Conditions: Thoracic Diseases Postoperative Pain Opioid Use
Keywords: Liposomal Bupivacaine Intercostal Nerve Block Minimally Invasive Thoracic Surgery
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 91
Healthy volunteers: yes

Brief summary:
The Minimally Invasive Thoracic Surgery Intercostal Nerve Block Trial is a single center, double-blind, randomized, active-comparator controlled clinical trial to assess the analgesic efficacy of intercostal nerve block by Liposomal Bupivacaine versus Standard Bupivacaine in subjects undergoing lung resection by robotic or video-assisted thoracoscopic surgery.

Detailed description:

Arms:
arm 1: 5cc of drug preparation will be percutaneously injected into each intercostal space 3-10 under direct intrathoracic vision and subcutaneously into each surgical wound at the conclusion of the surgery.

Drug Preparation: 266mg (20cc) Liposomal Bupivacaine admixed with 0.25% (2.5mg/cc) Standard Bupivacaine (maximum dose of 2mg/kg) and varied 0.9% normal saline volume for total volume of 60cc. arm 2: 5cc of drug preparation will be percutaneously injected into each intercostal space 3-10 under direct intrathoracic vision and subcutaneously into each surgical wound at the conclusion of the surgery.

Drug Preparation - 0.25% (2.5mg/cc) Standard Bupivacaine (maximum dose of 2mg/kg) admixed with varied 0.9% normal saline volume for total volume of 60cc.

Interventions: intervention 1: Liposomal bupivacaine intervention 2: Bupivacaine Injection
Intervention descriptions: intervention 1: 5cc of drug preparation will be percutaneously injected into each intercostal space 3-10 under direct intrathoracic vision and subcutaneously into each surgical wound at the conclusion of the surgery. intervention 2: 5cc of drug preparation will be percutaneously injected into each intercostal space 3-10 under direct intrathoracic vision and subcutaneously into each surgical wound at the conclusion of the surgery.

Protocol document:
Prot_SAP_000.pdf: 
Kratz, Johannes R. 
Confidential 
 
Version #: 9.0 
Version Date: 11/5/2019 
Page 1 of 37 
 
   
 
Clinical Research Protocol 
Minimally Invasive Thoracic Surgery Intercostal Nerve Block Trial 
 
NCT #: 
NCT03508830 
Institution Protocol #: 
18-25152 
Version Date: 
11/5/2019 
Investigational Product: 
Liposomal Bupivacaine 
IND Number: 
138986 
Development Phase: 
III 
Sponsor: 
Investigator-Initiated 
Funding Organization: 
UCSF Cardiothoracic Surgery 
Principal Investigator: 
Name: Johannes R. Kratz, MD 
Telephone: 415-353-8196 
Fax: 415-353-7151 
 
E-mail: johannes.kratz@ucsf.edu 
 
Medical Monitor: 
Name:  Lundy Campbell, MD 
Telephone: (415) 443-3692 
Fax: (415) 476-8444 
E-mail: lundy.campbell@ucsf.edu 
Coordinating Center: 
UCSF Cardiothoracic Surgery 
 
Approval: 
 
 
11/5/2019 
PI or Sponsor Signature (Name and Title)  
 
Date 
This confidential information about an investigational product is provided for the exclusive use of 
investigators of this product and is subject to recall at any time.  The information in this document 
may not be disclosed unless federal or state law or regulations require such disclosure.  Subject to the 
foregoing, this information may be disclosed only to those persons involved in the study who have a 
need to know, with the obligation not to further disseminate this information.   


Kratz, Johannes R. 
Confidential 
 
Version #: 9.0 
Version Date: 11/5/2019 
Page 2 of 37 
 
PROTOCOL AGREEMENT 
 
I have read the protocol specified below. In my formal capacity as Investigator, my duties 
include ensuring the safety of the study subjects enrolled under my supervision and 
providing complete and timely information, as outlined in the protocol.  It is understood 
that all information pertaining to the study will be held strictly confidential and that this 
confidentiality requirement applies to all study staff at this site. Furthermore, on behalf of 
the study staff and myself, I agree to maintain the procedures required to carry out the 
study in accordance with accepted GCP principles and to abide by the terms of this 
protocol. 
 
Protocol Number:  18-25152  
 
Protocol Title:     Minimally Invasive Thoracic Surgery Intercostal Nerve Block Study 
 
Protocol Date:  11/5/2019 
 
 
 
11/5/2019 
Investigator Signature  
 
Date 
Johannes R. Kratz, MD  
Print Name and Title 
Site # 
n/a 
 
Site Name 
UCSF Department of Surgery – Division of Cardiothoracic Surgery 
Address 
500 Parnassus Avenue 
 
Suite MUW-405 
 
San Francisco, CA  94143-0118 
 
 
Phone Number 
415-353-8196 
 


Kratz, Johannes R. 
Confidential 
 
Version #: 9.0 
Version Date: 11/5/2019 
Page 3 of 37 
 
TABLE OF CONTENTS 
1 
BACKGROUND ................................................................................................................. 10 
      1.1  Overview of Non-Clinical Studies .............................................................................. 10 
1.2 
Overview of Clinical Studies ...................................................................................... 10 
2 
STUDY RATIONALE ........................................................................................................ 11 
2.1 
Risk / Benefit Assessment ........................................................................................... 12 
3 
STUDY OBJECTIVES ....................................................................................................... 13 
3.1 
Primary Objective ....................................................................................................... 13 
3.2 
Secondary Objectives .................................................................................................. 13 
4 
STUDY DESIGN ................................................................................................................. 13 
4.1 
Study Overview ........................................................................................................... 13 
5 
CRITERIA FOR EVALUATION ..................................................................................... 14 
5.1 
Primary Efficacy Endpoint .......................................................................................... 14 
5.2 
Secondary Efficacy Endpoints .................................................................................... 14 
5.3 
Safety Evaluations ....................................................................................................... 15 
6 
SUBJECT SELECTION .................................................................................................... 16 
6.1 
Study Population ......................................................................................................... 16 
6.2 
Inclusion Criteria ......................................................................................................... 16 
6.3 
Exclusion Criteria ....................................................................................................... 16 
7 
CONCURRENT MEDICATIONS .................................................................................... 17 
7.1 
Allowed ....................................................................................................................... 17 
7.2 
Prohibited .................................................................................................................... 17 
8 
STUDY TREATMENTS .................................................................................................... 17 
8.1 
Method of Assigning Subjects to Treatment Groups .................................................. 17 
8.2 
Blinding ....................................................................................................................... 18 
8.3 
Test and Control Formulation ..................................................................................... 18 
8.4 
Supply of Study Medication at the Site ....................................................................... 19 
8.5 
Study Medication Accountability ............................................................................... 20 
8.6 
Measures of Treatment Compliance ........................................................................... 20 
9 
STUDY PROCEDURES AND GUIDELINES ................................................................. 21 
9.1 
Clinical Assessments ................................................................................................... 21 
9.2 
Clinical Laboratory Measurements ............................................................................. 22 
10 EVALUATIONS BY VISIT ............................................................................................... 22 
10.1 Visit 1 – Preoperative Clinic Visist ............................................................................. 22 
10.2 Visit 2 – Surgery with Hospitalization ........................................................................ 22 
10.3 Visit 3 – Postoperative Clinic Visit ............................................................................. 22 
11 ADVERSE EXPERIENCE REPORTING AND DOCUMENTATION ........................ 23 
11.1 Adverse Events ........................................................................................................... 23 
11.2 Serious Adverse Experiences (SAE) ........................................................................... 25 
11.3 Protocol Defined Important Medical Findings Requiring Real Time Reporting ........ 26 
11.4 Medical Monitoring .................................................................................................... 26 


Kratz, Johannes R. 
Confidential 
 
Version #: 9.0 
Version Date: 11/5/2019 
Page 4 of 37 
 
12 DISCONTINUATION AND REPLACEMENT OF SUBJECTS ................................... 26 
12.1 Withdrawal of Subjects ............................................................................................... 26 
12.3 Replacement of Subjects ............................................................................................. 26 
13 PROTOCOL VIOLATIONS ............................................................................................. 27 
14 DATA SAFETY MONITORING ...................................................................................... 27 
      14.1  DMC Charter………………………………………………………………………….26 
15 STATISTICAL METHODS AND CONSIDERATIONS ............................................... 27 
15.1 Data Sets Analyzed ..................................................................................................... 30 
15.2 Demographic and Baseline Characteristics ................................................................. 30 
15.3 Analysis of Primary Endpoint ..................................................................................... 30 
15.4 Analysis of Secondary Endpoints ............................................................................... 31 
15.5 Interim Analysis .......................................................................................................... 30 
15.6 Sample Size and Randomization ................................................................................. 30 
16 DATA COLLECTION, RETENTION AND MONITORING ....................................... 31 
16.1 Data Collection Instruments ........................................................................................ 31 
16.2 Data Management Procedures ..................................................................................... 31 
16.3 Data Quality Control and Reporting ........................................................................... 31 
16.4 Archival of Data .......................................................................................................... 31 
16.5 Availability and Retention of Investigational Records ............................................... 31 
16.6 Monitoring .................................................................................................................. 32 
16.7 Subject Confidentiality ................................................................................................ 32 
17 ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS .................. 32 
17.1 Protocol Amendments ................................................................................................. 32 
17.2 Institutional Review Boards and Independent Ethics Committees ............................. 32 
17.3 Informed Consent Form .............................................................................................. 33 
17.4 Publications ................................................................................................................. 33 
17.5 Investigator Responsibilities ....................................................................................... 34 
 
 
 
 
 


Kratz, Johannes R. 
Confidential 
 
Version #: 9.0 
Version Date: 11/5/2019 
Page 5 of 37 
 
LIST OF ABBREVIATIONS 
 
AE 
CC 
Adverse event 
Cubic Centimeter 
CFR 
Code of Federal Regulations 
CRF 
CT 
Case report form 
Computed Tomography 
DMC 
Data Monitoring Committee 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIPAA 
IV 
Health Insurance Portability and Accountability Act of 1996 
Intravenous Administration 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IRB 
KG 
MG 
MRI 
PET-CT 
Institutional Review Board 
Kilogram 
Milligrams 
Magnetic Resonance Imaging 
Positron Emission Tomography-Computed Tomography 
PI 
PO 
Principal Investigator 
Oral Administration 
SAE 
Serious adverse experience 
 
 
 
 
 
 
 
 
 
 
 
 


Kratz, Johannes R. 
Confidential 
 
Version #: 9.0 
Version Date: 11/5/2019 
Page 6 of 37 
 
PROTOCOL SYNOPSIS 
TITLE 
Minimally Invasive Thoracic Surgery Intercostal Nerve Block Trial 
SPONSOR 
Sponsor-Investigator 
FUNDING 
ORGANIZATION 
Internal – UCSF Department of Surgery, Division of Cardiothoracic 
Surgery 
NUMBER OF SITES 
1 
RATIONALE 
Subjects who undergo minimally invasive lung surgery have 
postoperative surgical pain.  Uncontrolled surgical pain of the chest 
wall can result in splinting, atelectasis, and pneumonia.  The optimal 
strategy to manage surgical pain from minimally invasive thoracic 
surgery is unknown.  With the development of Liposomal 
Bupivacaine, a sustained-release formulation of Standard 
Bupivacaine, there has been renewed interest in regional intercostal 
nerve blockade.  While Standard Bupivacaine loses efficacy after 8 
hours, Liposomal Bupivacaine has the potential efficacy of 96 hours.  
The trial data supporting Liposomal Bupivacaine were performed 
outside of thoracic surgery in local wound infiltration (not regional 
nerve blockage), and the data within thoracic surgery are limited and 
based upon observational studies. 
STUDY DESIGN 
Randomized, double-blind, active-comparator controlled clinical trial 
PRIMARY 
OBJECTIVE 
To assess the analgesic efficacy of intraoperative intercostal nerve 
block and wound infiltration by Liposomal Bupivacaine versus 
Standard Bupivacaine in subjects undergoing minimally invasive lung 
resection. 
SECONDARY 
OBJECTIVES 
To assess if there are changes in perioperative outcomes in intercostal 
nerve block by Standard Bupivacaine versus Liposomal Bupivacaine:  
pulmonary complications, length of stay, direct hospital costs, quality 
of life. 
NUMBER OF 
SUBJECTS 
80 
SUBJECT 
SELECTION 
CRITERIA 
Inclusion Criteria: 
- Robotic or video-assisted lung resection for all indications 
- Surgeons: Johannes R. Kratz MD, David M. Jablons MD, Melissa 
H. Coleman MD 
Exclusion Criteria: 
- Additional thoracic procedures and/or extra-thoracic procedures  
- Reported hypersensitivity to amide local analgesia 
- Cardiac Conduction Abnormalities  


Kratz, Johannes R. 
Confidential 
 
Version #: 9.0 
Version Date: 11/5/2019 
Page 7 of 37 
 
- Hepatic Dysfunction 
- Renal Dysfunction 
- Preoperative Neuropathic Pain requiring tricyclic antidepressants or 
calcium channel alpha 2-delta ligands 
- Preoperative Daily Opioid Usage 
- <18 years of age 
TEST PRODUCT, 
DOSE, AND ROUTE 
OF 
ADMINISTRATION 
Liposomal Bupivacaine 
- 5cc of drug preparation will be percutaneously injected into each 
intercostal space 3-10 under direct intrathoracic vision and 
subcutaneously into each surgical wound at the conclusion of the 
surgery.  
CONTROL 
PRODUCT, DOSE 
AND ROUTE OF 
ADMINISTRATION 
Standard Bupivacaine  
- 5cc of drug preparation will be percutaneously injected into each 
intercostal space 3-10 under direct intrathoracic vision and 
subcutaneously into each surgical wound at the conclusion of the 
surgery. 
DURATION OF 
SUBJECT 
PARTICIPATION 
AND DURATION OF 
STUDY 
Subjects will be on study for up to 30 days following their surgery. 
    Screening: Preoperative Clinic Visit 
    Treatment: Conclusion of surgery (all subjects admitted to the 
hospital for standard postoperative care) 
    Follow Up: Postoperative Clinic Visit 
The total duration of the study is expected to be 8 months. 
CONCOMMITANT 
MEDICATIONS 
Allowed: 
Standardized Hospital Pain Medication Regimen 
All subjects will receive a standardized postoperative pain regimen.  
Goal pain management is to allow the subject to ambulate and 
perform incentive spirometry per standard care.  Escalation of 
opioid dosing if needed will be at the discretion of the inpatient 
surgery team. 
Standardized Discharge Pain Medication Regimen 
All subjects to be discharged on a standardized pain regimen. 
Prohibited: 
None 
EFFICACY 
EVALUATIONS 
 
PRIMARY ENDPOINT 
 
Cumulative Daily In-Hospital Use of Opioids (morphine 
equivalents in mg) 
SECONDARY 
ENDPOINTS 
 
Cumulative Daily In-Hospital Pain Score (0-10) 
 
Mean Time to First Opioid Use (hours) 


Kratz, Johannes R. 
Confidential 
 
Version #: 9.0 
Version Date: 11/5/2019 
Page 8 of 37 
 
 
Mean Time to Ambulation (hours) 
 
Pulmonary Complications (y/n) 
 
Liposomal & Standard Bupivacaine Adverse Events (y/n) 
 
Total Opioid Prescription at Discharge (morphine equivalents in 
mg) 
 
Total Opioid Use as Outpatient (morphine equivalents in mg) 
 
Length of Stay (days) 
 
Direct Costs of Hospital Encounter (dollars) 
 
Quality of Life: Short-Form-8 Health Survey 
OTHER 
EVALUATIONS 
n/a 
SAFETY 
EVALUATIONS 
- All subjects will be monitored with continuous cardiac telemetry 
throughout the entirety of their hospitalization.  
- Nursing staff will assess the mental status of each participant at the 
start of each shift.  
- Surgical wounds will be monitored daily by the surgery inpatient 
team. 
- The minimum duration of inpatient monitoring is 24 hours. For 
subjects that are discharged on POD1 after 24 hours of monitoring, a 
safety assessment will be performed on POD2. 
- Adverse events will be assessed continuously, starting with the first 
patient enrollment and until study completion, and will be 
immediately reported to the Medical Monitor. 
- Serious and severe adverse events, regardless of causality, will be 
followed until resolution or stabilization. 
- Subjects will be discharged with specialized discharge instructions 
to alert them of potential adverse effects and instruct them when to 
call the clinic. 
PLANNED INTERIM 
ANALYSES  
When the study has reached 1/3 and 2/3 goal enrollment, interim 
analysis for safety will be conducted by an independent data 
monitoring committee.  Serious and severe adverse events will be 
monitored by the committee on an ongoing basis throughout the 
study. 
STATISTICS 
Primary Analysis Plan 
& Rationale 
Null Hypothesis:  There is no difference in cumulative daily in-
hospital use of opioids in subjects who receive intercostal nerve block 
and wound infiltration with Liposomal Bupivacaine or Standard 
Bupivacaine during minimally invasive lung resection. 
Statistical Method:  Student’s t-test. 
Rationale: 80 subjects will provide 80% power to detect a statistically 
significant effect with 2-sided alpha error set at 0.05 if the measured 
effect is 19% absolute reduction in cumulative daily in-hospital use of 
opioids.   


Kratz, Johannes R. 
Confidential 
 
Version #: 9.0 
Version Date: 11/5/2019 
Page 9 of 37 
 
The mean cumulative daily in-hospital usage of opioids is 35mg 
morphine equivalents with standard deviation of 12mg.  This was 
estimated by review of previously published studies and corroboration 
with UCSF clinical practice patterns.  A 19% reduction in cumulative 
daily in-hospital use of opioids corresponds to 1 fewer oxycodone 
dose per day, which was considered clinically significant. 
 


Kratz, Johannes R. 
Confidential 
 
Version #: 9.0 
Version Date: 11/5/2019 
Page 10 of 37 
 
1 
BACKGROUND 
In the study, subjects undergoing minimally invasive lung surgery will receive a one-time 
intraoperative intercostal nerve block and wound infiltration with Standard Bupivacaine or 
Liposomal Bupivacaine. 
Standard Bupivacaine 
Standard Bupivacaine (Marcaine®; Hospira Inc; Lake Forest, IL) is an amide local 
anesthetic that is commonly used in the operating room for wound infiltration and regional 
nerve block.  Onset of action is 5-10 minutes and duration is up to 8 hours [1]. 
Liposomal Bupivacaine 
Liposomal Bupivacaine (Exparel®; Pacira Pharmaceuticals Inc; Parsippany, NJ) is a 
sustained-release formulation of Standard Bupivacaine [2].  Onset of action is within 10 
minutes and duration is up to 96 hours [3].  Liposomal Bupivacaine is FDA-approved for 
single-dose infiltration into the surgical site to produce postsurgical analgesia since 2015 
and brachial plexus regional nerve block since 2018.  In clinical practice and research, it is 
also being used off-label for other forms of regional nerve block (including intercostal 
nerve block).  Liposomal Bupivacaine is being used at UCSF for all procedures associated 
with an enhanced recovery program, which includes thoracic surgery. 
1.1 
Overview of Non-Clinical Studies 
Liposomal Bupivacaine is a novel formulation of Standard Bupivacaine that is designed to 
provide sustained-release.  Multivesicular liposomes release Standard Bupivacaine over 
an extended period of time due to diffusion, lipid membrane erosion, and lipid membrane 
reorganization [4].  266mg Liposomal Bupivacaine (planned dose for the study) reaches 
peak plasma levels at 12 hours and levels can be detected up to 96 hours after 
administration.  About 3% of the Liposomal Bupivacaine formulation contains extra-
liposomal Standard Bupivacaine to provide immediate analgesic coverage until there is 
adequate liposomal release [3].  The active component Standard Bupivacaine is an amide 
local anesthetic that binds the voltage-gated sodium channels of the neuron and inhibits 
conduction of pain.  Standard Bupivacaine is metabolized in the liver by cytochrome P450 
and excreted by the kidneys [5].  The remnant liposomes and lipid membranes slowly 
degrade and are eliminated through systemic absorption [4]. 
1.2 
Overview of Clinical Studies 
Liposomal Bupivacaine has been studied in a variety of surgical specialties in both wound 
infiltration and regional nerve block.  Comparison of studies is limited by different 
surgical procedures, placebo versus active control, and varied primary and secondary 
outcomes.  
The initial trials of Liposomal Bupivacaine were in wound infiltration [6].  In comparison 
to placebo, subjects undergoing hemorrhoidectomy had lower cumulative pain score and 
lower cumulative opioid consumption in the first 72 hours after surgery [7].  In 
comparison to Standard Bupivacaine, subjects undergoing breast augmentation had lower 
mean pain score at 12 hours and no difference for the remaining hospital stay [8].  
Subsequent trials have evaluated Liposomal Bupivacaine in regional nerve block [9].  In 


Kratz, Johannes R. 
Confidential 
 
Version #: 9.0 
Version Date: 11/5/2019 
Page 11 of 37 
 
comparison to Standard Bupivacaine, subjects undergoing robotic-assisted hysterectomy 
with abdominal wall nerve block had lower cumulative opioid use in the first 72 hours 
after surgery and subjects undergoing shoulder arthroplasty had reduced pain scores and 
opioid consumption in the first 48 hours [10, 11].  The most common adverse events 
associated with Liposomal Bupivacaine from these studies were nausea, emesis, and/or 
constipation.  Cardiac and neurologic toxicity were not reported [6, 9].   
Liposomal Bupivacaine is FDA-approved for single-dose infiltration into the surgical site 
to produce postsurgical analgesia since 2015 and brachial plexus regional nerve block 
since 2018.  In clinical practice and research, it is also being used off-label for other forms 
of regional nerve block (including intercostal nerve block).   
In thoracic surgery, there are two published studies that were both observational and 
retrospective.  They evaluated intercostal nerve block versus epidural analgesia in subjects 
undergoing lung resection by both thoracotomy and minimally invasive techniques [12, 
13].  Rice et al showed that there was no difference in pain scores, opioid use, or 
postoperative complications between groups.  However, Khalil et al showed that there 
were lower mean pain scores on postoperative day one and three, no difference in opioid 
usage, and lower pulmonary complications in subjects that received Liposomal 
Bupivacaine [Error! Bookmark not defined.].  There is also an unpublished randomized, 
placebo-controlled trial in subjects that underwent thoracotomy and intercostal nerve 
block.  They did not find a difference in pain scores or total opioid consumption. 
There are currently three registered clinical trials at ClinicalTrials.gov evaluating 
Liposomal Bupivacaine in lung resection surgery.  The Mayo Clinic is performing a non-
inferiority trial of epidural analgesia versus intercostal nerve block with Liposomal 
Bupivacaine in subjects undergoing open lung resection [14].  Inova Health Care Services 
is performing a trial assessing local wound infiltration with Liposomal Bupivacaine versus 
Standard Bupivacaine in subjects undergoing thoracoscopy [15].  Massachusetts General 
Hospital is performing a trial evaluating intercostal nerve block with Liposomal 
Bupivacaine, Standard Bupivacaine, Standard Bupivacaine with epinephrine, and normal 
saline in subjects undergoing video-assisted lung resection [16].  Each of these studies 
address questions different from this proposal.  Moreover, the results from these studies 
are not expected within the next year. 
2 
STUDY RATIONALE 
Subjects who undergo minimally invasive thoracic surgery have acute, postoperative 
surgical pain.  Uncontrolled surgical pain of the chest wall can result in splinting, 
atelectasis, and pneumonia [17].  There are a variety of multimodality analgesic strategies 
currently employed in the clinical setting; however, the optimal strategy to provide 
analgesia while minimizing analgesic-related complications is unknown.  With the 
development of Liposomal Bupivacaine, a sustained-release formulation of Standard 
Bupivacaine, there has been renewed interest in regional intercostal nerve blockade. 
Currently, most centers utilize some combination of epidural analgesia, systemic opioids, 
acetaminophen, nonsteroidal anti-inflammatory drugs, and gabapentin [18].  While this 
approach has proven effective, systemic opioids and epidural analgesia have many 
limitations.  In the hospital, over 15% of patients receiving oxycodone will experience 


Kratz, Johannes R. 
Confidential 
 
Version #: 9.0 
Version Date: 11/5/2019 
Page 12 of 37 
 
altered mental status, nausea, or constipation [19].  In addition, it is essential to investigate 
other pain control strategies in consideration of the ongoing opioid abuse epidemic [20].  
In regard to epidural analgesia, its placement is operator dependent, is limited by subject 
habitus, cannot be used in subjects on antiplatelets or anticoagulants, requires frequent 
postoperative monitoring, is associated with postoperative hypotension and urinary 
retention, and can result in epidural hematomas and abscesses that can be life-threatening 
[21, 22]. 
Intercostal nerve blockage with Liposomal Bupivacaine is an alluring alternative analgesic 
strategy as it is a sustained-release formulation of Standard Bupivacaine.  Standard 
Bupivacaine loses efficacy after 8 hours, but Liposomal Bupivacaine has the potential 
efficacy of 96 hours [3].  Liposomal Bupivacaine is FDA-approved for single-dose 
infiltration into the surgical site to produce postsurgical analgesia since 2015 and brachial 
plexus regional nerve block since 2018.  Its use for other forms of regional nerve block 
(including intercostal nerve block) is considered off-label.  
Liposomal Bupivacaine is being used for local wound infiltration and regional nerve 
blocks across the surgical subspecialties, including thoracic surgery.  The actual volume 
and breakdown of use in thoracic surgery is unknown; nonetheless, over the half the 
audience at the Society of Thoracic Surgery Annual Conference in January 2018 indicated 
that they routinely used Liposomal Bupivacaine in their practice.  However, there is a 
clear deficit in data for thoracic surgery.  There have been only two observational studies 
within thoracic surgery [12, 13].  They compared Liposomal Bupivacaine to epidural 
analgesia and found equivalence between the techniques.  The results from these studies 
are subject to systematic error with selection bias and confounding.  In addition, as the 
proportion of minimally invasive to open surgery has increased with the use of robotic-
assisted thoracic surgery [23], many centers have eliminated epidural analgesia for the 
aforementioned reasons and the more pertinent question is Liposomal Bupivacaine versus 
Standard Bupivacaine. 
As discussed in Section 1.2, there are ongoing trials that will provide less biased evidence 
in thoracic surgery assessing both local wound infiltration and intercostal nerve block with 
Liposomal Bupivacaine.  The Minimally Invasive Thoracic Surgery Intercostal Nerve 
Block Study is unique, because it will assess intercostal nerve block and wound 
infiltration with Standard Bupivacaine and Liposomal Bupivacaine in both video-assisted 
and robotic-assisted lung resection. 
A final consideration is the economic impact of Liposomal Bupivacaine.  The direct costs 
of Liposomal Bupivacaine are 100 times the costs of Standard Bupivacaine, and at UCSF, 
the direct costs of Liposomal Bupivacaine are $340 [24].  If Liposomal Bupivacaine is 
found to be efficacious, there could be cost savings through a reduction in use of other 
pain medications and postoperative complications.  Alternatively, if Liposomal 
Bupivacaine is not found to be efficacious, it will only add to the economic burden on the 
health care system. 
2.1 
Risk / Benefit Assessment 
The risks associated with Liposomal Bupivacaine and Standard Bupivacaine are similar.  
The most common adverse events include nausea, emesis, and/or constipation and are 


Kratz, Johannes R. 
Confidential 
 
Version #: 9.0 
Version Date: 11/5/2019 
Page 13 of 37 
 
expected to occur in >10% of subjects.  Less common adverse events include dizziness, 
altered mental status, and hypersensitivity reactions with urticaria and/or pruritis.  Very 
rare, but serious adverse events include neurologic toxicity with seizures and apnea, 
cardiac toxicity with atrioventricular nodal conduction abnormalities and cardiac arrest, 
and hypersensitivity reaction with anaphylaxis.  Serious adverse events can be preventable 
with appropriate education, dosing, and administration.  Most serious adverse events are 
found to be dose-related due to improper intravascular injection, inappropriate dosing, or 
slow metabolic degradation in patients with hepatic dysfunction [6].  For more 
information regarding adverse events, see prescribing information [2].   
To minimize risk and limit the occurrence of serious adverse events, subjects will not be 
eligible for the study if they have evidence of hepatic dysfunction.  In the operating room, 
dosing of Standard Bupivacaine will be based upon subject weight (See Section 8.3.2).  
The medication will be administered with proper technique by drawing back before 
injection to ensure the tip of the needle is not located within the lumen of a blood vessel.  
On the hospital ward, continuous cardiac telemetry will be used on all subjects and 
nursing will assess the mental status of each subject per shift. 
3 
STUDY OBJECTIVES 
3.1 
Primary Objective 
The primary objective is to assess the analgesic efficacy of intercostal nerve block and 
wound infiltration by Liposomal Bupivacaine versus Standard Bupivacaine in subjects 
undergoing minimally invasive lung resection by robotic or video-assisted thoracoscopic 
surgery. 
3.2 
Secondary Objectives 
The secondary objective is to assess if analgesia from the aforementioned interventions 
improve perioperative outcomes with reduction in pulmonary complications, length of 
stay, and direct hospital costs as well as improvement in quality of life. 
4 
STUDY DESIGN 
4.1 
Study Overview 
This is a single center, double-blind, randomized, active-comparator controlled clinical 
trial.  80 subjects undergoing minimally invasive lung resection will be randomly assigned 
to one of two study groups: a one-time intraoperative intercostal nerve block and wound 
infiltration by Standard Bupivacaine or by Liposomal Bupivacaine.  Each subject will 
receive standardized postoperative pain management.  Evaluations will be taken at three-
time points - preoperative clinic visit, index hospitalization following surgery, and 
postoperative clinic visit.  Screening data will be reviewed to determine subject eligibility.  
Subjects who meet all inclusion criteria and none of the exclusion criteria will be entered 
into the study.  Total duration of subject participation will be 30 days.  Total duration of 
the study is expected to be 8 months.  The treatment regimens are outlined below.  
 
Study Treatment - Liposomal Bupivacaine  


Kratz, Johannes R. 
Confidential 
 
Version #: 9.0 
Version Date: 11/5/2019 
Page 14 of 37 
 
- 5cc of prepared drug will be percutaneously injected into each intercostal space 3-10 
with a 22-gauge spinal needle under direct intrathoracic vision and subcutaneously into 
each wound at the conclusion of the surgery.  
 
Active Comparator - Standard Bupivacaine 
- 5cc of prepared drug will be percutaneously injected into each intercostal space 3-10 
with a 22-gauge spinal needle under direct intrathoracic vision and subcutaneously into 
each wound at the conclusion of the surgery.  
5 
CRITERIA FOR EVALUATION 
5.1 
Primary Efficacy Endpoint 
 Cumulative Daily In-Hospital Use of Opioids measured in mg of Oral Morphine 
Equivalents 
The subjective sensation of pain is challenging to measure.  Cumulative daily in-hospital 
opioid use measured in mg of oral morphine equivalents acts as a surrogate endpoint of 
pain and is commonly used in the literature.  It provides objective data that are recorded 
on every subject in the medication administration record. 
5.2 
Secondary Efficacy Endpoints 
 
Cumulative Daily In-Hospital Pain Score: 0 (no pain) – 10 (most pain) 
Pain Scores are a measure of the subject’s postoperative pain that are recorded every four 
hours by the nursing staff.  They are limited by the subject’s perception of pain, 
concomitant pain medication use, and correlation with an abstract scaling system. 
 
 
Mean Time to First Opioid Use (hours) 
Time to first opioid use is a surrogate marker of postoperative pain.  It is limited by 
variations in anesthesiologist intraoperative analgesia techniques. 
 
 
Mean Time to Ambulation (hours) 
Time to ambulation is a downstream marker of postoperative pain control.  Ambulation is 
limited by subject motivation and/or physical disability. 
 
 
Pulmonary Complications: Pneumonia and Atelectasis requiring Bronchoscopy (y/n) 
Pulmonary complications are a downstream marker of postoperative pain control as 
subjects with chest wall postoperative pain commonly splint with respiration.  Splinting is 
associated with atelectasis and pneumonia. 
 
 
Liposomal Bupivacaine and Stand Bupivacaine Adverse Events (y/n):  
- 
Gastrointestinal- nausea, emesis, constipation 
- 
Hypersensitivity- pruritis, urticaria, anaphylaxis 
- 
Cardiac- atrioventricular heart block, cardiac arrest 


Kratz, Johannes R. 
Confidential 
 
Version #: 9.0 
Version Date: 11/5/2019 
Page 15 of 37 
 
- 
Neurologic- dizziness, altered mental status, seizure 
- 
Miscellaneous  
To assess if there are differences in the complications between the study groups. 
 
 
Length of Stay (days) 
Length of stay in the hospital can be used as downstream marker of overall postoperative 
course.  It is limited by attending practice patterns. 
 
 
Total Opioid Prescription at Discharge (morphine equivalents in mg) 
To assess if there are differences in the amount of opioid prescribed at discharge. 
 
 
Total Opioid Use as Outpatient (morphine equivalents in mg) 
To assess if there are differences in the amount of opioid used after discharge. 
 
 
Direct Costs of Hospital Encounter (dollars) 
The interventions in the study add costs over standard of care.  It is important to evaluate 
the burden on the health care system in addition to subject outcomes. 
 
 
Quality of Life: Short-Form-8 Health Survey (Rand Health) 
A change in quality of life before and after surgery will assessed.  This survey is limited 
by subject adherence to completion. 
5.3 
Safety Evaluations 
All subjects will be monitored for cardiac arrhythmias with continuous cardiac telemetry 
throughout the entirety of their hospitalization per standard postoperative care.  If cardiac 
arrhythmias occur, they will be managed by the surgery inpatient team and cardiology 
consultation if deemed necessary. 
 
The mental status of each subject will be assessed daily by the surgery inpatient team and 
each shift (every 12 hours) by the nursing staff.  Workup and management of altered 
mental status is at the discretion of the surgery team. 
 
Surgical wounds will be monitored daily by the surgery inpatient team and each shift 
(every 12 hours) by the nursing staff.  Evidence of hypersensitivity reaction will be treated 
with observation, antihistamines, and/or epinephrine depending upon the severity of 
reaction. 
 
The minimum duration of inpatient monitoring is 24 hours. For subjects that are 
discharged on POD1 after 24 hours of monitoring, a safety assessment will be performed 
by telephone on POD2.  If subject answers “Yes” to any of the questions, the subject will 
be brought into clinic for further evaluation.  See POD2 Safety Assessment below for more 
information. 


Kratz, Johannes R. 
Confidential 
 
Version #: 9.0 
Version Date: 11/5/2019 
Page 16 of 37 
 
 
 
Adverse events will be assessed continuously, starting with the first patient enrollment and 
until study completion, and will be immediately reported to the Medical Monitor.  Serious 
and severe adverse events, regardless of causality, will be followed until resolution or 
stabilization per Section 11 below. 
 
Subjects will be discharged with specialized discharge instructions to alert them of 
potential adverse effects and instruct them when to call the clinic. 
 
POD2 Safety Assessment 
 
The safety assessment will be conducted over the phone on POD2 for subjects that were 
discharged on POD1.  If the subject answers “yes” to any of these questions, the event 
will be recorded as an AE and the patient will be brought into clinic for further evaluation. 
 
 Is the subject oriented? 
 
_ Yes _ No _ Not Assessable 
 
 Since your last assessment have you had numbness of the lips, the tongue, or 
around the mouth? 
 
_ Yes _ No 
 
 Since your last assessment have you had a metallic taste in your mouth? 
 
_ Yes _ No 
 
 Since your last assessment, have you had problems with your hearing not related 
to the use of a hearing aid?  
 
_ Yes _ No 
 
 Since your last assessment, have you had problems with your vision not related to 
the use of eye glasses?  
 
_ Yes _ No 
 
 Since your last assessment, have your muscles been twitching? 
 


Kratz, Johannes R. 
Confidential 
 
Version #: 9.0 
Version Date: 11/5/2019 
Page 17 of 37 
 
_ Yes _ No 
 
 Since your last assessment, have you had heart palpitations in which you can feel 
your heart beating irregularly?  
 
_ Yes _ No 
 
6 
SUBJECT SELECTION 
6.1 
Study Population 
Subjects who are planned to undergo minimally invasive lung resection and meet the 
inclusion and exclusion criteria will be eligible for participation in this study.  Of note, 
subjects with non-English proficiency will be eligible for participation in this study: 
Spanish, Cantonese, Mandarin, Russian.  These subjects will be provided written Consent, 
Experimental Subject’s Bill of Rights, and HIPAA Authorization in their preferred 
language with use of a Qualified Interpreter. 
6.2 
Inclusion Criteria 
1. Robot or video-assisted lung resection for all indications  
Robotic or video-assisted techniques both use three to four incisions that are <15mm 
and there are no expected differences between the techniques.  The indication for 
surgery is not expected to influence the primary outcome. 
2. Surgeons: David M. Jablons MD, Melissa H. Coleman MD, or Johannes R. Kratz MD 
3. Written informed consent obtained from subject or subject’s legal representative and 
ability for subject to comply with the requirements of the study. 
6.3 
Exclusion Criteria 
1. Additional thoracic procedures performed beyond lung resection and mediastinal 
lymphadenectomy (such as chest wall resection, rib resection, muscle flap, etc) and/or 
extra-thoracic procedures (such as abdominal surgery, neck surgery, etc).   
Additional procedures will alter postoperative course and postoperative pain. 
2. Reported hypersensitivity to amide local analgesia (such as lidocaine, bupivacaine, 
ropivacaine). 
3. Reported Cardiac Conduction Abnormalities (Wolf-Parkinson-White, second degree 
Mobitz II or third degree atrioventricular heart block).   
Amide local analgesia can cause heart block and/or cardiac arrest. 
4. Hepatic Dysfunction defined as cirrhosis complicated by ascites, esophageal varices, 
or hepatic encephalopathy determined by preoperative history and physical.   
Amide local analgesia is metabolized by the liver. 


Kratz, Johannes R. 
Confidential 
 
Version #: 9.0 
Version Date: 11/5/2019 
Page 18 of 37 
 
5. Renal Dysfunction requiring hemodialysis or peritoneal dialysis determined by 
preoperative history and physical.   
Amide local analgesia excreted by the kidneys. 
6. Preoperative Neuropathic Pain requiring tricyclic antidepressants or calcium channel 
alpha 2-delta ligands (gabapentin, pregabalin).   
To compare subjects without preoperative neuropathic pain. 
7. Preoperative Daily Opioid Usage.   
To compare subjects without preoperative pain requiring opioids. 
8. Pregnant or breastfeeding during participation in the study.   
Subjects not eligible for surgery or the study. 
9. <18 years of age. 
10. Presence of a condition or abnormality that in the opinion of the investigator would 
compromise the safety of the patient or the quality of the data. 
7 
CONCURRENT MEDICATIONS 
Intraoperative analgesia provided by the anesthesia team will not be altered and will be 
performed per standard care.  All subjects will be started on the same postoperative pain 
medications in the hospital and when discharged as outlined in Section 7.1. 
7.1 
Allowed Medications and Treatments 
Standardized Hospital Pain Medication Regimen:   
Medication will not be given if there is known allergy.  Goal pain management is to allow 
the subject to ambulate and perform incentive spirometry per standard of care.  Escalation 
of opioid dosing if needed will be at the discretion of the inpatient surgery team. 
 PO Tylenol 1000mg every 6 hours 
 PO Gabapentin 300mg twice a day 
 IV Ketorolac 15mg every 6 hours for 24 hours, then PO Diclofenac 50mg BID (if <75 
years old and normal renal function) 
 PO Oxycodone 5-10mg every 4 hours as needed for moderate pain 
 IV Hydromorphone 0.2-0.4mg every 2 hours as needed for severe pain 
Standardized Discharge Pain Medication Regimen: 
All subjects to be discharged on the following pain regimen outlined below.  Medication 
will not be given if there is known allergy.   
- 
PO Acetaminophen 1000mg every 6 hours for 2 weeks 
- 
PO Gabapentin 300mg twice a day for 2 weeks 
- 
PO Diclofenac 50mg BID for 2 weeks 
- 
PO Oxycodone as needed for pain – 20 Pills in Total 


Kratz, Johannes R. 
Confidential 
 
Version #: 9.0 
Version Date: 11/5/2019 
Page 19 of 37 
 
8 
STUDY TREATMENTS 
8.1 
Method of Assigning Subjects to Treatment Groups 
80 eligible subjects will be randomly assigned to intraoperative intercostal nerve blocks 
and wound infiltration by Standard Bupivacaine or Liposomal Bupivacaine in a 1:1 ratio 
with varying block size (4-8) using Stata 15.1 (College Station, TX) ralloc.ado package.  
When the subject arrives in the operating room, the surgeon/study doctor will contact the 
pharmacy who will determine treatment assignment and prepare the medication as 
outlined in Sections 8.3-8.4. 
8.2 
Blinding 
All patients will be blinded to the treatment groups as they will receive the one-time 
treatment while under general anesthesia in the operating room. 
All study staff will be blinded to the treatment groups, except those staff involved in 
assigning treatment groups.  Access to the randomization code will be strictly controlled.  
The study blind will be broken on completion of the clinical study and after the study 
database has been locked.   
Investigators will be blinded to the medical treatment groups - Standard Bupivacaine and 
Liposomal Bupivacaine.  As Standard Bupivacaine is clear and Liposomal Bupivacaine is 
milky white, obscuring over-wraps will be placed over syringe.  See Section 8.3-8.3.2 for 
more information. 
During the study, the blind may be broken only in emergencies when knowledge of the 
patient’s treatment group is necessary for further patient management.  If this occurs, the 
investigator will contact the study staff involved in assigning treatment groups, and the 
blind will be broken.  When possible, the investigator should discuss the emergency with 
the Medical Monitor prior to unblinding.   
8.3 
Formulation of Test and Control Products 
Study Treatment 
Liposomal Bupivacaine - Exparel® 
- 
Manufacturer:  Pacira Pharmaceuticals Inc - Parsippany, NJ 
- 
Formulation:  Suspension, Injection 
- 
Preparation: See Section 8.3.1 
 
Active Comparator 
Standard Bupivacaine - Marcaine® 
- 
Manufacturer:  Hospira Inc - Lake Forest, IL 
- 
Formulation:  Suspension, Injection 
- 
Preparation: See Section 8.3.2 
 
The study treatment and active comparator will be prepared by the Investigational 
Pharmacy under aseptic conditions and used within 24 hours. 


Kratz, Johannes R. 
Confidential 
 
Version #: 9.0 
Version Date: 11/5/2019 
Page 20 of 37 
 
8.3.1 
Formulation of Test Product (See Table 1 in Section 8.3.2) 
Liposomal Bupivacaine   
- 
Drug Preparation: 266mg (20cc) Liposomal Bupivacaine admixed with 0.25% 
(2.5mg/cc) Standard Bupivacaine* and varied 0.9% normal saline volume for total 
volume of 60cc. 
 266mg (20cc) Liposomal Bupivacaine is the FDA-approved dose for 
wound infiltration. 
 Standard Bupivacaine is added to bridge the time to efficacy of Liposomal 
Bupivacaine, which occurs in 6-8 hours.  This is standard clinical practice. 
 Normal saline is used to the dilute the drug in order to have sufficient 
volume to perform the intervention. 
 As Standard Bupivacaine is clear and Liposomal Bupivacaine is milky 
white, obscuring over-wraps will be placed over syringe. 
*If subject weight ≥35kg, 30cc Standard Bupivacaine will be used.  If subject 
weight <35kg, maximum dose of 2mg/kg Standard Bupivacaine will be used. 
8.3.2 
Formulation of Control Product 
Standard Bupivacaine 
- 
Drug Preparation: 0.25% (2.5mg/cc) Standard Bupivacaine* admixed with varied 
0.9% normal saline volume for total volume of 60cc. 
 Normal saline is used to the dilute the drug in order to have sufficient 
volume to perform the intervention. 
 As Standard Bupivacaine is clear and Liposomal Bupivacaine is milky 
white, obscuring over-wraps will be placed over syringe. 
*If subject weight ≥35kg, 30cc Standard Bupivacaine will be used.  If subject 
weight <35kg, maximum dose of 2mg/kg Standard Bupivacaine will be used. 
 
Table 1: Drug Preparation 
 
Liposomal Bupivacaine 
0.25% Standard Bupivacaine 
Active Ingredient: cc (mg) 
20 (266) 
30 (75)* 
0.9 % Normal Saline: cc 
10 
30 
0.25% Standard Bupivacaine: 
cc (mg) 
30 (75)* 
n/a 
* If subject weight <35kg, maximum dose of 2mg/kg will be used. 
8.3.3 
Packaging and Labeling 
Study drugs (Liposomal Bupivacaine and Standard Bupivacaine) will be labeled with the 
required FDA warning statement, the protocol number, the subject number, and directions 
for use.   As Standard Bupivacaine is clear and Liposomal Bupivacaine is milky white, 
obscuring over-wraps will be placed over syringe.  The inpatient pharmacy will prepare 
and deliver the drug to the operating room. 


Kratz, Johannes R. 
Confidential 
 
Version #: 9.0 
Version Date: 11/5/2019 
Page 21 of 37 
 
8.4 
Supply of Study Drug at the Site 
Study drugs (Liposomal Bupivacaine and Standard Bupivacaine) are already stocked and 
available at the inpatient pharmacy for use in the operating room. 
8.4.1 
Dosage/Dosage Regimen 
See Sections 8.3.1 and 8.3.2 for Drug Preparation.  
 
Liposomal Bupivacaine  
- 5cc of drug preparation will be injected into each intercostal space 3-10 and 
subcutaneously into each wound. 
Standard Bupivacaine 
- 5cc of drug preparation will be injected into each intercostal space 3-10 and 
subcutaneously into each wound. 
8.4.2 
Dispensing 
The inpatient investigational pharmacist will dispense the drugs to the operating room. 
8.4.3 
Administration Instructions  
Liposomal Bupivacaine  
- 5cc of prepared drug will be percutaneously injected into each intercostal space 3-10 
with a 22-gauge spinal needle under direct intrathoracic vision and subcutaneously into 
each wound at the conclusion of the surgery.   
Standard Bupivacaine 
- 5cc of prepared drug will be percutaneously injected into each intercostal space 3-10 
with a 22-gauge spinal needle under direct intrathoracic vision and subcutaneously into 
each wound at the conclusion of the surgery.   
 
Prior to injection, the investigator will aspirate to ensure that the tip of the needle is not in 
the intravascular space. 
8.4.4 
Storage 
Study drugs will be stored per inpatient pharmacy standards. 
8.5 
Study Drug Accountability 
An accurate and current accounting of the dispensing and return of study drug for each 
subject will be maintained on an ongoing basis by a member of the study site staff.  The 
number of study drug dispensed and returned by the subject will be recorded on the 
Investigational Drug Accountability Record.  The study monitor will verify these 
documents throughout the course of the study. 
8.6 
Measures of Treatment Compliance 
Subject compliance is not an issue with this study as the treatment is given in a single 
episode by the investigators at the conclusion of surgery.  A standardized approach will be 


Kratz, Johannes R. 
Confidential 
 
Version #: 9.0 
Version Date: 11/5/2019 
Page 22 of 37 
 
used by all investigators as outlined in Section 8.4.3.  To ensure that each subject receives 
the same postoperative pain management, a standardized electronic orderset will be 
utilized. 
9 
STUDY PROCEDURES AND GUIDELINES 
A Schedule of Events representing the required testing procedures to be performed for the 
duration of the study is diagrammed in Appendix 1. 
Prior to conducting any study-related activities, written informed consent and the Health 
Insurance Portability and Accountability Act (HIPAA) authorization must be signed and 
dated by the subject. 
9.1 
Clinical Assessments 
9.1.1 
Concomitant Medications 
All concomitant medication will be documented at the preoperative and postoperative 
clinic visits.  Dose, route, unit frequency of administration, and indication for 
administration and dates of medication will be captured. 
9.1.2 Demographics  
Demographic information (date of birth, gender, race) will be recorded at the preoperative 
clinic visit. 
9.1.3 Medical History  
Relevant medical history, including history of current disease and information regarding 
underlying diseases will be recorded at the preoperative clinic visit. 
9.1.4 
Physical Examination 
A complete physical examination will be performed by either the investigator or a 
subinvestigator who is a physician within the Department of Surgery, Division of 
Cardiothoracic Surgery.  Qualified staff (MD, NP, RN, and PA) may complete the 
abbreviated physical exam at all other visits.  New abnormal physical exam findings must 
be documented and will be followed by a physician or other qualified staff at the next 
scheduled visit. 
9.1.5 
Vital Signs 
Body temperature, blood pressure, pulse and respirations will be performed after resting 
for 5 minutes at the preoperative and postoperative clinic visits.   
9.1.6 
Other Clinical Procedures 
Subjects will be given the Short Form-8-Health Survey at the preoperative and 
postoperative clinic visits.  In addition, subjects will be given a Pain Medication Survey at 
the postoperative clinic visit to capture what medications are still being used to control 
pain. 


Kratz, Johannes R. 
Confidential 
 
Version #: 9.0 
Version Date: 11/5/2019 
Page 23 of 37 
 
9.1.7 
Adverse Events 
Information regarding occurrence of adverse events will be captured throughout the study. 
Duration (start and stop dates), severity, outcome, treatment, and relation to study drug 
will be recorded on the case report form (CRF). 
9.2 
Clinical Laboratory Measurements 
9.2.1 
Pregnancy Test 
A urine pregnancy test will be obtained from female subjects who are of childbearing age 
on the day of their surgery. 
10 EVALUATIONS BY VISIT 
10.1 Visit 1 – Preoperative Clinic Visit 
1. 
Review the study with the subject and obtain written informed consent and HIPAA 
authorization. 
2. 
Assign the subject a unique screening number. 
3. 
Record demographics data. 
4. 
Record medical history, including indication for surgery and prior thoracic 
surgeries. 
5. 
Record concomitant medications. 
6. 
Perform a complete physical examination. 
7. 
Perform and record vital signs. 
8. 
Obtain routine preoperative studies as clinically indicated, including pulmonary 
function tests, cardiology evaluation, chest imaging (CT, PET-CT, MRI), 
bronchoscopy with endoscopic ultrasound, and lung biopsy.  
9. 
Administer Short Form-8-Health Survey 
10. 
Schedule subject for surgery. 
10.2 Visit 2 – Surgery with Hospitalization 
1. 
Collect urine pregnancy test in female patients of childbearing age in the 
preoperative suite. 
2. 
Randomize to Liposomal Bupivacaine or Standard Bupivacaine during surgery. 
3. 
Administer intervention during surgery. 
4. 
Record any Adverse Experiences and/or Review subject diary for adverse 
experiences and exclusionary medication use daily. 
5. 
Concomitant medications administration. 
6. 
Perform abbreviated physical examination daily. 
7. 
Perform and record vital signs every 4 hours. 
8. 
Monitor with Continuous Pulse Oximetry and Continuous Cardiac Monitoring 
throughout hospitalization. 


Kratz, Johannes R. 
Confidential 
 
Version #: 9.0 
Version Date: 11/5/2019 
Page 24 of 37 
 
10.3 Visit 3 – Postoperative Clinic Visit 
1. 
Record any Adverse Experiences. 
2. 
Record changes to concomitant medications. 
3. 
Perform abbreviated physical examination. 
4. 
Perform and record vital signs. 
5. 
Administer Short Form-8-Health Survey and Pain Medication Survey. 
11 ADVERSE EXPERIENCE REPORTING AND DOCUMENTATION 
11.1 Adverse Events 
An adverse event (AE) is any untoward medical occurrence in a clinical investigation of a 
patient administered a pharmaceutical product and that does not necessarily have a causal 
relationship with the treatment.  An AE is therefore any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom or disease temporally associated 
with the administration of an investigational product, whether or not related to that 
investigational product.  An unexpected AE is one of a type not identified in nature, 
severity, or frequency in the current Investigator’s Brochure or of greater severity or 
frequency than expected based on the information in the Investigator’s Brochure. 
The Investigator will probe, via discussion with the subject, for the occurrence of AEs 
during each subject visit and record the information in the site’s source documents.  
Adverse events will be recorded in the patient CRF.  Adverse events will be described by 
duration (start and stop dates and times), severity, outcome, treatment and relation to 
study drug, or if unrelated, the cause. 
AE Severity 
The National Cancer Institute’s Common Terminology Criteria for Adverse Events 
(CTCAE) Version 3.0 will be used to assess and grade AE severity, including laboratory 
abnormalities judged to be clinically significant. The modified criteria can be found in the 
study manual.  If the experience is not covered in the modified criteria, the guidelines 
shown in Table 1 below should be used to grade severity.  It should be pointed out that the 
term “severe” is a measure of intensity and that a severe AE is not necessarily serious. 


Kratz, Johannes R. 
Confidential 
 
Version #: 9.0 
Version Date: 11/5/2019 
Page 25 of 37 
 
Table 1.  AE Severity Grading 
Severity (Toxicity Grade) 
Description 
Mild (1) 
Transient or mild discomfort; no limitation in activity; no medical 
intervention or therapy required. The subject may be aware of the sign 
or symptom but tolerates it reasonably well. 
Moderate (2) 
Mild to moderate limitation in activity, no or minimal medical 
intervention/therapy required. 
Severe (3) 
Marked limitation in activity, medical intervention/therapy required, 
hospitalizations possible. 
Life-threatening (4) 
The subject is at risk of death due to the adverse experience as it 
occurred. This does not refer to an experience that hypothetically 
might have caused death if it were more severe. 
 
AE Relationship to Study Drug 
The relationship of an AE to the study drug should be assessed using the following the 
guidelines in Table 2. 
Table 2.  AE Relationship to Study Drug 
Relationship 
to Drug 
Comment 
Definitely 
Previously known toxicity of agent; or an event that follows a reasonable temporal 
sequence from administration of the drug; that follows a known or expected response 
pattern to the suspected drug; that is confirmed by stopping or reducing the dosage of 
the drug; and that is not explained by any other reasonable hypothesis. 
Probably 
An event that follows a reasonable temporal sequence from administration of the 
drug; that follows a known or expected response pattern to the suspected drug; that is 
confirmed by stopping or reducing the dosage of the drug; and that is unlikely to be 
explained by the known characteristics of the subject’s clinical state or by other 
interventions. 
Possibly 
An event that follows a reasonable temporal sequence from administration of the 
drug; that follows a known or expected response pattern to that suspected drug; but 
that could readily have been produced by a number of other factors. 
Unrelated 
An event that can be determined with certainty to have no relationship to the study 
drug. 
11.2 Serious Adverse Experiences (SAE) 
An SAE is defined as any AE occurring at any dose that results in any of the following 
outcomes: 
 
death 
 
a life-threatening adverse experience 
 
inpatient hospitalization or prolongation of existing hospitalization 
 
a persistent or significant disability/incapacity 


Kratz, Johannes R. 
Confidential 
 
Version #: 9.0 
Version Date: 11/5/2019 
Page 26 of 37 
 
 
a congenital anomaly/birth defect  
Other important medical events may also be considered an SAE when, based on 
appropriate medical judgment, they jeopardize the subject or require intervention to 
prevent one of the outcomes listed.  
11.2.1 Serious Adverse Experience Reporting 
The study site will document all SAEs that occur (whether or not related to study drug) 
per UCSF CHR Guidelines.  The collection period for all SAEs will begin after informed 
consent is obtained and end after procedures for the final study visit have been completed. 
In accordance with the standard operating procedures and policies of the local Institutional 
Review Board (IRB)/Independent Ethics Committee (IEC), the site investigator will report 
SAEs to the IRB/IEC.   
11.3 Protocol Defined Important Medical Findings Requiring Real Time Reporting 
The following medical findings that occur will require real time reporting by the inpatient 
surgical team to the medical monitoring team: 
 
Cardiovascular: Bradycardia, Heart Block, Ventricular Arrhythmia, and/or Cardiac 
Arrest requiring intervention 
 
Neurologic: Seizure 
 
Hypersensitivity: Anaphylaxis 
 
Death 
11.4 Medical Monitoring 
Lundy Campbell MD, should be contacted directly at these numbers to report medical 
concerns or questions regarding safety. 
Phone/Pager: (415) 443-3692 
Fax: (415) 476-8444 
12 DISCONTINUATION AND REPLACEMENT OF SUBJECTS 
12.1 Early Discontinuation of Study Drug  
Early discontinuation of study drug is not applicable as study drug is given in a single 
episode. 
12.3 
Withdrawal of Subjects from the Study 
A subject may be withdrawn from the study at any time if the subject or the investigator 
feel that it is not in the subject’s best interest to continue.   
All subjects are free to withdraw from participation at any time, for any reason, specified 
or unspecified, and without prejudice. 
Reasonable attempts will be made by the investigator to provide a reason for subject 
withdrawals.  The reason for the subject’s withdrawal from the study will be specified in 


Kratz, Johannes R. 
Confidential 
 
Version #: 9.0 
Version Date: 11/5/2019 
Page 27 of 37 
 
the subject’s source documents.  Subjects who withdraw after Visit 2 but prior to Visit 3 
will be encouraged to come in for a final visit.  
12.4 
Replacement of Subjects 
Subjects who withdraw from the study treatment will be replaced.   
13 PROTOCOL VIOLATIONS 
A protocol violation occurs when the subject or investigator fail to adhere to significant 
protocol requirements affecting the inclusion, exclusion, subject safety and primary 
endpoint criteria.  Protocol violations for this study include, but are not limited to, the 
following: 
Failure to meet inclusion/exclusion criteria 
Did not receive specified intervention 
Use of a prohibited concomitant medication 
Failure to comply with Good Clinical Practice (GCP) guidelines will also result in a 
protocol violation. The sponsor will determine if a protocol violation will result in 
withdrawal of a subject. 
When a protocol violation occurs, it will be discussed with the investigator and a Protocol 
Violation Form detailing the violation will be generated. This form will be signed by the 
Investigator. A copy of the form will be filed in the site’s regulatory binder and in the 
Sponsor’s files. 
14 DATA SAFETY MONITORING  
A Data Monitoring Committee (DMC) comprised of the Medical Monitor, External 
Investigator, and Clinical Pharmacist will review data relating to safety and efficacy, 
conduct and review interim analyses, and ensure the continued scientific validity and 
merit of the study, according to the UCSF Data Safety Monitoring Board Operations 
Manual and a DMC Charter to be established for this protocol.  There will be an interim 
review conducted at 1/3 and 2/3 goal enrollment by the DMC for the purpose of 
monitoring study conduct and assessing patient safety.  Further details regarding the 
timing and content of the interim reviews is included in the statistical section below. 
14.1 
DMC Charter 
Introduction 
The purpose of this charter is to define the responsibilities of the DMC, detail membership 
requirements, describe the data to be reviewed, delineate the meeting process, and outline 
the considerations and policies of the DMC.   The DMC will act in an expert, independent 
advisory capacity to monitor participant safety, and evaluate the efficacy and conduct of 
the study.  
Study Overview 


Kratz, Johannes R. 
Confidential 
 
Version #: 9.0 
Version Date: 11/5/2019 
Page 28 of 37 
 
 
Study title: Minimally Invasive Thoracic Surgery Intercostal Nerve Block Trial 
 
Study design: Randomized, double-blind, active-comparator controlled clinical 
trial to assess the analgesic efficacy of intercostal nerve block by Liposomal 
Bupivacaine versus Standard Bupivacaine in subjects undergoing minimally 
invasive lung resection. 
 
Phase: III 
 
Number of participants: 80 
 
Number of sites: 1 
DMC Responsibilities 
 
Review the research protocol, informed consent documents, and plans for data 
safety and monitoring prior to initiation of study, periodically during the study, 
and at the conclusion of the study; 
 
Conduct interim and final evaluation of the study, including safety data, quality 
and timeliness of data submission, participant recruitment, accrual and retention, 
risk versus benefit, including unanticipated problems and protocol violations, 
efficacy, statistical outcomes, and other factors that can affect study outcome, 
including aggregate and individual participant data related to safety, data integrity 
and overall conduct of the study; 
 
Protect the safety of the study participants; 
 
Review and evaluate ad hoc safety issues concerning the study at the request of the 
Investigator; 
 
Make recommendations to the Investigators concerning continuation, termination, 
or other modifications of the study based on the observed beneficial or adverse 
effects of the study; 
 
Operate according to the procedures described in this charter. 
DMC Membership 
The DMC will be comprised of an External Investigator, Clinical Pharmacist, and the Medical 
Monitor who will also serve as the Chairman of the DMC. 
- External Investigator: Ankit Sarin, MD, Assistant Professor of Surgery at UCSF.  Dr. Sarin is the 
Surgical Director of the Enhanced Recovery After Surgery Program in Colorectal Surgery and has 
expertise in postoperative analgesia. 
- Clinical Pharmacist:  Candy Tsourounis, PharmD at UCSF.  Candy has expertise pertaining to 
the efficacy and risks associated with local amide analgesia. 
- Medical Monitor / Chairman of the DMC:  Lundy Campbell MD, Clinical Professor of 
Anesthesia at UCSF.  Dr. Campbell was selected as he is an expert in local amide analgesia. 
Although DMC members are expected to serve for the duration of the study, in the 
unlikely event that a member is unable to continue participation, the reason will be 
documented and a replacement member will be selected by the Investigator.  The new 
member must have comparable expertise and qualifications to the DMC member he/she is 


Kratz, Johannes R. 
Confidential 
 
Version #: 9.0 
Version Date: 11/5/2019 
Page 29 of 37 
 
replacing.  DMC members must not have any real or perceived scientific, financial, 
professional, personal, proprietary, or other conflict of interest related to the conduct, 
outcome, or impact of the study.   
Review of Safety Data 
The primary charge of the DMC is to monitor the study for participant safety.  The safety 
and related data the DMC will review includes, 
 
Participant recruitment, accrual, retention, and withdrawal information 
 
Adverse events (AEs) and serious adverse events (SAEs)  
o Tabulated by body system, intensity, seriousness, duration, treatment 
given, and the relationship to the study drug and study procedure 
o Comparison of events that occur between treatment arms 
o Individual events of particular concern 
In particular, the following are adverse events of special interest pertinent to Liposomal 
Bupivacaine and Standard Bupivacaine: 
 Nausea, emesis, and/or constipation and are expected to occur in >10% of 
subjects.   
 Less common adverse events include dizziness, altered mental status, and 
hypersensitivity reactions with urticaria and/or pruritis.   
 Very rare, but serious adverse events include neurologic toxicity with seizures and 
apnea, cardiac toxicity with atrioventricular nodal conduction abnormalities and 
cardiac arrest, and hypersensitivity reaction with anaphylaxis.   
SAEs must be reported by the Investigator to the DMC Chair. 
Review of Other Data 
- Effectiveness 
The DMC monitors effectiveness outcomes to determine relative risk/benefit, futility, or 
for early termination due to overwhelming effectiveness. 
- Study Conduct 
The DMC reviews data related to study conduct.  Data to be reviewed and listed in the 
DMC reports regarding study conduct includes: summary of protocol violations, 
completeness and timeliness of study visit data, enrollment eligibility and ineligibility 
information, noncompliance, unanticipated problems, information concerning withdrawal 
of participants.  The DMC may issue recommendations regarding study conduct when 
concerns arise that aspects of study conduct may threaten participant safety or study 
integrity.  
DMC Meetings 
- Projected Schedule of Meetings   
An initial meeting of the DMC will be held prior to any participant enrollment in order for 
the members to review the charter, form an understanding of the protocol and definitions 
being used, establish a distribution and meeting schedule, review the study modification 
and/or termination guidelines, and finalize format and protocol-specified statistical 


Kratz, Johannes R. 
Confidential 
 
Version #: 9.0 
Version Date: 11/5/2019 
Page 30 of 37 
 
methods to be used in reports to be considered by the DSMB.  Subsequent DMC meetings 
will be held to review at 1/3 and 2/3 goal enrollment, and at the conclusion of the study. 
- Ad Hoc Meetings 
An ad hoc meeting of the DMC may be called at any time if immanent participant safety 
issues arise.  If a significant safety concern arises during the study, the DMC Chair may 
convene a meeting to review safety and any other aspect of the study.  Significant safety 
events may include, but are not limited to, the following: 
 
A death or life-threatening condition sustained by a participant, regardless of 
causality 
 
An unexpected serious safety issue newly identified during the development 
program that could expose participants to unnecessary risks 
 
Any other concern regarding participant safety raised by any DMC member 
- Meeting Format 
DMC meetings will be conducted in person. 
- Voting 
DMC recommendations will be agreed upon by formal majority vote.  In event of a split 
vote, the DMC Chair will cast the deciding vote. 
- Stopping Rules 
The DMC will determine whether the study should continue as planned, proceed with 
modifications, or be terminated.  The justification to terminate the study may be due to the 
DMC's analysis that there is overwhelming effectiveness, futility, or safety issues.  If the 
DMC votes to terminate the study, a final study report will be made. 
15 STATISTICAL METHODS AND CONSIDERATIONS 
Prior to the analysis of the final study data, a detailed Statistical Analysis Plan (SAP) will 
be written describing all analyses that will be performed.  The SAP will contain any 
modifications to the analysis plan described below.   
15.1 Data Sets Analyzed 
All eligible patients who are randomized into the study and receive the intervention will 
be included in the analysis. 
15.2 Demographic and Baseline Characteristics 
The following demographic variables at screening will be summarized: age, gender, race 
and ethnicity, height, weight, comorbid conditions, smoking history, lung function, 
indication for surgery, prior thoracic surgery. 
15.3 Analysis of Primary Endpoint 
Null Hypothesis: There is no difference in cumulative in-hospital use of opioids in 
subjects who receive intercostal nerve block and wound infiltration Liposomal 
Bupivacaine or Standard Bupivacaine during minimally invasive lung resection. 


Kratz, Johannes R. 
Confidential 
 
Version #: 9.0 
Version Date: 11/5/2019 
Page 31 of 37 
 
Student’s t-test will be used to assess the means of the cumulative total of in-hospital oral 
morphine equivalents.  It is presumed that the data will be normally distributed.  If this 
assumption is not met, transformation or nonparametric tests (Mann-Whitney U test) will 
be used.  Moreover, as there are only 40 subjects per group, it is possible that we do not 
achieve effective randomization.  If this occurs, we will utilize linear regression adjusting 
for age, sex, race, comorbidity, diagnosis, and procedure performed.  A power of 0.8 and 
2-sided alpha error set at 0.05 will be used to assess for statistical significance. 
15.4 Analysis of Secondary Endpoints 
 
Cumulative Daily In-Hospital Pain Score (0-10) 
 
Mean Time to First Opioid Use (hours) 
 
Mean Time to Ambulation (hours) 
 
Pulmonary Complications: Pneumonia and Atelectasis requiring Bronchoscopy (y/n) 
 
Liposomal Bupivacaine and Stand Bupivacaine Adverse Events (y/n):  
- 
Gastrointestinal- nausea, emesis, constipation 
- 
Hypersensitivity- pruritis, urticaria, anaphylaxis 
- 
Cardiac- atrioventricular heart block, cardiac arrest 
- 
Neurologic- dizziness, altered mental status, seizure 
- 
Miscellaneous  
Safety and tolerability data will be summarized by treatment group.  Adverse event 
rates will be coded by body system and will include the number of patients for whom 
the event occurred, the rate of occurrence, and the severity and relationship to study 
drug. 
 
Length of Stay (days) 
 
Total Opioid Prescription at Discharge (morphine equivalents in mg) 
 
Total Opioid Use as Outpatient (morphine equivalents in mg) 
 
Direct Costs of hospital encounter (dollars) 
 
Quality of life – Short-Form-8 Health Survey (Optum Health) 
Student’s t-test, Pearson’s chi-squared test, and Kaplan-Meier survival estimate will be 
used.  A 2-sided alpha error set at 0.05 will be used to assess for statistical significance. 
15.5 Interim Analysis 
There will be interim reviews conducted by the DMC for the purpose of monitoring study 
conduct and assessing patient safety at 1/3 and 2/3 goal enrollment.  Blinding will be 
maintained.  An O’Brien-Fleming alpha spending function with symmetric stopping 
boundaries for benefit and harm will be utilized.  If the stopping boundaries have been 
reached (absolute value of z-value >3), the data will be unblinded for review and the trial 
will be terminated.  Finally, there also will be consideration of terminating trial if there is 
consensus of futility.   


Kratz, Johannes R. 
Confidential 
 
Version #: 9.0 
Version Date: 11/5/2019 
Page 32 of 37 
 
15.6 Sample Size and Randomization 
80 Subjects will be randomized to 1:1 to Liposomal Bupivacaine or Standard Bupivacaine 
by varying block size (4-8).  80 subjects will provide 80% power to detect a statistically 
significant effect with 2-sided alpha error set at 0.05 if the measured effect is 19% 
absolute reduction in cumulative daily in-hospital use of opioids.   
The mean daily in-hospital usage of opioids is 35mg morphine equivalents with standard 
deviation of 12mg.  This was estimated by review of previously published studies and 
corroboration with UCSF clinical practice patterns [12].  A 19% absolute reduction in 
cumulative daily in-hospital use of opioids corresponds to 1 fewer oxycodone dose per 
day, which was considered the minimum clinically significant effect. 
16 DATA COLLECTION, RETENTION AND MONITORING 
16.1 Data Collection Instruments 
The Investigator will prepare and maintain adequate and accurate source documents 
designed to record all observations and other pertinent data for each subject treated with the 
study drug.   
Study personnel will enter data from source documents corresponding to a subject’s visit 
into the protocol-specific electronic Case Report Form (eCRF) in REDCap when the 
information corresponding to that visit is available.  If a correction is required for an 
eCRF, the time and date stamps track the person entering or updating eCRF data and 
creates an electronic audit trail.  The Short Form 8 Health Survey and Pain Medication 
Survey will be administered and recorded as a REDCap survey. 
The Investigator is responsible for all information collected on subjects enrolled in this 
study.  All data collected during the course of this study must be reviewed and verified for 
completeness and accuracy by the Investigator.  A copy of the CRF will remain at the 
Investigator’s site at the completion of the study. 
16.2 Data Management Procedures 
The data will be entered into REDCap.  The Data Management group will be responsible 
for data processing, in accordance with procedural documentation.  Database lock will 
occur once quality assurance procedures have been completed. 
All procedures for the handling and analysis of data will be conducted using good 
computing practices meeting FDA guidelines for the handling and analysis of data for 
clinical trials. 
16.3 Data Quality Control and Reporting 
After data have been entered into the study database, a system of computerized data 
validation checks will be implemented and applied to the database on a regular basis.  
Queries are entered, tracked, and resolved through the EDC system directly.  The study 
database will be updated in accordance with the resolved queries.  All changes to the 
study database will be documented. 


Kratz, Johannes R. 
Confidential 
 
Version #: 9.0 
Version Date: 11/5/2019 
Page 33 of 37 
 
16.4 Archival of Data 
The database is safeguarded against unauthorized access by established security 
procedures.  Appropriate backup copies of the database and related software files will be 
maintained.  Databases are backed up by the database administrator in conjunction with 
any updates or changes to the database.   
At critical junctures of the protocol (e.g., production of interim reports and final reports), 
data for analysis is locked and cleaned per established procedures. 
16.5 Availability and Retention of Investigational Records 
The Investigator must make study data accessible to the monitor, other authorized 
representatives of the IRB/IEC and Regulatory Agency (e.g., FDA) inspectors upon 
request.  A file for each subject must be maintained that includes the signed Informed 
Consent, HIPAA Authorization and copies of all source documentation related to that 
subject.  The Investigator must ensure the reliability and availability of source documents 
from which the information on the CRF was derived. 
All study documents (patient files, signed informed consent forms, copies of CRFs, Study 
File Notebook, etc.) must be kept secured for a period of two years after centers have been 
notified that the IND has been discontinued.  There may be other circumstances for which 
the Sponsor is required to maintain study records and, therefore, the Sponsor should be 
contacted prior to removing study records for any reason. 
16.6 Monitoring 
By signing this protocol, the Investigator grants permission to the appropriate regulatory 
authorities to conduct on-site monitoring and/or auditing of all appropriate study 
documentation. 
16.7 Subject Confidentiality 
In order to maintain subject confidentiality, all protected health information is stored in 
REDCap. 
17 ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS 
The study will be conducted according to the Declaration of Helsinki, Protection of 
Human Volunteers (21 CFR 50), Institutional Review Boards (21 CFR 56), and 
Obligations of Clinical Investigators (21 CFR 312). 
All study records will be stored on REDCap that contains a firewall with a secure server 
that is backed up regularly off-site.  Clinical information will not be released without 
written permission of the subject, except as necessary for monitoring.  The Investigator 
must also comply with all applicable privacy regulations (e.g., Health Insurance 
Portability and Accountability Act of 1996, EU Data Protection Directive 95/46/EC). 
17.1 Protocol Amendments 
Any amendment to the protocol will be written by the Investigator.  Protocol amendments 
cannot be implemented without prior written IRB/IEC approval except as necessary to 


Kratz, Johannes R. 
Confidential 
 
Version #: 9.0 
Version Date: 11/5/2019 
Page 34 of 37 
 
eliminate immediate safety hazards to patients.  A protocol amendment intended to 
eliminate an apparent immediate hazard to patients may be implemented immediately, 
provided the IRBs are notified within five working days. 
17.2 Institutional Review Boards and Independent Ethics Committees 
The protocol and consent form will be reviewed and approved by the IRB/IEC of each 
participating center prior to study initiation.  Serious adverse experiences regardless of 
causality will be reported to the IRB/IEC in accordance with the standard operating 
procedures and policies of the IRB/IEC, and the Investigator will keep the IRB/IEC 
informed as to the progress of the study.  The Investigator will obtain assurance of 
IRB/IEC compliance with regulations. 
Any documents that the IRB/IEC may need to fulfill its responsibilities (such as protocol, 
protocol amendments, Investigator’s Brochure, consent forms, information concerning 
patient recruitment, payment or compensation procedures, or other pertinent information) 
will be submitted to the IRB/IEC.  The IRB/IECs written unconditional approval of the 
study protocol and the informed consent form will be in the possession of the Investigator 
before the study is initiated.  The IRB/IECs unconditional approval statement will be 
transmitted by the Investigator to the Sponsor.  This approval must refer to the study by 
exact protocol title and number and should identify the documents reviewed and the date 
of review. 
Protocol and/or informed consent modifications or changes may not be initiated without 
prior written IRB/IEC approval except when necessary to eliminate immediate hazards to 
the patients or when the change(s) involves only logistical or administrative aspects of the 
study.  Such modifications will be submitted to the IRB/IEC and written verification that 
the modification was submitted and subsequently approved should be obtained.   
The IRB/IEC must be informed of revisions to other documents originally submitted for 
review; serious and/or unexpected adverse experiences occurring during the study in 
accordance with the standard operating procedures and policies of the IRB; new 
information that may affect adversely the safety of the patients of the conduct of the study; 
an annual update and/or request for re-approval; and when the study has been completed. 
17.3 Informed Consent Form  
Informed consent will be obtained in accordance with the Declaration of Helsinki, ICH 
GCP, US Code of Federal Regulations for Protection of Human Subjects (21 CFR 
50.25[a,b], CFR 50.27, and CFR Part 56, Subpart A), the Health Insurance Portability and 
Accountability Act (HIPAA, if applicable), and local regulations. 
The Investigator will prepare the informed consent form and HIPAA authorization and 
provide the documents to the Sponsor for approval prior to submission to the IRB/IEC.  
The consent form generated by the Investigator must be acceptable to the Sponsor and be 
approved by the IRB/IEC.  The written consent document will embody the elements of 
informed consent as described in the International Conference on Harmonisation and will 
also comply with local regulations.  
A properly executed, written, informed consent will be obtained from each subject prior to 
entering the subject into the trial.  Information should be given in both oral and written 


Kratz, Johannes R. 
Confidential 
 
Version #: 9.0 
Version Date: 11/5/2019 
Page 35 of 37 
 
form and subjects must be given ample opportunity to inquire about details of the study.  
If appropriate and required by the local IRB/IEC from the subject will also be obtained.  A 
copy of the signed consent form will be given to the subject and the original will be 
maintained with the subject’s records. 
17.4 Publications  
The preparation and submittal for publication of manuscripts containing the study results 
shall be in accordance with a process determined by mutual written agreement among the 
study Sponsor and participating institutions.  The publication or presentation of any study 
results shall comply with all applicable privacy laws, including, but not limited to, the 
Health Insurance Portability and Accountability Act of 1996.  
17.5 Investigator Responsibilities 
By signing the Agreement of Investigator form, the Investigator agrees to: 
1. Conduct the study in accordance with the protocol, except when to protect the safety, 
rights or welfare of subjects. 
2. Personally conduct or supervise the study (or investigation). 
3. Ensure that the requirements relating to obtaining informed consent and IRB review 
and approval meet federal guidelines, as stated in § 21 CFR, parts 50 and 56. 
4. Report to the DMC any AEs that occur in the course of the study, in accordance with 
§21 CFR 312.64. 
5. Ensure that all associates, colleagues and employees assisting in the conduct of the 
study are informed about their obligations in meeting the above commitments. 
6. Maintain adequate and accurate records in accordance with §21 CFR 312.62 and to 
make those records available for inspection with the Sponsor (or designee). 
7. Ensure that an IRB that complies with the requirements of §21 CFR part 56 will be 
responsible for initial and continuing review and approval of the clinical study. 
8. Promptly report to the IRB all changes in the research activity and all unanticipated 
problems involving risks to subjects or others (to include amendments and IND safety 
reports). 
9. Seek IRB approval before any changes are made in the research study, except when 
necessary to eliminate hazards to the patients/subjects. 
10. Comply with all other requirements regarding the obligations of clinical investigators 
and all other pertinent requirements listed in § 21 CFR part 312. 
 


Kratz, Johannes R. 
Confidential 
 
Version #: 1 
Version Date: 6/2/2018 
Page 36 of 37 
Protocol Template © CFFT TDN   Effective: 12 SEP 2007 
APPENDIX 1.  SCHEDULE OF STUDY VISITS 
 
VISIT 1 
PREOPERATIVE 
VISIT 2 
SURGERY/ADMISSION 
VISIT 3 
POSTOPERATIVE 
Informed Consent 
X 
 
 
Medical History 
X 
 
 
Complete Physical Exam 
X 
 
 
Abbreviated Physical Exam 
 
X 
X 
Height/Weight 
X 
X 
X 
Vital Signs  
X 
X 
X 
Pregnancy Test (Urine )  
 
X 
 
Randomization 
 
X 
 
Administration of Study Drug 
 
X 
 
Concomitant Medication Review 
X 
X 
X 
Adverse Experiences 
 
X 
X 
 
 
 
 
 
 
1 McGee, DL. Local and topical anesthesia. In: Clinical Procedures In Emergency Medicine, 5th edition, 
Roberts, JR, Hedges, JR (Eds), Saunders Elsevier, Philadelphia 2010. p.481. 
2 Exparel (bupivacaine liposomal injectable suspension) prescribing information. Parsippany, NJ: Pacira 
Pharmaceuticals, Inc.; 2018 
3 D. Hu et al., "Pharmacokinetic Profile of Liposome Bupivacaine Injection Following a Single 
Administration at the Surgical Site," Clin Drug Investig 33, no. 2 (2013). 
4 S. Mantripragada, "A Lipid Based Depot (Depofoam((R)) Technology) for Sustained Release Drug 
Delivery," Progress in Lipid Research 41, no. 5 (2002). 
5 M. Gantenbein et al., "Oxidative Metabolism of Bupivacaine into Pipecolylxylidine in Humans Is Mainly 
Catalyzed by Cyp3a," Drug Metab Dispos 28, no. 4 (2000). 
6 T. W. Hamilton et al., "Liposomal Bupivacaine Infiltration at the Surgical Site for the Management of 
Postoperative Pain," Cochrane Database Syst Rev 2 (2017). 
7 S. R. Gorfine et al., "Bupivacaine Extended-Release Liposome Injection for Prolonged Postsurgical 
Analgesia in Patients Undergoing Hemorrhoidectomy: A Multicenter, Randomized, Double-Blind, Placebo-
Controlled Trial," Dis Colon Rectum 54, no. 12 (2011). 
8 J. D. Smoot et al., "The Efficacy and Safety of Depofoam Bupivacaine in Patients Undergoing Bilateral, 
Cosmetic, Submuscular Augmentation Mammaplasty: A Randomized, Double-Blind, Active-Control Study," 
Aesthet Surg J 32, no. 1 (2012). 
9 T. W. Hamilton et al., "Liposomal Bupivacaine Peripheral Nerve Block for the Management of 
Postoperative Pain," Cochrane Database Syst Rev, no. 8 (2016). 
10 J. Hutchins et al., "Ultrasound Guided Subcostal Transversus Abdominis Plane (Tap) Infiltration with 
Liposomal Bupivacaine for Patients Undergoing Robotic Assisted Hysterectomy: A Prospective Randomized 
Controlled Study," Gynecol Oncol 138, no. 3 (2015). 
11 NCT01802411.  Intercostal Nerve Block with Liposome Bupivacaine in Subjects Undergoing 
Posterolateral Thoracotomy, 2013.  clinicaltrials.gov/ct2/show/NCT01802411.  Accessed April 19, 2018. 
12 D. C. Rice et al., "Posterior Intercostal Nerve Block with Liposomal Bupivacaine: An Alternative to 
Thoracic Epidural Analgesia," Ann Thorac Surg 99, no. 6 (2015). 


Kratz, Johannes R. 
Confidential 
 
Version #: 1 
Version Date: 6/2/2018 
Page 37 of 37 
Protocol Template © CFFT TDN   Effective: 12 SEP 2007 
 
13 K. G. Khalil et al., "Operative Intercostal Nerve Blocks with Long-Acting Bupivacaine Liposome for Pain 
Control after Thoracotomy," ibid.100. 
14 NCT02178553. Study of Exparel Versus Epidural for Pain Control After Thoracotomy, 2014.  
clinicaltrials.gov/ct2/show/ NCT02178553. Accessed March 19, 2018. 
15 NCT02499159.  Pain Management in Response to Exparel vs. Standard Bupivacaine, 2015.  
clinicaltrials.gov/ct2/show/ NCT02499159.  Accessed March 19, 2018. 
16 NCT03036085.  Liposomal Bupivacaine or Pain Control Following Thoracic Surgery, 2017.  
clinicaltrials.gov/ct2/show/ NCT03036085.  Accessed March 19, 2018. 
17 D. B. Craig, "Postoperative Recovery of Pulmonary Function," Anesth Analg 60, no. 1 (1981). 
18 R. G. Soto and E. S. Fu, "Acute Pain Management for Patients Undergoing Thoracotomy," Ann Thorac 
Surg 75, no. 4 (2003). 
19 Roxicodone (oxycodone) [prescribing information]. Hazelwood, MO: Mallinckrodt Pharmaceuticals; May 
2017. 
20 W. M. Compton, M. Boyle, and E. Wargo, "Prescription Opioid Abuse: Problems and Responses," Prev 
Med 80 (2015). 
21 L. B. Ready, "Acute Pain: Lessons Learned from 25,000 Patients," Reg Anesth Pain Med 24, no. 6 (1999). 
22 O. A. de Leon-Casasola et al., "Postoperative Epidural Bupivacaine-Morphine Therapy. Experience with 
4,227 Surgical Cancer Patients," Anesthesiology 81, no. 2 (1994). 
23 D. S. Oh et al., "Robotic-Assisted, Video-Assisted Thoracoscopic and Open Lobectomy: Propensity-
Matched Analysis of Recent Premier Data," Ann Thorac Surg 104, no. 5 (2017). 
24 J. Noviasky et al., "Bupivacaine Liposomal Versus Bupivacaine: Comparative Review," Hosp Pharm 49, 
no. 6 (2014).