Conditions: Pancreatic Cancer Pancreas Cancer Ampullary Cancer Pancreas Neuroendocrine Tumor Pancreatitis Distal Extrahepatic Cholangiocarcinoma Duodenal Cancer
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 56
Healthy volunteers: no

Brief summary:
The purpose of this study is to prospectively determine the effects of administering proton pump inhibitors (PPIs) following pancreaticoduodenectomy on postoperative outcomes. The findings of this study will help in avoiding the widespread use of PPIs during the immediate postoperative period following pancreatic surgery.

Detailed description:

Arms:
arm 1: -Visually equivalent placebo once daily from postoperative day 1 and continued for 10 doses or until the day of discharge (whichever is earlier). arm 2: -Pantoprazole once daily from postoperative day 1 and continued for 10 doses or until the day of discharge (whichever is earlier).

Interventions: intervention 1: Placebo intervention 2: Pantoprazole
Intervention descriptions: intervention 1: Placebo capsules contain pharmaceutical-grade lactose monohydrate NF, a naturally occurring disaccharide of galactose bound to glucose. intervention 2: The study will use commercial supply.

Protocol document:
Prot_SAP_000.pdf: 
Version date 09/25/23 
 
Page 1 of 33 
 
 
 
Evaluation of the Role of Proton Pump Inhibitors on the Postoperative Course Following 
Pancreaticoduodenectomy 
Washington University School of Medicine 
Department of Surgery 
660 South Euclid Avenue, Campus Box 8109 
St. Louis, MO  63110 
 
Protocol #: 202201171 
Version Date:  25 September 2023 
 
Principal Investigator: 
Natasha Leigh, M.D. 
 
 
 
 
Phone: 314-362-7147 
 
 
 
 
Email: leigh@wustl.edu 
 
 
Sub-Investigators 
 
 
  
 
Modality 
Ryan Fields, M.D., FACS 
 
  
 
Hepatobiliary Surgery 
William Hawkins, M.D., FACS 
 
 
Hepatobiliary Surgery 
Dominic Sanford, M.D., MPHS, FACS 
  
Hepatobiliary Surgery 
Adeel Khan, M.D., MPH, FACS 
 
  
Hepatobiliary Surgery 
Maria Majella Doyle, M.D., MBA, FACS 
  
Hepatobiliary Surgery 
William Chapman, M.D., FACS 
 
  
Hepatobiliary Surgery 
 
Esther Lu, Ph.D. 
 
 
  
 
Biostatistics 
 
 
 
Study Drug(s): 
 
Proton pump inhibitor  
NCT#: 
NCT05251233 
 
CONFIDENTIAL 
The information contained in this document is regarded as confidential and, except to the extent necessary to 
obtain informed consent, may not be disclosed to another party unless law or regulations require such 
disclosure.  Persons to whom the information is disclosed must be informed that the information is 
confidential and may not be further disclosed by them. 
 
 
 
 


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Evaluation of the Role of Proton Pump Inhibitors on the Postoperative Course Following 
Pancreaticoduodenectomy 
 
Protocol Revision History 
Initial Approval Version 
 
 
 
 
 
 
06 January 2022 
Amendment #1 
 
 
 
 
 
 
 
13 September 2022 
Amendment #2 
 
 
 
 
 
 
 
04 May 2023 
Amendment #2.1 
 
 
 
 
 
 
 
12 June 2023 
Amendment #2.2 
 
 
 
 
 
 
 
21 July 2023 
Amendment #3 
 
 
 
 
 
 
 
25 September 2023 
 
 


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STATEMENT OF COMPLIANCE 
The trial will be carried out in accordance with International Conference on Harmonisation Good 
Clinical Practice (ICH GCP) and the following:  
 
• United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 
CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812)  
 
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are 
responsible for the conduct, management, or oversight of NIH-funded clinical trials have 
completed Human Subjects Protection and ICH GCP Training. 
 
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the Institutional Review Board (IRB) for review and approval.  Approval of both 
the protocol and the consent form must be obtained before any participant is enrolled.  Any 
amendment to the protocol will require review and approval by the IRB before the changes are 
implemented to the study.  In addition, all changes to the consent form will be IRB-approved; a 
determination will be made regarding whether a new consent needs to be obtained from 
participants who provided consent, using a previously approved consent form. 
 
 
 


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Table of Contents 
PROTOCOL SUMMARY ........................................................................................................................ 5 
SCHEMA .................................................................................................................................................... 7 
SCHEDULE OF ASSESSMENTS .......................................................................................................... 8 
1.0 
BACKGROUND ............................................................................................................................ 9 
2.0 
OBJECTIVES ............................................................................................................................... 10 
3.0 
ELIGIBILITY CRITERIA .......................................................................................................... 11 
3.1 
Inclusion of Women and Minorities............................................................................... 11 
4.0 
REGISTRATION PROCEDURES ........................................................................................... 11 
4.1 
Confirmation of Patient Eligibility ................................................................................. 11 
4.2 
Patient Registration in the Siteman Cancer Center OnCore Database ........................... 12 
4.3 
Assignment of UPN ....................................................................................................... 12 
4.4 
Screen Failures ............................................................................................................... 12 
4.5 
Measures to Minimize Bias:  Randomization and Blinding .......................................... 12 
5.0 
STUDY PROCEDURES ............................................................................................................. 13 
5.1 
Definitions of Evaluability ............................................................................................. 13 
5.2 
Concomitant Therapy and Supportive Care Guidelines ................................................. 13 
5.3 
Duration of Follow-up .................................................................................................... 14 
6.0 
REGULATORY AND REPORTING REQUIREMENTS .................................................... 14 
6.1 
WU PI Reporting Requirements .................................................................................... 14 
7.0 
PHARMACEUTICAL INFORMATION ................................................................................. 15 
7.1 
Pantoprazole Sodium...................................................................................................... 15 
7.2 
Placebo ........................................................................................................................... 18 
8.0 
DATA SUBMISSION SCHEDULE ......................................................................................... 19 
8.1 
Adverse Event Collection in the Case Report Forms ..................................................... 19 
9.0 
DATA AND SAFETY MONITORING ................................................................................... 19 
10.0 STATISTICAL CONSIDERATIONS ...................................................................................... 20 
10.1 Statistical Hypotheses .................................................................................................... 21 
10.2 Sample Size Determination ............................................................................................ 21 
10.3 Randomization ............................................................................................................... 21 
10.4 Population for Analyses ................................................................................................. 22 
10.5 Statistical Analyses ........................................................................................................ 22 
11.0 REFERENCES ............................................................................................................................. 24 
APPENDIX A: Definitions for Adverse Event Reporting ................................................................. 26 
APPENDIX B: Reporting Timelines ..................................................................................................... 28 
APPENDIX C: ISGPS Criteria for Delayed Gastric Emptying ......................................................... 30 
APPENDIX D: Modified Accordion Grading System ........................................................................ 31 
APPENDIX F: Study-Specific DSM Tables ........................................................................................ 33 
 
 


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PROTOCOL SUMMARY 
 
Title: 
Evaluation of the Role of Proton Pump Inhibitors on the 
Postoperative Course Following Pancreaticoduodenectomy 
Study Description: 
This is a randomized placebo-controlled study of patients who will 
undergo pancreaticoduodenectomy at Washington University in St. 
Louis/Barnes-Jewish Hospital. The study aims to determine the 
impact of administration of Proton Pump Inhibitors (PPIs) on the 
postoperative course in these patients.  Postoperative administration 
of PPI and no intervention are both considered standard of care 
approaches. 
Objectives: 
Primary Objective: 
Determine the effect of PPIs on the incidence of delayed gastric 
emptying within 90 days in patients after pancreaticoduodenectomy. 
 
Secondary Objectives: 
• Determine the effect of PPIs on the incidence of overall 
postoperative 
complications 
in 
the 
patients 
after 
pancreaticoduodenectomy. 
• Determine the marginal ulcer-free survival (MUFS) within 
90 days after surgery in the patients undergoing 
pancreaticoduodenectomy. 
Endpoints: 
Primary Endpoint:  
Incidence of delayed gastric emptying using the ISGPS criteria and 
MAGS grading. 
 
Secondary Endpoints:  
• Incidence of surgical complication defined by the Modified 
Accordion Grading System.  
• MUFS.  
Study Population: 
Two hundred forty patients who will undergo standard of care 
pancreaticoduodenectomy and receive at least one dose of study 
treatment (PPI/placebo) at Washington University/Barnes-Jewish 
Hospital 
Phase: 
II 
Description of Sites / 
Facilities Enrolling: 
This study will take place at Washington University School of 
Medicine and associated hospitals/clinics. 
Description 
of 
Study 
Intervention: 
Immediately post-op, patients will be randomly assigned to one of 
the two standard of care approaches (“PPI” or “placebo”) on a 1:1 
basis in a blinded fashion. Patients will be initiated on pantoprazole 
or a visually equivalent placebo once daily from Postoperative Day 
1 and continued for 10 doses or until the day of discharge (whichever 
is earlier). 
Study Duration: 
39 months 
Participant Duration: 
90 days  
 
 
 
 
 


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SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomize 
Placebo 
Proton pump inhibitor 
Patient scheduled for 
pancreaticoduodenectomy 
Surgery 
Consent 


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SCHEDULE OF ASSESSMENTS 
 
Measure 
Baseline2 
Pre-op Visit3 Day of Surgery Post-op Visit4 
90 Days 
Post-Op 
Confirmation of surgical 
plan 
X 
 
 
 
 
Patient consent 
 
X5 
 
 
Medical history 
 
X 
 
 
 
Randomization 
 
 
X6 
 
 
Demographics captured 
from EMR1 
 
X 
 
 
 
Drug/placebo 
administration 
 
 
X7 
 
 
Notes from surgery related 
hospitalization captured 
from EMR 
 
 
 
X 
 
Information on surgical 
complications captured 
from EMR/HPB Whipple 
Database 
 
 
 
 
X 
Adverse event assessment 
 
Continuous through 30 days after last day of 
PPI/placebo 
X8 
1. Patient characteristics will include gender, age, weight, BMI, surgery indication, staging, etc. 
2. ≤ 30 days prior to surgery 
3. ≤ 30 days prior to surgery at routine pre-surgery clinic visit 
4. 2 (±1) weeks after surgery at routine post-surgery clinic visit 
5. Consent may occur at the pre-op visit or on the day of surgery 
6. Randomization will occur immediately post-op only for patients who successfully undergo pancreaticoduodenectomy 
7. PPI/placebo will be given taken once daily for 10 days or until day of discharge (whichever is earlier) 
8. Follow through 90 days for post op surgical complications 
 
 


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1.0 
BACKGROUND 
 
Proton Pump Inhibitors (PPIs) are widely recommended for common upper gastrointestinal acid-
related disorders such as gastroesophageal reflux disease, peptic ulcer disease, Helicobacter 
Pylori Infection, and functional dyspepsia (1, 2). They are also frequently used in critically ill 
patients to avoid the development of stress ulcers and related upper gastrointestinal bleeding (3, 
4). Studies estimate that between 53% and 69% of all PPI prescriptions are for inappropriate 
indications such as nonspecific abdominal symptoms without acid-related features; co-prescription 
with aspirin, NSAIDs, or corticosteroids in asymptomatic patients; and repeat prescription for a 
prior problem that has already resolved (5-7).  
 
Moreover, PPIs are frequently initiated in the inpatient setting in non-ICU patients who are at very 
low risk of developing stress ulcers. In many cases, they are continued beyond discharge in primary 
care (8, 9). However, their strong efficacy has resulted in their overutilization in both outpatient 
and inpatient care, which can cause serious adverse events, including cardiovascular disease, 
pneumonia, osteoporotic fractures, acute kidney injury, chronic kidney disease, and dementia (4, 
10-13). PPIs are also associated with an excess of mortality from cardiovascular disease and 
chronic kidney disease.  These adverse effects highlight the need for judicious use of PPIs, which 
can be achieved by avoiding prescription of these agents for undocumented and unsubstantiated 
diagnoses, discouraging prolonged therapy, and adhering to step-down therapy per guidelines (14-
17). In addition, PPI use in the inpatient setting should be limited to documented upper 
gastrointestinal tract indications and stress ulcer prophylaxis in the ICU population, and these 
medications should be discontinued before discharge unless indicated (17).  
 
According to a meta-analysis performed by Butler et al., PPIs are frequently used in patients 
undergoing pancreaticoduodenectomy, with 86% of surgeons prescribing them after pancreatic 
resection. Forty-six percent of surgeons continue their patients on these medications for life, while 
25% give the prescriptions for 30 days postoperatively (18). The main indication for their use is to 
reduce the occurrence of postoperative marginal ulcers, a morbid complication of 
pancreaticoduodenectomy with a reported average incidence of 2.0% after pylorus-preserving 
pancreaticoduodenectomy and 2.6% after classic pancreaticoduodenectomy (18). However, the 
onset of marginal ulcers is often delayed, with the median time for development of marginal 
ulceration after pancreaticoduodenectomy being 15.5 months (18, 19).  
 
PPIs have been effective in decreasing the incidence of postoperative marginal ulcers. The 
development of marginal ulcers is driven by two mechanisms: 
1. Local inflammation, ischemic changes at the anastomotic site, foreign bodies (sutures, 
staples), which is the primary mechanism in the immediate postoperative period, and  
2. The direct effect of gastric acid on jejunal mucosa which is the primary mechanism in later 
periods (19).  
 
Increased gastric acid production, low gastric pH, and prolonged duration of low pH are associated 
with marginal ulcers (20). However, the recommendations regarding the timing and duration of 
their use after pancreaticoduodenectomy remain unclear and need to be defined.  
 
In our recently completed retrospective chart review (IRB ID: 201711053), we evaluated the 


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impact of gastric acid inhibitors (PPIs and H2Receptor antagonists) on postoperative outcomes 
following pancreatic resection i.e., pancreaticoduodenectomy, distal pancreatectomy, and 
completion pancreatectomy. H2Receptor antagonists are associated with postoperative delirium 
and, therefore, are not frequently used (21). In our study cohort, 66.5% of patients were 
administered gastric acid inhibitors postoperatively, with the majority of these patients (76.4%) 
receiving PPIs. Comparative analysis of postoperative complications in patients who received acid 
suppression and those who did not showed a significantly higher incidence of all complications 
(73.8 % vs 56.4%) (p=0.003), delayed gastric emptying (20.9% vs 6.4%) (p=0.002), postoperative 
hemorrhage (23% vs 8.5%) (p=0.003), failure to thrive (4.3% vs 0%) (p=0.042), and all infectious 
complications (23.5% vs 11.7%) (p=0.018) in the acid suppression group. Multivariate logistic 
regression analysis demonstrated a significant association between the use of gastric acid inhibitors 
and the incidence of all postoperative complications (Odds Ratio=2.176), including delayed gastric 
emptying (Odds Ratio=3.7148) in the patients undergoing pancreatic resection. Our analysis also 
showed a significant association between the use of these agents and postoperative complications 
(Odds Ratio=2.469) and delayed gastric emptying (Odds Ratio=2.355) in patients that underwent 
pancreaticoduodenectomy.  
 
Our results highlight the need for promoting pharmacovigilance when it comes to prescribing 
gastric acid inhibitors after pancreatectomies. Utilizing PPIs in the immediate postoperative period 
as prophylaxis against marginal ulcers that generally occur months after surgery at the cost of an 
increase in postoperative complications such as delayed gastric emptying is not in the patient’s 
best interest, and therefore, should be avoided. The purpose of this study is to prospectively 
determine the effects of administering PPIs following pancreaticoduodenectomy on postoperative 
outcomes. The findings of this study will help in avoiding the widespread use of PPIs during the 
immediate postoperative period following pancreatic surgery.  
 
 
2.0 
OBJECTIVES 
 
This 
is 
a 
randomized 
placebo-controlled 
study 
of 
patients 
who 
will 
undergo 
pancreaticoduodenectomy at Washington University in St. Louis/Barnes-Jewish Hospital. The 
study aims to determine the impact of administration of PPIs on the postoperative course in these 
patients. 
 
Objectives 
Endpoints 
Justification for 
Endpoints 
Primary 
Determine the effect of PPIs on 
the incidence of delayed gastric 
emptying within 90 days in 
patients after 
pancreaticoduodenectomy. 
Incidence of delayed gastric 
emptying using the ISGPS 
criteria and MAGS grading. 
International criteria for 
diagnosis and grading of 
the delayed gastric 
emptying. Incidence in 
the two groups will 
indicate the effect of PPI. 


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Secondary 
• Determine the effect of PPIs 
on the incidence of overall 
postoperative complications in 
the patients after 
pancreaticoduodenectomy. 
• Determine the marginal ulcer-
free survival (MUFS) within 
90 days in the patients 
undergoing 
pancreaticoduodenectomy.  
 
• Incidence of surgical 
complication defined by 
MAGS Grading Criteria 
• MUFS 
Complications graded by 
MAGS. Grade 1-6 will be 
tabulated across the two 
groups to evaluate any 
differences from PPI use. 
 
Treatment/Diagnosis of 
marginal ulcers.  
 
 
3.0 
ELIGIBILITY CRITERIA 
 
1. All consecutive patients who will undergo pancreaticoduodenectomy with gastric/biliary 
reconstruction performed as definitive management for a benign or malignant disease at 
Washington University/Barnes-Jewish Hospital. 
 
2. At least 18 years of age. 
 
3. Ability to understand and willingness to sign an IRB approved written informed consent 
document. 
 
3.1 
Inclusion of Women and Minorities 
 
Both men and women and members of all races and ethnic groups are eligible for this 
trial.   
 
 
4.0 
REGISTRATION PROCEDURES 
 
Patients must not start any protocol intervention prior to registration through the Siteman 
Cancer Center. 
 
The following steps must be taken before registering patients to this study: 
 
1. Confirmation of patient eligibility  
2. Registration of patient in the Siteman Cancer Center database 
3. Assignment of unique patient number (UPN) 
 
4.1 
Confirmation of Patient Eligibility 
 
Confirm patient eligibility by collecting the information listed below 
1. The registering MD’s name 


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2. Patient’s race, sex, and DOB 
3. Three letters (or two letters and a dash) for the patient’s initials 
4. Copy of signed consent form  
5. Completed eligibility checklist, signed and dated by a member of the study team 
6. Copy of appropriate source documentation confirming patient eligibility 
 
4.2 
Patient Registration in the Siteman Cancer Center OnCore Database 
 
All patients must be registered through the Siteman Cancer Center OnCore database. 
 
4.3 
Assignment of UPN 
 
Each patient will be identified with a unique patient number (UPN) for this study.  All data 
will be recorded with this identification number on the appropriate CRFs. 
 
4.4 
Screen Failures 
 
Screen failures are defined as participants who consent to participate in the clinical trial 
but are not subsequently randomized to the study intervention or entered in the study.  A 
minimal set of screen failure information is required to ensure transparent reporting of 
screen failure participants, to meet the Consolidated Standards of Reporting Trials 
(CONSORT) publishing requirements and to respond to queries from regulatory 
authorities.  Minimal information includes demography, screen failure details, eligibility 
criteria, and any serious adverse event (if applicable).   
 
4.5 
Measures to Minimize Bias:  Randomization and Blinding 
 
Randomization will occur in the research pharmacy using a computer-generated 
randomization sequence. Consenting patients will be randomly assigned to receive 
pantoprazole or an identical appearing placebo in a 1:1 ratio. Medications will be prepared 
by the pharmacy and delivered to the treating nurse.  The research team and the study 
participants will be blinded to treatment assignment. 
 
Post-operative oral doses will be dispensed in identical capsules; active capsules will 
contain an over-encapsulated pantoprazole 40 mg delayed-release tablet with lactose 
monohydrate backfill and placebo capsules will contain lactose monohydrate to give equal 
weight and feel. 
 
The research pharmacy will maintain documentation of medication procurement and 
preparation, as well as randomization, dispensing, and accountability logs. All medications 
and blinding supplies will be stored in a secure location within the research pharmacy and 
maintained under controlled environmental conditions. 
 
 


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5.0 
STUDY PROCEDURES 
 
We have set our criteria to review any pancreaticoduodenectomies with gastric/biliary 
reconstruction performed as definitive management for a benign or malignant disease in the 
Department of Surgery at Washington University/ Barnes Jewish Hospital.  
 
Written consent will be obtained from the patients at their preoperative visit or at time of admission 
to BJH for pancreaticoduodenectomy.  Patients may have their surgery postponed for up to 6 
months and will be given the option to continue participation in the study.  Subjects that decide to 
continue to participate will continue to be eligible for participation. 
 
Immediately post-op, the patients will be randomly assigned to the “PPI” or “placebo” groups in 
a 1:1 ratio as described in Section 4.5. The patients will be initiated on pantoprazole or a visually 
equivalent placebo once daily from Postoperative Day 1 and continued for 10 doses or until the 
day of discharge (whichever is earlier).  Other postoperative management will be performed as per 
institutional standard of care. 
 
Any patient who appears to require administration of a PPI secondary to a postoperative indication, 
i.e. stress ulcer prophylaxis in ICU, gastrointestinal bleeding, will discontinue trial treatment and 
initiated on the indicated PPI.  These participants will not be unblinded, nor will they be replaced. 
 
The patients will be followed as per standard of care to record incidence of any postoperative 
complications, including marginal ulcers.  There are no follow-up visits mandated by participation 
in this protocol. Patients’ medical records will be reviewed to collect information about 
complications for 90 days post-op. The division’s Whipple database  will also be used to collect 
information regarding post-operative complications. 
 
5.1 
Definitions of Evaluability and Patient Replacement 
 
Endpoint 
In order to be evaluable for this endpoint, 
a patient must have… 
Primary: Incidence of delayed gastric 
emptying using the ISGPS criteria and 
MAGS grading 
Received at least one dose of study 
treatment (PPI/placebo) 
Secondary: 
Incidence 
of 
surgical 
complication defined by MAGS grading 
criteria 
Secondary: Marginal ulcer-free survival 
 
Note: Patients who do not receive at least one dose of study treatment (PPI/placebo) are 
inevaluable for the primary endpoint and will be replaced.  Patients who receive a PPI 
secondary to a postoperative indication will not be replaced. 
 
5.2 
Concomitant Therapy and Supportive Care Guidelines 
 
Use of any investigational agent or device within 30 days before the first dose of study 


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drug and until last dose of study drug.  
 
All other concomitant medications that are necessary for the health and well-being of the 
patient that are not specifically prohibited by the protocol are permitted. 
 
5.3 
Duration of Follow-up 
 
Patients will be passively followed by review of the medical record for 90 days after 
surgery or until death, whichever occurs first.  
 
 
6.0 
REGULATORY AND REPORTING REQUIREMENTS 
 
The entities providing oversight of safety and compliance with the protocol require reporting as 
outlined below.  Please refer to Appendix A for definitions and Appendix B for a grid of reporting 
timelines. 
 
Adverse events will be tracked from start of treatment through 30 days after discontinuation of 
PPI/placebo.  Adverse events that have been associated with PPI inhibitors include the following:  
allergic reaction; blurred vision; dry mouth; flushed, dry skin; fruit-like breath odor; increased 
hunger; increased thirst; increased urination; nausea; and stomach pain, sweating, trouble 
breathing, unexplained weight loss, vomiting  All adverse events must be recorded on the toxicity 
tracking case report form (CRF) with the exception of: 
• Baseline adverse events, which shall be recorded on the medical history CRF 
• Adverse events that are considered surgical complications and are unrelated to treatment 
with PPI/placebo (followed for 90 days post op); these will be recorded on the Post-
Operative Complications CRF and are not considered reportable per protocol but are 
collected for evaluation of the study endpoints 
 
Refer to the data submission schedule in Section 8 for instructions on the collection of AEs in the 
EDC. 
 
6.1 
WU PI Reporting Requirements 
 
6.1.1 Reporting to the Human Research Protection Office (HRPO) at 
Washington University 
 
Reporting will be conducted in accordance with Washington University IRB 
Policies. 
 
Pre-approval of all protocol exceptions must be obtained prior to implementing the 
change. 
 
6.1.2 Reporting to the Quality Assurance and Safety Monitoring 
Committee (QASMC) at Washington University 
 


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The PI (or designee) is required to notify the QASMC of any unanticipated 
problems involving risks to participants or others occurring at WU or any BJH or 
SLCH institution that has been reported to and acknowledged by HRPO.  
(Unanticipated problems reported to HRPO and withdrawn during the review 
process need not be reported to QASMC.) 
 
QASMC must be notified within 10 days of receipt of IRB acknowledgment via 
email to qasmc@wustl.edu.  Submission to QASMC must include the myIRB form 
and any supporting documentation sent with the form. 
 
 
7.0 
PHARMACEUTICAL INFORMATION 
 
7.1 
Pantoprazole Sodium  
 
7.1.1 Description 
 
Pantoprazole is a proton pump inhibitor (PPI) indicated for the following: 
 
• Short-Term Treatment of Erosive Esophagitis Associated with 
Gastroesophageal Reflux Disease (GERD) 
• Maintenance of Healing of Erosive Esophagitis 
• Pathological Hypersecretory Conditions Including Zollinger-Ellison (ZE) 
Syndrome 
 
7.1.2 Clinical Pharmacology 
 
Mechanism of Action 
Pantoprazole is a PPI that suppresses the final step in gastric acid production by 
covalently binding to the (H, K)-ATPase enzyme system at the secretory surface of 
the gastric parietal cell. This effect leads to inhibition of both basal and stimulated 
gastric acid secretion, irrespective of the stimulus. The binding to the (H, K)-
ATPase results in a duration of antisecretory effect that persists longer than 24 
hours for all doses tested (20 mg to 120 mg). 
 
Pharmacodynamics 
Antisecretory Activity 
Under maximal acid stimulatory conditions using pentagastrin, a dose-dependent 
decrease in gastric acid output occurs after a single dose of oral (20-80 mg) 
pantoprazole in healthy subjects. Pantoprazole given once daily results in 
increasing inhibition of gastric acid secretion. Following the initial oral dose of 40 
mg pantoprazole, a 51% mean inhibition was achieved by 2.5 hours. With once-a-
day dosing for 7 days, the mean inhibition was increased to 85%. Pantoprazole 
suppressed acid secretion in excess of 95% in half of the subjects. Acid secretion 
had returned to normal within a week after the last dose of pantoprazole; there was 
no evidence of rebound hypersecretion. 


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In a series of dose-response studies, pantoprazole, at oral doses ranging from 20 to 
120 mg, caused dose-related increases in median basal gastric pH and in the percent 
of time gastric pH was > 3 and > 4. Treatment with 40 mg of pantoprazole produced 
significantly greater increases in gastric pH than the 20 mg dose. Doses higher than 
40 mg (60, 80, 120 mg) did not result in further significant increases in median 
gastric pH.  
 
Serum Gastrin Effects 
Fasting serum gastrin levels were assessed in two double-blind studies of the acute 
healing of EE in which 682 patients with gastroesophageal reflux disease (GERD) 
received 10, 20, or 40 mg of Pantoprazole for up to 8 weeks. At 4 weeks of 
treatment there was an increase in mean gastrin levels of 7%, 35%, and 72% over 
pretreatment values in the 10, 20, and 40 mg treatment groups, respectively. A 
similar increase in serum gastrin levels was noted at the 8-week visit with mean 
increases of 3%, 26%, and 84% for the three pantoprazole dose groups. Median 
serum gastrin levels remained within normal limits during maintenance therapy 
with Pantoprazole Sodium Delayed-Release Tablets. 
 
In long-term international studies involving over 800 patients, a 2- to 3-fold mean 
increase from the pretreatment fasting serum gastrin level was observed in the 
initial months of treatment with pantoprazole at doses of 40 mg per day during 
GERD maintenance studies and 40 mg or higher per day in patients with refractory 
GERD. Fasting serum gastrin levels generally remained at approximately 2 to 3 
times baseline for up to 4 years of periodic follow-up in clinical trials. Following 
short-term treatment with Pantoprazole, elevated gastrin levels return to normal by 
at least 3 months. 
 
Enterochromaffin-Like (ECL) Cell Effects 
In 39 patients treated with oral pantoprazole 40 mg to 240 mg daily (majority 
receiving 40 mg to 80 mg) for up to 5 years, there was a moderate increase in ECL-
cell density, starting after the first year of use, which appeared to plateau after 4 
years. In a nonclinical study in Sprague-Dawley rats, lifetime exposure (24 months) 
to pantoprazole at doses of 0.5 to 200 mg/kg/day resulted in dose-related increases 
in gastric ECL cell proliferation and gastric neuroendocrine (NE)-cell tumors. 
Gastric NE-cell tumors in rats may result from chronic elevation of serum gastrin 
concentrations. The high density of ECL cells in the rat stomach makes this species 
highly susceptible to the proliferative effects of elevated gastrin concentrations 
produced by PPIs. However, there were no observed elevations in serum gastrin 
following the administration of pantoprazole at a dose of 0.5 mg/kg/day. In a 
separate study, a gastric NE-cell tumor without concomitant ECL-cell proliferative 
changes was observed in 1 female rat following 12 months of dosing with 
pantoprazole at 5 mg/kg/day and a 9 month off-dose recovery. 
 
Endocrine Effects 


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In a clinical pharmacology study, Pantoprazole 40 mg given once daily for 2 weeks 
had no effect on the levels of the following hormones: cortisol, testosterone, 
triiodothyronine (T), thyroxine (T), thyroid-stimulating hormone (TSH), thyronine-
binding protein, parathyroid hormone, insulin, glucagon, renin, aldosterone, 
follicle-stimulating hormone, luteinizing hormone, prolactin, and growth hormone. 
In a 1-year study of GERD patients treated with Pantoprazole 40 mg or 20 mg, there 
were no changes from baseline in overall levels of T, T, and TSH. 
 
7.1.3 Pharmacokinetics and Drug Metabolism 
 
Pantoprazole Sodium Delayed-Release Tablets are prepared as enteric-coated 
tablets so that absorption of pantoprazole begins only after the tablet leaves the 
stomach. Peak serum concentration (C) and area under the serum concentration 
time curve (AUC) increase in a manner proportional to oral doses from 10 mg to 
80 mg. Pantoprazole does not accumulate, and its pharmacokinetics are unaltered 
with multiple daily dosing. Following oral administration, the serum concentration 
of pantoprazole declines biexponentially, with a terminal elimination half-life of 
approximately one hour. 
 
In extensive metabolizers with normal liver function receiving an oral dose of the 
enteric-coated 40 mg pantoprazole tablet, the peak concentration (C) is 2.5 
mcg/mL; the time to reach the peak concentration (t ) is 2.5 h, and the mean total 
area under the plasma concentration versus time curve (AUC) is 4.8 mcg·h/mL 
(range 1.4 to 13.3 mcg·h/mL). 
 
Absorption 
After administration of a single or multiple oral 40 mg doses of Pantoprazole 
Sodium Delayed-Release Tablets, the peak plasma concentration of pantoprazole 
was achieved in approximately 2.5 hours, and C was 2.5 mcg/mL. Pantoprazole 
undergoes little first-pass metabolism, resulting in an absolute bioavailability of 
approximately 77%. Pantoprazole absorption is not affected by concomitant 
administration of antacids. 
 
Administration of Pantoprazole Sodium Delayed-Release Tablets with food may 
delay its absorption up to 2 hours or longer; however, the C and the extent of 
pantoprazole absorption (AUC) are not altered. Thus, Pantoprazole Sodium 
Delayed-Release Tablets may be taken without regard to timing of meals. 
 
Distribution 
The apparent volume of distribution of pantoprazole is approximately 11 to 23.6 L, 
distributing mainly in extracellular fluid. The serum protein binding of 
pantoprazole is about 98%, primarily to albumin. 
 
Elimination 
Metabolism 


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Pantoprazole is extensively metabolized in the liver through the cytochrome P450 
(CYP) system. Pantoprazole metabolism is independent of the route of 
administration (oral). The main metabolic pathway is demethylation, by CYP2C19, 
with subsequent sulfation; other metabolic pathways include oxidation by 
CYP3A4. There is no evidence that any of the pantoprazole metabolites have 
significant pharmacologic activity. 
 
Excretion 
After a single oral dose of C-labeled pantoprazole to healthy, normal metabolizer 
subjects, approximately 71% of the dose was excreted in the urine, with 18% 
excreted in the feces through biliary excretion. There was no renal excretion of 
unchanged pantoprazole. 
 
Specific Populations 
Geriatric Patients 
Only slight to moderate increases in the AUC (43%) and C (26%) of pantoprazole 
were found in elderly subjects (64 to 76 years of age) after repeated oral 
administration, compared with younger subjects. 
 
7.1.4 Supplier 
 
The study will use commercial supply. 
 
7.1.5 Dosage Form and Preparation 
 
Pantoprazole Sodium Delayed-Release Tablets, USP are supplied as 40 mg white 
to off-white, oval-shaped, coated tablet, debossed with “17” on one side and are 
available as follows: Unit dose packages of 80 (8 x 10) NDC 68084-813-09. 
 
7.1.6 Storage and Stability 
 
Store Pantoprazole Sodium Delayed-Release Tablets, USP at 20° to 25°C (68° to 
77°F); excursions permitted to 15° to 30°C (59° to 86°F). 
 
7.1.7 Administration 
 
Pantoprazole will be given at a dose of 40 mg once daily for up to 10 days (POD 1 
through POD 10), or until discharge, whichever is earlier. 
 
7.2 
Placebo 
 
Placebo capsules contain pharmaceutical-grade lactose monohydrate NF, a naturally 
occurring disaccharide of galactose bound to glucose. Lactose monohydrate is a free-
flowing, dry powder that is water soluble, inert, nontoxic, and chemically stable. 
 
 


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8.0 
DATA SUBMISSION SCHEDULE 
 
Case report forms with appropriate source documentation will be completed according to the 
schedule listed in this section. 
Case Report Form 
Submission Schedule 
Original Consent Form 
Prior to registration 
On-Study Form 
Medical History Form 
Prior to starting treatment 
Surgery Form 
Randomization Form 
Time of surgery 
Treatment Form 
End of treatment 
Post-Operative Form 
Day 30 Post-Op 
Post-Operative Complication Form 
Day 14 Post-Op 
Day 30 Post-Op 
Day 90 Post-Op 
90-Day Follow-Up Form 
Day 90 Post-Op 
Adverse Event Form 
End of treatment 
Day 14 Post-Op 
Day 30 Post-Op 
Day 90 Post-Op 
Toxicity Form 
Start of treatment through 30 days after 
discontinuation of PPI/placebo 
 
8.1 
Adverse Event Collection in the Case Report Forms 
 
All adverse events that occur beginning with start of treatment (minus exceptions defined 
in Section 6.0) must be captured in the Post-Operative Complication Form.  Baseline AEs 
should be captured on the Medical History Form. 
 
9.0 
DATA AND SAFETY MONITORING 
 
In compliance with the Washington University Institutional Data and Safety Monitoring Plan, an 
independent Data and Safety Monitoring Board (DSMB) will be specifically convened for this 
trial to review toxicity data.  A DSMB will consist of no fewer than 3 members including 2 clinical 
investigators and a biostatistician.  DSMB members must be employed by Washington University, 
Barnes-Jewish Hospital, or St. Louis Children’s Hospital.  Like investigators, DSMB members are 
subject to the Washington University School of Medicine policies regarding standards of conduct. 
Individuals invited to serve on the DSMB will disclose any potential conflicts of interest to the 
trial principal investigator and/or appropriate university officials, in accordance with institution 
policies. Potential conflicts that develop during a trial or a member’s tenure on a DSMB must also 
be disclosed. 
 
The DSM report for the DSMB will be prepared by the study team with assistance from the study 
statistician, will be reviewed by the DSMB, and will be submitted to the Washington University 


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Quality Assurance and Safety Monitoring Committee (QASMC).  The DSMB must meet at least 
every six months beginning six months after accrual has opened (if at least one patient has been 
enrolled), no more than one month prior to the due date of the DSM report to QASMC. This report 
will include: 
• HRPO protocol number, protocol title, Principal Investigator name, data coordinator 
name, regulatory coordinator name, and statistician 
• Date of initial HRPO approval, date of most recent consent HRPO approval/revision, 
date of HRPO expiration, date of most recent QA audit, study status, and phase of study 
• History of study including summary of substantive amendments; summary of accrual 
suspensions including start/stop dates and reason; and summary of protocol exceptions, 
error, or breach of confidentiality including start/stop dates and reason 
• Study-wide target accrual and study-wide actual accrual 
• Protocol activation date 
• Average rate of accrual observed in year 1, year 2, and subsequent years 
• Expected accrual end date and accrual by cohort 
• Objectives of protocol with supporting data and list the number of participants who 
have met each objective 
• Measures of efficacy  
• Early stopping rules with supporting data and list the number of participants who have 
met the early stopping rules 
• Summary of toxicities separated by cohorts 
• Abstract submissions/publications 
• Summary of any recent literature that may affect the safety or ethics of the study  
 
Further DSMB responsibilities are described in the DSMB charter. 
 
The study principal investigator and coordinator will monitor for serious toxicities on an ongoing 
basis. Once the principal investigator or Research Patient Coordinator becomes aware of an 
adverse event, the AE will be reported to the HRPO and QASMC according to institutional 
guidelines. 
 
Refer to the Washington University Quality Assurance and Data Safety Monitoring Committee 
Policies and Procedures for full details on the responsibilities of the DSMB. This is located on the 
QASMC website at https://siteman.wustl.edu/research/clinical-research-resources/protocol-
office-prmcqasmc/.   
 
 
10.0 
STATISTICAL CONSIDERATIONS 
 
This 
is 
a 
randomized 
placebo-controlled 
study. 
Patients 
who 
will 
undergo 
pancreaticoduodenectomy at Washington University in St. Louis/Barnes-Jewish Hospital will be 
randomized on a 1:1 basis to receive either PPI or placebo. 
 


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10.1 
Statistical Hypotheses 
 
10.1.1 Primary Objective and Endpoint 
 
The primary objective is to determine the effect of PPIs on the incidence of delayed 
gastric emptying within 90 days in patients after pancreaticoduodenectomy. The 
primary endpoint is the incidence of post-operative delayed gastric emptying using 
the ISGPS criteria and MAGS grading. 
 
10.1.2 Secondary Objectives and Endpoints 
 
1. Determine the effect of PPIs on the incidence of overall postoperative 
complications in the patients after pancreaticoduodenectomy. 
2. Determine the marginal ulcer free survival (MUFS) within 90 days after surgery 
in the patients undergoing pancreaticoduodenectomy. 
 
Secondary endpoints include: the incidence of surgical complication defined by the 
modified accordion grading system and MUFS. 
 
10.2 
Sample Size Determination 
 
For primary endpoint, our preliminary study showed that the rates of delayed gastric 
emptying in the control the PPI groups are 7% and 21%, respectively. 110 patients per 
group achieve 80.4% power to detect a 14% difference between two groups using the two-
sided Fisher's Exact test at the significance level of 5%. 
 
For the endpoint of surgical complication, our preliminary study showed that the rates in 
the control the PPI groups are 56% and 74%, respectively. 120 patients per group achieve 
80.0% power to detect a 18% difference between two groups using the two-sided Fisher's 
Exact test at the significance level of 5%. 
 
The preliminary data show approximate 27% of randomized patients did not receive at 
least one dose of study treatment (PPI/placebo) and were replaced. We will randomize 330 
patients in order to obtain 80% power for these two endpoints and account for possible 
27% drop-out. We estimate that 12 patients per month would be eligible for the trial and 
the enrollment could be complete within 36 months. 
 
10.3 
Randomization 
 
Three hundred thirty patients will be randomized on a 1:1 basis to receive either PPI or 
placebo. A computer-generated randomization scheme with a various block size will be 
used to assign patients. It is maintained centrally by the study statistician. Randomization 
will take place after surgery in REDCap. 
 


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10.4 
Population for Analyses 
 
10.4.1 Efficacy Analyses Set 
 
The Intent-to-Treat (ITT) population will consist of all randomized patients. 
 
10.4.2 Safety Analyses Set 
 
The safety analysis set will consist of all patients who receive the assigned 
treatment. 
 
10.5 
Statistical Analyses 
 
10.5.1 General Approach 
 
Descriptive statistics will be calculated on all variables by treatment group. 
Frequencies will be computed for all binary/categorical variables, and continuous 
variables will be summarized using medians, quartiles, and ranges. Data from 
schedules may be pooled. Exploratory and post hoc analyses may be conducted at 
the discretion of the PI.  
 
10.5.2 Analysis of the Primary Endpoint 
 
The primary outcome is the incidence of post-operative delayed gastric emptying 
using the ISGPS criteria and MAGS grading, coded as yes and no. The rate per 
group, odds ratio (OR) and the associated 95% confidence intervals (CIs) will be 
calculated assuming a binomial distribution. The logistic regression model will 
considered to investigate the effect of PPIs accounting for the interested variables 
on the incidence of post-operative delayed gastric emptying. The interested 
variables include age, gender, body mass index, comorbidities, preoperative proton 
pump inhibitor usage, and surgical reconstruction method. The relationships 
between these variables and the endpoint may exist. 
 
10.5.3 Analysis of Secondary Endpoint(s) 
 
Secondary endpoints include the incidence of surgical complication and marginal 
ulcer free survival. Surgical complication is defined by the Modified Accordion 
Grading System, coded as yes and no. The similar statistical approach to the 
primary endpoint will be employed. Any clinical diagnosis is used to define a 
marginal ulcer within 90 days after surgery. MUFS is defined as the days from the 
date of randomization to diagnosis of a marginal ulcer. The patients without 
marginal ulcer are censored at the date of last follow-up. The Kaplan-Meier method 
will be used to calculate the probability of marginal ulcer free survival at specific 
time points, e.g. 30 days, 90 days after surgery. The 95% CIs will be also provided. 
Differences between groups will be determined by log-rank tests.  Cox 


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proportional-hazards models will be used to evaluate the effect of PPIs accounting 
for the other interested variables.  
 
10.5.4 Planned Interim Analysis 
 
Not applicable. 
 
10.5.5 Sub-Group Analyses 
 
Not applicable. 
 
10.5.6 Tabulation of Individual Participant Data 
 
Individual patient data will be listed by group.  
 
A tabulation of patient disposition, including the number screened, the number 
enrolled in each schedule, the number in each patient population for analysis, the 
number of protocol deviations, the number that discontinued treatment and reasons 
for treatment discontinuation, and the number that withdrew from study and reasons 
for withdrawal will be presented.  
 
 
 
 


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11.0 
REFERENCES 
 
1. 
Sanaka M, Yamamoto T, Kuyama Y. Effects of proton pump inhibitors on gastric 
emptying: a systematic review. Dig Dis Sci. 2010;55(9):2431-40. 
2. 
de Jongh E, Numans ME, de Wit NJ, Heemstra-Borst CG, Geijer RM, Burgers JS. 
[Summary of the Dutch College of General Practitioners' (NHG) practice guideline 'Gastric 
symptoms']. Ned Tijdschr Geneeskd. 2013;157(22):A6101. 
3. 
Shin S. Evaluation of costs accrued through inadvertent continuation of hospital-initiated 
proton pump inhibitor therapy for stress ulcer prophylaxis beyond hospital discharge: a 
retrospective chart review. Ther Clin Risk Manag. 2015;11:649-57. 
4. 
Heidelbaugh JJ, Kim AH, Chang R, Walker PC. Overutilization of proton-pump inhibitors: 
what the clinician needs to know. Therap Adv Gastroenterol. 2012;5(4):219-32. 
5. 
Xie Y, Bowe B, Li T, Xian H, Yan Y, Al-Aly Z. Risk of death among users of Proton Pump 
Inhibitors: a longitudinal observational cohort study of United States veterans. BMJ Open. 
2017;7(6):e015735. 
6. 
Batuwitage BT, Kingham JGC, Morgan NE, Bartlett RL. Inappropriate prescribing of 
proton pump inhibitors in primary care. Postgraduate Medical Journal. 2007;83(975):66-8. 
7. 
Gwee KA, Goh V, Lima G, Setia S. Coprescribing proton-pump inhibitors with 
nonsteroidal anti-inflammatory drugs: risks versus benefits. J Pain Res. 2018;11:361-74. 
8. 
van Vliet EP, Otten HJ, Rudolphus A, Knoester PD, Hoogsteden HC, Kuipers EJ, et al. 
Inappropriate prescription of proton pump inhibitors on two pulmonary medicine wards. Eur J 
Gastroenterol Hepatol. 2008;20(7):608-12. 
9. 
Grant K, Al-Adhami N, Tordoff J, Livesey J, Barbezat G, Reith D. Continuation of Proton 
Pump Inhibitors from Hospital to Community. Pharmacy World and Science. 2006;28(4):189-93. 
10. 
Xie Y, Bowe B, Yan Y, Xian H, Li T, Al-Aly Z. Estimates of all cause mortality and cause 
specific mortality associated with proton pump inhibitors among US veterans: cohort study. Bmj. 
2019;365:l1580. 
11. 
Xie Y, Bowe B, Li T, Xian H, Balasubramanian S, Al-Aly Z. Proton Pump Inhibitors and 
Risk of Incident CKD and Progression to ESRD. J Am Soc Nephrol. 2016;27(10):3153-63. 
12. 
Filion KB, Chateau D, Targownik LE, Gershon A, Durand M, Tamim H, et al. Proton 
pump inhibitors and the risk of hospitalisation for community-acquired pneumonia: replicated 
cohort studies with meta-analysis. Gut. 2014;63(4):552-8. 
13. 
Eom CS, Jeon CY, Lim JW, Cho EG, Park SM, Lee KS. Use of acid-suppressive drugs 
and risk of pneumonia: a systematic review and meta-analysis. Cmaj. 2011;183(3):310-9. 
14. 
Metz DC, Inadomi JM, Howden CW, van Zanten SJ, Bytzer P. On-demand therapy for 
gastroesophageal reflux disease. Am J Gastroenterol. 2007;102(3):642-53. 
15. 
Inadomi JM, Jamal R, Murata GH, Hoffman RM, Lavezo LA, Vigil JM, et al. Step-down 
management of gastroesophageal reflux disease. Gastroenterology. 2001;121(5):1095-100. 
16. 
Inadomi JM, McIntyre L, Bernard L, Fendrick AM. Step-down from multiple- to single-
dose proton pump inhibitors (PPIs): a prospective study of patients with heartburn or acid 
regurgitation completely relieved with PPIs. Am J Gastroenterol. 2003;98(9):1940-4. 
17. 
Grant K, Al-Adhami N, Tordoff J, Livesey J, Barbezat G, Reith D. Continuation of proton 
pump inhibitors from hospital to community. Pharm World Sci. 2006;28(4):189-93. 
18. 
Butler JR, Rogers T, Eckart G, Martens GR, Ceppa EP, House MG, et al. Is antisecretory 
therapy after pancreatoduodenectomy necessary? Meta-analysis and contemporary practices of 
pancreatic surgeons. J Gastrointest Surg. 2015;19(4):604-12. 


Version date 09/25/23 
 
Page 25 of 33 
 
19. 
Sulieman I, Strobel O, Scharenberg C, Mihaljevic AM, Müller BM, Diener MK, et al. 
Symptomatic marginal ulcer after pancreatoduodenectomy. Surgery. 2020;168(1):67-71. 
20. 
Hedberg J, Hedenström H, Nilsson S, Sundbom M, Gustavsson S. Role of gastric acid in 
stomal ulcer after gastric bypass. Obes Surg. 2005;15(10):1375-8. 
21. 
Yamasaki M, Fukuda Y, Tanimoto A, Narahara M, Kawaguchi Y, Ushiroda H, et al. 
Reduction in the rate of postoperative delirium by switching from famotidine to omeprazole in 
Japanese hepatectomized recipients. J Pharm Health Care Sci. 2019;5:10. 
 
 
 


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APPENDIX A: Definitions for Adverse Event Reporting 
 
A. Adverse Events (AEs) 
 
As defined in 21 CFR 312.32: 
 
Definition: any untoward medical occurrence associated with the use of a drug in humans, 
whether or not considered drug-related. 
 
Grading: the descriptions and grading scales found in the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for all toxicity reporting.  A 
copy of the CTCAE version 5.0 can be downloaded from the CTEP website. 
 
Attribution (relatedness), Expectedness, and Seriousness: the definitions for the terms 
listed that should be used are those provided by the Department of Health and Human Services’ 
Office for Human Research Protections (OHRP).  A copy of this guidance can be found on 
OHRP’s website: 
http://www.hhs.gov/ohrp/policy/advevntguid.html 
 
B. Suspected Adverse Reaction (SAR) 
 
As defined in 21 CFR 312.32: 
 
Definition: any adverse event for which there is a reasonable possibility that the drug caused 
the adverse event.  “Reasonable possibility” means there is evidence to suggest a causal 
relationship between the drug and the adverse event.  “Suspected adverse reaction” implies a 
lesser degree of certainty about causality than adverse reaction, which means any adverse event 
caused by a drug. 
 
C. Life-Threatening Adverse Event / Life Threatening Suspected Adverse Reaction  
 
As defined in 21 CFR 312.32: 
 
Definition: any adverse drug event or suspected adverse reaction is considered “life-
threatening” if, in the view of the investigator, its occurrence places the patient at immediate 
risk of death. It does not include an adverse event or suspected adverse reaction that, had it 
occurred in a more severe form, might have caused death. 
 
D.  Serious Adverse Event (SAE) or Serious Suspected Adverse Reaction 
 
As defined in 21 CFR 312.32: 
 
Definition:  an adverse event or suspected adverse reaction is considered “serious” if, in the 
view of the investigator, it results in any of the following outcomes: 
o Death 
o A life-threatening adverse event 


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o Inpatient hospitalization or prolongation of existing hospitalization 
o A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
o A congenital anomaly/birth defect 
o Any other important medical event that does not fit the criteria above but, based upon 
appropriate medical judgment, may jeopardize the subject and may require medical or 
surgical intervention to prevent one of the outcomes listed above 
 
E. Protocol Exceptions 
 
Definition: A planned change in the conduct of the research for one participant. 
 
F. Deviation 
 
Definition: Any alteration or modification to the IRB-approved research without prospective 
IRB approval.  The term “research” encompasses all IRB-approved materials and documents 
including the detailed protocol, IRB application, consent form, recruitment materials, 
questionnaires/data collection forms, and any other information relating to the research study. 
 
A minor or administrative deviation is one that does not have the potential to negatively impact 
the rights, safety, or welfare of participants or others or the scientific validity of the study. 
 
A major deviation is one that does have the potential to negatively impact the rights, safety, or 
welfare of participants or others or the scientific validity of the study. 
 


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APPENDIX B: Reporting Timelines 
 
Expedited Reporting Timelines 
Event 
HRPO 
QASMC 
Serious AND unexpected 
suspected adverse reaction 
 
 
Unexpected fatal or life-
threatening suspected adverse 
reaction 
 
 
Unanticipated problem 
involving risk to participants 
or others 
Report within 10 working days.  If the 
event results in the death of a participant 
enrolled at WU/BJH/SLCH, report within 
1 working day. 
Report via email after IRB 
acknowledgment 
Major deviation 
Report within 10 working days.  If the 
event results in the death of a participant 
enrolled at WU/BJH/SLCH, report within 
1 working day. 
 
A series of minor deviations 
that are being reported as a 
continuing noncompliance 
Report within 10 working days.   
 
Protocol exception 
Approval must be obtained prior to 
implementing the change 
 
Clinically important increase 
in the rate of a serious 
suspected adverse reaction of 
that list in the protocol or IB 
 
 
Complaints 
If the complaint reveals an unanticipated 
problem involving risks to participants or 
others OR noncompliance, report within 
10 working days.  If the event results in the 
death of a participant enrolled at 
WU/BJH/SLCH, report within 1 working 
day.  Otherwise, report at the time of 
continuing review. 
 
Breach of confidentiality 
Within 10 working days. 
 
Incarceration 
If withdrawing the participant poses a 
safety issue, report within 10 working 
days.   
 
If withdrawing the participant does not 
represent a safety issue and the patient will 
be withdrawn, report at continuing review. 
 
 
Routine Reporting Timelines 
Event 
HRPO 
QASMC 
Adverse event or SAE 
that does not require 
expedited reporting 
If they do not meet the definition of an 
unanticipated problem involving risks to 
participants or others, report summary 
information at the time of continuing review 
Adverse events will be 
reported in the toxicity 
table in the DSM report 
which is typically due 
every 6 months. 


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Routine Reporting Timelines 
Event 
HRPO 
QASMC 
Minor deviation 
Report summary information at the time of 
continuing review. 
 
Complaints 
If the complaint reveals an unanticipated problem 
involving risks to participants or others OR 
noncompliance, report within 10 working days.  If 
the event results in the death of a participant 
enrolled at WU/BJH/SLCH, report within 1 
working day.  Otherwise, report at the time of 
continuing review. 
 
Incarceration 
If withdrawing the participant poses a safety 
issue, report within 10 working days.   
 
If withdrawing the participant does not represent a 
safety issue and the patient will be withdrawn, 
report at continuing review. 
 
 
 
 


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APPENDIX C: ISGPS Criteria for Delayed Gastric Emptying 
 
 
 
 


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APPENDIX D: Modified Accordion Grading System 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX E:  Expected Post-Surgical Adverse Events 
 
Gastrointestinal: 
• 
Delayed gastric emptying 
• 
Pancreatic fistula 
• 
Intraabdominal abscess 
• 
Clostridium difficile infection 
• 
Leak (chyle, biliary, pancreatic, gastric, enteric) 
• 
Anastomotic ulcer 
• 
Bowel obstruction 
• 
Bowel perforation 
• 
Bowel ischemia 
• 
Mesenteric ischemia 
• 
Colitis 
• 
Gastritis/esophagitis 
 
Cardiovascular: 
• 
Myocardial infarction 
• 
Arrhythmia 
• 
Cardiac arrest 
• 
Congestive heart failure 
• 
Hemorrhage 
• 
Deep vein thrombosis 
• 
Pulmonary embolism 
• 
Ischemic stroke 
• 
Hemorrhagic stroke 
• 
Venous or arterial thrombosis 
• 
Hypotension 
 
Urinary: 
• 
Urinary retention 
• 
Urinary tract infection 
• 
Acute kidney injury/failure 
 
Respiratory: 
• 
Pneumonia 
• 
Subcutaneous emphysema 
 
Neurological: 
• 
Delirium/agitation 
 
General: 
• 
Surgical site infection 
• 
Pancreas endocrine insufficiency 
• 
Pancreas exocrine insufficiency 
• 
Bacteremia/sepsis 
• 
Failure to thrive 
• 
Death 
 
 
 


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APPENDIX F: Study-Specific DSM Tables 
 
Protocol Objectives and Subject Evaluability 
Objective 
# of patients 
evaluable for this 
endpoint to date 
Primary 
Determine the effect of PPIs on the incidence of delayed gastric 
emptying within 90 days in patients after pancreaticoduodenectomy. 
  
Secondary 
Determine the effect of PPIs on the incidence of overall 
postoperative complications in the patients after 
pancreaticoduodenectomy. 
Determine the marginal ulcer-free survival (MUFS) within 90 days 
in the patients undergoing pancreaticoduodenectomy. 
  
 
 
Interim Analysis and Early Stopping Rules 
Does the study design include an interim toxicity analysis? 
No 
Does the study design include an interim futility analysis? 
No 
Are there early stopping rules that outline circumstances under which the study must be 
suspended or closed? 
No 
 
 
Response and Survival 
UPN 
On tx 
date 
# 
doses 
Pt 
replaced? 
(y/n) 
Delayed 
gastric 
emptying? 
(y/n) 
Off tx reason 
Vital 
status 
If dead, cause 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Summary of Specimen Collections 
Type of specimen 
Time point 
# of patients 
eligible for 
collection at this 
time point 
% of patients who 
have reached this 
time point and had 
the specimen collected 
N/A (no research specimens collected on this study)