eXtended Antibiotic Prophylaxis for Intermediate- and High-risk Glands After Pancreatoduodenectomy to Reduce Clinically Relevant PostOperative Pancreatic Fistula: A Phase 2 Randomized Control Trial (X-POPF)
Phase: PHASE2
Conditions: Pancreatic Fistula
Sponsor: Case Comprehensive Cancer Center

CASE 2223
Page 1
Version date: 2/5/2024
STUDY NUMBER: CASE 2223
ClinicalTrials.gov NCT #: NCT05753735
Protocol Date: 2/5/2024
STUDY TITLE: eXtended antibiotic prophylaxis for intermediate- and high-risk glands 
after pancreatoduodenectomy to reduce clinically relevant PostOperative Pancreatic 
Fistula: A phase 2 randomized control trial (X-POPF)
PRINCIPAL INVESTIGATOR: 
PRINCIPAL INVESTIGATOR:  Lee M. Ocuin, MD
Division of Surgical Oncology
University Hospitals Cleveland Medical Center
Seidman Cancer Center
11100 Euclid Avenue
Cleveland, OH 44106
CO-INVESTIGATORS:             Jordan M. Winter, MD
Division of Surgical Oncology
University Hospitals Cleveland Medical Center
Seidman Cancer Center
11100 Euclid Avenue
Cleveland, OH 44106
Jeffrey M. Hardacre, MD
Division of Surgical Oncology
University Hospitals Cleveland Medical Center
Seidman Cancer Center
11100 Euclid Avenue
Cleveland, OH 44106

CASE 2223
Page 3
Version date: 2/5/2024
Title: eXtended antibiotic prophylaxis for intermediate- and high-risk glands after 
pancreatoduodenectomy to reduce clinically relevant PostOperative Pancreatic Fistula: A 
phase 2 randomized control trial (X-POPF)
Principal Investigator: Lee M. Ocuin
PRINCIPAL INVESTIGATOR SIGNATURE:
_______________________________________
Date: ___________________

CASE 2223
Page 4
Version date: 2/5/2024
SUMMARY OF CHANGES
Protocol 
Date
Section
Change
2/17/2023
Initial PRMC approval
2/23/2023
4.1
IRB pre-review clarifications: Age 18-90 years included in study
2/23/2023
3.1
Protocol clarification: patients with FRS >3 and soft gland.
2/23/2023
3.4
Follow-up clarified

CASE 2223
Page 5
Version date: 2/5/2024
STUDY SCHEMA

CASE 2223
Page 6
Version date: 2/5/2024
PROTOCOL SUMMARY
Protocol Number/Title
TBD
Study Phase
Phase 2 Randomized Clinical Trial 
Brief Background/Rationale
This is a prospective, randomized, controlled, single center 
study. Up to 96 patients will be randomized after 
pancreaticoduodenectomy in 2:1 fashion to either Extended 
Antibiotic Prophylaxis or Standard Care. 
Primary Objective 
Primary Endpoint(s)
Clinically relevant (Grade B/C) postoperative pancreatic 
fistula rate at 90 days.
Secondary Objective(s)
Secondary Endpoint(s) Major 90-day complications, 90-day 
mortality, 90-day composite length of stay, 90-day 
readmission, delayed gastric emptying, acute kidney injury, 
C. difficile colitis, postpancreatectomy hemorrhage
Sample Size
96 patients
Disease sites/Conditions
Pancreatectomy and Duodenectomy: A350, A360, A370, 
A700
Interventions
Piperacillin/Tazobactam 3.375 g IV every 6 hours while 
inpatient following surgery, not to exceed 10 days
Amoxicillin/ Clavulanic acid 875/125 mg every 12 hours 
after discharge to complete 10 days total antibiotics

CASE 2223
Page 7
Version date: 2/5/2024
ABBREVIATIONS Please update table with relevant abbreviations used in the protocol
CCCC
Case Comprehensive Cancer Center
CRF
Case Report Form
DCRU
Dahm’s Clinical Research Unit
DSTC
Data Safety and Toxicity Committee
FDA
Food and Drug Administration
ICF
Informed Consent Form
IRB
Institutional Review Board
PRMC
Protocol Review and Monitoring Committee
SOC
Standard of Care
CCF
Cleveland Clinic Foundation
UH
University Hospitals
CMC
Cleveland Medical Center
POPF
Postoperative Pancreatic Fistula 
CS-POPF
Clinically Significant Postoperative Pancreatic Fistula
PD
Pancreaticoduodenectomy
I.V.
Intravenous
PO
By mouth (from Latin per os)
Q6H
Every 6 hours (from Latin quaque 6 hora)
BID
Twice a Day (from Latin bis in die)

CASE 2223
Page 8
Version date: 2/5/2024
TABLE OF CONTENTS
1.0 
INTRODUCTION 
1.1
Background of Postoperative Pancreatic Fistula 
1.2 
Name/description of commercial agents
1.3
Rationale
2.0
OBJECTIVES
2.1
Primary Objective
2.2 
Secondary Objective(s)
3.0
STUDY DESIGN
3.1
Study design and cohorts
3.2
Number of Subjects
3.3
Replacement of Subjects
3.4
Expected Duration of Treatment and Subject Participation
4.0 
SUBJECT SELECTION
4.1
Inclusion Criteria
4.2 
Exclusion Criteria
4.3
Inclusion of Women and Minorities
5.0
REGISTRATION 
6.0 
TREATMENT PLAN
6.1
Treatment Regimen Overview 
6.2
Criteria for Removal from Study
6.3
Duration of Follow-Up
7.0
DOSE DELAYS / DOSE MODIFICATIONS
8.0
ADVERSE EVENTS AND POTENTIAL RISKS
8.1 
Agent Adverse events
8.2
Definitions
8.3
Serious Adverse Event Report Form
8.4
Reporting Procedures for Serious Adverse Event 
8.5
Serious Adverse Events and OnCoreTM
8.6 
Data Safety and Toxicity Committee   
8.7
Data and Safety Monitoring Plan
9.0
PHARMACEUTICAL INFORMATION 
9.1
Commercial Agent(s)
10.0
STUDY PARAMETERS AND CALENDAR
10.1
Study Parameters
10.2
Calendar

CASE 2223
Page 9
Version date: 2/5/2024
11.0
MEASUREMENT OF EFFECT 
12.0
RECORDS TO BE KEPT/REGULATORY CONSIDERATIONS
12.1
Data Reporting
12.2
Regulatory Considerations 
13.0
STATISTICAL CONSIDERATIONS
REFERENCES
 
APPENDICES 

CASE 2223
Page 10
Version date: 2/5/2024
1.0
Introduction
1.1
Background of Study Disease 
Pancreatoduodenectomy (PD) is a commonly performed surgical procedure utilized 
in the treatment of either localized malignancies or benign conditions that involve the 
pancreatic head, 2nd/3rd portions of the duodenum, ampulla of Vater, and distal biliary 
system. This procedure, also known as the Whipple procedure, was historically associated 
with high mortality and morbidity after being initially described in 1909 by Kausch and 
later in 1935 by Whipple. With improvements in surgical technique, suture, hemostasis, 
anesthesiology, and critical care, the PD is a routinely performed, safe operation with low 
mortality rates in appropriately selected patients in the current era.1 In high-volume centers, 
surgical mortality has been further reduced by increased recognition and advanced 
treatment of complications when they occur, and resultant high salvage rate of patients who 
experience post-pancreatectomy complications.2 However there has been little 
improvement in the rate of postoperative pancreatic fistula (POPF), which occurs in 
approximately 10-40% of patients, and is influenced by a number of factors, including 
surgeon experience, pancreatic gland texture, pancreatic duct size, and underlying 
diagnosis.3 POPF is the leaking of enterically contaminated and amylase-rich fluid from 
the pancreatic-jejunal anastomosis created during PD.4 This leak may be self-limited or 
lead to serious complications such as superficial and deep space surgical site infections, 
sepsis, and contribute to post-pancreatectomy hemorrhage or even death. 
Pancreatic fistulae are defined and graded based upon the International Study 
Group of Pancreatic Fistula (ISGPF) into the categories of biochemical leak, grade B 
POPF, and grade C POPF, with grade C being the most severe.5 Grades B and C POPF are 
also known as clinically relevant POPF (CR-POPF). Table 1 summarizes the diagnosis 
and definitions of POPF.
Table 1. Definitions of biochemical leak and Grade B/C postoperative pancreatic fistula
Event
Biochemical leak
Grade B POPF
Grade C POPF
Increased amylase >3 
times upper limit of 
normal serum value
Yes
Yes
Yes
Persistent drainage >3 
weeks
No
Yes
Yes
Clinically 
relevant 
change in management
No
Yes
Yes
Percutaneous 
or 
endoscopic 
intervention
No
Yes
Yes
Angiographic 
intervention for POPF-
related hemorrhage
No
Yes
Yes
Reoperation
No
No
Yes

CASE 2223
Page 11
Version date: 2/5/2024
Signs 
of 
infection 
related to POPF
No
Yes (no organ 
failure)
Yes (with organ 
failure)
POPF-related 
organ 
failure
No
No
Yes
POPF-related death
No
No
Yes
Given the prevalence and potential life-threatening consequences of CR-POPF, 
multiple mitigation strategies have been studied in both prospective and retrospective 
fashion. Studies have examined anastomotic techniques for pancreaticojejunostomy6,7 and 
pharmacologic interventions with somatostatin analogues,8,9 but no study with positive 
results has demonstrated reproducible efficacy, and overall results have been 
heterogenous.10–14
By definition, any leak from the pancreaticojejunostomy is infected, and antibiotics are a 
mainstay of treatment of CR-POPF. Therefore, the concept of antibiotic mitigation prior 
to development of a CR-POPF in patients at higher risk of developing CR-POPF is an 
attractive option. 
The fistula risk score (FRS) is a prospectively validated 10-point score that assigns point 
values to several non-modifiable variables in patients undergoing pancreatoduodenectomy, 
with higher scores predictive of higher risk of any POPF and CR-POPF (Table 2).15 
Patients with negligible/low FRS (0-2) have a predicted <10% risk of CR-POPF, those 
with intermediate FRS (3-6) have a predicted 10-30% risk of CR-POPF, and those with 
high FRS (7-10) have a predicted 30-50% risk of CR-POPF (Table 3).16
Table 2. Fistula risk score for prediction of CR-POPF
Risk factor
Parameter
Points
Gland texture
Firm
Soft
0
2
Pathology
Pancreatic adenocarcinoma/pancreatitis
Other
0
1
Pancreatic duct diameter (mm)
>5mm
4mm
3mm
2mm
<1mm
0
1
2
3
4
Estimated blood loss (ml)
<400
400-700
701-1000
>1000
0
1
2
3
TOTAL
Table 3. Predicted rate of CR-POPF based on FRS score category
Negligible 
(FRS 0)
Low
(FRS 1-2)
Intermediate
(FRS 3-6)
High
(FRS 7-10)
<5%
<10%
10-30%
30-50%

CASE 2223
Page 12
Version date: 2/5/2024
Shubert and colleagues from Mayo Clinic created a risk-based postoperative pathway, with 
extended antibiotic prophylaxis as a component in patients with intermediate or high FRS. 
The risk-based pathways were associated with decreased length of stay and overall cost 
savings, but no change in the overall rate of any POPF or CR-POPF. However, in patients 
with CR-POPF, the risk-based pathway was associated with having a lower CR-POPF 
grade.17
Table 4 summarizes the modified version of the antibiotic component of the risk-based 
pathway that has been adopted at University Hospitals Cleveland Medical Center for 
patients who undergo pancreatoduodenectomy by the four pancreatic surgeons within the 
Division of Surgical Oncology.
Table 
4. 
Antibiotic 
mitigation 
protocol 
for 
patients 
who 
undergo 
pancreatoduodenectomy
FRS Category
Treatment
Negligible/low (FRS 0-2)
Standard 
perioperative 
antibiotics, 
discontinued within 24 hours.
Intermediate (FRS 3-6) or high (FRS 7-10)
Piperacillin/Tazobactam 
3.375mg 
IV 
Q6hrs 
x10 
days 
(converted 
to 
amoxicillin/clavulanic acid at discharge; 
total of 10 days of antibiotics).
Preliminary data
We have recently analyzed our initial results since the antibiotic mitigation protocol was 
adopted, and data are summarized in Tables 5 and 6. A total of 59 patients have undergone 
pancreatoduodenectomy since the pathway was introduced off-protocol. Patients who 
received extended antibiotic prophylaxis had smaller duct size (2mm vs. 3mm, p=0.04; 
Table 5). Median FRS and FRS categories were similar. One surgeon (LO) utilized the 
pathway exclusively, one surgeon (JH) adopted the pathway into routine practice, and two 
surgeons (JA and JW) did not utilize the pathway at any time.
Table 5. Clinical and demographic factors for patients with intermediate/high FRS treated with 
or without extended antibiotic prophylaxis.
Demographics
Antibiotics
(n=18)
No Antibiotics
(n=41)
p-value
Age (median, IQR)
64 (55, 73)
63 (55, 70)
0.86
Female (n, %)
11 (61.1%)
18 (43.9%)
0.22
Non-White
4 (22.2%)
7 (17.1%)
0.72
Pathology
Cyst/IPMN
Cholangiocarcinoma
Ampullary carcinoma
1 (5.6%)
6 (33.3%)
4 (22.2%)
5 (12.2%)
6 (14.6%)
11 (26.8%)
--

CASE 2223
Page 13
Version date: 2/5/2024
Duodenal cancer
Neuroendocrine
Other
3 (16.6%)
2 (11.1%)
2 (11.1%)
3 (7.3%)
9 (22.0%)
7 (17.1%)
Duct size (mm) (median, 
IQR)
2 (2, 4)
3 (3, 4)
0.04
Fistula risk score
6 (5, 7)
5 (4, 6)
0.39
FRS category (n, %)
Intermediate
High
13 (72.2)
5 (27.8)
33 (80.5)
8 (19.5)
0.48
Surgeon
JA
JW
JH
LO
0 (0%)
0 (0%)
6 (33.3%)
12 (66.7%)
8 (19.5%)
18 (43.9%)
15 (36.6%)
0 (0%)
Patients who received extended antibiotic prophylaxis had lower rates of CR-POPF as 
compared to those who received standard perioperative antibiotic prophylaxis (11.1 vs. 
36.6%, p=0.04; Table 6). Additionally, those who received extended antibiotic prophylaxis 
has shorter index length of stay (7 vs. 8 days, p=0.04), fewer superficial wound (5.6 vs. 
35.0%, p=0.02) and deep space (16.7 vs. 43.9%, p=0.04) infections, and lower frequency 
of image-guided drain placement (5.6 vs. 14.6%, p=0.03). The composite 90-day length of 
stay was also shorter in those who received extended antibiotic prophylaxis (8 vs. 11 days), 
but this did not reach statistical significance. Importantly, there were no documented C. 
difficile colitis infections in patients who received extended antibiotics. 
Table 6. Postoperative outcomes after pancreatoduodenectomy in patients with intermediate/high 
fistula risk scores, stratified by extended or standard perioperative antibiotics.
Outcomes
Antibiotics
(n=18)
No antibiotics
(n=41)
p-value
CR-POPF (n, %)
2 (11.1%)
15 (36.6%)
0.04
90-day Readmission 
8 (44%)
14 (34.2)
0.45
Index LOS (median, IQR)
7 (6, 8)
8 (6, 14)
0.04
Composite 90 Day LOS
8 (6, 10)
11 (7, 17)
0.08
30 Day Mortality (n, %)
0 (0%)
2 (4.9)
0.34
90 Day Mortality 
1 (5.6%)
3 (7.3%)
0.80
DGE
7 (38.9%)
6 (14.6%)
0.04
Post Pancreatectomy 
Hemorrhage
0 (0%)
3 (7.3%)
0.24
Superficial Wound Infection
1 (5.6%)
14 (35.0%)
0.02
Deep Space Infection
3 (16.7%)
18 (43.9%)
0.04
Image-guided drain placed
1 (5.6%)
13 (31.7%)
0.03
Return to OR
1 (5.6%)
6 (14.6%)
0.32
Bile Leak
0 (0%)
2 (4.9%)
0.34
 
 

CASE 2223
Page 14
Version date: 2/5/2024
1.2 
Name and Description of Pharmacologic Agents 
Piperacillin/Tazobactam is an FDA-approved broad spectrum antibiotic, delivered 
only by I.V. route. It is a combination of piperacillin sodium, a bactericidal agent that 
inhibits bacterial septum and cell wall synthesis, and tazobactam, a beta-lactamase inhibitor 
that stop bacteria from breaking down penicillins.   
Amoxicillin/Clavulanic acid is an FDA-approved antibiotic that is orally dosed. It 
is a combination of amoxicillin, a bactericidal agent that inhibits bacterial cell wall 
synthesis, and clavulanic acid, a beta-lactamase inhibitor that serves to increase the activity 
of amoxicillin, particularly in gram-negative bacteria.
Both antibiotics are frequently used for intraabdominal infections given their 
extended gram-negative coverage. Adverse events are most commonly mild 
gastrointestinal symptoms and are fully detailed below.
1.3
Rationale 
Our preliminary data suggest that extended broad-spectrum antibiotic prophylaxis 
may reduce the rate of CR-POPF in patients who undergo PD and have intermediate- or 
high FRS. CR-POPF drives many of the downstream postoperative outcomes following 
PD. The risks of administration of the proposed antibiotics are relatively low. Adverse drug 
reactions and the development of drug resistant bacterial strains are the two potential 
drawbacks of antibiotic exposure in this population. However, patients who undergo PD 
are all exposed to piperacillin/tazobactam in the perioperative setting, and patients who 
develop a CR-POPF will be exposed to a prolonged antibiotics course as part of the 
therapeutic management of CR-POPF, often exceeding the 10-day duration of prophylaxis 
in the treatment arm of this trial.
2.0 
Objectives
2.1 
Primary Objective 
Our primary objective is to demonstrate that extended antibiotic prophylaxis in 
patients with intermediate/high FRS who undergo PD reduces the rate of CR-POPF in the 
intervention group, as defined by the ISGPF taskforce guidelines. We hypothesize that 
extended antibiotic prophylaxis will reduce the odds of CR-POPF by 79%, from 37% to 
11% (OR=0.21).
2.2
Secondary Objective(s)
Our secondary objectives are to analyze other pertinent postpancreatectomy 
outcomes between treatment arms. These include 30- and 90-day postoperative mortality, 
30- and 90-day readmission rates, index postoperative length of stay, composite 90-day 
length of stay, delayed gastric emptying, post-pancreatectomy hemorrhage, superficial 

CASE 2223
Page 15
Version date: 2/5/2024
surgical site infections, deep surgical site infections, deep space infections/intra-abdominal 
abscess, and rate of image-guided drain placement. 
3.0
Study Design
3.1 
Study design and cohorts 
This study will be a randomized, controlled, unblinded, double arm study with 2:1 
randomization to the intervention group.
This study will enroll patients who are planned to undergo elective 
pancreatoduodenectomy at UH CMC for any indication. Patients will be consented for 
participation in trial at their preoperative clinic visit. During surgery, if patient has 
undergone a successful pancreatoduodenectomy, the fistula risk score will be calculated as 
described in Table 2. If the FRS is >3 and the patient has a soft gland, the subject will be 
randomized to intervention or control arms in 2:1 fashion.
3.2
Number of Subjects
A total of 96 subjects will be enrolled in this trial. More may need to be consented 
if they do not meet criteria for randomization intraoperatively (e.g., low/negligible FRS 
[FRS <2]) or if procedures are aborted based on intraoperative findings (e.g., non-
resectability, metastases, need for total pancreatectomy, etc). 
3.3
Replacement of Subjects 
Patients will not be replaced after enrollment and randomization and are assigned 
to intervention vs control. Subjects who have been consented but are not eligible for 
randomization at time of surgery will be removed from trial and additional subjects 
consented. 
3.4 
Expected Duration of Treatment and Subject Participation
Patients who are enrolled in the study and who undergo successful 
pancreatoduodenectomy with fistula risk score >3 will be randomized to either standard 
care or intervention. The intervention group will receive a total of 10 days of antibiotics. 
While in the hospital, patients will receive piperacillin/tazobactam, 3.375 g I.V. Q6H. 
Upon discharge, patients will be converted to oral amoxicillin/clavulanic acid 875/125 mg 
PO BID to finish a 10-day total course of antibiotics. For example, if a patient is admitted 
7 days, then they would receive PO antibiotics for the next 3 days outpatient to cover 10 
days total. 
After this course is completed there will be no intervention remaining for this study. 
Subjects will be followed for primary and secondary outcomes for up to 90 days 
postoperatively, with planned interval follow-ups at 2 weeks, 30 days, and 90 days 
postoperatively. Additional follow-ups will be as clinically indicated depending on 
patient’s postoperative recovery.

CASE 2223
Page 16
Version date: 2/5/2024
The control group will be treated according to current standard perioperative antibiotic 
practice, and perioperative antibiotics will not exceed 24 hours postoperatively. 
4.0
Subject Selection
Each of the criteria in the sections that follow must be met in order for a subject to be 
considered eligible for this study. Use the eligibility criteria to confirm a subject’s 
eligibility. 
Subject’s Name 
_____________________________________________________________
Medical Record # 
___________________________________________________________
Research Nurse / Study Coordinator Signature: 
_________________________________________________
Date __________
Treating Physician [Print] 
____________________________________________________
Treating Physician Signature: 
_________________________________________________
Date __________
4.1
Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be eligible for enrollment: 
 
4.1.1 Subject undergoing planned, elective pancreatoduodenectomy at UH CMC 
for any indication.
 
 
4.1.2 Age 18-90 years
Pancreatoduodenectomy is rarely, if ever performed in the elective setting for the 
pediatric population at UH CMC. Therefore, this study will not include this small 
and different population of patients undergoing pancreatoduodenectomy. 
 
4.1.3 Subjects must have the ability to understand and the willingness to sign a 
written informed consent document.
 
4.1.4 Creatinine Clearance greater than 40 ml/min

CASE 2223
Page 17
Version date: 2/5/2024
4.2
Exclusion Criteria
 
4.2.1 Concurrent participation in another clinical trial, where participation in the 
proposed clinical trial that prohibits participation in this clinical trial, or where 
subjects would be actively receiving another investigational agent during the 90-
day evaluation period of this study.
 
4.2.2 History of allergic reactions attributed to compounds of similar chemical or 
biologic composition to Piperacillin, Tazobactam, Amoxicillin, Clavulanic Acid or 
other agents used in this study.
 
4.2.3 Subjects who are found to have another active infection or presumed infection 
at time of surgery who will be treated per standard of care with antibiotics 
regardless of randomization status. 
 
4.2.4 Subjects who are found to have metastatic disease at time of planned 
pancreatoduodenectomy, if surgery is otherwise aborted, or if total pancreatectomy 
is performed due to interoperative considerations
 
4.2. Any subject who, while not having history of adverse reaction to similar 
chemical or biologic composition to Piperacillin, Tazobactam, Amoxicillin, 
Clavulanic Acid or other agents used in this study, develops a suspected drug 
reaction to the standard perioperative dose of antibiotic, prior to randomization. 
4.3
Inclusion of Women and Minorities 
Men, women and members of all races and ethnic groups are eligible for this trial.
5.0
Registration
All subjects who have been consented are to be registered in the OnCore™ Database. For 
those subjects who are consented, but not enrolled, the reason for exclusion must be 
recorded.
This trial may have a relatively large number of patients who are consented but not enrolled 
due to the intraoperative nature of the randomization and the unpredictable disease process. 
All subjects will be registered through University Hospitals Cleveland Medical Center and 
will be provided a study number by contacting the study coordinator (Nikola Anusic) as 
listed on the cover page. 
This trial will utilize merged block randomization with 2:1 allocation to the treatment arm 
(extended antibiotics).

CASE 2223
Page 18
Version date: 2/5/2024
6.0 
Treatment Plan
6.1
Treatment Regimen Overview
6.1.1
Standard 
perioperative 
antibiotics: 
patients 
will 
receive 
piperacillin/tazobactam 3.375 g prior to surgical incision, with intraoperative re-dosing 
every 2 hours. At surgeon’s discretion, antibiotics may be dosed every 6 hours following 
completion of surgery for up to, but not exceeding, 24 hours from completion of surgery.
6.1.2
Extended 
antibiotic 
prophylaxis: 
patients 
will 
receive 
piperacillin/tazobactam 3.375 g prior to surgical incision, with intraoperative re-dosing 
every 2 hours. Following completion of surgery, piperacillin/tazobactam, available from 
the UH CMC inpatient pharmacy, will be ordered 3.375 g Q6H and timed per protocol on 
the assigned hospital ward. Piperacillin/tazobactam will continue while the patient remains 
hospitalized for up to 10 days. If a patient meets discharge criteria prior to 10 days, they 
will continue  amoxicillin/clavulanic acid 875/125 mg by mouth BID to complete 10 days 
of total antibiotic prophylaxis.
6.1.3
Intraoperative drain placement: patients in both treatment arms will have 
2 operative drains placed (15 or 19 French) prior to abdominal closure. The drains will be 
placed posterior and anterior to the pancreaticojejunostomy. Drain exit site on the 
abdominal wall is at the discretion of the operating surgeon. Additional drains may be 
placed at the discretion of the operating surgeon if it is felt they are indicated (e.g., in 
Morrison’s pouch, etc.). Drains will be placed to passive (gravity) drainage.
6.1.4
Assessment for biochemical leak and postoperative pancreatic fistula: 
drain amylase from operatively placed drains will be checked on postoperative days 1 and 
4. By definition, biochemical leak or CR-POPF requires that at least one drain contains 
amylase levels 3 times the upper limit of normal serum amylase on postoperative day 3 or 
after.
6.1.5
Operative drain removal: at the discretion of the surgeon, operatively 
placed drains may be removed any time after testing of drain fluid for amylase levels is 
performed, and biochemical leak or CR-POPF has been ruled out, generally on or after 
postoperative day 4.
6.1.6
Workup and management of suspected CR-POPF: at the operating 
surgeon’s discretion, workup and treatment of a suspected CR-POPF may begin on or after 
postoperative day 3. Workup includes standard labs (complete blood count, metabolic 
panels) and cross-sectional imaging (typically contrast-enhanced CT scan). If a CR-POPF 
is confirmed based on ISGPF definition (Table 1), antibiotics may be initiated in patients 
who were not randomized to extended prophylaxis. Initiation of antibiotics in patients 
randomized to the control arm will require consensus from the four pancreatic surgeons 
after group discussion. Other management (initiation of somatostatin analogues, image-
guided drain placement, transfer to ICU, return to operating room, placement of existing 
operative drains to suction, etc.) will be determined by the operating surgeon. 

CASE 2223
Page 19
Version date: 2/5/2024
6.1.7
Workup for other post-pancreatectomy complications: for non-POPF-
related complications (e.g., early post-pancreatectomy hemorrhage, anastomotic concerns 
related to the hepaticojejunostomy or gastrojejunostomy, concerns related to operatively 
placed enteral feeding tubes, concerns related to synchronous procedures [e.g., partial 
colectomy]), workup and management may occur at any time at the discretion of the 
surgeon.
6.1.8
Workup of diarrhea: all patients with significant diarrhea following 
surgery will be tested for C. difficile colitis.
6.1.9
Postoperative infections: for patients with documented postoperative 
infections based on cultures of blood, urine, or drain fluid, antimicrobial sensitivities of 
organisms that grow will be documented.
6.2
Criteria for Removal from Study
Treatment will continue for a total of 10 days, while inpatient on IV Piperacillin 
Tazobactam as described above and to complete 10 days as outpatient on 
amoxicillin/clavulanic acid if patient is discharged prior to postoperative day 10. 
• Subject decision to withdraw from treatment (partial consent) or from the study (full 
consent)
• Any severe adverse drug reaction
• The investigator considers it, for safety reasons, to be in the best interest of the subject. 
This would be most clinically relevant in the case of acute kidney injury thought to be due 
to piperacillin/tazobactam, and the patient appearing clinically well.  
• Death
6.3
Duration of Follow-Up
Subjects will be followed for postoperative outcomes for 90 days after surgery or until 
death, whichever occurs first. 
The clinical course of each event will be followed until resolution, stabilization, or until it 
has been determined that the study treatment or participation is not the cause. 
Serious adverse events that are still ongoing at the end of the study period will necessitate 
follow-up to determine the final outcome of the event. Any serious adverse event that 
occurs after the study period and is possibly related to the study treatment or study 
participation will be recorded and reported immediately.
7.0 
Dose Delays/Dose Modifications
Patients will be monitored while inpatient as part of their standard postoperative care. As 
part of this their creatinine clearance will be monitored. If it drops below 40 ml/min the 

CASE 2223
Page 20
Version date: 2/5/2024
piperacillin/tazobactam dose will be adjusted per manufacturer’s recommendations for 
renal function, in association with the inpatient unit’s clinical pharmacist. 
Amoxicillin/Clavulanic acid will also be renally dosed, with reduction per manufacturer’s 
recommendations if creatine clearance is below 30 ml/min. However, it is possible that if 
renal impairment is felt to be due to the antibiotics they may be halted prior to dose 
adjustment. Amoxicillin/Clavulanic acid will be provided to patients by prescription, and 
the medication will be delivered to the patient’s room prior to hospital discharge.
8.0
Adverse Events and Potential Risks 
8.1
Piperacillin/Tazobactam 
The most common adverse events associated with piperacillin/tazobactam are listed 
below with the percentages given in piperacillin/tazobactam monotherapy trials:
Gastrointestinal disorders
Diarrhea (11.3%)
Constipation (7.7%)
Nausea (6.9%)
Vomiting (3.3%)
Dyspepsia (3.3%)
Abdominal pain (1.3%)
General disorders and administration site conditions
Fever (2.4%)
Injection site reaction (≤1%)
Rigors (≤1%)
Immune system disorders
Anaphylaxis (≤1%)
Infections and infestations
Candidiasis (1.6%)
Pseudomembranous colitis (≤1%)
Metabolism and nutrition disorders
Hypoglycemia (≤1%)
Musculoskeletal and connective tissue disorders
Myalgia (≤1%)
Arthralgia (≤1%)
Nervous system disorders
Headache (7.7%)
Psychiatric disorders
Insomnia (6.6%)
Skin and subcutaneous tissue disorders
Rash (4.2%, including maculopapular, bullous, and urticarial)
Pruritus (3.1%)
Purpura (≤1%)
Vascular disorders
Phlebitis (1.3%)

CASE 2223
Page 21
Version date: 2/5/2024
Thrombophlebitis (≤1%)
Hypotension (≤1%)
Flushing (≤1%)
Respiratory, thoracic and mediastinal disorders
Epistaxis (≤1%)
For a comprehensive list of adverse events please refer to package insert, full information 
is available at:  https://labeling.pfizer.com/showlabeling.aspx?format=PDF&id=1177
8.1.1     Amoxicillin/Clavulanic Acid
The most common adverse events associated with Amoxicillin/Clavulanic Acid 
use are listed below:
Gastrointestinal
Diarrhea/Loose Stools (9%)
Nausea (3%)
Vomiting (1%)
Dermatologic 
Skin rashes and Urticaria (3%)
Genitourinary 
Vaginitis (1%)
For a comprehensive list of adverse events please refer to package insert: 
www.accessdata.fda.gov/drugsatfda_docs/label/2011/050564s052,050720s025lbl.pdf
8.2
Definitions 
8.2.1
Adverse Event  
An adverse event (AE) is any unfavorable or unintended event, physical or psychological, 
associated with a research study, which causes harm or injury to a research participant as 
a result of the participant’s involvement in a research study. The event can include 
abnormal laboratory findings, symptoms, or disease associated with the research study. 
The event does not necessarily have to have a causal relationship with the research, any 
risk associated with the research, the research intervention, or the research assessments. 
Adverse events may be the result of the interventions and interactions used in the research; 
the collection of identifiable private information in the research; an underlying disease, 
disorder, or condition of the subject; and/or other circumstances unrelated to the research 
or any underlying disease, disorder, or condition of the subject. 
8.2.2  Serious Adverse Events 
A serious adverse event (SAE) is any adverse experience occurring at any dose that results 
in any of the following outcomes: 

Results in death. 

CASE 2223
Page 22
Version date: 2/5/2024

Is a life-threatening adverse experience.  The term life-threatening in the 
definition of serious refers to an adverse event in which the subject was at risk 
of death at the time of the event.  It does not refer to an adverse event which 
hypothetically might have caused death if it were more severe. 

Requires 
inpatient 
hospitalization 
or 
prolongation 
of 
existing 
hospitalization.  Any adverse event leading to hospitalization or prolongation 
of hospitalization will be considered as Serious, UNLESS at least one of the 
following expectations is met:
o
The admission results in a hospital stay of less than 24 hours OR
o
The admission is pre-planned (e.g., elective or scheduled surgery 
arranged prior to the start of the study) OR
o
The admission is not associated with an adverse event (e.g., social 
hospitalization for purposes of respite care.
However it should be noted that invasive treatment during any hospitalization may 
fulfill the criteria of “medically important” and as such may be reportable as a 
serious adverse event dependant on clinical judgment.  In addition, where local 
regulatory authorities specifically require a more stringent definition, the local 
regulation takes precedent. 

Results in persistent or significant disability/incapacity.  The definition of 
disability is a substantial disruption of a person’s ability to conduct normal life’s 
functions.

Is a congenital anomaly/birth defect. 

Is an important medical event.  Important medical events that may not result 
death, be life-threatening, or require hospitalization may be considered a serious 
adverse experience when, based upon appropriate medical judgment, they may 
jeopardize the subject and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition.  Examples of such medical 
events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood disease or disorders, or convulsions that do 
not result in inpatient hospitalization, or the development of drug dependency 
or drug abuse. The development of a new cancer is always considered an 
important medical event.
8.2.3
Adverse Event Evaluation 
The investigator or designee is responsible for ensuring that all adverse events (both serious 
and non-serious) observed by the clinical team or reported by the subject which occur after 
the subject has signed the informed consent are fully recorded in the subject’s medical 
records. Source documentation must be available to support all adverse events. 
A laboratory test abnormality considered clinically relevant should be reported as an 
adverse event.  
The investigator or sub-investigator (treating physician if applicable) will provide the 
following for all adverse events (both serious and non-serious):

Event term (as per CTCAE)

CASE 2223
Page 23
Version date: 2/5/2024

Description of the event

Date of onset and resolution

Expectedness of the toxicity

Grade of toxicity 

Attribution of relatedness to the investigational agent- (this must be assigned 
by an investigator, sub-investigator, or treating physician)

Action taken as a result of the event, including but not limited to; no changes, dose 
interrupted, reduced, discontinued, etc. or action taken with regard to the event, i.e. 
no action, received conmed or other intervention, etc.

Outcome of event
Descriptions and grading scales found in the NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 6.0 will be utilized for AE reporting. 
An expected adverse event is an event previously known or anticipated to result from 
participation in the research study or any underlying disease, disorder, or condition of the 
subject. The event is usually listed in the Investigator Brochure, consent form or research 
protocol. 
An unexpected adverse event is an adverse event not previously known or anticipated to 
result from the research study or any underlying disease, disorder, or condition of the 
subject. 
Attribution is the relationship between an adverse event or serious adverse event and the 
study drug.  Attribution will be assigned as follows:

Definite – The AE is clearly related to the study drug.

Probable – The AE is likely related to the study drug.

Possible – The AE may be related to the study drug.

Unlikely – The AE is doubtfully related to the study drug.

Unrelated – The AE is clearly NOT related to the study drug.
Protocol must specify if attribution is required for individual components of the treatment 
regimen or the treatment regimen as a whole.
8.3
SAE Report Form
SAEs will be recorded on the FDA Form 3500A (MedWatch) but should only be reported 
as instructed below.  The electronic FDA SAE reporting forms should not be used.  
8.4
Reporting Procedures for Serious Adverse Events
For the purposes of safety reporting, all adverse events will be reported that occur from 
surgery through 30 days after the final dose prophylactic antibiotic. Adverse events, both 
serious and non-serious, and deaths that occur during this period will be recorded in the 
source documents. All SAEs should be monitored until they are resolved or are clearly 
determined to be due to a subject’s stable or chronic condition or intercurrent illness(es). 
Related AEs will be followed until resolution to baseline or grade 1 or stabilization. 

CASE 2223
Page 24
Version date: 2/5/2024
8.4.1
SAE Reporting Requirements

Participating investigators (all sites) must report all serious adverse events to the 
Lead Site Principal Investigator (e.g. Sponsor-Investigator) within 24 hours of 
discovery or notification of the event. The participating investigator must also 
provide follow-up information on the SAE until final resolution. 
o
Lee.ocuin@uhhospitals.org

Cell 4045805343

The Lead Site Principal Investigator will review the SAE and report the event to 
the FDA, external collaborator(s), and IRB as applicable.

It is the Sponsor-Investigator’s responsibility (e.g. lead site PI) to ensure that ALL 
serious adverse events that occur on the study (e.g. ALL SAEs that occur at each 
enrolling institution) are reported to all participating sites.
Institutional Review Board Reporting Requirements:

Investigative sites will report adverse events to their respective IRB according to 
the local IRB’s policies and procedures in reporting adverse events. 
8.5
SAEs and OnCore

All SAEs will be entered into OnCore.  

A copy of the SAE form(s) submitted to the sponsor-investigator is also uploaded 
into Oncore.
8.6 
Data Safety and Toxicity Committee
It is the responsibility of each site PI to ensure that ALL SAEs occurring on this trial 
(internal or external) are reported to the Case Comprehensive Cancer Center’s Data and 
Safety Toxicity Committee. This submission is simultaneous with their submission to the 
sponsor and/or other regulatory bodies. 
The sponsor-investigator is responsible for submitting an annual report to the DSTC as per 
CCCC Data and Safety Monitoring Plan.
 
8.7
Data and Safety Monitoring Plan (DSMP)
This protocol will adhere to the policies of the Case Comprehensive Cancer Center Data 
and Safety Monitoring Plan in accordance with NCI guidelines. 
9.0
PHARMACEUTICAL INFORMATION 
A list of the adverse events and potential risks associated with the investigational or 
commercial agents administered in this study can be found in Section 8.
9.1 
Commercial Agent
9.1.1 Name of Agent
Piperacillin/Tazobactam
Other Names: 
Zosyn

CASE 2223
Page 25
Version date: 2/5/2024
Product description: Piperacillin/tazobactam is an injectable antibacterial combination 
product consisting of the semisynthetic antibacterial piperacillin sodium and the beta-
lactamase inhibitor tazobactam sodium for intravenous administration. It is supplied in a 
powder either in bulk vials or single dose vitals.  
Solution preparation/Storage Requirments/Stability: 
Per Inpatient Phamacy Standard Practice at UH CMC, below are manufacturer’s 
recommendations:
Reconstitution of piperacillin/tazobactam for Injection for Adult Patients and Pediatric 
Patients Weighing Over 40 kg Pharmacy Bulk Vials Reconstituted pharmacy bulk vial 
solution must be transferred and further diluted for intravenous infusion. The pharmacy 
bulk vial is for use in a hospital pharmacy admixture service only under a laminar flow 
hood. After reconstitution, entry into the vial must be made with a sterile transfer set or 
other sterile dispensing device, and contents should be dispensed as aliquots into 
intravenous solution using aseptic technique. Use entire contents of pharmacy bulk vial 
promptly. Discard unused portion after 24 hours if stored at room temperature (20°C to 
25°C [68°F to 77°F]), or after 48 hours if stored at refrigerated temperature (2°C to 8°C 
[36°F to 46°F]). Reconstitute the pharmacy bulk vial with exactly 152 mL of a compatible 
reconstitution diluent, listed below, to a concentration of 200 mg/mL of piperacillin and 25 
mg/mL of tazobactam. Shake well until dissolved. Parenteral drug products should be 
inspected visually for particulate matter and discoloration prior to and during 
administration whenever solution and container permit. 7 Single-Dose Vials Reconstitute 
piperacillin/tazobactam single-dose vials with a compatible reconstitution diluent from the 
list provided below. 2.25 g, 3.375 g, and 4.5 g piperacillin/tazobactam should be 
reconstituted with 10 mL, 15 mL, and 20 mL, respectively. Swirl until dissolved. After 
reconstitution, the single-dose vials will have a concentration of 202.5 mg/mL (180 mg/mL 
of piperacillin and 22.5 mg/mL of tazobactam). Compatible Reconstitution Diluents for 
Pharmacy Bulk Vials and Single-Dose Vials 0.9% sodium chloride for injection Sterile 
water for injection Dextrose 5% Bacteriostatic saline/parabens Bacteriostatic 
water/parabens Bacteriostatic saline/benzyl alcohol Bacteriostatic water/benzyl alcohol 
Dilution of the Reconstituted piperacillin/tazobactam Solution for Adult Patients and 
Pediatric Patients Weighing Over 40 kg Reconstituted piperacillin/tazobactam solutions 
for both pharmacy bulk vials and single-dose vials should be further diluted (recommended 
volume per dose of 50 mL to 150 mL) in a compatible intravenous solution listed below. 
Administer by infusion over a period of at least 30 minutes. During the infusion it is 
desirable to discontinue the primary infusion solution. Compatible Intravenous Solutions 
for Pharmacy Bulk Vials and Single-Dose Vials 0.9% sodium chloride for injection Sterile 
water for injection (Maximum recommended volume per dose of sterile water for injection 
is 50 mL) Dextran 6% in saline Dextrose 5% Lactated Ringer's Solution (compatible only 
with reformulated piperacillin/tazobactam containing EDTA and is compatible for co-
administration via a Y-site) piperacillin/tazobactam should not be mixed with other drugs 
in a syringe or infusion bottle since compatibility has not been established. 

CASE 2223
Page 26
Version date: 2/5/2024
piperacillin/tazobactam is not chemically stable in solutions that contain only sodium 
bicarbonate and solutions that significantly alter the pH.
Route of administration: 
Intravenous infusion over 30 minutes
9.1.2    Name of Agent
Amoxicillin/Clavulanic Acid
Other Names: 
Augmentin
Product Description:
Amoxicillin/Clavulanic Acid is an oral antibacterial combination consisting of the 
semisynthetic antibiotic amoxicillin and the β-lactamase inhibitor, clavulanate potassium 
(the potassium salt of clavulanic acid). Amoxicillin is an analog of ampicillin, derived from 
the basic penicillin nucleus, 6-aminopenicillanic acid. Amoxicillin/Clavulanic Acid
 875-mg Tablets: Each scored white capsule-shaped tablet contains 875 mg amoxicillin as 
the trihydrate and 125 mg clavulanic acid as the potassium salt.
Solution preparation/Storage Requirments/Stability: 
This medication will be supplied and available in clinical pharmacies, and they will 
follow their protocols for storage and handling of medication. 
Route of administration: 
P.O.
10.0 
STUDY PARAMETERS AND CALENDAR 
10.1
Study Parameters
Patients will have all labs and imaging required by study done as part of the standard of 
care following pancreatoduodenectomy. 
10.2
Calendar 
Pre-operative
Intra-operative
Postoperative
Day 0-10
Postoperative
Day 0-90
Informed consent
X
Demographics
X
Standard 
antibiotics 
(pre-incision, 
intraop 
redosing)
X
Pancreatoduodenectomy
X
Fistula 
risk 
score 
assessment
X

CASE 2223
Page 27
Version date: 2/5/2024
Randomization
X
Extended antibiotics
X
Monitoring 
for 
CR-
POPF
X
X
Monitoring of creatinine 
clearance
X
X
Monitoring 
for 
any 
postoperative 
complications
X
X
Monitoring 
for 
any 
antibiotic-associated 
AEs
X
X
Two-week 
follow-up 
(assuming discharged)
X
One month follow-up
X
30-day baseline imaging 
(standard of care)
X
90-day follow-up
X
90-day 
imaging 
(standard of care if 
malignancy; otherwise 
only ordered if clinically 
indicated)
X
11.0 
MEASUREMENT OF EFFECT 
Clinical outcomes will be studied 90-days post operatively or until any 
complications have reached their conclusion. Standard clinic visits will occur at 2 weeks 
postoperatively (assuming the patient is discharged), 30 days postoperatively, and 90 days 
postoperatively. Assessment for complications will occur throughout index hospitalization 
and at follow-up visits. Labs and imaging will be obtained per standard of care.
12.0
DATA REPORTING / REGULATORY CONSIDERATIONS 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 
8.0 (Adverse Events: List and Reporting Requirements).
12.1
Data Reporting 
The OnCore™ Database will be utilized, as required by the Case Comprehensive Cancer 
Center, to provide data collection for both accrual entry and trial data management. 
OnCore™ is a Clinical Trials Management System housed on secure servers maintained at 
Case Western Reserve University. OnCore™. Access to data through OnCore™ is 
restricted by user accounts and assigned roles. Once logged into the OnCore™ system with 
a user ID and password, OnCore™ defines roles for each user which limits access to 
appropriate data. User information and password can be obtained by contacting the 
OnCore™ Administrator at 
.

CASE 2223
Page 28
Version date: 2/5/2024
OnCore™ is designed with the capability for study setup, activation, tracking, reporting, 
data monitoring and review, and eligibility verification. This study will utilize electronic 
Case Report Form completion in the OnCore™ database. A calendar of events and required 
forms are available in OnCore™.
12.2
Regulatory Considerations
The study will be conducted in compliance with ICH guidelines and with all applicable 
federal (including 21 CFR parts 56 & 50), state or local laws.
12.2.1 Written Informed consent
Provision of written informed consent must be obtained prior to any study-related 
procedures. The Principal Investigator will ensure that the subject is given full and 
adequate oral and written information about the nature, purpose, possible risks and benefits 
of the study as well as the subject’s financial responsibility. Subjects must also be notified 
that they are free to discontinue from the study at any time. The subject should be given 
the opportunity to ask questions and be allowed time to consider the information provided. 
The original, signed written Informed Consent Form must be kept with the Research Chart 
in conformance with the institution’s standard operating procedures. A copy of the signed 
written Informed Consent Form must be given to the subject. Additionally, documentation 
of the consenting process should be located in the research chart.
12.2.2 Subject Data Protection
In accordance with the Health Information Portability and Accountability Act (HIPAA), a 
subject must sign an authorization to release medical information to the sponsor and/or 
allow the sponsor, a regulatory authority, or Institutional Review Board access to subject’s 
medical information that includes all hospital records relevant to the study, including 
subjects’ medical history. 
12.2.3 Retention of records
The Principal Investigator of The Case Comprehensive Cancer Center supervises the 
retention of all documentation of adverse events, records of study drug receipt and 
dispensation, and all IRB correspondence for as long as needed to comply with local, 
national and international regulations. No records will be destroyed until the Principal 
Investigator confirms destruction is permitted. 
12.2.4 Audits and inspections 
Authorized representatives of the sponsor, a regulatory authority, an Independent Ethics 
Committee (IEC) or an Institutional Review Board (IRB) may visit the site to perform 
audits or inspections, including source data verification. The purpose of an audit or 
inspection is to systematically and independently examine all study-related activities and 
documents to determine whether these activities were conducted, and data were recorded, 
analysed, and accurately reported according to the protocol, Good Clinical Practice (GCP), 
guidelines of the International Conference on Harmonization (ICH), and any applicable 

CASE 2223
Page 29
Version date: 2/5/2024
regulatory requirements.  For multi-center studies, participating sites must inform the 
sponsor-investigator of pending audits. 
13.0  STATISTICAL CONSIDERATIONS 
13.1 Study design
13.1.1 This will be a randomized controlled trial testing the efficacy of extended 
antibiotic prophylaxis with piperacillin/tazobactam in decreasing the rate of CR-POPF 
following PD in patients with intermediate- and high-risk FRS (FRS >3), as compared to 
standard perioperative administration of piperacillin/tazobactam, not to exceed 24 hours.
13.1.2 Primary endpoint: the rate of clinically relevant POPF within 90 days of 
surgery, defined as Grade B or Grade C POPF based on ISGPF consensus statement.
13.1.3 Secondary endpoints: major complications (Clavien-Dindo >3)18, post-
pancreatectomy hemorrhage, delayed gastric emptying, 30- and 90-day readmission rates, 
30- and 90-day mortality rates, wound complications (superficial and deep), deep space 
infections, composite 90-day length of stay (index and any associated readmissions), rate 
of additional drain placement, unplanned return to OR, acute kidney injury, C. difficile 
colitis.
13.2 Sample size and power
13.2.1 Hypothesis: extended antibiotic prophylaxis will reduce the rate of CR-
POPF from 37% to 11%, corresponding to an odds ratio of 0.21.
13.2.2 Power: the study will have 80% power with a 2-sided alpha level of 0.05.
13.2.3 Sample size: a total of 96 patients are required to achieve 80% power with 
2-sided alpha level of 0.05 to reject the null hypothesis of 37% CR-POPF rate in patients 
who are managed with standard perioperative antibiotics. 64 patients will be randomized 
to extended antibiotic prophylaxis, and 32 patients will be randomized to standard 
perioperative antibiotics.
13.3 Statistical methodology
13.3.1 Categorical outcomes will be analyzed by Pearson’s chi-squared.
13.3.2 Continuous variables will be analyzed by the Student’s t-test (normally 
distributed) or Wilcoxon rank-sum test (non-normally distributed).
13.3.3 Statistical significance is indicated by p-value of <0.05.
13.4 Accrual rate
13.4.1 Surgical volume: the Division of Surgical Oncology at UH CMC performs 
approximately 120-130 pancreatectomies annually, with approximately 90-100 
pancreatoduodenectomies.
13.4.2 Accrual rate: we would anticipate an accrual rate of 4 patients per month 
and would expect to complete accrual by 36 months.

CASE 2223
Page 30
Version date: 2/5/2024
REFERENCES
1.
Winter JM, Cameron JL, Campbell KA, et al. 1423 Pancreaticoduodenectomies for 
Pancreatic Cancer: A Single-Institution Experience. Journal of Gastrointestinal 
Surgery. 2006;10(9):1199-1211. doi:10.1016/j.gassur.2006.08.018
2.
Birkmeyer JD, Siewers AE, Finlayson EVA, et al. Hospital Volume and Surgical 
Mortality in the United States. New England Journal of Medicine. 
2002;346(15):1128-1137. doi:10.1056/NEJMsa012337
3.
Xiang C, Chen Y, Liu X, Zheng Z, Zhang H, Tan C. Prevention and Treatment of 
Grade C Postoperative Pancreatic Fistula. J Clin Med. 2022;11(24). 
doi:10.3390/jcm11247516
4.
Ciprani D, Bannone E, Marchegiani G, Nessi C, Salvia R, Bassi C. Progression 
from biochemical leak to pancreatic fistula after distal pancreatectomy. Don’t cry 
over spilt amylase. Pancreatology. Published online 2022. 
doi:10.1016/j.pan.2022.06.257
5.
Bassi C, Marchegiani G, Dervenis C, et al. The 2016 update of the International 
Study Group (ISGPS) definition and grading of postoperative pancreatic fistula: 11 
Years After. Surgery. 2017;161(3):584-591. doi:10.1016/j.surg.2016.11.014
6.
Kang YH, Kang JS, Lee M, et al. Comparisons of short-term outcomes of 
anastomotic methods of duct-to-mucosa pancreaticojejunostomy: out-layer 
continuous suture versus modified Blumgart method. Ann Surg Treat Res. 
2022;103(6):331. doi:10.4174/astr.2022.103.6.331
7.
Halloran CM, Neoptolemos JP, Jackson R, et al. A Multicenter, Randomized, 
Double-Blinded, Clinical Trial Comparing Cattell-Warren and Blumgart 
Anastomoses Following Partial Pancreatoduodenectomy. Annals of Surgery Open. 
2022;3(3):e198. doi:10.1097/as9.0000000000000198
8.
Bootsma BT, Plat VD, van de Brug T, et al. Somatostatin analogues for the 
prevention of pancreatic fistula after open pancreatoduodenectomy: A nationwide 
analysis. Pancreatology. 2022;22(3):421-426. doi:10.1016/j.pan.2022.03.006
9.
Pillarisetty VG, Abbasi A, Park JO, Sham JG. A phase II trial of lanreotide for the 
prevention of postoperative pancreatic fistula. HPB. 2022;24(11):2029-2034. 
doi:10.1016/j.hpb.2022.07.011
10.
Russell TB, Aroori S. Procedure-specific morbidity of pancreatoduodenectomy: a 
systematic review of incidence and risk factors. ANZ J Surg. 2022;92(6):1347-
1355. doi:10.1111/ans.17473

CASE 2223
Page 31
Version date: 2/5/2024
11.
Pande R, Halle-Smith JM, Phelan L, et al. External validation of postoperative 
pancreatic fistula prediction scores in pancreatoduodenectomy: a systematic 
review and meta-analysis. HPB. 2022;24(3):287-298. 
doi:10.1016/j.hpb.2021.10.006
12.
Kamarajah SK, Bundred JR, Lin A, et al. Systematic review and meta-analysis of 
factors associated with post-operative pancreatic fistula following 
pancreatoduodenectomy. ANZ J Surg. 2021;91(5):810-821. doi:10.1111/ans.16408
13.
Zhao Z, Yin Z, Hang Z, Ji G, Feng Q, Zhao Q. A systemic review and an updated 
meta-analysis: Minimally invasive vs open pancreaticoduodenectomy. Sci Rep. 
2017;7(1). doi:10.1038/s41598-017-02488-4
14.
Dou CW, Liu ZK, Jia YL, et al. Systematic review and meta-analysis of 
prophylactic abdominal drainage after pancreatic resection. World J Gastroenterol. 
2015;21(18):5719-5734. doi:10.3748/wjg.v21.i18.5719
15.
Callery MP, Pratt WB, Kent TS, Chaikof EL, Vollmer CM. A Prospectively 
Validated Clinical Risk Score Accurately Predicts Pancreatic Fistula after 
Pancreatoduodenectomy. J Am Coll Surg. 2013;216(1):1-14. 
doi:10.1016/j.jamcollsurg.2012.09.002
16.
Shubert CR, Wagie AE, Farnell MB, et al. Clinical Risk Score to Predict 
Pancreatic Fistula after Pancreatoduodenectomy: Independent External Validation 
for Open and Laparoscopic Approaches. J Am Coll Surg. 2015;221(3):689-698. 
doi:10.1016/j.jamcollsurg.2015.05.011
17.
Shubert CR, Kendrick ML, Habermann EB, et al. Implementation of prospective, 
surgeon-driven, risk-based pathway for pancreatoduodenectomy results in 
improved clinical outcomes and first year cost savings of $1 million. Surgery. 
2018;163(3):495-502. doi:10.1016/j.surg.2017.10.022
18.
Breitenstein S, Deoliveira ML, Raptis DA, et al. Novel and simple preoperative 
score predicting complications after liver resection in noncirrhotic patients. In: 
Annals of Surgery. Vol 252. ; 2010:726-733. doi:10.1097/SLA.0b013e3181fb8c1a