Clinical trial NCT03359811
Conditions: Peritoneal Cancer
Keywords: Local Anesthetic Solution Bupivacaine HCl Liposomal Bupivacaine Peritoneal Cancer
Sponsor: M.D. Anderson Cancer Center
Start date: 2017-11-27; Completion date: 2020-11-24
Enrollment: 75 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The goal of this clinical research study is to compare the effects of 4 quadrant TAP block (4Q-TAP block) with the standard-of-care thoracic epidural analgesia (TEA) in patients recovering from cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC).

A 4Q-TAP block is also known as an abdominal wall block and TEA is also known as a thoracic epidural. Both are types of anesthetics but are given in different ways. A 4Q-TAP block is when anesthetic injections are given in 4 different parts of the abdomen. A TEA is when an anesthetic injection is given in the space surrounding the spinal cord through your back.

This is an investigational study. The surgery and the levels of anesthetic participant is receiving are standard-of-care. It is investigational to compare 4Q-TAP block with TEA.

Up to 140 participants will be enrolled in this study. All will take part at MD Anderson.

Detailed description:
Baseline Tests:

If participant agrees to take part in this study, within 60 days before participant's surgery:

* Participant will have a physical exam.
* Blood (about 8 teaspoons) will be drawn for routine tests.
* Participant will complete a questionnaire about the quality of recovery. Participant's responses before surgery will be compared to participant's responses after surgery. It should take about 5 minutes to complete.

Study Groups/Procedures:

Participant will be randomly assigned (as in the flip of a coin) to 1 of 2 study groups on the morning of participant's surgery. This is done because no one knows if one study group is better, the same, or worse than the other group.

* If participant is in Group 1, participant will receive standard-of-care TEA before participant goes to sleep.
* If participant is in Group 2, participant will receive the 4Q-TAP block injections after participant is asleep.

If participant is in Group 1, participant will have a catheter placed in participant's back before surgery so that the TEA can be infused. If needed, participant may receive an injection of numbing medication and/or pain medication before the catheter is placed. Participant will sign a separate consent for the placement of the catheter.

If participant is in Group 2, participant will receive up to four (4) injections of 4Q-TAP block directly into different parts of the abdomen. These injections will take place after participant has been given general anesthesia. An ultrasound will be used to guide these injections. Participant will not be awake for these injections.

Both groups will sign a separate consent for the surgery that explains the procedures and the risks. Participant may receive standard drugs during surgery. The study staff can tell participant about the risks of these drugs and how they are given.

For both groups, information about the surgery will be collected while participant is in the operating room.

Post-Surgery:

After surgery, participant will receive standard drugs for pain as needed. Participant will be asked to complete a questionnaire about the quality of participant's recovery on the following days after surgery:

* Days 1-3
* Day 5
* Day 7
* Day 10 and
* Day 30

The questionnaire should take about 5 minutes each time. Participant will complete the questionnaire in person or participant will be called on the phone to complete it if participant has already left the hospital.

On Days 1, 2, and 7 after surgery, blood (about 8 teaspoons each time) will be drawn for routine tests.

After participant leaves the hospital, researchers will collect information from participant's medical record about participant's standard follow-up visits.

Length of Study Participation:

Active participation in this study will be complete 30 days after the surgery.

Arms: arm 1: An epidural catheter placed before induction of anesthesia by an anesthesiologist. A bolus or infusion of the local anesthetic solution with or without the addition opioids given before surgical incision according to anesthesia provider's clinical judgment. arm 2: Participants have an ultrasound guided 4Q-TAP block. A maximum of 80 cc of a solution consisting of 30 mg of bupivacaine HCl in 10 cc of preservative free normal saline (PFNS) and 65 mg of liposomal bupivacaine in 10 cc of PFNS injected before surgical incision in each of the four quadrants.
Interventions: intervention 1: Local Anesthetic Solution intervention 2: Bupivacaine HCl intervention 3: Liposomal Bupivacaine
Intervention descriptions: intervention 1: A bolus or infusion of local anesthetic solution with or without the addition opioids given before surgical incision according to anesthesia provider's clinical judgment. intervention 2: 30 mg of Bupivacaine HCl in 10 cc of preservative free normal saline (PFNS) injected before surgical incision in each of the four quadrants. intervention 3: 65 mg of Liposomal Bupivacaine in 10 cc of PFNS injected before surgical incision in each of the four quadrants.

Protocol documents:
Prot_SAP_000.pdf: 
1 
Four quadrant Transverse Abdominus Plane (4Q-TAP) block with plain and 
liposomal bupivacaine vs. Thoracic Epidural Analgesia (TEA) in patient’s 
undergoing cytoreductive surgery with hyperthermic intraperitoneal 
chemotherapy (CRS-HIPEC) on an enhanced recovery pathway: a single-
blinded, randomized, non-inferiority study. 
Study Chair and Co-chairs. 
Juan. P. Cata M.D. 
Vijaya Gottumukkala M.D. 
Pascal Owusu-Agyemang M.D. 
Keith Fournier M.D. 
Collaborators. 
Jose Soliz M.D. 
Uduak U Williams M.D. 
Antoinette Van Meter M.D. 
 
Ravish Kapoor M.D. 
Acsa M Zavala M.D. 
Richard E Royal M.D. 
            Brian D Badgwell M.D. 
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Table of Contents 
1. STUDY SYNOPSIS 
2. STUDY OBJECTIVES 
3. BACKGROUND  
A. Postoperative pain after CRS-HIPEC surgery 
B. Thoracic Epidural Analgesia for CRS-HIPEC and side effects  
C. Transverses Abdominus Plane (TAP) Blocks 
D. Liposomal bupivacaine (Exparel) 
E. Rationale for the study 
4. METHODS and STUDY DESIGN  
A. Setting and Population  
i. Inclusion Criteria  
ii. Exclusion Criteria  
B. Protocol  
C. Measurements  
D. Statistical Analysis  
i. Sample Size Considerations  
E. References 
 
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1. STUDY SYNOPSIS 
Four quadrant TAP (4Q-TAP) block with plain and liposomal bupivacaine vs. 
Thoracic Epidural Analgesia (TEA) in patient’s undergoing cytoreductive surgery 
with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) on an enhanced 
recovery pathway: a single-blinded, randomized, non-inferiority study. 
Objectives 
To evaluate the impact of 4 quadrants TAP blocks (4Q-TAP) versus 
Thoracic Epidural Analgesia (routine care) on the quality of recovery 
and other clinically relevant outcomes after CRS-HIPEC surgery. 
 
To study the incidence of adverse events associated with (4Q-TAP) 
blocks versus Thoracic Epidural Analgesia (routine care) after CRS-
HIPEC surgery. 
AIms 
a. 
Primary Aim: To compare the efficacy of 4 quadrants TAP 
blocks (4Q-TAP) versus Thoracic Epidural Analgesia (routine care) on 
the quality of recovery 48 hours after CRS-HIPEC surgery. 
b. 
Secondary Aim 1: To compare the efficacy of 4 quadrants TAP 
blocks (4Q-TAP) versus Thoracic Epidural Analgesia (routine of care) 
on postoperative pain 48 hours after CRS-HIPEC surgery. 
c. 
Secondary Aim 2: To compare the total opioid consumption 
between patients with 4 quadrants TAP blocks (4Q-TAP) versus 
Thoracic Epidural Analgesia (routine care) intraoperatively and up to 
48 hours after CRS-HIPEC surgery. 
d. 
Secondary Aim 3: To compare the length of stay (LOS) 
between patients with 4 quadrants TAP blocks (4Q-TAP) versus 
Thoracic Epidural Analgesia (routine care) after CRS-HIPEC surgery. 
e. 
Secondary Aim 4. To compare the incidence of adverse events 
(i.e. postoperative hypotension, failed block) related to 4 quadrants 
TAP blocks (4Q-TAP) versus Thoracic Epidural Analgesia (routine 
care) 48 hours after CRS-HIPEC surgery. 
f. 
Secondary Aim 5. To compare the incidence of opioid-related 
adverse (i.e. respiratory depression, pruritus, sedation, delirium) 
events related to 4 quadrants TAP blocks (4Q-TAP) versus Thoracic 
Epidural Analgesia (routine care) 48 hours after CRS-HIPEC surgery. 
g. 
Secondary Aim 6. To compare the incidence postoperative 
complications and morbidity in patients receiving 4 quadrants TAP 
blocks (4Q-TAP) versus Thoracic Epidural Analgesia (routine care) 48 
hours after CRS-HIPEC surgery. 
Study Design 
This is a randomized controlled trial designed to test efficacy of 4Q-
TAP against TEA (routine of care) on quality of recovery 48 hours after 
CRS-HIPEC surgery. All patients will be enrolled at MD Anderson 
Cancer Center. 
Number of 
Patients 
160 patients randomized to the 2 study arms (80 patients per arm) 
Sites 
MD Anderson Cancer Center 
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Duration of 
Study 
It is expected that this will take up to 36 months.  
Duration of 
Patient 
Participation 
Patients who consented to participate in the study will remain in the 
study until last planned outcome is collected on postoperative day 30. 
Patient will have the opportunity to withdraw from the study at any 
time.    
Primary 
Endpoint 
Definition 
Quality of recovery (QoR) 48 hours after CRS-HIPEC surgery. 
Secondary 
Endpoints 
x Postoperative pain 48 hours 
x The total opioid consumption within 48 hours after surgery 
x Length of stay 
x Incidence of adverse events 
x Incidence of opioid-related adverse events 
x Postoperative complications and morbidity 
x QoR on postoperative day 3, 7 10 and 30. 
Primary Safety 
Endpoint 
All reported adverse events. 
 
Follow-Up 
Schedule 
The study will be considered complete after all randomized patients 
have had 30 days of follow-up data collection. 
Inclusion 
Criteria 
1. Written informed consent; 
2. 18 years old or older; 
3. American Society of Anesthesiologists physical status (ASA) 1-3; 
4. Scheduled surgery: open elective CRS-HIPEC; 
5. Able to complete the QoR 15 questionnaire; 
6. Patients scheduled to receive intraoperative chemotherapy; 
Exclusion 
Criteria 
1. Contraindications to epidural analgesia due to thrombocytopenia 
(platelet count: <100,000 cell/dL), coagulopathy (International 
Normalized Ratio > 1.5, PT>16.5 seconds or aPTT > 35.9 
seconds); 
2. Bupivacaine or liposomal bupivacaine sensitive or known allergy; 
3. Pregnancy or breastfeeding patients; 
4. Patients with recent (within 60 days preoperatively) history severe 
hepatic disease; 
5. Patients with recent (within 15 days preoperatively) history 
deteriorate kidney function (creatinine serum concentrations > 2.5 
mg/dL or eGFR < 30 mL/kg/min); 
 
 
Study Sponsorship: None 
Study Monitoring: MDACC DMSB 
 
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Abbreviations 
 
aPTT 
Activated partial thromboplastin time 
AE 
Adverse Event 
ASA 
CFR 
American Society of Anesthesiologist 
Code of Federal Regulations 
CRF 
CRS-HIPEC 
 
eGFR 
Case Report Form 
Cytoreductive surgery with hyperthermic 
intraperitoneal chemotherapy 
Estimated glomerular filtration rate 
FDA 
Food and Drug Administration 
Hb 
Hemoglobin 
Hct 
Hematocrit 
IFU 
INR 
Instructions for Use 
International normalized ratio 
IRB 
Institutional Review Board 
LOS 
PACU 
PT 
Length of stay 
Postoperative acute care unit 
Prothrombin time 
POD 
SAE 
TAP 
TEA 
QoR 
VNRS 
4Q-TAP 
Postoperative Day  
Serious adverse events 
Transverse Abdominus Plane 
Thoracic epidural analgesia 
Quality of Recovery 
Verbal numeric rating scale 
Four quadrant TAP block 
 
2. STUDY OBJECTIVES 
a. To evaluate impact of 4 quadrants TAP blocks (4Q-TAP) versus 
Thoracic Epidural Analgesia (routine care) on the quality of recovery and other 
clinically relevant outcomes after CRS-HIPEC surgery. 
 
b. To study the incidence of adverse events associated with (4Q-TAP) 
blocks versus Thoracic Epidural Analgesia (routine care) after CRS-HIPEC 
surgery. 
 
3. STUDY AIMS 
a. Primary Aim: To compare the efficacy of 4 quadrants TAP blocks 
(4Q-TAP) versus Thoracic Epidural Analgesia (routine care) on the quality of 
recovery 48 hours after CRS-HIPEC surgery. 
 Hypothesis: The quality of recovery with 4 quadrants TAP blocks (4Q-
TAP) 48 hs after CRS-HIPEC surgery is not inferior to Thoracic Epidural Analgesia 
(routine care).  
 
b. Secondary Aim 1: To compare the efficacy of 4 quadrants TAP 
blocks (4Q-TAP) versus Thoracic Epidural Analgesia (routine of care) on 
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postoperative pain 48 hours after CRS-HIPEC surgery. 
Hypothesis: Postoperative pain 48 hours after CRS-HIPEC surgery is 
not inferior with 4 quadrants TAP blocks (4Q-TAP) than Thoracic Epidural 
Analgesia (routine care).  
 
c. Secondary Aim 2: To compare the total opioid consumption 
between patients with 4 quadrants TAP blocks (4Q-TAP) versus Thoracic Epidural 
Analgesia (routine care) intraoperatively and up to 48 hours after CRS-HIPEC 
surgery. 
Hypothesis: Perioperative opioid consumption after CRS-HIPEC 
surgery is not higher in patients with 4 quadrants TAP blocks (4Q-TAP) than 
epidural analgesia (routine care). 
 
d. Secondary Aim 3: To compare the length of stay (LOS) between 
patients with 4 quadrants TAP blocks (4Q-TAP) versus Thoracic Epidural 
Analgesia (routine care) after CRS-HIPEC surgery. 
Hypothesis: The LOS after CRS-HIPEC surgery is shorter in patients 
with 4 quadrants TAP blocks (4Q-TAP) than Thoracic Epidural Analgesia (routine 
care). 
 
e. Secondary Aim 4. To compare the incidence of adverse events (i.e. 
postoperative hypotension, failed block) related to 4 quadrants TAP blocks (4Q-
TAP) versus Thoracic Epidural Analgesia (routine care) 48 hours after CRS-HIPEC 
surgery. 
Hypothesis: The incidence of adverse events (i.e. postoperative 
hypotension, failed block) related to 4 quadrants TAP blocks (4Q-TAP) is lower 
than Thoracic Epidural Analgesia (routine care) 48 hours after CRS-HIPEC 
surgery. 
 
f. Secondary Aim 5. To compare the incidence of opioid-related 
adverse (i.e. respiratory depression, pruritus, sedation, delirium) events related to 
4 quadrants TAP blocks (4Q-TAP) versus Thoracic Epidural Analgesia (routine 
care) 48 hours after CRS-HIPEC surgery. 
Hypothesis: The incidence of opioid-related adverse events is lower in 
patients receiving 4 quadrants TAP blocks (4Q-TAP) versus Thoracic Epidural 
Analgesia (routine care) 48 hours after CRS-HIPEC surgery. 
 
g. Secondary Aim 6. To compare the incidence postoperative 
complications and morbidity in patients receiving 4 quadrants TAP blocks (4Q-
TAP) versus Thoracic Epidural Analgesia (routine care) 48 hours after CRS-HIPEC 
surgery. 
Hypothesis: The incidence of postoperative complications and 
morbidity is lower in patients receiving 4 quadrants TAP blocks (4Q-TAP) versus 
Thoracic Epidural Analgesia (routine care) 48 hours after CRS-HIPEC surgery. 
 
h. Secondary Aim 6. To compare the quality of recovery on 
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postoperative days 3, 7, 10 and 30 in patients receiving 4 quadrants TAP blocks 
(4Q-TAP) versus Thoracic Epidural Analgesia (routine care) 48 hours after CRS-
HIPEC surgery. 
                     Hypothesis: The quality of recovery with 4 quadrants TAP blocks 
(4Q-TAP) after CRS-HIPEC surgery is not inferior to Thoracic Epidural Analgesia 
(routine care) on postoperative days 3, 7, 10 and 30. 
 
 
4. BACKGROUND  
 
A. Quality of recovery after CRS-HIPEC surgery 
Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy 
(CRS-HIPEC) is an extensive and complicated surgical procedure that has been 
shown to provide long-term survival in select groups of patients with peritoneal 
carcinomatosis.1-6 The procedure typically entails an extensive cytoreduction, 
multiple visceral resections and peritonectomies.7-10 Due to the extensiveness of 
CRS-HIPEC the postoperative quality of recovery of patients undergoing this 
type of surgery is poor. Incisional pain, nausea and vomiting, postoperative 
ileus, fatigue, poor social interaction and sleep deprivation are the most 
common factor that diminishes the quality of recovery after major abdominal 
surgery. Furthermore, inadequate pain control may lead to poor outcomes. In fact, 
poor pain control is one of the leading causes of readmission after CRS-HIPEC,11 
and postoperative pain has been shown to significantly impact the quality of 
life.12,13  
High requirements of opioids and their side effects (i.e. ileus, delirium, 
nausea and vomiting and dry mouth) play a significant role in the recovery of a 
significant portion of the patients undergoing CRS-HIPEC.10 This was 
demonstrated in our recently published study of 215 CRS-HIPEC patients, where 
the median intraoperative and postoperative opioid consumption were 92 and 595 
mg of morphine equivalents, respectively.14 Attaining adequate pain control while 
minimizing opioid intake and their side effects, is therefore essential to attain better 
outcomes and improve the quality of recovery in this patient population. With 
regard to this, results of previous studies in patients undergoing CRS-HIPEC have 
demonstrated decreased opioid consumption by the use of thoracic epidural 
analgesia (TEA) as part of a multimodal analgesia strategy.10,14 Unfortunately, 
not all patients undergoing CRS-HIPEC are candidates to receive TEA. 
 
B. Thoracic Epidural Analgesia for CRS-HIPEC and side effects  
 
Thoracic  Epidural analgesia is the most commonly used technique to 
manage postoperative pain during and after CRS-HIPEC surgery. A recent study 
from our institution demonstrates that more than two-thirds of the patients who 
undergo HIPEC surgery receive TEA.14 This analgesia technique entails the 
placement of a catheter in the epidural space to administer a solution based on the 
combination of local anesthetics (ropivacaine or bupivacaine) and opioids (fentanyl 
or hydromorphone). Epidural catheters are almost always placed before patients 
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are induced to receive general anesthesia to avoid potential damage to neural 
structures.  
In comparison with intravenous opioids, the related benefits to the use of 
epidural analgesia include adequate postoperative pain control and opioid-
sparing effects.15-17 As a result of these two factors and a reduction in the stress 
response to surgery, some studies demonstrated that thoracic epidural analgesia 
for abdominal surgery decreased respiratory, cardiovascular and gastrointestinal 
complications.18,19 Unfortunately, recent studies indicate that the rate of failure for 
epidural catheter placement is approximately 10% but it can be as high as 30%.20-
22 Difficult identification of anatomical landmarks as it occurs in obese patients or 
displacement of the catheters are the most common reasons of epidural failure. 
Moreover, suboptimal functioning of successfully inserted epidural catheters are 
commonly observed and widely described in the literature.21,23 In this clinical 
scenario, intravenous opioids are given to achieve optimal pain control.  
To complicate the matter, not all patients who are scheduled for CRS-
HIPEC surgery are candidates to receive epidural analgesia. A large 
retrospective study from our group demonstrated that close to 25% of the patients 
who had HIPEC surgery at MD Anderson Cancer Center did not receive epidural 
analgesia and were treated with large amounts of intravenous opioids. The most 
common reasons why epidural analgesia is contraindicated in patients undergoing 
CRS-HIPEC are a reduced number of platelets (thrombocytopenia), anticoagulant 
therapies or patient refusal. Both clinical conditions are associated with an 
increased risk of epidural hematomas. A small fraction of patients might also refuse 
the placement of epidural analgesia because of concerns such as neurological 
complications or past experience with epidural failures.  
Furthermore, intraoperative coagulation derangements and postoperative 
thrombocytopenia and coagulopathies are also the most common reasons why 
epidural catheter cannot be removed immediately after surgery because they can 
also increase the risk of bleeding in the epidural space.24 A recent study from our 
group has shown that most of the coagulopathies observed in CRS-HIPEC 
patients occur within the first 72 hours after surgery, however there are a portion 
of patients who remain coagulopathic at day 7 postoperatively.25 It is in this group 
of patients that the risk of catheter-related infections and epidural abscess is 
increased if the catheters are not removed.26    
While epidural analgesia may be considered the “gold standard” for 
postoperative pain management after HIPEC,27 adverse events, and need for 
active postoperative management make the use of this analgesia technique 
undesirable in some cases.28,29 Perioperative hypotension, urine retention as a 
result of opioids and motor weakness secondary to epidural local anesthetic 
administration are noted potential drawbacks that might reduce the quality of 
recovery of patients. Respiratory depression is another complication related to 
the administration of opioids administered into the epidural space particularly in 
elder patients.  
 
Considering that a large number of patients undergoing CRS-HIPECs are 
not suitable candidates to receive epidural analgesia, a high failure rate, and a 
significant portion of patients suffer from epidural-related adverse effects, there is 
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a need for an alternative less invasive regional analgesia technique that can 
provide similar analgesia while improving their quality of recovery. 
 
C. Traditional Transverse Abdominus Plane (TAP) Block 
The TAP block is a regional analgesia technique that entails the unilateral 
or bilateral administration of a local anesthesia solution (15-20 cc) into the 
transverse abdominus plane. This virtual plane lies above the transverse 
abdominus muscle in the abdominal wall where spinal nerves that supply the 
abdominal wall run from posterior to the anterior aspect of the abdomen. The 
traditional TAP block is performed in the lateral abdominal wall between iliac crest 
and costal margin and only provides effective analgesia to the distal or lower half 
of the abdomen.30 The benefits of TAP blocks are well documented in 
randomized control trials and meta-analysis.31-35  
 
4-quadrant TAP block 
 
To enhance the analgesic efficacy of the traditional TAP block, several 
authors have added a subcostal approach to provide analgesia to the upper half 
of the abdomen. In a cadaveric study of the four-quadrant TAP block (4QTAP), 
dermatomes T8-L1 were adequately covered with the solution of local anesthetic.  
Therefore, it was originally hypothesized that the 4QTAP block may be more 
beneficial in major abdominal surgery compared to the traditional TAP approach 
alone.36 In a prospective study of 124 patients, the surgical incision for abdominal 
surgery was within the dermatomal limits of the 4QTAP in 70% of patients.37 In a 
later study by Niraj et al, the authors demonstrated that 4QTAP with 
levobupivacaine resulted in similar pain scores and tramadol consumption when 
compared to epidural analgesia for laparoscopic colorectal surgery.38 39 
The 4QTAP block may provide some advantages over epidural 
analgesia as TAP blocks are associated with more stable hemodynamics and less 
use of vasopressor and intravenous fluids during and after surgery.40 In addition, 
4QTAP blocks are not associated with postoperative urine retention neither the 
risk of epidural hematoma or infections. Lastly, the use of 4QTAP blocks can 
reduce the use of resources and personnel because there is no need for frequent 
monitoring of the epidural catheter and infusions pumps.  
With the increased safety of ultrasound guided needle placement and ‘real-
time’ visualization through dynamic scanning, serious complications are rare 
with the 4QTAP block.37 Needle puncture thru the peritoneum causing bowel or 
diaphragm perforation is unlikely, but is still a possibility.  The abundance of 
structures in the peritoneal cavity makes the viewing of the needle in plane at all 
times during needle advancement of utmost importance.  Lacerations of the liver 
have been reported during placement of right-sided TAP blocks.41 Abdominal wall 
hematoma, vascular injury, local anesthetic toxicity and are also potential, but rare 
complications.34 
 
D. Liposomal bupivacaine: A long-acting local anesthetic 
The longer duration of analgesia (48-72 hours) with the use of liposomal 
bupivacaine presents advantages over traditional local anesthetics. A number of 
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studies support the benefits of liposomal bupivacaine for TAP blocks over standard 
bupivacaine alone.42 In a randomized prospective trial by Hutchins et al, patients 
undergoing robotic hysterectomy and received subcostal TAP with liposomal 
bupivacaine had lower opioid requirements for the first 72 hours after surgery and 
lower pain scores when compared to bupivacaine hydrochloride.43 Giving the 
relative large volume of local anesthetics required for adequate TAP block 
analgesia, systemic toxicities are a potential complication. However, staying within 
the reported maximum local anesthetic volumes significantly decreases the risk. 
D1. Pharmacokinetics.  
Absorption. Following its release from the liposomal bupivacaine particles, 
the rate of systemic absorption of bupivacaine is dependent upon the total dose of 
drug administered, the route of administration, and the vascularity of the 
administration site. At dosing ratios of greater than 2:1, liposomal bupivacaine and 
bupivacaine may be co-administered through a single injection.  At ratios <2:1, 
substantial displacement of free bupivacaine from the liposomes may result.44  In 
a study by Kharitonov, the compatibility of liposomal bupivacaine with epinephrine, 
corticosteroids, and opioids were not associated with adverse events.44 
Distribution. After bupivacaine has been released from liposomal 
bupivacaine and is absorbed systemically, bupivacaine distribution is expected to 
be the same as for any bupivacaine HCl solution formulation.  To some extent, 
local anesthetics are distributed to all body tissues, with high concentrations found 
in highly perfused organs such as the liver, lungs, heart, and brain.  
The rate and degree of diffusion are governed by: 
1. The degree of plasma protein binding 
2. The degree of ionization 
3. The degree of lipid solubility 
Metabolism. Amide-type local anesthetics such as bupivacaine HCl are 
metabolized primarily in the liver via conjugation with glucuronic acid.  Patients 
with hepatic disease, especially those with severe hepatic disease, may be more 
susceptible to the potential toxicities of the amide-type local anesthetics.  
Pipecolylxylidine (PPX) is the (largely inactive) major metabolite of bupivacaine 
HCl: approximately 5% of bupivacaine HCl is converted to PPX. 
Excretion. After bupivacaine has been released from liposomal 
bupivacaine and is absorbed systemically, bupivacaine excretion is expected to be 
the same as for other bupivacaine formulations. 
Various pharmacokinetic parameters can be significantly altered by: 
x 
The presence of hepatic or renal disease 
x 
Factors affecting urinary pH 
x 
Renal blood flow 
The kidney is the main excretory organ for bupivacaine and its metabolite; only 6% 
of bupivacaine is excreted unchanged in the urine. 
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Hepatic Impairment. The effects of decreased hepatic function on 
bupivacaine pharmacokinetics following administration of liposomal bupivacaine 
were studied in patients with moderate hepatic impairment. Consistent with the 
hepatic impairment of bupivacaine, mean plasma concentrations were higher in 
patients with moderate hepatic impairment than in the healthy control volunteers.   
Because amide-type local anesthetics, such as bupivacaine, are 
metabolized by the liver, these drugs should be used cautiously in patients with 
hepatic disease. Patients with severe hepatic disease, because of their inability to 
metabolize local anesthetics normally, are at a greater risk of developing toxic 
plasma concentrations. 
Renal Impairment. Bupivacaine is primarily excreted by the kidneys, and 
the risk of toxic reactions to liposomal bupivacaine may be greater in patients with 
impaired renal function.  
Storage Liposomal bupivacaine vials should be stored refrigerated 
between 2°C to 8°C (36°F to 46°F). Liposomal bupivacaine may be held at a 
controlled room temperature of 20°C to 25°C (68°F to 77°F) for up to 30 days in 
sealed, intact (unopened) vials. Vials should not be re-refrigerated. As a 
convenience to the pharmacist, each vial label includes space to record the date 
when the vial has been removed from refrigeration. 
Liposomal bupivacaine should not be frozen or exposed to high temperatures 
(greater than 40°C or 104°F) for an extended period. Liposomal bupivacaine 
should not be administered if it is suspected of having been frozen or exposed to 
high temperatures. 
 
 
 
E. Rationale for Study. 
 
Quality of recovery after surgery is a patient-related outcome that integrates 
postoperative psychosocial and physiologic parameters as perceived by patients. 
While TEA is the standard of care in patients undergoing CRS-HIPEC surgery, it 
cannot be offered to a large number of patients, and it is associated with adverse 
events in those treated with the technique. Therefore, 4Q-TAP block is an 
attractive and safe analgesic technique to be offered to patients undergoing CRS-
HIPEC surgery. However, it is unknown if a 4Q-TAP block with the use of plain 
and liposomal bupivacaine combination is equally effective in providing the same 
or better quality of recovery than TEA in patients undergoing CRS-HIPEC surgery. 
 
4Q-TAP blocks with plain and liposomal bupivacaine combination are 
currently used in our institution in patients undergoing major abdominal surgery, 
therefore the results of our study could be extrapolated to a larger number of 
patients. Unpublished results from a retrospective analysis of a group (n=15) of 
patients who had CRS-HIPEC surgery with 4Q-TAP blocks with liposomal 
bupivacaine in our institution suggests that the quality of analgesia provided by this 
technique is similar to that achieved with epidural analgesia. Furthermore, we 
observed no major complications related to the technique.  
 
We hypothesize that patients who undergo CRS-HIPEC surgery with 4Q-
TAP block will have a non-inferior postoperative quality of recovery (QoR) 
compared to those treated with epidural analgesia. 
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12 
 
 
 
5. Methods and Study Design 
 
This is a randomized controlled trial designed to test efficacy of 4Q-TAP 
against TEA (routine of care) on quality of recovery 48 hours after CRS-HIPEC 
surgery. All patients will be enrolled at MD Anderson Cancer Center. 
 
 
A. Setting and Population 
 
Inclusion criteria: 
1. Written informed consent; 
2. 18 years old or older; 
3. American Society of Anesthesiologists physical status (ASA) 1-3; 
4. Scheduled surgery: open elective CRS-HIPEC; 
5. Able to complete the QoR 15 questionnaire; 
6. Patients scheduled to receive intraoperative chemotherapy; 
 
Exclusion criteria: 
1. Contraindications to epidural analgesia due to thrombocytopenia 
(platelet count: <100,000 cell/dL), coagulopathy (International 
Normalized Ratio > 1.5, PT>16.5 seconds or aPTT > 35.9 seconds); 
2. Bupivacaine or liposomal bupivacaine sensitive or known allergy; 
3.   Pregnancy or breastfeeding patients; 
                4.  Patients with recent (within 60 days preoperatively) history severe  
hepatic disease (defined as liver injury with encephalopathy plus impaired 
synthetic liver function (i.e. > 1.5)) 
                5.  Patients with recent (within 15 days preoperatively) history deteriorate 
kidney function (creatinine serum concentrations > 2.5 mg/dL or eGFR < 30 
mL/kg/min); 
 
B. Withdrawal of Patients 
Patients may withdraw from the study at any time, with or without reason and 
without prejudice to further treatment.  In all cases of withdrawal, the reason(s) 
for withdrawal (if given) will be recorded upon study termination. 
In addition, the investigator may withdraw the patient due to any of the following 
situations: 
x 
adverse event 
x 
any other reason determined by the investigator to be in the best interest 
of the patient. 
Patients withdrawn due to an adverse event should be followed until the event 
has been resolved or is stable, if at all possible.  
 
 
 
Protocol Number 2017-0492 
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13 
 
B. Interventions 
 
Patients will be randomized 1:1 on the morning of surgery to one of the 
following 2 interventions: 
 
TEAgroup: Patients in this group will be treated as standard of care. An 
epidural catheter will be placed before induction of anesthesia by an 
anesthesiologist. The catheter will be placed between the thoracic vertebral 
spaces 8 and 12 according to routine care. A bolus or infusion of local anesthetic 
solution with or without the addition opioids will be given before surgical incision 
according to anesthesia provider’s clinical judgment. If deemed appropriate, a pre-
incision epidural bolus of hydromorphone (300-800 micrograms) may be 
administered according to the anesthesia provider’s clinical judgment. 
4Q-TAP block group: Patients in this group will have an ultrasound guided 
4Q-TAP block. A maximum of 80 cc of a solution consisting of 30 mg of 
bupivacaine HCl in 10 cc of PFNS and 65 mg of liposomal bupivacaine in 10 cc of 
PFNS will be injected before surgical incision in each of the four quadrants. 
 
 
 
C. Protocol and procedures 
 
 
Patients will be screened from surgical and preoperative anesthesia clinic 
schedules and visits. The study team including the PI, Co-PIs or collaborators will 
approach patients for consenting only after confirmation of inclusion and exclusion 
criteria. After consenting, patients will be free to withdraw from study at any 
time.  
 
 After enrolling to the study and prior randomization, all data pertinent to the 
study and the QoR 15 will be obtained by the research personnel involved in the 
study. After randomization, all patients will have surgery under general anesthesia 
according routine care. All patients will receive intra- and postoperative multimodal 
analgesia according to the standard of care and judgment of the attending 
anesthesiologists. Before surgery, p.o. celecoxib, tramadol extended release 
and/or pregabalin will be administered according to clinical judgment. 
Intraoperative infusions of propofol, dexmedetomidine and ketamine will be 
permitted per standard of care. Intravenous infusion of lidocaine will not be 
permitted at any time. Intravenous fentanyl, sufentanil or hydromorphone will be 
administered according to clinical judgment of the attending anesthesiologist. 
Prophylactic antibiotics will be given per surgical routine care. Medications for 
prophylaxis of nausea and vomiting (dexamethasone 8-10 mg, ondasentron 4-8 
mg and/or aprepitant 80-125 mg) will be given according to the judgment of the 
attending anesthesiologists.  
 
Upon arrival to the postoperative anesthesia care unit or intensive care unit, 
postoperative analgesia will consist of the administration of boluses of 
hydromorphone or fentanyl to achieve a pain score < 4 (on a 0-10 NRS). If needed, 
patients will receive intravenous patient-controlled analgesia with hydromorphone 
or fentanyl. Once patients can tolerate p.o. medications, they will transition to oral 
Protocol Number 2017-0492 
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14 
 
analgesics according to standard of care. Patients in the epidural group will have 
the catheter removed per routine care.  
 
Patients will be encouraged out of bed mobilization per standard of care. 
Foley catheter will be removed 48 hours after surgery if clinically indicated.  
 
 
D. Data collection and measurements 
 
Preoperaive data: Demographic data to be obtained includes height (cm), 
weight (kg), age (yr), gender, (ASA) physical status, and self-declared ethnicity. 
Patients will be questioned for social history (tobacco) and medical history to 
calculate Charlson comorbidity index score. QoR 15 will be obtained before 
surgery. Pain meds (type, dose and frequency) 
 
The following intraoperative data will be obtained from electronic medical 
records: surgery and anesthesia time, surgery type and extent of resection, 
intraoperative chemotherapy (type and dose), highest temperature, intraoperative 
anesthetic and opioid consumption. Blood loss, fluid therapy and urinary output will 
also be collected at the end of surgical procedure. 
The following postoperative data will be obtained from electronic medical 
records: Postoperative opioid consumption, breakthrough pain medication 
requirements and oxygen requirements in PACU and in nursing floor (first 48 hours 
postoperatively). QoR score and pain scores will be obtained on postoperative day 
1, 2, 3, 5, 7, 10(±1) and 30(±2) days if the patient is still admitted to the hospital. 
Nausea and vomiting, requirement of antiemetics, pruritus, requirement of 
antihistaminic medications and requirement of naloxone in PACU and first and 
second postoperative morning after surgery will be collected. Ambulation time, 
flatus and bowel movements (first time), constipation, length of stay will be 
obtained. Incentive spirometry will be measured on postoperative day 1 and 2. 
Postoperative complications (Clavien-Dindo scale during hospital admission) and 
perioperative morbidity scores (POMS day 7) will be obtained from medical records 
and 30 days after surgery. Preoperative and postoperative routine laboratory data 
results will also be collected from electronic medical records.  
Duration of Patient Participation 
Patients that consent to the optional MDASI questionnaires will participate 
until the POMS data has been completed on postoperative day 30.  
 
 
E. Outcomes definitions 
Quality of Recovery will be measured using the QoR-15 scale. The QoR scale is 
a validated scoring system that allows for the quantification of a patient’s early 
postoperative health status.   
 
Pain Intensity at rest and cough will be measure using a VNRS (0 = no pain  - 
10 = worst pain ever). Data will be reported as time-weighted pain scores from 
discharge from the PACU until 48 hours after the end of surgery. 
 
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15 
 
Opioid Consumption will be reported as morphine equivalents required during 
the 48 hours after the end of surgery. 
 
Length of stay will be calculated from day of surgery to date of hospital discharge. 
 
 
Adverse Event Definition 
An adverse event is any symptom, sign, illness, or experience which develops or 
worsens during the course of the study, whether or not the event is considered 
related to study drug. Adverse events (AEs) related to the study interventions 
will be recorded within the first 48 hours after the end of surgery. AEs related to 
the study will include postoperative hypotension needed pharmacological 
intervention including fluid resuscitation or temporary holding or discontinuation of 
epidural infusions, failed block (defined as patchy block or unilateral block needing 
pharmacological interventions or catheter removal), epidural space infection or 
abscess and epidural hemathoma.  
 
 
Serious Adverse Event 
A serious adverse event is defined as any adverse medical experience that 
results in any of the following outcomes: 
x death; 
x is life-threatening; 
x requires inpatient hospitalization or prolongation of existing hospitalization; 
x results in persistent or significant disability/incapacity; 
x is a congenital anomaly/birth defect; or 
x requires medical or surgical intervention to prevent permanent impairment 
or damage. 
 
Opioid-related adverse (i.e. respiratory depression, pruritus, sedation, delirium) 
within the first 48 hours after the end of surgery. 
 
Postoperative complications will be recorded using Clavien-Dindo scale and 
POMS.  
 
Statistical Considerations 
The primary objective of evaluating the impact of 4 quadrants TAP blocks (4Q-
TAP) versus Thoracic Epidural Analgesia (TEA - routine care) on the quality of 
recovery (QoR) will be conducted using total scores on each patient acquired from 
the QoR-15.  The QoR-15, as previously mentioned, is a validated instrument with 
well-studied psychometric properties used to measure postoperative quality of 
recovery.  The QoR-15 consists of 15 items. All 15 items follow a Likert scale 
ranging from 0 to 10 (where “0” refers to none of the time [poor] and “10” refers to 
all of the time [excellent]).  A patient’s total score is the sum score across all 15 
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16 
 
items (note: the last 5 items are reverse scored).  The lowest score a patient can 
receive is “0” and the highest score is “150”; where higher total scores indicate 
better quality of recovery.  To evaluate the trial changes in QoR-15 total scores will 
be computed for each treatment arm.  The changes will be compared between 
patients receiving 4Q-TAP Block and patients receiving TEA. Figure 1 illustrates 
the trial’s development over time.  Once a patient is randomized and the 
preoperative QoR-15 is administered, which takes approximately 2.4 minutes to 
complete, patients will be provided postoperative QoR-15 approximately 26 hours 
after surgery (Figure 1: [A]; Stark et al).  Within patient changes from baseline will 
be computed for each treatment arm.  These changes will be compared between 
treatment arms (Figure 1: [B]).   
 
 
 
Figure 1: Trial Schema  
         
 
This randomized trial will be used to determine if 4Q-TAP Block is non-inferior to 
TEA based on postoperative changes in QoR-15 using a non-inferiority margin of 
10 units.  According to Stark et al., the reported mean change in QoR-15 before 
and after surgery is -22 (95%CI: -26 to -18) based on 127 adults.  This 
information allowed us to assume of a common standard deviation of 23 units for 
the change in QoR-15’s total score pertaining to each treatment arm, which was 
ultimately used to derive the study’s sample size.      
The following hypothesis test will be used to evaluate the trial: 
 
H0:  μ4Q-TAP Block –  μTEA ≥  10.0 
 
Ha:  μ4Q-TAP Block –  μTEA = 0 (rejecting H0 implies non-inferiority) 
 
We will use a one-sided t-test test with a significance level of 0.05 and power of 
80%.  A non-inferiority margin of 10 was considered by assuming an average 
change in QoR-15 of -25 units in the TEA arm and that the average change in 
QoR-15 for the 4Q-TAP Block treatment arm would be no greater than -35.   
Protocol Number 2017-0492 
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17 
 
Figure 2:  Non-inferiority assessment 
 
 
 
These specifications require an approximate sample size of 140 patients as 
indicated in Table 1.  Moreover, an interim analysis will be conducted at after 70 
patients are randomized using stopping boundaries provided by the method of 
Pock and Simon.  At the interim, the trial will stop early if p < 0.006 for efficacy 
and p > 0.367 for futility (East v6).   
 
 
Table 1:  Estimated sample size given projected study parameters  
Expected QoR-
15 
Non-inferiority 
Power 
Alpha 
Approx Sample 
Size 
Avg.  Change * 
Margin 
(1-
sided) 
  for Epidural 
group 
 
  
 -25 
10 
 80% 
5% 
140 
*Avg. Change before and after surgery;  Assumed SD = 23;  A non-inferiority 
margin of 10 implies the Avg. Change for TAP will be -35 [ie. -25 - (-35) = 10] 
*Sample size for the difference of two means using a two sample test (East v6). 
 
 
 
The data will be evaluated per protocol for patients contributing analyzable data.   
 
 
Safety 
All patients who receive any portion of the intended treatments (TEA or 
4Q-TAP) will be included in safety analysis.  
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Patient demographics, baseline characteristics and medical history will be 
summarized descriptively by treatment arm. Mean, standard deviation, median, 
minimum and maximum will be reported for continuous variables.  Frequencies 
and proportions will be reported for categorical variables.  An independent 
samples t-test will be used to evaluate the difference between QoR-15 change 
scores between treatment arms.  Change scores within treatment arms will be 
summarized using the mean and 95%CIs.  Linear regression analysis will be 
used to assess QoR-15 change scores between treatment arms while adjusting 
for select covariates of interest.   
 
The association between dichotomous outcomes (dependent variables) and 
treatment-related factors will be assessed using univariable and multivariable 
logistic regression.  Time-to-event outcomes will be summarized at critical time 
points using the method of Kaplan-Meier.  Kaplan-Meier plots will be used to 
visualize the time-to-event information.  Cox proportional hazards regression will 
be used to model the time-to-event outcomes using select covariates of interest.     
 
Upon any modifications to the eligibility criteria and with the intention of 
broadening patient characteristics, for example: by including patients with prior 
opioid use, we will address this issue by adjusting the treatment effect using a 
regression model that includes prior opioid use as an indicator variable and 
assess the relative difference between the unadjusted treatment 
effect.  Moreover, subgroup analyses will be explored even though we anticipate 
randomization will maintain covariate balance between treatment arms.   
 
 
Primary Outcome Analysis 
Secondary Outcomes Analyses 
Safety 
Safety will be summarized using the number and proportion of patients 
reporting any given event and will be tabulated by treatment received according 
to the worst severity experienced. Separate tables will be constructed for (a) all 
reported events, (b) procedure related events, (c) serious events. Event rates 
will be compared between treatment arms by Fisher’s exact test. 
Data Management – Data Collection and Processing 
Study data will be collected and managed using REDCap16 (Research 
Electronic Data Capture) electronic data capture tools hosted at MD Anderson. 
REDCap (www.project-redcap.org) is a secure, web-based application with 
controlled access designed to support data capture for research studies, 
providing: 1) an intuitive interface for validated data entry; 2) audit trails for 
tracking data manipulation and export procedures; 3) automated export 
procedures for seamless downloads to common statistical packages; and 4) 
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procedures for importing data from external sources.  
REDCap (https://redcap.mdanderson.org) is hosted on a secure server by 
MD Anderson Cancer Center's Department of Research Information Systems & 
Technology Services. REDCap has undergone a Governance Risk & 
Compliance Assessment (May 2014) by MD Anderson's Information Security 
Office and found to be compliant with HIPAA, Texas Administrative Codes 202-
203, University of Texas Policy 165, federal regulations outlined in 21 CFR Part 
11, and UTMDACC Institutional Policy #ADM0335. Those having access to the 
data file include the study PI and research team personnel. Users are 
authenticated against MDACC's Active Directory system. The application is 
accessed through Secure Socket Layer (SSL). All protected health information 
(PHI) will be removed from the data when it is exported from REDCap for 
analysis. All dates for a given patient will be shifted by a randomly generated 
number between 0 and 160, thus preserving the distance between dates. Dates 
for each patient will be shifted by a different randomly generated number.  
Following publication study data will be archived in REDCap. Since study 
data may be useful for future research studies performed under separate IRB 
approved protocols, study data will be archived indefinitely in REDCap. Since 
REDCap is a secure electronic database with controlled access, and because 
patient identifiers may be needed to link study data to data from other sources 
under future IRB approved protocols, patient identifying information will be 
retained in the archived database. 
Investigators are responsible for the accurate completion and timely 
submission of the data collected during the study. Quality assurance procedures 
will be established to ensure that complete, accurate and timely data are 
submitted, that protocol requirements are followed and that complications, 
adverse events and adverse device effects are correctly reported and 
investigated, as appropriate. Investigators are to maintain all source documents 
as required by the protocol, including laboratory results, supporting medical 
records, and signed Informed Consent forms.  The source documents will be 
used during the regular monitoring visits to verify information from the database 
against data contained on the completed CRFs.  
The Principal Investigator must maintain detailed records on all patients who 
sign the Informed Consent and begin the pre-procedure evaluation. Data for 
enrolled patients will be entered directly into the electronic Case Report Forms 
(eCRFs) in REDCap. For source documents, corrections should be made in a 
manner that does not obscure or eliminate the original error, by striking through 
the original data with one line, and initialing and dating the change, along with the 
reason for the change. 
Study exit eCRFs are completed for all enrolled patients, regardless of 
whether they did or did not complete the Study (e.g., patient discontinuation, 
study termination). 
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Monitoring Procedures  
Monitoring visits to the clinical sites will be made periodically during the 
study, to ensure that all aspects of the current, approved protocol/amendment(s) 
are followed. Original source documents will be reviewed for verification of data 
in the database. In the event that the original medical records cannot be obtained 
for a patient that is seen by a non-study physician at a non-study institution, 
photocopies of the original source documents must be made available for review. 
It is important that the Investigator and relevant study personnel are available 
during the monitoring visits and that sufficient time is devoted to the process. 
Phone contacts and site visits will be conducted to ensure that the protocol is 
being followed and that any protocol deviations are properly documented.  
Clinical monitoring will include a verification that Informed Consent was properly 
obtained for all enrolled study participants, a review of clinical records for 
accuracy and completeness, resolution of missing or inconsistent results and a 
review of source documents.  The clinical monitor will verify that the CRFs are in 
agreement with the source documentation and other records.  The investigator 
will make available to the clinical monitor for review all Informed Consent 
documents, Internet access to completed CRFs, source documentation, original 
laboratory data and other relevant records for all enrolled patients at the site.  It is 
important that the investigator and other relevant site personnel are available for 
consultation with the clinical monitors during the monitoring visits and that 
sufficient time is devoted at the site to the monitoring process. 
Additionally, telephone and/or e-mail contact will be conducted on a regular basis 
with the investigator and the site staff to ensure that the protocol is being 
followed and to address any issues that may occur during the course of the 
study. 
If a deficiency is noted during an on-site visit (or at any other time during 
the course of the study), the clinical monitor is required to discuss the situation 
with the investigator to secure compliance. Monitoring visit will begin after 
enrollment of first 3 patients.  
 
Data Safety Monitoring Board (DSMB): The monitoring of this trial will be 
provided by MD Anderson Cancer Center DSMB 
Visit Schedule 
Table 1, below outlines the required study assessments.  
Table 1 
Study Event Schedule 
 
Baseline 
(within 60 
days prior to 
surgery) 
Day of 
surgical 
Procedure 
First  
48 hours 
after surgery 
Procedures 
until Discharge 
Procedures 
After 
Discharge 
Informed Consent 
Xa 
 
 
 
 
Inclusion / Exclusion Criteria 
Assessment 
X 
 
 
 
 
Demographics/ Medical History 
X 
 
 
 
 
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21 
 
Randomization and Intent to 
Treat 
 
Xb 
 
 
 
Vital Signs 
Xc 
Xc 
 
 
 
Physical Examination 
X 
 
 
 
 
Laboratory Tests 
Xd 
 
 
 
 
Data collection 
Xe 
Xe 
QoR15, pain 
scores, opioid 
consumption, 
QoR15, pain 
scores, opioid 
consumption, 
LOS 
QoR15, pain 
scores, opioid 
consumption, 
Adverse Events 
 
Xf 
ORADE, AE, SAE, complications (Clavien-Dindo) 
 
a After confirmation of eligibility and 30 days after surgery. 
b After confirmation of eligibility and before surgery.  
c Height, weight, systolic/diastolic blood pressure, heart rate, and respiratory rate 
(height and weight will only be measured at baseline) 
c Data will be collected from the patients standard of care lab tests. These 
typically include creatinine, platelet and white blood cells count, and hemoglobin 
and hematocrit 
d Complete blood counts, routine electrolyte determinations and renal function 
laboratory tests.  
collected 
e ORADE: opioid related adverse effects, AE: adverse events, SAE: serious 
adverse events, QoR: quality of recovery, LOS: length of stay 
f During surgery, at PACU discharge and POD1 and 2.  
 
 
Adverse Events 
General  
All adverse events (AE) and serious adverse events (SAE) will be monitored from 
the time of procedure through end of the study.  
An AE is defined as any undesirable clinical occurrence in a patient whether or 
not it is considered to be device related. In addition, the definition of AE applies 
to any event with an onset post study procedure or to any underlying diseases, 
present at baseline, that exacerbate in severity post study procedure. Therefore, 
an underlying disease that was present at the time of enrollment is not reported 
as an AE, but any increase in the severity of the underlying disease is to be 
reported as an AE. All reported AEs must be recorded in the database. A 
description of the event, including the start date, resolution date, action taken, 
and the outcome should be provided, along with the Investigator’s assessment of 
the relationship between the AE, the study treatment and the study procedure. 
This protocol will use common terminology criteria for adverse events (CTCAE) 
version 4.0. For the AEs not characterized in the CTACE, the following definitions 
for rating severity of AEs will be used:   
Mild: 
Awareness of signs or symptoms, but easily tolerated; are of minor 
irritant type; causing no loss of time from normal activities; 
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22 
 
symptoms would not require medication or a medical evaluation; 
signs or symptoms are transient. 
Moderate: 
Interferes with the patient’s usual activity and/or requires 
symptomatic treatment. 
Severe: 
Symptom(s) causing severe discomfort and significant impact of 
the patient’s usual activity and requires treatment. 
 
A serious adverse event (SAE) is defined as an event which leads to:   
x 
Death due to any cause 
x 
Life-threatening condition 
x 
Results in persistent or significant disability/incapacity 
x 
Requires in-patient hospitalization or prolonged hospitalization 
x 
Necessitates an intervention to prevent a permanent impairment of a 
body function or permanent damage to a body structure 
x 
Results in congenital abnormality 
All SAE’s will be reported. 
 
Device-Related Adverse Event: Not applicable  
 
Procedure-Related Adverse Event: an adverse event is considered to be 
procedure-related when, in the judgment of the Investigator; it is reasonable to 
believe that the event is associated with the assigned study procedure.  Other 
products, surgical techniques, or medications required specifically for the 
procedure are likely to have contributed to the occurrence of the event. 
 
Concomitant Medication-Related Adverse Event: Not applicable 
 
Pre-Existing Condition-Related Adverse Event: an adverse event is considered 
to be related to a pre-existing condition when, in the judgment of the Investigator, it 
is reasonable to believe that the event is associated with the patient’s pre-existing 
condition and is not specific to the STUDY procedures. Pre-existing conditions that 
are aggravated or become more severe during or after the procedure should be 
evaluated on a case-by-case basis to determine if the event may be more 
appropriately classified as procedure-related. 
The Investigator should follow all unresolved serious adverse events until the 
events are resolved, the patient is lost to follow-up, the patient has withdrawn 
consent, or the adverse event is otherwise explained. 
For purposes of this study, the following events are not considered adverse events, 
because they are normally expected to occur in conjunction post-surgery, or are 
associated with customary, standard care of patients undergoing these procedures: 
x Early post-operative pain (within 48hours post-index procedure) at the 
incision site and/or related to position on procedure table 
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23 
 
x Post-anesthesia emesis, nausea, or headache (within 24 hours post-
index procedure) 
x Chest pain without associated ECG changes  
x Hematocrit decrease from baseline not associated with hemodynamic 
changes, remaining above 30% and not requiring transfusion 
x Electrolyte imbalance without clinical sequalea following endoscopic 
procedure, even if requiring correction 
x Low grade temperature increase (d38.3qC/d101qF)  
x Sinus bradycardia/tachycardia that does not require treatment or 
intervention 
x Systolic or diastolic blood pressure changes that do not require 
treatment or intervention 
x Any pre-planned surgical procedures 
This listing of events is intended to provide guidance to the investigational sites for 
purposes of adverse event reporting.  The Investigator at the investigational site should 
utilize his/her own clinical judgment in evaluating adverse experiences, and may 
decide that the above events should be reported as adverse events.   
Reporting of Serious and Non-Serious Adverse Events  
Serious Adverse Events, regardless of attribution, will be reported per 
MDACC’s standard practice and requirements, and per sponsor guidelines.  
Device Failures and Malfunctions. Not applicable 
Ethical Considerations 
Institutional Review Board/Ethics Committee 
A copy of the protocol, proposed Informed Consent form, other written patient 
information and any proposed advertising material must be submitted to the 
IRB/IEC for written approval.   
The Investigator must submit and, where necessary, obtain approval from the 
IRB/IEC for all subsequent significant protocol amendments and significant 
changes to the Informed Consent form.   
The Investigator will be responsible for obtaining annual IRB/IEC approval and 
renewal throughout the duration of the study.  
Informed Consent Form 
The written Informed Consent documents should be prepared in the language(s) 
of the potential patient population. 
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24 
 
The reviewing IRB/IEC must first approve the Informed Consent forms that are 
used. The Informed Consent forms that are used should be in accordance with 
the current guidelines as outlined by the Good Clinical Practices (GCP) 
guidelines, Declaration of Helsinki and the International Conference on 
Harmonization (ICH).  
Prior to participation in the clinical Study, each patient must give written Informed 
Consent after the context of the study has been fully explained to the patient in 
language that is easily understood by the patient. The patients must also be 
given the opportunity to ask questions and have those questions answered to 
their satisfaction. 
Written Informed Consent must be recorded appropriately by means of the 
patient’s, or their legal representative’s dated signature. The patient will receive a 
copy of the Informed Consent form. 
Amending the Protocol 
All significant protocol changes that may affect the following must be submitted 
and approved by the IRB before initiating the change: 
x validity of the data or information resulting from the completion of the 
approved protocol; 
x relationship of the likely patient risk to benefit relied upon to approve 
the protocol; 
x scientific soundness of the investigational plan, or; 
x rights, safety, or welfare of the human patients involved in the 
investigation. 
Emergency Actions 
The Investigator must give notice of any emergency deviations and justification 
for the deviation to the IRB/IEC as quickly as possible after the episode, in any 
event no later than 24 hours after the emergency. 
Protocol Deviations 
A protocol deviation is defined as an event where the Clinical Investigator or site 
personnel did not conduct the study according to the protocol.  
Investigators will adhere to procedures for reporting study deviations to their IRB 
in accordance with their specific IRB reporting policies and procedures. 
Deviations will be submitted annually per MDA policy.  
Coverage of Expenses 
The treated patients will not be reimbursed or compensated for participating in 
the Study. 
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25 
 
Confidentiality  
Confidentiality of patients will be maintained throughout the study.  A unique 
identification code will be assigned to each patient participating in this Study.  
Any data that may be published in abstracts, scientific journals, or presented at 
medical meetings will reference a unique patient code and will not reveal the 
patient’s identity.   
All laboratory and clinical data gathered in this protocol will be stored in a 
password-protected database. All patient information will be handled using 
anonymous identifiers. Linkage to patient identity is only possible after accessing 
a password-protected database. Access to the database is only available to 
individuals directly involved in the study. 
 
Information gathered for this study will not be reused or disclosed to any other 
person or entity, or for other research. Once the research has been completed, 
identifiers will be retained for as long as is required by law and by institutional 
regulations, and at that point will be destroyed. 
Source Documentation 
The Principal Investigator must maintain detailed source documents on all study 
patients who are enrolled in the study or who undergo screening.  Source 
documents include patient medical records, hospital charts, clinic charts, 
Investigator’s patient study files, as well as the results of diagnostic tests (e.g., 
laboratory tests). 
The following minimum information should be recorded in the patient’s 
medical records: 
x 
The date the patient entered the study and the patient number 
x 
The study protocol number 
x 
The date that informed consent was obtained 
x 
Evidence that the patient meets Study eligibility requirements (e.g., 
medical history, Study procedures and/or evaluations) 
x 
The dates of all Study related patient visits 
x 
Evidence that required procedures and/or evaluations were completed 
x 
Use of any concurrent medications 
x 
All lab reports taken for this study 
x 
Occurrence and status of any Adverse Events 
x 
The date the patient exited the Study, and a notation as to whether the 
patient completed the Study or was discontinued, including the reason 
for discontinuation. 
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Record Retention 
The Investigator will maintain all essential study documents and source 
documentation, in original format, that support the data collected on the study 
patients in compliance with the ICH/GCP guidelines.  
Following publication study data will be archived in REDCap. Since study data 
may be useful for future research studies performed under separate IRB 
approved protocols, study data will be archived indefinitely in REDCap. Since 
REDCap is a secure electronic database with controlled access, and because 
patient identifiers may be needed to link study data to data from other sources 
under future IRB approved protocols, patient identifying information will be 
retained in the archived database. 
Publication Policy 
All manuscripts associated with the data collected on this study are not to 
be submitted for publication without the written consent of the MD 
Anderson Principal Investigator. 
Role of Investigator 
The Investigator has the overall responsibility for the conduct of the study, 
including assurance that the study meets the regulatory requirements of the Food 
and Drug Administration (FDA).  In this study, Investigator will have certain direct 
responsibilities and will delegate other responsibilities to Consultants.  Together, 
the investigators will ensure adherence to general duties including any regulations 
applicable to a post-market, Physician Preference Study.   
Definitions 
For those AEs not listed on CTACE 4.0, the following severity rating will 
apply: 
Mild: 
Awareness of signs or symptoms, but easily tolerated; are of minor 
irritant type; causing no loss of time from normal activities; 
symptoms would not require medication or a medical evaluation; 
signs or symptoms are transient. 
Moderate
: 
Interferes with the patient’s usual activity and/or requires 
symptomatic treatment. 
Severe: 
Symptom(s) causing severe discomfort and significant impact of 
the patient’s usual activity and requires treatment. 
 
ALLERGIC REACTION: A state of abnormal and individual hypersensitivity 
acquired through exposure to a particular allergen. 
 
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27 
 
APPROVAL (IN RELATION TO INSTITUTIONAL REVIEW BOARDS (IRBs): The 
affirmative decision of the IRB that the clinical investigation has been reviewed 
and may be conducted at the institutional site within the constraints set forth by 
the IRB, the institution, Good Clinical Practice (GCP), and the applicable 
regulatory requirements. 
 
CO-INVESTIGATOR / SUB-INVESTIGATOR: Any individual member of the 
clinical investigation team designated and supervised by the Investigator at an 
investigational site who performs critical investigation-related procedures and/or 
makes important investigation-related observations.  See also Investigator.  
 
CONFIDENTIALITY: Prevention of disclosure, to other than authorized 
individuals, of proprietary information or of a patient's identity / Protected Health 
Information (PHI) in compliance with the Health Insurance Portability and 
Accountability Act of 1996 (HIPAA). 
 
CASE REPORT FORM (CRF): A document designed to record all of the 
protocol-required information on each patient. 
 
INFORMED CONSENT: A process by which a patient voluntarily confirms in 
writing his or her willingness to participate in a particular investigation, after 
having been informed of all aspects of the investigation that are relevant to the 
patient's decision to participate.  Informed consent is documented by means of a 
written, signed, and dated Informed Consent form.  
INVESTIGATOR: The person responsible for the conduct of the clinical 
investigation at an investigational site.  If an investigation is conducted by a team 
of individuals at an investigational site, the Investigator is the responsible leader 
of the team and may be called the Principal Investigator.  See also Co-
Investigator.  
 
PAIN SCALE: The 11-point Pain Intensity Numeric Rating Scale (NRS) is a pain 
assessment method using a numerically based scale allowing the patient to 
indicate the intensity of pain that he/she experiences.  The scale begins at 0 for 
“no pain” and has a maximum of 10 for “pain as bad as it could be.” (Appendix A) 
 
 
SERIOUS ADVERSE EVENT (SAE): Any untoward medical occurrence that 
results in death, is life threatening, requires patient hospitalization or prolongation 
of existing hospitalization, or results in persistent or significant 
disability/incapacity.  
 
PATIENT: An individual who participates in a clinical investigation. 
 
UNANTICIPATED ADVERSE DEVICE EFFECTS (UADE): Any serious adverse 
effect on health or safety or any life-threatening problem or death caused by, or 
associated with the study device, if that effect, problem or death was not 
previously identified in nature, severity, or degree of incidence in the 
Protocol Number 2017-0492 
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28 
 
Investigational Plan or any other unanticipated serious problem associated with a 
device that relates to the rights, safety, or welfare of patients. 
 
Investigator Responsibilities 
The investigator is responsible for ensuring that this study is conducted 
according to this protocol and that signed Informed Consent is obtained from 
each patient prior to their inclusion in this study. 
It is the investigator’s responsibility to ensure that all staff assisting with this 
Study have the appropriate qualifications and are fully instructed on the Study 
procedures and RPN patient confidentiality. 
The investigator is responsible for ensuring that the conduct of the Study 
conforms to the IRB/EC requirements and provides all necessary communication 
with the IRB/EC including, but not limited to, annual Study reports and required 
adverse event notifications. 
Investigator Records 
Case REPORT FORMS 
The standardized Case Report Forms (CRFs) will be used to collect complete 
and accurate records of the clinical data from the Study according to the Good 
Clinical Practice (GCP) requirements.  The investigator is responsible for 
collecting and accurately recording the data generated for this Study. 
SCREENING LOG 
Investigators will maintain a screening log that will record the date of informed 
consent, the date of screening, the enrollment status (enrolled/excluded) and the 
reason for exclusion for all screen failures. 
Investigator Reports 
FINAL STUDY REPORT 
A summary of the final report will be prepared and provided to each Principal 
Investigator for submission to their respective IRB/EC after completion of the 
Study. 
SERIOUS ADVERSE EVENTS (SAES) 
The investigators will report by CRF any SAEs including serious, and/or 
potentially device- or procedure-related adverse events as soon as possible, 
within 24 hours of the investigator becoming aware of the event, to the IRB/C as 
per the committee’s reporting requirements.  
 
 
 
 
References 
 
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29 
 
 
 
 
 
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Protocol Number 2017-0492 
Revised June 12, 2020