
medication usage. During the clinic visit, the following trial procedures will be completed:  
• Surgical Site Examination and Assessment of Surgical Site AEs including bruising, 
bleeding or drainage from the incision(s), hematoma, dehiscence, infection and abnormal 
healing 
• Review LogPad for compliance, rescue medication use, and solicited AEs 
• Review of Adverse Events– All reported AEs will be documented as noted in Section 9.3 
o Follow-up on details of any AEs the patient reported on the LogPad 
• Rescue Medication Reconciliation and Pill Count 
o Follow-up with the patient regarding any discrepancy between the pill count and 
the number of pills recorded in the LogPad and document in the rescue 
medication accountability log and eCRF. 
• Review of Concomitant Medications – All other reported concomitant medications will 
be documented as noted in Section 7.6 
• Vital Signs 
• Safety Laboratory Tests (chemistry, hematology, urinalysis) 
• Inquire about Level of Activity including ambulation, sleeping, and eating -
 
• Medical Resource Utilization Assessment –including any hospital admissions, 
Emergency Department visits, or calls to their physician or surgeon with complaint of 
surgical complications, unmanageable pain, nausea/vomiting, or refills of rescue opioid 
prescription - 
 
7.4.6 
Patient Completed Evaluations (Study Day 5 to 8)  
Postoperative Day 4 to 7 
Patients will complete the following evaluations: 
• Rescue Medication – Postoperative pain relief will be prescribed according to the 
instructions in Section 7.6.3.  The time, name, and number of pills for all oral rescue 
opioids or acetaminophen will be recorded in the LogPad.   
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7.4.7 
Visit 4 (Study Day 8 ± 1 day) 
Postoperative Day 7 ± 1day 
A clinic visit will be conducted for assessment of AEs, surgical site examination, and rescue 
medication usage. During the clinic visit, the following trial procedures will be completed: 
• Surgical Site Examination and Assessment of Surgical Site AEs including bruising, 
bleeding or drainage from the incision(s), hematoma, dehiscence, infection and abnormal 
healing  
• Review LogPad for rescue medication use and any solicited AEs reported  
o Collect LogPad 
• Adverse Events – All reported AEs will be documented as noted in Section 9.3 
o Follow-up on details of any AEs the patient reported on the LogPad 
• Rescue Medication Reconciliation and Pill Count 
o Follow-up with the patient regarding any discrepancy between the pill count and 
the number of pills recorded in the LogPad and document in the rescue 
medication accountability log and eCRF. 
• Review of Concomitant Medications – All other reported medications will be 
documented as noted in Section 7.6 
• Vital Signs 
• Inquire about Level of Activity including ambulation, sleeping, eating, and current 
surgical wound pain - 
 
• Medical Resource Utilization Assessment –including any hospital admissions, 
Emergency Department visits, or calls to their physician or surgeon with complaint of 
surgical complications, unmanageable pain, nausea/vomiting, or refills of rescue opioid 
prescription - 
 
7.4.8 
Visit 5 (Study Day 15 ± 2 days) 
Postoperative Day 14 ± 2 days 
Approximately 14 days after surgery, a clinic visit will be conducted for assessment of AEs, 
surgical site examination, and rescue medication usage. During the clinic visit, the following trial 
procedures will be performed:  
• Surgical Site Examination and Assessment of Surgical Site AEs including bruising, 
bleeding or drainage from the incision(s), hematoma, dehiscence, infection and abnormal 
healing   
• Adverse Events – All reported AEs will be documented as noted in Section 9.3 
• Rescue Medication Reconciliation and Pill Count 
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• Review of Concomitant Medications – As noted in Section 7.6, all medications 
(including rescue medications) taken since the last visit will be documented. 
• Vital Signs 
• Inquire about Level of Activity including ambulation, sleeping, eating, and current 
surgical wound pain - 
 
• Medical Resource Utilization Assessment –including any hospital admissions, 
Emergency Department visits, or calls to their physician or surgeon with complaint of 
surgical complications, unmanageable pain, nausea/vomiting, or refills of rescue opioid 
prescription - 
 
7.4.9 
Visit 6 (Study Day 29 ± 3 days)  
Postoperative Day 28 ± 3 days 
Approximately 4 weeks after surgery, a clinic visit will be conducted for assessment of AEs, 
surgical site examination, and rescue medication usage. During the clinic visit, the following trial 
procedures will be performed:  
• Surgical Site Examination and Assessment of Surgical Site AEs including bruising, 
bleeding or drainage from the incision(s), hematoma, dehiscence, infection and abnormal 
healing   
• Adverse Events – All reported AEs will be documented as noted in Section 9.3 
• Rescue Medication Reconciliation and Pill Count and collect Sponsor supplied 
acetaminophen 
• Review of Concomitant Medications – As noted in Section 7.6, all medications 
(including rescue medications) taken since the last visit will be documented. 
• Physical Exam (including weight)  
• 12-lead ECG 
• Vital Signs 
• Safety Laboratory Tests (chemistry, hematology, urinalysis) 
• Inquire about Level of Activity including ambulation, sleeping, eating, current surgical 
wound pain, and return to work status - 
 
• Medical Resource Utilization Assessment –including any hospital admissions, 
Emergency Department visits, or calls to their physician or surgeon with complaint of 
surgical complications, unmanageable pain, nausea/vomiting, or refills of rescue opioid 
prescription - 
 
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7.4.10 
Visit 7 (Study Day 60 ± 3 days)  
Postoperative Day 59 ± 3 days 
Approximately 2 months after surgery, a clinic visit will be conducted for assessment of AEs and 
surgical site examination. During the clinic visit, the following trial procedures will be 
performed:  
• Surgical Site Examination and Assessment of Surgical Site AEs including bruising, 
bleeding or drainage from the incision(s), hematoma, dehiscence, infection and abnormal 
healing   
• Adverse Events – All reported AEs will be documented as noted in Section 9.3 
• Review of Concomitant Medications – As noted in Section 7.6, all medications 
(including pain medications) taken since the last visit will be documented.  
• Physical Exam (including weight)  
• 12-lead ECG 
• Vital Signs 
• Safety Laboratory Tests (chemistry, hematology, urinalysis) 
All AEs, of whatever etiology and location, occurring after informed consent should be recorded 
on the eCRF as an AE.  All AEs will be followed until resolution unless the patient is lost to 
follow up. Resolution means no further changes in the event are expected, i.e., the point at which 
a subject experiencing such an AE is appropriately treated and stabilized even though they may 
continue to experience lingering sequelae that may never resolve.  
NOTE: Patients enrolled prior to IRB approval of Amendment 5 will not need to return for a 
Study Day 60 visit. 
7.4.11 
Early Termination Visit 
If a patient terminates the study early the following study procedures should be performed unless 
the patient withdraws consent.  If a patient withdraws consent they will be encouraged to 
complete an early termination visit and AE follow-up: 
• Surgical Site Examination and Assessment of Surgical Site AEs including bruising, 
bleeding or drainage from the incision(s), hematoma, dehiscence, infection and abnormal 
healing   
• Adverse Events – All reported AEs will be documented as noted in Section 9.3 
• Rescue Medication Reconciliation and Pill Count and collect Sponsor supplied 
acetaminophen 
• Review of Concomitant Medications – As noted in Section 7.6, all medications 
(including rescue medications) taken since the last visit will be documented. 
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• 12-lead ECG 
• Vital Signs 
• Safety Laboratory Tests (chemistry, hematology, urinalysis) 
• Inquire about Level of Activity including ambulation, sleeping, eating, current surgical 
wound pain, and return to work status - 
 
• Medical Resource Utilization Assessment –including any hospital admissions, 
Emergency Department visits, or calls to their physician or surgeon with complaint of 
surgical complications, unmanageable pain, nausea/vomiting, or refills of rescue opioid 
prescription - 
 
7.5 
Electronic Diary (LogPad) 
The LogPad is a handheld electronic device that records data entered by the patient and transfers 
it directly into a database maintained by the specific service provider.  These devices will be 
provided to the patient by the investigative site at screening, the patient will bring the device 
with them on the day of surgery, the site will re-dispense the device to the patient in the PACU 
following surgery, and patients will return the device to the investigative site at Visit 4 (POD 7).   
 
 
The test drug administration time will be entered by the investigative site staff into the patient’s 
LogPad via the Site Gateway within one hour post-dose. 
 
  
The LogPad will be used to record pain intensity 
 on movement (defined as sitting up, 
or attempting to do so, from a supine position) from Study Day 1 (day of surgery) through Study 
Day 4 (POD 3) (see Section 8.2.1 
 oral rescue medication (oxycodone IR or 
acetaminophen) till Study Day 8 (POD 7), the associated pre-rescue 
 on 
movement scores through Study Day 4 (POD 3), and the solicited AE checklist (which includes 
dizziness, somnolence, constipation, nausea, vomiting, pruritus, headache, dysgeusia, 
hypoesthesia, and paresthesia) from Study Day 1 to Study Day 4 (see Table 2: Patient LogPad 
Schedule of Events).  If the patient reports an AE on the LogPad, an email alert will be sent to 
the investigative site personnel.  
Data collected in the LogPad device will automatically transmit following completion of each 
assessment.  Trial staff will access the transmitted data via the
  
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7.6 
Medication other than Test Drug 
Any use of concomitant medications taken since 30 days prior screening will be recorded on the 
appropriate source document and concomitant medication (CM) eCRFs.  This includes 
concomitant medications taken between screening and the surgery, medications taken during 
surgery, medications taken post-surgery (e.g. rescue medications, including titration and oral 
opioids, and acetaminophen), and for treatment of adverse events (AEs).  
7.6.1 
Prohibited Concomitant Medications 
• Epidural or spinal analgesia, regional nerve blocks, intra-abdominal application of local 
anesthetics, and peri-incisional injection of local anesthetics other than the test drug have 
been prohibited
• Use of systemic steroids, antidepressants, anticonvulsants or antiepileptics has been 
.   
prohibited
o Inhalational or topical corticosteroids are permitted 
 from screening until Visit 6 (Study Day 29).  
• Long-acting anticoagulants, such as warfarin, and long-acting antiplatelet drugs, such as 
clopidogrel, should be discontinued one week prior to surgery. Short-acting newer oral 
anticoagulants should be discontinued prior to surgery according to the labeled 
instructions.  Low dose aspirin (81 mg) may be continued throughout surgery (Joseph et. 
al., 2015).  The anticoagulants and antiplatelet agents may be restarted after surgery when 
hemostasis is assured and there are no bleeding complications from surgery. 
• NSAIDs, both prescribed (including Toradol® [ketorolac] Injection and Caldolor® 
[ibuprofen] Injection) and over the counter (OTC), are not allowed for one week prior to 
surgery and for 1 week after surgery (Study Day 8). Restricted OTC medications include 
(but are not
o Aleve® (naproxen sodium), Advil® (ibuprofen), Motrin® (ibuprofen), Aspirin 
(except low dose [81 mg] aspirin taken as an antithrombotic), Alka-Seltzer®, 
Excedrin®, Midol® 
 limited to): 
• Other OTC combination products containing acetaminophen are not allowed for one 
week prior to surgery and for 1 week after surgery (Study Day 8). Restricted OTC 
medications include (but are not
o Products containing acetaminophen for the following brands:  NyQuil®, 
DayQuil®, Robitussin®, Benadryl®, Sudafed®, Theraflu®,  and generic equivalents 
 limited to): 
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• The use of combination and extended/sustained release opioid analgesic medications are 
prohibited from screening until the final visit (Study Day 60). Prohibited medications 
include (but are not
o Combination products: Norco®, Lortab®, Percocet®, Vicodin®, Xodol®, 
Vicoprofen®, Zydone®, Percodan®, promethazine/codeine syrup, and generic 
equivalents 
 limited to): 
o Extended/Sustained Release/Long-acting products: Avinza®, Butrans®, 
Dolophine®, Duragesic®, Embeda®, EXALGO®, Hysingla™ ER, Kadian®, 
Methadose™, MS Contin®, Nucynta® ER, Opana® ER, OxyContin®, 
Zohydro® ER, and generic equivalents 
• Participants are prohibited from using investigational, unapproved, or recreational drugs.  
“Medical” marijuana and opioids (other than immediate-release oxycodone and IV 
fentanyl) may not
• Naltrexone should not be taken after surgery. 
 be used from screening until the final visit (Study Day 60).  
7.6.2 
Anesthesia  
The surgery will be performed under general endotracheal anesthesia.  Epidural or spinal 
analgesia, regional nerve blocks, intra-abdominal application of local anesthetics, and 
peri-incisional injection of local anesthetics other than the test drug have been prohibited. 
Intra-operative opioid analgesia will be limited to IV fentanyl with a maximum dose of 
2.5 mcg/kg/hr, including the induction dose. The duration of the surgical procedure is anticipated 
to be approximately 1 hour.  See Section 5.5 Anesthesia Requirements for additional details. 
7.6.3 
Rescue Analgesia for Postoperative Pain Management 
• IV fentanyl 12.5 or 25 mcg bolus doses given at no less than 5-minute intervals 
PACU 
• Oxycodone IR 5 mg tablets 
Home Use 
• Acetaminophen 500 mg tablets 
7.6.3.1 
PACU Rescue Medication Regimen 
In the PACU, pain may be treated with rescue analgesia (IV fentanyl in 12.5 or 25 mcg doses 
given at no less than 5-minute intervals).  IV fentanyl should be given only as necessary to 
control pain, only at the patient’s request, and not as a scheduled or prophylactic dose.  The 
patient’s pain score 
 on movement (defined as sitting up, or attempting to do so, from a 
supine position) should be assessed immediately before giving each rescue dose of IV fentanyl.  
If the patient is unable to sit up completely due to severe pain, weakness, or lack of recovery 
from anesthesia, the patient should be instructed to make his or her best attempt, and that score 
will be recorded.  The dose and time of administration of IV fentanyl and associated pain scores 
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must be recorded on the patient’s chart and on the eCRF.  No IV acetaminophen, IV NSAIDs, or 
any analgesic drug (including Toradol® [ketorolac] Injection, Caldolor® [ibuprofen] Injection, 
and Ofirmev® [acetaminophen] Injection) other than IV fentanyl should be given during the 
PACU stay.  However, the following exception will apply: at sites where patients are transferred 
prior to discharge to a Phase 2 recovery unit (or step down unit), then oral oxycodone or oral 
acetaminophen may be given according to the instructions described in Section 7.6.3.2 for the 
use of oral rescue medication. 
7.6.3.2 
Oral Rescue Medication Regimen for Home Use 
Patients will be provided written instructions regarding rescue medication usage prior to 
discharge. Prior to rescue dosing, the patient must record pain intensity 
 
on movement. Each dose of rescue medication will be recorded by the patient on the 
LogPad. 
From PACU discharge through Study Day 8 (POD 7), analgesic rescue medications have 
been limited to oxycodone IR 5 mg tablets, prescribed by the surgeon (or surgeon's DEA 
licensed delegate), and acetaminophen 500 mg tablets, supplied by the Sponsor. 
Patients must be instructed to not take both oxycodone and acetaminophen within 4 hours 
of each other.  Generally, oxycodone should be taken for moderate to severe pain and 
acetaminophen should be taken for mild to moderate pain and the two drugs should not
No Combination products (e.g., Percocet, Vicodin, Vicoprofen, Zydone, Percodan) or extended 
release opioid products (e.g., Oxycontin, Opana ER, Kadian, Ultram ER) will be permitted from 
screening to trial completion (Study Day 60). 
 be taken 
together. 
Patients will be instructed that they must bring any unused rescue medication (oxycodone IR and 
acetaminophen) with them to the clinic visits (through Visit 6 or early termination) for 
reconciliation purposes. The number of tablets dispensed will be recorded and the number of 
remaining tablets will be counted at each clinic visit.   
7.6.3.2.1 Rescue Oral Opioid 
For the treatment of moderate to severe pain, patients will be prescribed oxycodone IR 5 mg 
tablets.  Exactly 24 tablets should be prescribed.  One or two tablets may be taken every 4 hours 
for moderate to severe pain.  Each dose of oxycodone will be recorded by the patient on their 
LogPad.  
7.6.3.2.2 Rescue Oral Acetaminophen  
For the treatment of mild to moderate pain, patients will be supplied by the sponsor with 
acetaminophen 500 mg tablets (one bottle of 24 tablets).  One or two tablets may be taken every 
4 hours as required for pain.  No more than 8 tablets (4000 mg) may be taken in any 24 hour 
period.  Each dose of acetaminophen will be recorded by the patient on their LogPad.  A screen 
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will display an alert that they have reached the maximum allowed dose when a patient takes an 
8th tablet (4000 mg total) in any 24 hour period. 
7.6.3.2.3 No Concomitant Use of Oxycodone and Acetaminophen 
Oxycodone and acetaminophen may not be taken concomitantly within the same four hour 
interval. 
7.6.3.3 
Recording of Rescue Analgesia Data 
Identity, dose and time of administration of rescue analgesia, will be recorded as follows: 
• IV rescue medication and associated pre-rescue pain scores 
 on movement – 
On the appropriate source document and eCRF from patient awakening from anesthesia 
to discharge. 
o If the patient is unable to sit up all the way due to severe pain, weakness, or lack 
of recovery from anesthesia, the patient should be instructed to make his or her 
best attempt, and that score will be recorded (e.g. if patient can only sit up 
partway, then the pain that the patient feels in that position will be recorded). 
• Oral rescue medication (oxycodone or acetaminophen) in the LogPad till Study Day 8 
(POD 7) and associated pre-rescue pain scores 
 on movement through Study 
Day 4 (POD 3). 
• Rescue medication including NSAIDs taken for pain relief after Study Day 8 (POD 7) 
will be recorded on the appropriate source document and CM eCRF. 
• The number of oxycodone and acetaminophen tablets prescribed/dispensed and the 
number of tablets remaining at each clinic visit will be recorded on the appropriate source 
document and eCRF.  
The LogPad will be the primary data source for oral opioid rescue medication taken through 
Study Day 8 (POD 7) and the eCRF will be the primary data source for IV rescue medication 
taken throughout the trial and oral rescue medication taken after Study Day 8 (POD 7).  
8.0 
Assessment of Efficacy 
8.1 
Efficacy Assessments 
• Pain intensity on movement measured at scheduled time points from 0-48 hours 
following test drug administration, adjusted for prior rescue medication use and analyzed 
by a mixed effect ANOVA model of repeated measures (MMRM). 
Primary Efficacy Endpoint: 
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To account for the impact of rescue medication use on the scheduled pain scores, the half-life 
substitution method will be used. Specifically, if the scheduled pain score has been assessed 
within one plasma half-life after the use of rescue medication (IV or oral opioid or oral 
acetaminophen), and if the pre-rescue medication pain score is higher than the scheduled one, 
then the pain score recorded at the time of rescue medication administration will be 
substituted for the scheduled pain score (FDA, 2014).  If a rescue medication pain score is 
missing, then the worst pain score up to that point will be substituted instead 
Pain intensity on movement measured at scheduled time points from 0-72 hours following test 
drug administration, adjusted for prior rescue medication use and analyzed by a mixed effect 
ANOVA model of repeated measures (MMRM).
Key Secondary Efficacy Endpoint: 
Total IV morphine-equivalent dose of rescue opioids used during 0-72 hours following 
test drug administration (standard conversion factors are used to convert different opioids 
to IV morphine-equivalents; 
Additional Secondary Efficacy Endpoints:  
 
• Composite endpoint of Silverman’s Integrated Analgesic (SIA) assessment score 
(Dai et al, 2013 and Silverman et al, 1993) over 0-72 hours following test drug 
administration 
• Proportion of patients taking no opioid rescue medication from PACU discharge until 
72 hours after test drug administration 
• Time to first opioid rescue medication use after PACU discharge 
• Time to PACU discharge eligibility as assessed by mPADSS (Chung, 1995; Awad and 
Chung, 2006)   
 
 
 
 
 
 
 
 
 
 
 
 
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8.2 
Method and Rationale for Assessments 
8.2.1 
Pain Intensity Endpoints 
Pain intensity evaluations will be completed 
 on movement (defined as sitting up, or 
attempting to do so, from a supine position).  
 
 Patients should then record 
their pain-on-movement score by sitting up, or attempting to do so, from a supine position and 
recording the worst pain experienced during the movement.  
Patients will assess their pain intensity using an 11-point Numeric Pain Rating Scale (NPRS) 
(Breivik et al. 2008; Hjermstad et al 2011; Cook et al 2013), 
 with numerical 
rating scale (NRS) scores ranging from 0 (no pain) to 10 (worst pain imaginable).  Each patient 
completes the NPRS by selecting the appropriate score on the scale and recording the score in 
the LogPad at the scheduled times noted in Table 2: Patient LogPad Schedule of Events and prior 
to taking an oral rescue medication through Study Day 4 (POD 3). Prior to receiving each dose 
of IV rescue medication in the PACU, the patient’s pain scores 
 on movement (defined 
as sitting up, or attempting to do so, from a supine position) should be assessed and site 
personnel will record it on the appropriate source document and eCRF.  
• 
If the patient is unable to sit up all the way due to severe pain, weakness, or 
incomplete recovery from anesthesia, the patient should be instructed to make his or 
her best attempt, and that score will be recorded (e.g. if patient can only sit up 
partway, then the pain score that the patient feels in that position will be recorded).  
• 
Patients must not
• 
All patients will watch the training video which is designed to inform the patient of 
the research goals of the trial, how to properly estimate their pain scores and how to 
appropriately use rescue medications. 
 use motorized bed or recliner controls to sit up or receive assistance 
from a caregiver for the pain on movement assessments.  
Patient-reported pain is an established variable to capture postoperative analgesic effects 
(FDA, February 2014).   
8.2.2 
Rescue Opioid Endpoints   
Rescue opioid medication (both IV and oral) may be taken for postoperative pain relief and will 
be recorded as noted in Section 7.6.3. 
All opioid doses, whether administered IV or orally, will be converted into IV morphine 
milligram (mg) equivalents, a standard procedure to allow the calculation of analgesic effects 
even if opioids of different potency are used 
 
Reduction of opioid consumption after surgery is an important potential benefit of 
SABER®-Bupivacaine.  Total opioid use over the first 72 hours following surgery will therefore 
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be evaluated as a secondary endpoint. The 72-hour assessment period corresponds with the 
expected duration of SABER®-Bupivacaine activity and the interval during which postoperative 
pain scores will be assessed. All opioid medications consumed during this period, including 
those administered intravenously in the PACU and those taken orally by the patient at home will 
be counted toward the total. 
Two other measures of opioid use will also be assessed as secondary endpoints: (1) the time to 
first use of opioid rescue medication by the patient after discharge from the PACU (oral 
oxycodone in all cases except possibly those in which the subject has an unplanned admission to 
the hospital after surgery) and (2) the percentage of patients not requiring any opioid rescue 
medication after discharge from the PACU until 72 hours after test drug administration. In both 
these cases, only opioid analgesics administered after PACU discharge will be counted. The 
rationale for this arrangement is twofold. First, such opioid-sparing effects would likely be more 
meaningful if demonstrated in the uncontrolled environment of the patient’s home than in the 
controlled and carefully monitored setting of the PACU, where use of postoperative opioids has 
been routine. Second, data from trial C803-025, Cohort 2 indicate that nearly all laparoscopic 
cholecystectomy patients receive at least 1 dose of opioid rescue medication in the PACU, which 
would render both these endpoints effectively moot. 
In previous studies of SABER®-Bupivacaine in inguinal hernia repair (CLIN-803-006-0006) and 
sub-acromial decompression of the shoulder (BU-002-IM), outcomes related to reduced opioid 
consumption consistent with the three aforementioned endpoints were explored as primary, co-
primary, or secondary endpoints. In both trials, SABER®-Bupivacaine 5 mL significantly 
reduced total postoperative opioid use and prolonged the time to first opioid use compared with 
SABER®-Placebo.  
8.2.3 
Modified Post-Anesthesia Discharge Scoring System (mPADSS) 
PACU discharge eligibility will be assessed with the mPADSS, starting at 30 minutes after 
arrival in the PACU and repeated at 15 minute intervals (±5 minutes) until the patient is eligible 
for discharge (i.e. an mPADSS score of 9 or greater). The results will be recorded on the 
appropriate source document and eCRF.  NOTE: patients must be monitored for vital signs for at 
least 2 hours after surgery as described in Section 9.2.4, even if their mPADSS score indicates 
that they may be discharged.  Conversely, patients must continue to be monitored and may not be 
discharged until the mPADSS score has reached 9 or greater.  The time of arrival 
 
 from PACU will also be recorded on the appropriate source document and 
eCRF.   
mPADSS is a widely recognized, published tool used to determine eligibility for discharge from 
the PACU after ambulatory surgery (Chung, 1995; Awad and Chung, 2006).  The mPADSS 
includes an assessment of five parameters: vital signs, activity level, nausea/vomiting, pain, and 
surgical bleeding. For pharmacoeconomic purposes, this trial will evaluate eligibility for PACU 
discharge using a version of mPADSS that has been slightly modified for ease of administration 
and to suit the surgical model under study 
 The mPADSS tool provides a 
standardized means of assessing eligibility for PACU discharge across multiple investigative 
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sites and also ensures that nonmedical complications, such as a missing ride home, do not 
interfere with evaluation of test drug effects. 
9.0 
Assessment of Safety 
9.1 
Safety Assessments: Patient Visits and Follow-Up Phone Calls 
• Adverse events  
o Spontaneously reported AEs; either volunteered by the patient, prompted by non-
directed questioning or reported by an investigator will be documented on the 
eCRF. 
o The following AEs will be solicited and recorded at specified time points (see 
Table 2) using the Log Pad: dizziness, somnolence, constipation, nausea, 
vomiting, pruritus, headache, dysgeusia, hypoesthesia, and paresthesia  
• Standard 12-lead ECG  
• Safety Laboratory Tests (Serum chemistry, hematology, urinalysis)  
• Vital Signs and Physical Examination  
• Surgical site examination for 
 bruising, bleeding or drainage 
from the incision(s), hematoma, dehiscence, infection and healing  
9.2 
Method and Timing of Assessments 
9.2.1 
Adverse Event Recording  
Pain that has been evaluated as part of the efficacy endpoints will not
Adverse events will be recorded from the time the patient signs the informed consent form 
through trial completion final visit/early termination (see Section 
 be considered an 
adverse event.   
9.3).   
9.2.1.1 
Spontaneously Reported Adverse Events 
At each contact between the investigative site and the patient (visit or phone call), after the 
patient has had an opportunity to spontaneously mention any problems, the Investigator should 
inquire about the occurrence of AEs.  All AE details including severity and causality from 
screening through trial completion will be recorded by trial staff on the appropriate source 
document and AE eCRF.  
9.2.1.2 
Solicited Patient-Reported Adverse Events 
The solicited patient-reported AEs that must be recorded at specified times on the LogPad (see 
Table 2) are: dizziness, somnolence (drowsiness), constipation, nausea, vomiting, pruritus 
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(itching), headache, Dysgeusia (metallic taste in mouth), paresthesia (tingling or pins and 
needles), and hypoesthesia (numbness) (see Section 7.5). 
These ten adverse events were chosen for detailed study by solicitation on the LogPad for two 
reasons.  First, many of these AEs are common symptoms associated with opioid administration 
(Zhao et al, 2004; Daniels et al, 2009; YaDeau et al, 2011).  If treatment with SABER®-
Bupivacaine results in a reduced consumption of rescue opioids compared to placebo or 
bupivacaine HCl, there may also be a concomitant reduction in the incidence of these adverse 
events.  This reduction in opioid-related adverse events could then be regarded as an additional 
benefit of SABER®-Bupivacaine treatment.  
 
 
If the patient reports an AE on the LogPad investigative site personnel will receive an alert. At 
each point of contact, investigative site personnel will follow-up with the patient regarding 
severity, frequency, duration and action taken of any AEs reported on the LogPad and 
appropriately document this data and causality in the source and AE eCRF.   
9.2.2 
12-Lead ECGs  
Standard resting 12-lead ECGs will be obtained at the Screening Visit, Visit 6, and Visit 7, or 
Early Termination Visit.  Overall interpretation and machine read intervals (HR, PR, QRS, QT, 
and QTc) will be recorded on the ECG eCRF.  Clinically significant ECG findings that emerge 
after treatment will be recorded on the AE eCRF. 
9.2.3 
Laboratory Tests 
All routine laboratory analyses will be conducted by a central laboratory and have been listed 
below.  Laboratory tests will be obtained as indicated on the Schedule of Events table. 
Instructions on sample collection, processing and shipment will be provided in a separate 
laboratory manual.   
Female patients of childbearing potential will have a serum pregnancy test at Screening and a 
urine pregnancy test on the day of surgery.  The urine pregnancy test will be performed locally at 
the investigative site.   
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Table 4: Safety Laboratory Tests 
Blood Chemistry 
ALT (SGPT)  
Creatine Kinase (CK)  
Albumin  
Glucose  
Amylase (screening only) 
Lactate dehydrogenase (LDH) 
AST (SGOT)  
Lipase (screening only) 
Alkaline Phosphatase  
Phosphorus  
Bilirubin (direct and total)  
Potassium  
BUN  
Protein (total)  
Serum Creatinine  
Sodium  
Calcium  
Triglycerides  
Cholesterol (total)  
Uric Acid  
Chloride 
Bicarbonate 
Hematology 
Hematocrit  
Red blood cell (RBC) count 
Hemoglobin  
Platelet count 
White blood cell (WBC) count with differential (absolute count and percent of neutrophils, lymphocytes, 
monocytes, eosinophils, and basophils) 
Other 
Serum and Urine Pregnancy hCG 
Routine Urinalysis including Color, Appearance, Specific Gravity, pH, Protein, Glucose, Ketones, 
Bilirubin, Blood, Urobilinogen, Nitrite and Leukocyte Esterase 
Urine drug toxicology screen for opiates, oxycodone, cannabinoids, amphetamines, cocaine, and 
methadone (screening only) 
 
Laboratory values that are out of range for the Central lab will be identified and may be repeated 
at the Investigator's discretion and sent to the Central lab.  The Investigator will classify 
laboratory values outside the normal range as either clinically significant or not clinically 
significant.  Clinically significant laboratory values outside the normal range that emerge after 
treatment will be recorded on the AE eCRF.  Clinically significant out of range laboratory values 
that emerge after treatment will be followed and treated (if appropriate) by the Investigator until 
they return to normal.   
9.2.4 
Vital Signs 
Systolic/diastolic blood pressure, heart rate, respiratory rate, and temperature will be measured.  
Blood pressure and heart rate will be measured after the patient has been resting (supine or 
sitting) for 5 minutes.  Pulse oxygen saturation will be continuously measured on Visit 2 pre- and 
post-surgery, and recorded at 15 minute intervals for a period of at least 2 hours after surgery.  
Measurements will be taken at the times specified in the Schedule of Events table and will be 
recorded on the appropriate source document and Vital Sign eCRF. 


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9.2.5 
Physical Examination 
A physical examination including height and weight will be conducted at the Screening Visit to 
confirm if the patient meets trial criteria.  
A physical examination (including weight) will be conducted at Visit 6 (Study Day 29) and 
Visit 7 (Study Day 60), or Early Termination Visit. Any changes from baseline outside the 
normal range that emerge after treatment will be recorded on the AE eCRF.   
9.2.6 
Surgical Site Examination and Assessment of Surgical Site AEs 
At each clinic visit, the wound evaluator (an investigator or other medically qualified 
investigative site personnel who will remain blinded to treatment assignment) will assess the 
surgical sites for the presence or absence of bruising, bleeding or drainage from incision(s), 
hematoma, dehiscence, or infection.  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Surgical site healing will also be assessed with a questionnaire at the Study Day 2 and Study 
Day 3 Follow-up Phone Calls 
 This questionnaire may elicit clinically 
significant alterations in surgical site healing.  During the next clinic visit (or earlier if medically 
necessary) investigative site personnel will follow-up on questionnaire responses suggesting 
clinically significant alterations in surgical site healing.  
9.3 
Adverse Events  
9.3.1 
Definitions 
An adverse event (AE) is any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product and which does not necessarily have to have a 
causal relationship with this treatment.  An AE can therefore be any unfavorable and unintended 
sign or symptom, including clinically significant laboratory values and test results, concomitant 
illness, accident, or worsening of an existing medical condition. 
Adverse Event 
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The following should not
• A pre-planned procedure for an illness included in the patient’s medical history, unless the 
condition for which the procedure was planned has worsened since baseline.  Please observe 
that complications to pre-planned procedures should be recorded as AEs 
 be recorded as an AE if noted at screening: 
• A pre-existing condition found as a result of screening procedures 
Any worsening in severity or frequency of a baseline concomitant illness or any new illness 
diagnosed in the trial period must be regarded as an AE. 
Pain that is evaluated as part of the efficacy endpoints will not be considered an adverse 
event.   
A serious adverse event (SAE) is any adverse event that, at any dose: 
Serious Adverse Event 
• Results in death  
• Is life-threatening  
o Life-threatening refers to an event in which the patient is at risk of death at the time 
of the event.  It does not include an event that, had it occurred in a more severe form, 
might have caused death 
• Requires inpatient hospitalization or prolongation of existing hospitalization – Inpatient 
hospitalization includes an overnight admission 
• Results in persistent or significant disability/incapacity  
o Disability is defined as a substantial disruption of a person’s ability to conduct normal 
life functions 
• Results in the birth of a child with a congenital anomaly/birth defect 
• Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered an SAE (when based upon appropriate medical judgment). 
These events may jeopardize the patient and may require medical or surgical intervention to 
prevent one of the outcomes listed above 
Three serious adverse events are pre-specified as SAEs of special interest and were chosen for 
close monitoring by the sponsor medical monitor because of their clinical importance: 
Serious Adverse Events of Special Interest 
1) Wound dehiscence reported as an SAE 
2) Wound hematoma reported as an SAE 
3) Surgical site infection reported as an SAE 
The detailed definitions for these surgical complications are in Section 9.2.6.  Details of the 
monitoring procedures are in Section 9.3.4. 


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An adverse reaction (AR) is any untoward and unintended response to a test drug that has been 
considered to have a causal relationship with the treatment. 
Adverse Reaction  
A suspected unexpected serious adverse reaction (SUSAR) is an adverse reaction that is serious 
and where the nature or severity of which is not consistent with information in the current 
Investigator’s Brochure. 
Suspected Unexpected Serious Adverse Reaction 
An abnormal laboratory value (i.e. any clinical laboratory abnormality or change that suggests a 
disease and/or organ toxicity and is of a severity that requires active management [i.e. change of 
test drug dose, discontinuation of test drug, medical treatment, more frequent follow-up or 
diagnostic investigation]), will be regarded as an AE.  If clinical sequelae have been associated 
with a laboratory abnormality the diagnosis or medical condition should be reported (e.g. renal 
failure, hematuria) to replace the laboratory abnormality (e.g. elevated creatinine, urine RBC 
increased).   
Abnormal Laboratory Value as an AE 
9.3.1.1 
Classifications 
A blinded Investigator will evaluate the severity of each adverse event using the following 
definitions: 
Severity  
Mild – Transient symptoms, no interference with the patient’s daily activities 
Moderate – Marked symptoms, moderate interference with the patient’s daily activities 
Severe – Considerable interference with the patient’s daily activities 
An AE that has been assessed as severe should not be confused with an SAE.  Severity is a 
category utilized for rating the intensity of an event; and both AEs and SAEs can be assessed as 
severe.  An event should be described as ‘serious’ when it meets one of the pre-defined outcomes 
as described in Section 9.3.1. 
A blinded Investigator is obligated to assess the relationship between test drug and the 
occurrence of each AE/SAE.  The Investigator will use clinical judgment to determine if there is 
a reasonable possibility that the pharmacological action of the test drug was responsible for the 
AE/SAE being reported.  Alternative causes such as natural history of the underlying diseases, 
concomitant therapy, other risk factors, and the temporal relationship of the event to the test drug 
will be considered and investigated.  The Investigator will also consult the Clinical Investigator’s 
Brochure and/or Product Information, for marketed products, in the determination of his/her 
assessment. 
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After careful medical consideration, the Investigator will evaluate the relationship of each 
adverse event to test drug applying the following definitions: 
Probably Related – Good reasons and sufficient documentation to assume a causal relationship 
Possibly related – A causal relationship is conceivable  
Unlikely related – The event is most likely related to etiology other than the test drug   
Not Related – Good reasons and sufficient documentation to exclude a causal relationship. 
There may be situations when an SAE has occurred and the Investigator has minimal information 
to include in the initial report.  However, it is very important that the Investigator always make 
an assessment of causality for every event prior to transmission of the SAE Report Form to the 
Sponsor (or designee). 
9.3.2 
Adverse Event Reporting 
All events that meet the definition of an AE that occur in the period from when the patient has 
signed the informed consent form (ICF) through trial completion (final visit), or early 
termination, must be recorded on the adverse event eCRF. All SAEs will be recorded on the 
appropriate eCRF and on the Serious Adverse Event Report Form from the time written 
informed consent has been obtained through trial completion (final visit), or early termination. 
At each contact between the investigative site and the patient (visit or phone), after the patient 
has had an opportunity to spontaneously mention any problems, the Investigator should inquire 
about the occurrence of AEs.  The following are examples of open-ended questions that may be 
used to obtain this information:  
“How are you feeling?” 
“Have you had any medical problems since your last visit/assessment?”  
“Have you taken any new medicines, other than those given to you in this study, since your last 
visit/assessment?”  
All AEs and SAEs will be documented in source records at each assessment time or when 
otherwise volunteered by the patient and recorded on the appropriate eCRF. Information to be 
collected includes the nature, date and time of onset, severity, duration, relationship to test drug, 
and outcome of the event.  Even if the Investigator assesses the AE as not reasonably attributable 
to the test drug, its occurrence must be recorded in the source documents and reported on the 
eCRF along with the assessment of association. 
The Investigator will treat the patient as medically required, and this may extend beyond the 
duration of the trial.  The Investigator will record treatment and medications required to treat 
AEs on the appropriate eCRF(s). All AEs will be followed until resolution (no further changes in 


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the event are expected, i.e., the point at which a subject experiencing such an AE is appropriately 
treated and stabilized even though they may continue to experience lingering sequelae that may 
never resolve) unless the patient is lost to follow up.   
DURECT will evaluate all AEs with respect to seriousness, causality and expectedness in 
accordance with Directive 2001/20/EC (3) and FDA Guidelines.  The expectedness of an AE 
will be determined according to the current version of the Investigators Brochure. 
9.3.3 
Reporting of Serious Adverse Events 
Regardless of causality, the investigator must complete and submit an SAE form to 
 Safety Surveillance within 24 hours of 
knowledge of the event for all serious adverse events. 
SAEs will be reported to:  
 Safety Surveillance  
Fax:  
 (toll free)  
The Investigator must indicate the SAE’s relationship to test drug and sign the SAE form.  When 
additional relevant information (final diagnosis, outcome, results of specific investigations, etc.) 
becomes available, the investigator must record that follow-up information in the eCRF.  Follow-
up information should be recorded according to the process used for reporting the initial event as 
described above.  The investigator will follow all reportable events (i.e., SAEs) until resolution. 
Resolution means no further changes in the event would be expected, i.e., the point at which a 
subject experiencing such an AE is appropriately treated and stabilized even though they may 
continue to experience lingering non-serious sequelae that may never resolve.    
Safety Surveillance will follow all SAEs until resolution (no further changes in the event are 
expected, i.e., the point at which a subject experiencing such an AE is appropriately treated and 
stabilized even though they may continue to experience lingering sequelae that may never 
resolve).  Safety Surveillance will report all SAEs to DURECT within 1 business day of receipt.    
All serious adverse events will also be reported on the AE CRF and concomitant medications 
administered in association with the serious AE will be documented on the CM CRF. 
If a serious adverse event occurs and comes to the attention of the Investigator after trial 
completion/termination within 60 days of test drug dosing or within 30 days of the last trial visit 
(whichever occurs later), it must be reported immediately to Safety Surveillance in the same 
manner as the serious adverse events occurring during the trial. Investigators are not obligated to 
actively seek AEs from former study participants. 
The Investigator must report SAEs to the IRB/IEC (per the IRB/IEC guidelines/SOPs), including 
all SAEs that have occurred at the investigative site and all trial related SAEs that have resulted 
in an expedited safety report to a regulatory agency.  Concurrently, the Investigator must send 
DURECT documentation of such IRB/IEC notification or if reporting is not required 
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immediately per IRB/IEC guidelines, then a copy of the local SOP stating the reporting 
guidelines should be supplied by the site to DURECT and the CRO.   
DURECT complies with applicable regulatory requirement(s) related to the reporting of 
SUSARs to the competent authorities and the IRBs/IECs.  In addition, DURECT will prepare 
annual safety reports covering all SUSARs that have occurred in clinical studies with the 
concerned test drug during the reporting period. 
9.3.4 
Serious Adverse Events of Special Interest 
Based on previous clinical experience, three serious adverse events are being pre-specified for 
close monitoring. The following pre-specified surgical wound complications, when reported as 
SAEs, are of special interest to DURECT 
 (see Section 9.2.6 for detailed 
definitions): 
1) Wound dehiscence reported as an SAE 
2) Wound hematoma reported as an SAE 
3) Surgical site infection reported as an SAE 
The sponsor medical monitor will carefully monitor the blinded safety data for any occurrence of 
these pre-specified SAEs.  SAEs of special interest will be reported both to the Safety 
Assessment Committee (SAC), 
 and to the FDA in accordance with 
safety reporting regulations.  The expected incidence rate of the individual SAEs of special 
interest will be less than 1% based on the previous clinical experience with SABER-Bupivacaine 
and the published literature (Richards et al, 2003; Fahrner et al, 2014; Keus et al, 2009; Shea et 
al, 1996).  Non-serious instances of these surgical wound complications will be analyzed as AEs 
(as described in Section 9.2.6 and 9.3.2) 
 
9.3.5 
Cardiac or Neurological Serious Adverse Events 
If a cardiac or neurological SAE occurs within 48 hours of dosing, a blood sample 
(approximately 8 mL) will be collected as soon as possible for measurement of plasma 
bupivacaine 
  The collection date and time should be 
documented.  Refer to the sample processing, shipping and handling instructions provided within 
the laboratory manual.  
9.3.6 
Adverse Event Follow-up 
During and after participation by a patient in a clinical trial, the Investigator will ensure that 
adequate medical care has been provided to the patient for any AEs including clinically 
significant laboratory values related to the trial.  The Investigator will inform the patient when 
medical care will be needed for intercurrent illness(es) of which Investigator becomes aware.  
All AEs must be followed by the Investigator until resolution (no further changes in the event are 
expected, i.e., the point at which a subject experiencing such an AE has been appropriately 
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treated and stabilized even though they may continue to experience lingering sequelae that may 
never resolve), until the subject is lost to follow-up, or died and until all queries related to the 
AEs have been resolved.  Investigators will make at least 3 documented attempts to contact a 
subject before considering the subject lost to follow-up.  The first two attempts may be by letter, 
email or documented phone call and the third and final attempt must be by Registered Mail, 
Return Receipt Requested. If a subject dies during participation in the study or during a 
recognized follow-up period, the Sponsor (or designee) must be notified immediately and then 
provided with a copy of any post-mortem findings, including histopathology.   
 
9.4 
Pregnancy 
Female patients will be advised to notify the Investigator immediately if they become pregnant 
during the course of the trial.   
The Investigator must complete the appropriate pregnancy reporting forms and send them to 
DURECT (or DURECT’s designee) within 14 calendar days of obtaining information of the 
pregnancy.  The Investigator will follow the pregnancy through its course and complete the 
appropriate documentation and forward immediately to DURECT (or DURECT’s designee).  
The infant must be followed at least until one month of age. Consent of a parent must be 
obtained before registration of infant data. 
Abortion, stillbirth and any malformation/disease must be reported as an SAE.  A pregnancy 
outcome other than abortion, stillbirth and any malformation/disease as well as follow-up of the 
infant must be reported by the Investigator within 14 calendar days of obtaining the information 
using the appropriate pregnancy reporting forms. 
10.0 
Pharmacokinetics 
No PK assessments have been planned for this trial. 
 
11.0 
  Statistical Methods and Data Analysis 
11.1 
Trial Design Considerations  
This part will be a randomized, parallel-group, double-blind, placebo-controlled, multi-center 
trial evaluating the safety and efficacy of SABER®-Bupivacaine 5 mL in patients undergoing 
elective outpatient laparoscopic cholecystectomy.   
Part 1  
 
 
 
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This part will be a randomized, parallel-group, double-blind, active-controlled, multi-center trial 
evaluating the safety and efficacy of SABER®-Bupivacaine 5 mL in patients undergoing elective 
outpatient laparoscopic cholecystectomy.   
Part 2 
The primary efficacy objective will be to investigate whether SABER®-Bupivacaine will 
significantly reduce pain compared to bupivacaine HCl (75 mg) over 48 hours following 
test drug administration in patients undergoing laparoscopic cholecystectomy.  
It has been planned that the data from centers that participate in this trial will be combined such 
that an adequate number of subjects will be available for analysis.  
Unless otherwise specified, all statistical tests will be conducted employing a two-sided 
significance level of 0.05. 
11.2 
Sample Size Determination 
One hundred fifty three subjects enrolled in each treatment group of the study will result in 90% 
power (assuming type 1 error rate of 5%) to detect a difference between 5 mL of  SABER®-
Bupivacaine and 5 mL of saline placebo 
 
 
Part 1 
 
  
 
 The size of the final enrollment will be approximately 90 
subjects determined by the readiness of sites to enroll subjects under IRB-approved Part 2. 
One hundred thirty-two subjects enrolled in each treatment group of the study will result in 90% 
power (assuming type 1 error rate of 5%) to detect a difference between 5 mL of  
SABER®-Bupivacaine and 15 mL of 0.5% bupivacaine HCl 
 
 
 
 
Part 2 
 
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11.3 
Patient Randomization  
It was planned that approximately 320 eligible patients would be randomized, in order to obtain 
306 evaluable patients (i.e., patients who received any test drug and have at least one post-
surgical pain intensity score).  It had been estimated that 5% of randomized patients may not 
receive any test drug due to unforeseeable intra-operative exclusion.  Patients would be 
randomized in a 1:1 ratio to receive one of two treatments based on a computer-generated 
randomization schedule prepared before the study:  
Part 1 
• Treatment Group 1: SABER®-Bupivacaine 5 mL (132 mg/mL, 660 mg bupivacaine base) 
• Treatment Group 2: Sterile normal saline 5 mL (0.9% sodium chloride injection, USP) 
(placebo) 
Due to the early administrative stopping, only approximately 90 subjects will be enrolled and 
randomized in Part 1. 
Approximately 274 eligible patients will be randomized, in order to obtain 264 evaluable patients 
(i.e., patients who are randomized and received any test drug).  It has been estimated that 4% of 
randomized patients may not receive any test drug due to unforeseeable intra-operative 
exclusion.  Patients will be randomized in a 1:1 ratio to receive one of two treatments based on a 
computer-generated randomization schedule prepared before the study:  
Part 2 
• Treatment Group 3: SABER®-Bupivacaine 5 mL (132 mg/mL, 660 mg bupivacaine base) 
• Treatment Group 4: Bupivacaine HCl without epinephrine, 15 mL of 0.5% solution 
(75 mg) 
For both Part 1 and 2, the randomization will be balanced by using randomly permuted blocks 
(block size of 4) and will be stratified by sex.  The rationale for stratification by sex was 
differences in pain response reported in the literature for both acute/chronic pain (Fillingim et al, 
2009), postoperative pain studies in cholecystectomy (De Cosmo et al, 2008; Uchiyama et al, 
2006) and a previous laparoscopic cholecystectomy trial (C803-025, Cohort 2) conducted by 
DURECT.  De Cosmo et al found that females had a higher mean pain score (4.3 ± 2.1) than 
males (2.9 ± 1.6) during 24 hours postoperatively (p=0.003 from repeated measure ANOVA).  A 
significant sex effect on 24-hour postoperative pain was also reported by Uchiyama et al.  
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If a given study center approaches randomization of 20% of the total number of evaluable 
subjects (264) into Part 2 of the trial, the Sponsor will assess the appropriateness of allowing the 
center to continue randomizing additional subjects into the trial based upon factors such as 
monitored site performance including documentation and protocol compliance. An IWRS system 
will be used to assign subjects to a treatment group. 
If all Screening (i.e. pre-operative) Inclusion/Exclusion criteria are met, randomization can be 
done up to 1 business day prior to surgery. In the event that a randomized patient does not have 
the surgical procedure for unforeseen circumstances (such as conversion to open surgery, or the 
need to use more than 4 laparoscopic ports) or does not receive any test drug, replacement of the 
patient has been planned. IWRS system will be algorithmically instructed to issue the appropriate 
randomization replacement and to ensure the balance of treatment as planned. Precise details on 
the IWRS algorithm will be described in the IWRS specifications.  
11.4 
Definition of Analysis Population 
ITT Population: The ITT population will consist of all randomized patients in both Part 1 and 
Part 2 independent of their exposure to test drug or completion of surgery.  However, the primary 
efficacy analysis will include only Part 2 data. 
Safety Population: The Safety population will consist of all subjects in both Part 1 and Part 2 
who received any amount of test drug.  The Safety population will be used for all safety 
analyses. 
Modified Intention-to-Treat (mITT) Population: All randomized patients in both Part 1 and 
Part 2 who receive any test drug.  However, the primary efficacy analysis will include only 
Part 2 data. 
All efficacy endpoints will be analyzed using the mITT set.  
11.5 
General Statistical Analysis Considerations  
The primary efficacy analysis will include only Part 2 data.  Due to the early stopping of Part 1 
enrollment, for secondary and exploratory efficacy endpoints, the efficacy data from the 
SABER®-Bupivacaine arm from Part 1 will be integrated with the same treatment arm from Part 
2 and be compared to bupivacaine HCl (75 mg) over 72 hours.  Inferential statistics will be 
derived from the comparison. Due to lack of full enrollment of subjects from Part 1, the efficacy 
will be descriptive, presented as either mean or ratio and its 95% confidence interval as 
appropriately applied. 
Continuous variables will be generally summarized using descriptive statistics such as mean, 
median, standard deviation, standard error and ranges.  Categorical variables will be summarized 
using frequencies and percentages. 95% confidence intervals will also be provided when 
appropriate. Inferential tests for the analysis of continuous variables will be primarily based on 
parametric general linear models and will be 2-sided and conducted at the overall 
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The multiplicity of comparisons impact on the Type 1 error rate will be addressed below 
(Section 11.8.4).  In the case where the general linear model assumptions appear to be 
significantly violated, nonparametric methods of analysis such as the Wilcoxon Rank-Sum test 
will be used.  A data transformation will also be made in an attempt to achieve a successful 
normalization of non-normal data. Inferential tests for categorical variables will be based on 
logistic regression models and categorical data analysis models.  In cases where the cell counts 
(i.e. percentages) are too small for asymptotic methods to be valid, exact tests such as Fisher’s 
exact test will be used. 
Unless otherwise specified, all statistical tests will be conducted employing a two-sided 
significance level of 0.05. 
11.6 
Methodology for Dropouts and/or Missing Data 
For the primary efficacy endpoint (scheduled pain on movement, adjusted for prior rescue 
medication use) the repeated measures ANOVA will handle data missing at random.  However, 
detailed tabulation of the amount, percentage of subjects, and pattern of missing data by 
treatment group over time will be presented.  Two approaches will be used to impute a missing 
pain score. For any dropout prior to 72 hours due to adverse event or lack of efficacy, a single 
imputation of worst value carried forward (WOCF; 
Imputation for Missing Pain Score 
FDA, 2014) will be used. For dropouts due 
to other reasons or intermittent missing values, a multiple imputation algorithm (Markov Chain 
Monte Carlo method [MCMC]) will be used (Yuan, 2010).  The detailed implementation of these 
analyses will be described in a separate Statistical Analysis Plan (SAP). 
If it is indicated on the LogPad that no rescue medication was used, a dose of zero milligrams 
will be imputed.  The lack of rescue medication use will be verified using data from the site 
rescue medication reconciliation/pill count.  If there is a discrepancy between the rescue 
medication entered in the LogPad and the pill count at the study visit, the LogPad results will be 
used for analysis. 
Rescue Medication Use 
 
For any time to event variable (e.g., time to the first use of a rescue opioid after discharge from 
the PACU), the Kaplan-Meier method will be used to analyze it by using the event time when a 
subject has the first event or the entire follow-up time when a subject does not have the event. 
For the latter, the variable will be censored at the time of last follow-up.  No imputation will be 
made. 
Time-to-Event Variables 
11.7 
Demographic and Baseline Characteristics 
For Part 1 and 2, continuous variables will be summarized using descriptive statistics such as 
mean, median, standard deviation, standard error and ranges.  Categorical variables will be 


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summarized using frequencies and percentages. 95% confidence intervals will also be provided 
when appropriate. 
11.8 
Statistical Analyses of Efficacy Endpoints 
The principal analyses of the primary efficacy endpoint will be carried out based on the modified 
Intention-to-Treat (mITT) set comprising all randomized patients who receive trial drug in 
Part 2. 
11.8.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint is:  
Part 2 
• Pain intensity on movement measured at scheduled time points from 0-48 hours 
following test drug administration, adjusted for prior rescue medication use and analyzed 
by a mixed effect ANOVA model of repeated measures (MMRM) 
To account for the impact of rescue medication use on the scheduled pain scores, the following 
substitution method will be used. If the scheduled pain on movement score has been assessed 
within one plasma half-life after the use of rescue medication (IV or oral opioid, or 
acetaminophen), and if the pre-rescue medication pain score is higher than the scheduled one, the 
pain score will be censored and the rescue medication pain score will substitute for it (FDA, 
2014).  If any of the rescue pain scores are missing, then the worst pain score up to that point will 
be used instead.   
Data derived from the assessment of pain intensity on movement will be used to test the 
hypotheses as described below: 
Null hypothesis: 
There is no difference in analgesic effect between subjects treated with SABER®-Bupivacaine 
and those treated with bupivacaine HCl, as measured by pain intensity on movement scores over 
0-48 hours following test drug administration, with adjustment for sex effect and imputation for 
missing pain scores. 
Alternate hypothesis: 
There is a difference in analgesic effect between subjects treated with SABER®-Bupivacaine and 
those treated with bupivacaine HCl, as measured by pain intensity on movement scores over 
0-48 hours following test drug administration, with adjustment for sex effect and imputation for 
missing pain scores. 
The pain scores will be analyzed by a mixed effect ANOVA model of repeated measures 
(MMRM). The model includes the following fixed effects: sex stratum, treatment, sex by 


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treatment, time, interaction of treatment and time, study site and interaction of study site and 
treatment, with time as the repeating factor and subject as a random effect. 
11.8.1.1 
Sensitivity analysis of the primary endpoint 
In addition to the primary analysis, several sensitivity analyses will also be employed as below: 
• Pain intensity on movement measured at scheduled time points from 0-48 hours 
following test drug administration, adjusted for rescue medication use. The adjustment 
algorithm will be as such: If the scheduled pain on movement score has been assessed 
within one plasma half-life after the use of rescue medication (IV or oral opioid, or 
acetaminophen), the worst pain score from all observed ones prior to using rescue 
medication, if this score is higher than the pre-rescue pain score, will be used to substitute 
the scheduled pain score. 
• Pain intensity on movement measured at scheduled time points from 0-48 hours 
following test drug administration will be analyzed by a mixed effect ANOVA model of 
repeated measures (MMRM) (i.e. no adjustments for rescue medication use) 
• Analyze the observed cases without imputation for missing pain scores 
• Analyze completers over 0-48 hours following test drug administration only 
• Treat all missing pain as “failures” using WOCF imputation. 
11.8.2 
Secondary Efficacy Endpoints 
For all secondary efficacy endpoints, data from SABER®-Bupivacaine arm in Part 1 will be 
combined with the same treatment arm in Part 2. The integrated data will be compared to 
Bupivacaine HCl. 
• Pain intensity on movement measured at scheduled time points from 0-72 hours 
following test drug administration, adjusted for prior rescue medication use and analyzed 
by a mixed effect ANOVA model of repeated measures (MMRM).  
The key secondary efficacy endpoint: 
The adjustment algorithm for rescue medication use is the same as described for the primary 
endpoint in Section 11.8.1. 
• Total IV morphine-equivalent dose of rescue opioids used during 0-72 hours following 
test drug administration (standard conversion factors will be used to convert different 
opioids to IV morphine-equivalents; 
Additional secondary efficacy endpoints: 
 
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• Composite endpoint of Silverman’s Integrated Analgesic (SIA) assessment score 
(Dai et al, 2013 and Silverman et al, 1993) over 0-72 hours following test drug 
administration 
• Proportion of patients taking no opioid rescue medication from PACU discharge until 
72 hours after test drug administration  
• Time to first opioid rescue medication use after discharge from the PACU 
• Time to PACU discharge eligibility as assessed by mPADSS (Chung, 1995; Awad and 
Chung, 2006).   
The total IV morphine-equivalent dose of opioid rescue medication used during the first 72 hours 
post-dose will be analyzed by an ANOVA model adjusted for the stratification or by the 
van Elteren test (a stratified Wilcoxon Rank Sum test), depending on whether normality 
assumptions have been met.  
A composite endpoint, Score of Integrated Analgesia (SIA) (Dai et al, 2013 and Silverman et al, 
1993), that integrates pain assessment score with opioid use will be derived at 24, 48 and 72 
hours post-surgery.  The score derived for each subject represents a sum of the ranks (ranging 
from -200 to 200 with -200 being the best case and 200 the worst case).  SIA will be analyzed by 
repeated measures ANOVA.  The model will have treatment, sex, sex*treatment interaction and 
study site as the main effects, subject as the random effect and time as the repeating factor. 
The categorical efficacy endpoint, proportion of patients taking no opioid rescue medication will 
be compared between the two treatment groups using the Cochran-Mantel-Haenszel (CMH) test 
stratified by sex.  
Time to the first use of rescue opioid after discharge from PACU will be analyzed using the 
Kaplan-Meier method. Subjects who do not use any rescue opioids will be censored at 72 hours.  
The stratified Log rank test will be used to compare the treatment groups.  
Time to PACU discharge eligibility by mPADSS will be analyzed by Kaplan-Meier method and 
compared between the treatment groups by stratified Log rank test. 
 
 
 
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11.8.4 
Adjustment for Multiple Hypotheses Testing 
The serial gate-keeping approach (proposed by Westfall and Krishen, 2001) will be used to test 
the primary and secondary endpoints (order by its clinical relevance and importance) in the 
above specified sequence. It will be implemented in the following way: If (and only if) the null 
hypothesis associated with primary endpoint has been rejected at the 0.05 level, then the first 
secondary endpoint, movement pain adjusted for rescue medication use during the first 72 hours 
following administration of test drug will then be tested. If this second gate-keeping step has 
been passed, the next secondary endpoint will be tested until the p-value > 0.05, then no more 
formal hypothesis testing will be performed.  Once this occurs, the additional endpoints will be 
analyzed in order to engender additional hypotheses concerning their effects. 
11.8.5 
Subgroup Analysis  
Subgroup analyses will be conducted by age (< 45, 45-to-65, > 65), sex, and race for the primary 
and secondary efficacy endpoints. ANOVA analyses described for the analysis of the primary 
and secondary efficacy endpoints will be repeated at the subgroup level for the above-mentioned 
subgroups. In the subgroup analysis by sex, the sex stratum and the interaction of sex by 
treatment effects will not be included in the model. 
Similar subgroup summaries will be also be provided for adverse events, where appropriate. 
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11.8.6 
Analyses Strategy for Pooling Trial Centers 
In order to have an adequate number of subjects represented from each trial site, data from any 
site that enrolls 3 or less subjects will be evaluated as a pooled site in the primary or secondary 
endpoints analysis. 
11.9 
Interim Analyses and Data Monitoring 
There is no planned interim analysis. An interim analysis will only be implemented if the Safety 
Assessment Committee (SAC) stops the trial (see 11.9.1) for safety.  Safety data will be 
monitored in a blinded manner throughout the study in accordance with the Safety Monitoring 
Plan.  Unblinded review of SAEs will be conducted by the SAC at its discretion, in accordance 
with the SAC Charter and as described below in Section11.9.1.  The Safety Assessment 
Committee comprises three members that are independent of the study (medical professionals 
and a statistician).     
11.9.1 
Study-Stopping Criteria 
The following study stopping criteria, extracted from the SAC Charter 
 will be 
used for Part 2 of the trial.   
11.9.1.1 
General Provisions 
• The Sponsor medical monitor will carefully and routinely monitor the blinded 
safety data for any occurrence of SAEs, will promptly provide all SAE data to the 
SAC and will convene an SAC meeting if any safety events require an immediate 
review by the committee. 
• The period of observation will be based on safety data reported during the 60-day 
post-treatment period.   
• The SAC will be responsible for determining whether SAEs provided to them 
meet the requirements for stopping the trial, as set forth in SAC Charter sections 
4.2 and 4.3. To make this determination, the SAC at its discretion, may choose to 
un-blind the case for detailed examination. 
• The bupivacaine control patients are receiving standard of care for this low-risk 
surgical procedure and will be at no greater risk than those undergoing 
laparoscopic cholecystectomy outside of the PERSIST clinical trial.  For that 
reason, SAEs occurring in the control group will not constitute trial-stopping 
events, although they could prompt revision of the trial protocol if deemed 
appropriate. 
11.9.1.2 
Stopping due to Fatal Events 
The SAC will convene in the event that any post-treatment fatality has been reported. The 
reported fatality will be un-blinded and all available clinical data will be investigated and 
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evaluated by the SAC.  The SAC will recommend stopping the trial if, in its judgment, all of the 
following provisions (1), (2) and (3) have been met: 
(1) SABER-Bupivacaine was administered to the patient. 
(2) The fatal event had a temporal relationship to administration of  SABER-Bupivacaine  
(3) A clear alternate cause for the fatal SAE is not readily apparent 
If the SAC recommends that the trial not be stopped because the fatality under review fails to 
meet the stopping criteria, it may instead recommend revisions to the study protocol to enhance 
patient safety and may also recommend a pause in enrollment until such revisions can be 
implemented. 
11.9.1.3 
Stopping due to Non-Fatal Serious Adverse Events 
The SAC will review all SAEs reported during the PERSIST trial.  The SAC may un-blind the 
patient data relating to any SAE it wishes to examine in detail for the purpose of determining 
whether stopping criteria have been met. The study will be stopped upon the occurrence of three 
non-fatal SAEs (including any wound hematoma, dehiscence, pruritus, and bruising), each of 
which, in the judgment of the SAC, meets all of the following provisions (1), (2), and (3): 
(1) SABER-Bupivacaine was administered to the patient. 
(2) The SAE had a temporal relationship to administration of SABER-Bupivacaine 
(3) A clear alternate cause for the SAE is not readily apparent 
If the SAC recommends that the trial not be stopped because the SAEs under review fail to meet 
the stopping criteria, it may instead recommend revisions to the study protocol to enhance patient 
safety and may also recommend a pause in enrollment until such revisions can be implemented. 
11.10 Statistical Analysis of Safety Endpoints 
11.10.1 
  Safety Variables and Summaries 
Safety summaries will be based on the safety population.  The safety population will include all 
subjects treated with SABER®-Bupivacaine 5 mL (660 mg bupivacaine base) or 0.9% sterile 
normal saline 5 mL (placebo) in Part 1; and all subjects treated with SABER®-Bupivacaine 5 mL 
or 15 mL of 0.5% bupivacaine HCl in Part 2. It will include summaries in the form of tables and 
patient listings by three treatment arms; SABER®-Bupivacaine 5 mL (660 mg bupivacaine base), 
15 mL of 0.5% solution bupivacaine HCl (75 mg) or 0.9% sterile, normal saline 5 mL (placebo). 
Safety variables include:  
• Subject incidence rate of adverse events (both pre-specified patient-reported AEs 
solicited on LogPad through Study Day 4 [POD 3], as well as spontaneous AEs reported 
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• Subject incidence rate of solicited AEs occurring in the first 6 hours after dosing of test 
drug. 
• Time to the first occurrence of the solicited AEs 
• Time to PACU discharge 
• Change in standard 12-lead ECG at Screening, Visit 6 (Study Day 29), and Visit 7 (Study 
Day 60) 
• Change in safety Laboratory Tests (serum chemistry, hematology, urinalysis) (Screening, 
Study Day  4, Study Day 29, Study Day 60) 
• Change in vital Signs (heart rate, blood pressure, temperature, respiratory rate) (at each 
scheduled visit) and height, weight, BMI (Screening, Study Day 29, Study Day 60) 
• 
 
  
The subject incidence rate (number and percentage) of treatment emergent adverse events will be 
tabulated in each treatment group by MedDRA System Organ Class and Preferred Term.  
Summaries will also be presented by the severity of the adverse event and by relationship to test 
drug. 
The individual rate of solicited patient-reported AEs (dizziness, somnolence, constipation, 
nausea, vomiting, pruritus, headache, dysgeusia, hypoesthesia, and paresthesia) will be derived.  
The risk ratio and 95% confidence interval (CI) for the individual AE rate will be presented with 
saline placebo and bupivacaine HCl as the control groups.  For example, if the 95% CI for the 
risk ratio contains 1, the AE risk is considered comparable between the active and control 
groups. 
Time to the first occurrence of the solicited AEs will be analyzed by the Kaplan Meier method. 
For subjects who do not have the AE, the observation will be censored in the analyses.  Median 
time and 95% confidence interval (CI) will be determined. 
The change in safety laboratory, ECG and vital signs parameters from baseline will be analyzed 
by shift tables. Descriptive statistics (means, medians, SD, minimum/maximum) for the safety 
variables and change from baseline will be summarized. Subjects found to have abnormal safety 
values considered clinically significant will be summarized. 
The presence/absence of surgical site AEs (see definitions in Section 9.2.6) will be tabulated by 
treatment and study visit. The overall rate of each AE across study visits will be tabulated by 
treatment.  The risk ratio and 95% CI will be derived for each AE.  Known risk factors related to 
wound healing, such as being diabetic or having higher BMI, may be used for adjusted relative 
risk if they are not balanced by randomization alone.  Time to the first occurrence of each AE 
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will be derived from the end of surgery. The data will be censored for subjects who do not have 
the AE.  The median, 95% CI, 25th and 75th percentile for the time to each AE will be 
summarized by treatment.  The time to resolution of each AE will also be derived and 
summarized. 
 
 
  
 
 
  
11.11 Changes and Deviations to the Statistical Analysis Plan 
Prior to unbinding the trial, any deviations from the planned analyses methods and the rationale 
for such deviations will be carefully documented in the Statistical Analysis Plan (SAP) and as a 
protocol amendment, if applicable. 
 
   
 
12.0 
Access to Source Data/Documentation 
The investigative site will permit trial-related monitoring, audits, IRB/IEC review and regulatory 
inspections by providing direct access to source data/documentation (e.g. medical records, 
original laboratory records and original informed consent forms).  The Investigator should 
immediately notify DURECT of any Health Authority inspection.  Essential documents must be 
maintained at the investigative site throughout the trial. 
12.1 
Confidentiality  
By consenting to participate in this trial, each patient will agree that Sponsor personnel, their 
representatives or the respective Health Authorities personnel may require direct access to the 
patient’s data/personal records including photocopying source data in an anonymous form.  The 
patient will also agree that his/her data will be processed and stored in an anonymous form for 
evaluation of this trial and any later overviews.  Data may also be transferred in an anonymous 
form to third parties (e.g., other companies or authorities that may be located in other countries 
with potentially different regulations for data).  Data will follow the development of the test drug 
and will be used for documentation of the product’s efficacy and safety.  Data will be transferred 
to involved parties only within the authority given by official agencies.  The informed consent 
form will state that any data already obtained during trial participation will be kept if consent is 
withdrawn. 
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12.2 
Data Identification 
Pain intensity evaluations, solicited patient-reported AE checklists, and oral rescue analgesia 
completed by the patient on LogPads, electronic patient-reported data capture device, will be 
considered source data. Safety laboratory results from the central safety laboratory will be 
considered source data. All other data will be recorded on a source document prior to being 
entered into the eCRF. 
 
13.0 
Quality Control and Quality Assurance 
13.1 
Monitoring  
DURECT or DURECT’s designee will monitor the trial for regulatory and protocol adherence at 
all stages of trial conduct from inception to completion in accordance with ICH-GCP.  This 
monitoring will be in the form of site visits and other communication and will include review of 
original source documents and eCRFs.  DURECT’s monitor or designee will notify the 
Investigator prior to conducting any site visit.  These visits will include monitoring to assess 
facilities, required certifications, IRB/IEC records, equipment, patient recruiting ads, 
record-keeping, protocol adherence, data verification and transmission, adverse event reporting, 
e-diary email alerts and other factors. Final quality assurance visits by the Sponsor should be 
expected, and possibly by the FDA. 
The completed eCRFs will be reviewed against source documents by the blinded monitor at each 
monitoring visit.  If any data, signatures, or forms are missing or discrepant, the Investigator will 
be informed and appropriate written corrections will be made in a timely manner.   
13.2 
Protocol Deviations 
All departures from the protocol will be referred to as protocol deviations and not protocol 
violations (ICH E3R1 Guidance, June 2012). 
Definitions: 
• A protocol deviation is “any change, divergence, or departure from the study design or 
procedures defined in the protocol.” 
• An important protocol deviation is “a subset of protocol deviations that might 
significantly affect the completeness, accuracy, and/or reliability of the study data or that 
might significantly affect a subject's rights, safety, or well-being” 
The Investigator should not deviate from the protocol.  Except for changes intended to eliminate 
any immediate hazard to patients, the trial should be conducted as described in the approved 
protocol.  In medical emergencies, the Investigator will use medical judgment and will remove 
the trial participant from immediate hazard followed by notification to DURECT and the 


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IRB/IEC regarding the type of emergency and the course of action taken.  All protocol deviations 
will be documented by the investigative site or monitor on the designated log.   
13.3 
Case Report Forms  
Electronic case report forms will be used for this trial.  Data entry will occur at the investigative 
site and will be performed by trained and qualified site personnel.  The Investigator will ensure 
all eCRFs are completed after each patient visit in a timely manner.  Specific instructions are 
provided in the eCRF completion guidelines.  
The eCRF system and services for this study will be provided by BioClinica, Inc., with its 
principal place of business located at 800 Adams Avenue, Audubon, Pennsylvania 19403. The 
software version in place at study start is Express 5.4 (validation report dated June 2014). 
13.4 
Coding  
MedDRA will be used to code adverse events.  WHO-Drug will be used to code concomitant 
medications. 
13.5 
Data Safety Monitoring Committee 
A Data Safety Monitoring Committee has not been planned for this trial, which involves using 
only a single dose administration and short trial duration.  However, periodic reviews of blinded 
safety data will be performed by the Sponsor's medical monitor.   
13.6 
Safety Assessment Committee 
If pre-specified serious adverse events of interest (see Section 9.3.1) reach a specified threshold 
incidence, an independent Safety Assessment Committee will review unblinded safety data for 
the affected patients (see Section 9.3.4). 
 
14.0 
Ethical Considerations 
This trial will be conducted according to US and international standards of Good Clinical 
Practice (FDA regulations 21 CFR 312 for IND studies and ICH guidance E6) for all studies. 
All patients for this trial will be provided a consent form describing this trial and providing 
sufficient information for subjects to make an informed decision about their participation in this 
trial.  This consent form will be submitted with the protocol for review and approval by the IRB.  
The formal consent of a subject, using the IRB-approved consent form, will be obtained before 
that subject is submitted to any trial procedure.  This consent form must be signed by the subject 
or legally acceptable surrogate, and the investigator-designated research professional obtaining 
the consent. Each subject will be given a copy of the signed consent form. 


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All patients will have access to supplemental rescue analgesia as needed with IV, and/or oral 
opioids per common clinical practice to ensure ethical treatment and assess the magnitude of 
analgesic contribution by SABER®-Bupivacaine. 
14.1 
Institutional Review Board / Ethics Committee 
The protocol, consent form, advertisements and any other information for patients will be 
reviewed and approved by DURECT Corporation (or DURECT’s designee) and by the 
Institutional Review Board (IRB) / Independent Ethics Committee (IEC) of the participating 
investigative site prior to the start of the trial at that site in accordance with the International 
Conference on Harmonization (ICH) and institutional IRB/IEC policies.  All protocol 
amendments and changes to the consent form occurring during the trial must also be IRB/IEC 
approved. 
14.2 
Regulatory Compliance  
The trial will be conducted in accordance with the principles of Good Clinical Practice (GCP) set 
forth in the International Conference on Harmonization (ICH) Good Clinical Practice, the US 
Code of Federal Regulations (CFR Title 21), the Health Insurance Portability and Accountability 
Act of 1996 (HIPAA) and any local requirements. 
14.3 
Regulatory Status 
SABER®-Bupivacaine has not yet been approved by the US Food and Drug Administration or 
any other Health Authority. 
14.4 
Patient Information and Informed Consent 
Prior to participation in the trial, the Investigator or designee will obtain written consent from 
each patient using the IRB/IEC-approved informed consent form that explains the nature, 
purpose, possible risks and benefits of the trial, and the duration of an individual’s participation.  
The basic elements of the informed consent as specified by the FDA (21 CFR §50.25), and 
HIPAA will be followed.   
Before consenting, the patient must be left with ample time to consider and to pose questions. 
The Investigator and/or the designated investigative site personnel who conduct the informed 
consent discussion must also sign and date the consent form.  Each patient will be given a copy 
of the signed consent form.  The original, signed consent forms will be maintained at the 
investigative site.   
14.4.1 
Patient Withdrawal 
Patients will be informed during the informed consent process (in writing and verbally) that they 
are free to withdraw from the trial at any time.  The Investigator may exercise his medical 
judgment to terminate a patient’s participation in the trial due to clinically relevant changes in 
any clinical or laboratory parameter.  DURECT Corporation also reserves the right to terminate 


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the trial at any time.  All trial procedures normally performed at completion of the trial must be 
done at the time of the patient’s early termination, before the scheduled final clinic visit, or on 
the scheduled final clinic visit as described in Section 7.4.11 unless the patient withdraws 
consent.  If a patient withdraws consent they will be encouraged to complete an early termination 
visit and AE follow-up.  All AEs will be followed until resolution. Resolution means no further 
changes in the event are expected, i.e., the point at which a subject experiencing such an AE is 
appropriately treated and stabilized even though they may continue to experience lingering 
sequelae that may never resolve.   
Patients who withdraw prior to assignment of test drug will be considered as screen failures and 
will not be considered randomized (See Section 11.4).   
 
15.0 
Data Handling and Record Retention 
15.1 
Data Ownership 
The eCRFs, associated documents and reports from the trial are the property of DURECT.  
DURECT has the right to use the results for registration purposes, internal presentation and 
promotion. 
15.2 
Retention of Trial Records 
The Investigator will retain all trial documents (e.g., approved protocol, copies of completed 
eCRFs and electronic diaries, original informed consent forms, relevant source documents) in a 
secure place protected from fire and theft until:  
• At least 2 years after the last approval of an NDA by the US FDA; 
• At least 2 years after the last approval of a marketing application in an ICH region; 
• There are no pending or contemplated marketing applications in an ICH region; or 
• At least 2 years have elapsed since the formal discontinuation of the clinical development of 
the test drug 
These documents should be retained for a longer period if required by the local/regional 
regulations or by an agreement with DURECT.  It is the responsibility of the Sponsor to inform 
the Investigator/Institution when these documents no longer need to be archived. 
The medical files of trial patients must be retained in accordance with national legislation and in 
accordance with the maximum period of time permitted by the hospital, institution or private 
practice. 
DURECT will maintain the documentation pertaining to the trial as long as the test drug is on the 
market. 


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Trial records must be made available by the Investigator for inspection upon reasonable request 
by authorized representatives of DURECT, the Food and Drug Administration (FDA), or the 
corresponding regulatory Health Authorities of the relevant countries. 
DURECT will provide the Investigator with information concerning the current status of the test 
drug as it relates to the Investigator’s responsibility for the retention of trial records.  The 
Investigator should contact DURECT prior to disposing of any such records. DURECT will 
arrange for continued storage of all records, if necessary. 
 
16.0 
Finance and Insurance 
Financing and insurance statements are addressed in the Clinical Trial Agreements and 
Indemnity Agreements. 
17.0 
Publication Plan 
17.1 
Confidentiality 
Information concerning the test drug and patent applications, scientific data or other pertinent 
information is confidential and remains the property of DURECT. 
Investigators are not allowed to disclose or publish any information concerning patent 
applications, manufacturing processes or formulation information about the test drug to others 
without permission from DURECT Corporation. 
17.2 
Clinical Trial Report 
DURECT is responsible for finalizing a clinical trial report within 12 months of completion of 
the treatment and follow-up phase of this protocol.  A publication has also been planned (see 
Section 17.3). 
In this multi-center trial, the lead principal investigator will be designated to sign the final 
clinical trial report. 
17.3 
Publications 
DURECT’s publication policy of trial results will be included within the clinical trial agreement 
with each investigator.   Results of this protocol will only be published if the Publication 
Committee of DURECT initiates such publication or provides written approval of a concept 
prepared by the investigative site.  In case the investigator has no interest to publish, DURECT is 
free to use the data for publication.  The investigator may be invited to be co-author. DURECT 
will submit the manuscript to the investigator, who will have the right to insist he/she is 
represented in such publications. 
If an Investigator is invited to act as co-author for the publication, he/she can only be mentioned 
in the manuscript if giving permission.  DURECT will provide the manuscript to the Investigator 


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for review and comments and the Investigator has the right to have his/her interpretation of the 
data properly represented in the publication.  If the agreed upon timeline for submission of a 
draft publication to DURECT is not kept by the Investigator, DURECT holds the right to publish 
the data.  After publication of the results of a multi-center trial or 24 months after the clinical 
trial report has been finalized, whichever comes first, DURECT acknowledges the Investigator's 
rights to publish results from this trial.  Any such scientific paper, presentation, communication 
or other information concerning the trial described in this protocol must be submitted to 
DURECT for review prior to submission for publication/presentation. Review comments will be 
given approximately within a month from receipt of the manuscript. 
In this multi-center trial, based on collaboration of all sites, any publication of results should 
reflect the entire trial and must acknowledge all sites enrolling patients into the trial.  The 
Publication Committee will designate the principal author of the publication.  Additional authors 
may include representatives of the Sponsor. 


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18.0 
References 
1. 
American College of Surgeons (ACS). Horizon scanning in surgery: application to 
surgical education and practice - Single incision laparoscopic surgery (SILS) for 
cholecystectomy. April 2012. 
https://www.facs.org/~/media/files/education/ceste/sils%20cholecystectomy.ashx  
2. 
Awad, IT and Chung F. Factors affecting recovery and discharge following ambulatory 
surgery. Canadian Journal of Anesthesia 2006, Vol 53:9, 858-872 
3. 
Baron TH, Grimm IS, Swanstrom LL. Interventional approaches to Gallbladder 
disease. N Engl J Med, 2015; 373:357-365 
4. 
Beaver WT and McMillan D.  Methodological Considerations in the Evaluation of 
Analgesic Combinations:  Acetaminophen (Paracetamol) and Hydrocodone in 
Postpartum Pain. Br. J. Clin. Pharmac. 1980;10:215S-223S. 
5. 
Bergese, SD  et al, “Efficacy profile of liposome bupivacaine, a novel formulation of 
bupivacaine for postsurgical analgesia”. Journal of Pain Research, 2012:5 107-116. 
 
6. 
Bisgaard T. Analgesic treatment after laparoscopic cholecystectomy. Anesthesiology. 
2006;104:(4):835-846. 
7. 
Bisgaard T, Klarskov B, Kristiansen VB, Callesen T, Schulze S, Kehlet H, Rosenberg 
J. Multi-regional local anesthetic infiltration during laparoscopic cholecystectomy in 
patients receiving prophylactic multi-modal analgesia: a randomized, double-blinded, 
placebo-controlled study. Anesth Analg.1999 Oct;89(4):1017-24. 
8. 
Bisgaard T, Klarskov B, Rosenberg J, Kehlet H. Characteristics and prediction of early 
pain after laparoscopic cholecystectomy. Pain. 2001 Feb 15;90(3):261-9. 
9. 
Breivik H, Borchgrevink PC, Allen SM, et al. Assessment of Pain. Br J 
Anaesthesia.2008;101:17-24. 
10. Centers for Disease Control National Healthcare Safety Network (CDC/NHSN). 
Procedure-associated module - surgical site infection. 
http://www.cdc.gov/nhsn/pdfs/pscmanual/9pscssicurrent.pdf. January 2015, modified 
April 2015 (accessed July 6, 2015) 
11. Chung F, Chan VW, Ong D. A post-anesthetic discharge scoring system for home 
readiness after ambulatory surgery. J Clin Anesth. 1995 Sep;7(6):500-6.  
12. Cook KF, Dunn W, Griffith JW, et al.  Pain assessment using the NIH Toolbox.  
Neurology.  2013;80(3):S49-S53. 
13. Csikesz N, Ricciardi R, Tseng JF, Shah SA. Current status of surgical management of 
acute cholecystitis in the United States. World J Surg. 2008 Oct;32(10):2230-6. 


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14. Csikesz NG, Singla A, Murphy MM, Tseng JF, Shah SA. Surgeon volume metrics in 
laparoscopic cholecystectomy. Dig Dis Sci. 2010 Aug;55(8):2398-405.  
15. Dai F, Silverman DG, Chelly JE, Li J, Belfer I, Qin L. Integration of pain score and 
morphine consumption in analgesic clinical studies. Journal of Pain. 2013; 14(8): 
767-777. 
16. Daniels SE, Upmalis D, Okamoto A, Lange C, Häeussler J. A randomized, double-
blind, phase III study comparing multiple doses of tapentadol IR, oxycodone IR, and 
placebo for postoperative (bunionectomy) pain. Curr Med Res Opin. 2009 
Mar;25(3):765-76.  
17. Dasta J., Ramamoorthy S., Patou G., Sinatra R. Bupivacaine liposome injectable 
suspension compared with bupivacaine HCl for the reduction of opioid burden in the 
postsurgical setting. Curr Med Res Opin. 2012;28:1609–1615.  
18. De Cosmo G, Congedo E, Lai C, Primieri P, Dottarelli A, Aecto P. Preoperative 
psychological and demographic predictors of pain perception and tramadol 
consumption using intravenous patient-controlled analgesia. Clin J Pain. 2008; 
24:399-405. 
19. Directive 2001/20/EC of the European Parliament and of the Council of 4 April 2001 
on the approximation of the laws, regulations and administrative provisions of the 
Member States relating to the implementation of good clinical practice in the conduct 
of clinical trials on medicinal products for human use. Official Journal of the European 
Communities L/21/34 1.5.2001. 
20. Elsevier Business Intelligence. Medtech insight, medical market and technology 
reports: US surgical procedure volumes. June 2013. Report #A632. 
21. Ethicon Endo-Surgery. Value dossier: minimally invasive procedures in hysterectomy, 
appendectomy, cholecystectomy & colectomy. 2009, DSL#09-0590. 
http://www.ethicon.com/sites/default/files/payors/pdf/09-0590-MIP_Value_Dossier.pdf 
accessed August 16, 2015. 
22. FDA. Guidance for Industry, Analgesic Indications: Developing Drug and Biological 
Products. Draft Guidance. February 2014. 
23. Fahrner R, Malinka T, Klasen J, et al. Additional surgical procedure is a risk factor for 
surgical site infections after laparoscopic cholecystectomy. Langenbecks Arch 
Surg.2014; 399:595-599. 
24. Fillingim RB, King CD, Ribeiro-Dasilva MC, Rahim-Williams B, Riley JL. Sex, 
gender, and pain: A review of recent clinical and experimental findings. J Pain. 2009; 
10(5); 447-485. 


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25. Gurusamy KS, Vaughan J, Toon CD, Davidson BR. Pharmacological interventions for 
prevention or treatment of postoperative pain in people undergoing laparoscopic 
cholecystectomy (Review). The Cochrane Library. 2014;3:1-119. 
26. Hjermstad MJ, Fayers PM, Haugen DF, et al. Studies Comparing Numerical Rating 
Scales, Verbal Rating Scales, and Visual Analog Scales for Assessment of Pain 
Intensity in Adults: A Systematic Literature Review. J Pain Symptom Management. 
2011;41:1073-1093. 
27. ICH Harmonised Tripartite Guideline for Good Clinical Practice, E6 
28. Joseph B, Rawashdeh B, Aziz H, et al.  An acute care surgery dilemma: emergent 
laparoscopic cholecystectomy in patients on aspirin therapy. Am J Surgery. 2015; 
209:689-694. 
29. Keus F, Gooszen HG, Van Laarhoven JHM. Systematic review: open, small-incision or 
laparoscopic cholecystectomy for symptomatic cholecystolithiasis.   Aliment 
Pharmacol Ther.2009;29:359-378. 
30. Liu SS, Richman JM, Thirlby RC, and Wu CL. Efficacy of continuous catheters 
delivering local anaesthetic for postoperative analgesia: a quantitative and qualitative 
systematic review of randomized controlled trials. J Am Coll Surg. 2006; 203(6); 
914-932. 
31. Loizides S, Gurusamy KS, Nagendran M, et al. Wound infiltration with local 
anaesthetic agents for laparoscopic cholecystectomy (Review). Cochrane Database of 
Systematic Reviews 2014, Issue 3. Art No.:CD007049. 
32. Mulroy MF. Systemic toxicity and cardiotoxicity from local anesthetics: Incidence and 
preventive measures. Regional Anesthesia and Pain Medicine, 2002; 27(6):556-561. 
33. Richards C, Edwards J, Culver D, et al. Does using a laparoscopic approach to 
cholecystectomy decrease the risk of surgical site infection?.  Annals of Surgery. 
2003;237(3):358-362. 
34. Society of American Gastrointestinal and Endoscopic Surgeons (SAGES). Guidelines 
for the clinical application of laparoscopic biliary tract surgery. January, 2010. 
http://www.sages.org  
35. Shea JA, Healey MJ, Berlin JA, et al. Mortality and Complications Associated with 
Laparoscopic Cholecystectomy. A meta-Analysis.  Annals of Surgery. 
1996;225(5):609-620. 
36. 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.  
37. Uchiyama K, Kawai M, Tani M, Ueno M, Hama T, Yamaue H. Gender differences in 
postoperative pain after laparoscopic cholecystectomy. Surg Endosc. 2006; 20(3): 
448-451. 


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38. U.S. Dept of Health and Human Services, Food and Drug Administration, CDER and 
CBER.  Safety Assessment for IND Safety Reporting. Guidance for Industry. Draft 
Guidance. December 2015, Drug Safety. 
39. Westfall PH, Krishen A. Optimal weighted, fixed sequence, and gatekeeping multiple 
testing procedures. J Stat Planning Inference, 2001;99:25-40. 
40. White PF, Schooley GL, Ardeleanu M. Analgesia following a single administration of 
depobupivacaine intraoperatively in patients undergoing inguinal herniorrhaphy: 
preliminary dose-ranging studies [abstract S-242]. Anesth Analg; 2009:108 (Suppl 
3S):S-242. 
41. YaDeau JT, Liu SS, Rade MC, Marcello D, Liguori GA. Performance characteristics 
and validation of the Opioid-Related Symptom Distress Scale for evaluation of 
analgesic side effects after orthopedic surgery. Anesth Analg. 2011 Aug;113(2):369-77. 
42. Yuan, YC. Multiple imputation for missing data: Concepts and new development 
(Version 9.0). SAS Institute Inc, Rockville, MD, 2010;49. 
43. Zhao SZ, Chung F, Hanna DB, et al. Dose-response relationship between opioid use 
and adverse effects after ambulatory surgery. J Pain Symptom Manage. 2004;28:35-46. 
 


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19.0 
Appendices  


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Appendix 5: CDC/NHSN Surgical Site Infection Definitions and Diagnostic Criteria 
CDC/NHSN Surgical Site Infection (SSI) definitions and diagnostic criteria (Table 2) are 
provided below. The full document may be accessed at the following website: 
http://www.cdc.gov/nhsn/pdfs/pscmanual/9pscssicurrent.pdf 
 
Table 2. Surgical Site Infection Criteria 
Criterion 
Su1·gical Site Infection (SSI) 
Superficial incisional SSI 
Must meet the following criteria: 
Infection occurs within 30 days after any NHSN operative procedure 
(where day 1 = the procedure date), including those coded as 'OTH'* 
AND 
involves only skin and subcutaneous tissue of the incision 
AND 
patient has at least Q!!£ of the following: 
a. purulent drainage from the superficial incision. 
b. organisms isolated from an aseptically-obtained culture 
from the superficial incision or subcutaneous tissue. 
C. superficial incision that is deliberately opened by a surgeon, 
attending physician** or other designee and is culnire positive 
or not cultured 
AND 
patient has at least Q!!£ of the following signs or symptoms: pain 
or tenderness; localized swelling; erythema; or heat. A culture 
negative finding does not meet this criterion. 
d. diagnosis of a superficial incisional SSI by the surgeon or 
attending physician':":' or other designee. 
*http://www.cdc.gov/nhsn/XLS/ICD-9-cmCODEScurrent.xlsx 
,:, ,:, The tenn attending physician for the purposes of application of the 
NHSN SSI criteria may be interpreted to mean the surgeon(s), infectious 
disease, other physician on the case, emergency physician or physician's 
designee (nurse practitioner or physician's assistant). 
Comments 
There are two specific types of superficial incisional SSis: 
1. Superficial Incisional Primary (SIP) - a superficial incisional SSI 
that is identified in the primmy incision in a patient that has had an 
operation with one or more incisions (e.g., C-section incision or 
chest incision for CBGB) 
2. Superficial Incisional Secondary (SIS) - a superficial incisional 
SSI that is identified in the secondary incision in a patient that has 
had an operation with more than one incision (e.g., donor site 
incision for CBGB) 


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Reporting 
Insh'uctions 
for 
Superficial 
SSI 
The following do not qualify as critel"ia for meeting the NHSN 
definition of superficial SSI: 
• 
Diagnosis/treatment of cellulitis (redness/warmth/swelling), by itself, 
does not meet criterion d for superficial incisional SSI. An incision 
that is draining or culture(+) is not considered a cellulitis. 
• 
A stitch abscess alone (minimal inflammation and discharge confined 
to the points of suture penetration) 
• 
A localized stab wound or pin site infection. While it would be 
considered either a skin (SKIN) or soft tissue (ST) infection, 
depending on its depth, it is not reportable under this module. 
Note: a laparoscopic trocar site for an NHSN operative procedure is 
not considered a stab wound. 
• 
Circumcision is not an NHS 
operative procedure. An infected 
circumcision site in newborns is classified as CIRC and is not 
reportable under this module. 
• 
An infected bum wound is classified as BURN and is not reportable 
under this module. 
Deep incisional SSI 
Must meet the following criteria: 
Infection occurs within 30 or 90 days after the NHSN operative procedure 
(where day 1 = the procedure date) according to the list in Table 3 
AND 
involves deep soft tissues of the incision (e.g., fascia! and muscle layers) 
AND 
patient has at least !ll!£. of the following: 
a. purulent drainage from the deep incision. 
b. a deep incision that spontaneously dehisces, or is deliberately 
opened or aspirated by a surgeon, attending physician':'* or other 
designee and is culture positive or not cultured 
AND 
patient has at least !ll!£. of the following signs or symptoms: fever 
(>38°C); localized pain or tenderness. A culture negative finding 
does not meet this criterion. 
c. an abscess or other evidence of infection involving the deep 
incision that is detected on gross anatomical or histopathologic 
exam, or imaging test. 
*':' The term attending physician for the purposes of application of the 
NHSN SSI criteria may be interpreted to mean the surgeon(s), infectious 
disease, other physician on the case, emergency physician or physician's 
designee (nurse practitioner or physician's assistant). 


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Comments 
There are two specific types of deep incisional SSis: 
I. Deep Incisional Primary (DIP) - a deep incisional SSI that is 
identified in a primary incision in a patient that has had an 
operation with one or more incisions (e.g., C-section incision or 
chest incision for CBGB) 
2. Deep Incisional Secondary (DIS) - a deep incisional SSI that is 
identified in the secondary incision in a patient that has had an 
operation with more than one incision (e.g., donor site incision for 
CBGB) 
01·gan/Space SSI 
Must meet the following criteria: 
Infection occurs within 30 or 90 days after the NHSN operative procedure 
(where day l = the procedure date) according to the list in Table 3 
AND 
infection involves any part of the body deeper than the fascial/muscle 
layers, that is opened or manipulated during the operative procedure 
AND 
patient has at least!!!!.! of the following: 
a. purulent drainage from a drain that is placed into the organ/space 
(e.g., closed suction drainage system, open drain, T-tube drain, CT 
guided drainage) 
b. organisms isolated from an aseptically-obtained culture of fluid or 
tissue in the organ/space 
C. an abscess or other evidence of infection involving the 
organ/space that is detected on gross anatomical or histopathologic 
exam, or imaging test 
AND 
meets at least!!!!.! criterion for a specific organ/space infection site listed 
in Table 4. These criteria are in the Surveillance Definitions for Specific 
Tvoes oflnfections chanter. 


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Appendix 6: Investigator Responsibilities 
 
The responsibilities of the Investigator conducting the trial are:  
 
• Supervise the conduct of the trial and ensure that all trial personnel under their 
supervision are qualified and adequately trained to perform the tasks delegated to 
them. 
• Obtain appropriate IRB/IEC approval to conduct the trial in a timely manner 
• Provide DURECT with written documentation that the trial protocol, any protocol 
amendments, and the informed consent form have received IRB/IEC approval.  
• Provide DURECT with a list of IRB/IEC members, including their affiliations and 
qualifications. As an alternative in the United States, a General Assurance number 
(as assigned by the Department of Health and Human Services) fulfils this 
requirement 
• Report to the IRB/IEC as required. The IRB/IEC must assume continued 
responsibility for the trial and review the research on at least an annual basis, 
however some require more frequent periodic reviews. 
• Maintain a file of all communications with the IRB/IEC on issues related to the trial. 
• Complete sign and return to DURECT an original copy of the Statement of 
Investigator Form (Form FDA 1572). 
• Provide DURECT current curriculum vitae of the Investigator and Sub-
Investigator(s). 
• Review the protocol and Investigator’s Brochure. A copy of the protocol will be 
retained by the Investigator in the site’s file. The Investigator’s signature on the 1572, 
protocol signature page, and Sponsor contract are evidence of agreement with the 
conduct of the trial.  
• All amendments to the protocol must be reviewed by the Investigator and submitted 
to the IRB/IEC in accordance with their requirements.  A copy of protocol 
amendments will be retained by the Investigator in the site’s file.  
• Submit the Investigator’s Brochure to the IRB/IEC for review.  Provide DURECT 
with written documentation that the Investigator’s Brochure was received and 
reviewed by the IRB/IEC.  
• Conduct the trial in strict adherence to the protocol and ICH Good Clinical Practices. 
• Supervise the use of the test drug as outlined in the protocol. Only staff working 
under the supervision of the Investigator for the purposes of this trial will be allowed 
to handle the test drug.  
• Store the test drug in a secure and locked area. The storage custody and security of 
the test drug is the responsibility of the Investigator. 


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• The test drug should be administered to patients under the Investigator’s direct 
supervision or that of his/her Sub-Investigators.  
• Maintain adequate record of the receipt and disposition of all test drug, including 
dates and quantities dispensed to individual patients. 
• Ensure that each patient is informed of the risks and benefits of participating in the 
trial, and a properly signed and witnessed informed consent forms for each patient has 
been obtained at the time of screening. 
• Provide appropriate health care or referral for the patient throughout the trial. 
• Document all adverse events on the Adverse Event CRF. Document all serious, life-
threatening, or unexpected events on the appropriate CRF, and notify DURECT via 
telephone and facsimile report within 24 hours as required by the regulatory 
authorities. 
• Report all serious, life-threatening, or unexpected adverse events to the IRB/IEC. 
• Document and maintain adequate and accurate CRFs for all patients receiving test 
drug as required at the designated times. Review all CRFs affirming the completeness 
and accuracy of the data recorded. Storage, custody and security of all trial records 
are the responsibility of the Investigator. 
• Provide the Trial Monitor with the original completed CRFs and all source documents 
for review at the investigative site during monitoring visits. Retain the CRFs, source 
documents, and informed consent forms at the investigative site.  
• Maintain a file of all trial correspondence.  
• Adhere to standard record retention policy as stated in the protocol. 
• Cooperate with Sponsor auditor(s) and health authority inspector(s).  Facilitate 
activities related to audits/inspections.   
 


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Appendix 7: Sponsor’s Responsibilities 
 
DURECT is responsible for ensuring that the trial is conducted in accordance with the 
principles of Good Clinical Practice (GCP) set forth in ICH Good Clinical Practice, the 
US Code of Federal Regulations (CFR Title 21), the HIPAA law and any additional local 
requirements.  
 
DURECT is responsible for selecting qualified investigators.  DURECT will maintain a 
list of all investigators and important trial personnel and their current qualifications and 
curriculum vitae (CV). 
 
DURECT will maintain a list and qualification records of all relevant sponsor trial 
personnel. 
 
DURECT will provide investigators with the information they need to conduct an 
investigation properly, ensuring proper monitoring of the investigation(s), ensuring that 
the investigation is conducted in accordance with the general investigational plan and 
protocols contained in the IND, maintaining an effective IND with respect to the 
investigations, and ensuring that the regulatory authorities and all participating 
investigators are promptly informed of significant new adverse effects or risks with 
respect to the test drug. 
 
DURECT or its designee (CRO) has the responsibility of ensuring the proper conduct of 
the trial in regard to protocol adherence.  DURECT or its designee will assign Monitors 
for this trial.  Their duties will be to aid the Investigator and DURECT in maintaining 
complete, legible, well-organized, and easily readable data.  In addition, Trial Monitors 
will assure the Investigator’s understanding of all applicable regulations concerning the 
clinical evaluation of a test drug, and assure an understanding of the protocol, reporting 
responsibilities, and the validity of the data.   
 
The patients will be covered by DURECT Corporation's insurance according to 
applicable regulatory requirements. 
 
 


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