Post ERCP Pancreatitis Prophylaxis, Effectiveness of Rectal Indomethacin vs Intravenous Ketorolac in the Pediatric Population
Phase: PHASE4
Conditions: Post-ERCP Acute Pancreatitis
Sponsor: David Vitale MD

IRB Protocol #: 2022-0640 
 
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IRB# 
NCT# 
Version Date 
Study Title 
2022-
0640 
NCT05664074 03.13.23 
Post-ERCP Pancreatitis Prophylaxis, Effectiveness of Rectal 
Indomethacin vs Intravenous Ketorolac in the Pediatric 
Population 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Study Title: Post-ERCP Pancreatitis Prophylaxis, Effectiveness of Rectal Indomethacin vs Intravenous 
Ketorolac in the Pediatric Population 
 
Principal Investigator: David S. Vitale 
 
Sub-Investigators: Sherif Y. Ibrahim, Tom K. Lin, Lindsey Hornung, Ethan Estes, Tyler Thompson, Lin Fei, 
Maisam Abu-El-Haija 
 
1.0 Background 
Endoscopic retrograde cholangiopancreatography (ERCP) is an essential interventional procedure but 
can be complicated by post-ERCP pancreatitis (PEP). Rectal indomethacin has been shown to reduce 
rates of PEP adult populations and a recent study showed reduced rates of PEP in pediatric patients 
receiving intravenous (IV) ketorolac in a retrospective study[1]. There have been no studies comparing 
the effectiveness of these prophylactic medications in preventing PEP in pediatric patients. Both rectal 
indomethacin and IV ketorolac are currently standards of care. In a retrospective analysis at our 
institution involving 80 ERCPs for 57 unique patients, when directly comparing medication prophylaxis, 
the odds of developing PEP were 3.4 times higher for those given rectal indomethacin compared to 
those given IV ketorolac (OR 3.4, CI 0.6-21.2). Additionally, a variety of risk factors can be associated 
with PEP and rates can vary. Particularly in high-risk patients with pancreatic duct injection, ketorolac 
was more effective than indomethacin in preventing PEP (IV ketorolac OR of 0.5 and Rectal 
indomethacin OR of 3.8) in our retrospective analysis. Unfortunately, this study was a retrospective 
analysis with limited sample size. Therefore, further studies are required to help identify possible 
modalities to improve rates of PEP and patient outcomes. 
 
Purpose: 
1. To compare effectiveness of therapy with rectal indomethacin versus IV ketorolac in affecting 
the rate of PEP.   
2. To identify risk factors associated with increased rates of PEP in pediatric patients who 
underwent ERCP for pancreatic or biliary indications, and to review the effectiveness of 
techniques commonly employed to prevent PEP.  
3. To identify possible biomarkers to predict PEP.  
 
1.1 Clinical Relevance 
ERCP is a safe and beneficial therapeutic option in treatment of children with pancreatobiliary disease 
but can be complicated by PEP in up to 10 - 20% in high risk patients [2]. Ketorolac and indomethacin 
are both viable options for prophylaxis but the superior modality has not been studied in the pediatric 
population. 
 
1.2 Definitions 
We will use the Classification of Acute Pancreatitis in the Pediatric Population: Clinical Report from the 
North American Society for Pediatric Gastroenterology, Hepatology & Nutrition (NASPGHAN) Pancreas 
Committee to define Acute Pancreatitis and severity of Acute Pancreatitis. [3] 
1. Acute Pancreatitis (AP): We will use the previously established definition of pediatric AP. A patient 
must have at least 2 of the following to establish a diagnosis of AP: 

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a. Characteristic physical exam findings- pain worse than admission per pain scales (please see 
point 4 and 5 below) and/or nausea  
b. Amylase or lipase greater than 3 times the age appropriate upper limit of normal 
c. Confirmatory imaging (Ultrasound, CT or MRI) that suggests or demonstrates pancreatic 
inflammation 
2. Severity of AP: Severity of AP in patients in this study will be classified as mild, moderately severe, or 
severe in accordance with the NASPGHAN Classification system. The following definitions in quotations 
are taken directly from this source.  
a. Mild: “AP that is not associated with any organ failure, local or systemic complications, and 
usually resolves within the first week after presentation.” 
b. Moderately Severe: “AP with either the development of transient organ failure/dysfunction 
(lasting no >48 hours) or development of local or systemic complications. Local complications would 
include development of (peri) or pancreatic complications including fluid collections or necrosis. 
Systemic complications would include exacerbation of previously diagnosed co-morbid disease (such as 
lung disease or kidney disease).” 
c. Severe: “AP with development of organ dysfunction per International pediatric sepsis 
consensus conference (please see definition 9) that persists >48 hours. Persistent organ failure may be 
single or multiple, and may develop beyond the first 48 hours of presentation.” 
3. Post ERCP Pancreatitis (PEP): Defined as development of AP within 2 weeks of ERCP per American 
Society for Gastrointestinal Endoscopy (ASGE) guidelines[4]. 
4. Face, Legs, Activity, Cry, and Consolability (FLACC): Pain scale for patients 0-5 years of age and 
patients unable to verbalize pain [5] 
 
Table 1. FLACC pain scale 
Criteria 
Score 0 
Score 1 
Score 2 
Face 
No particular expression 
or smile 
Occasional grimace or frown, 
withdrawn, uninterested 
Frequent to constant 
quivering chin, clenched jaw 
Legs 
Normal position or 
relaxed 
Uneasy, restless, tense 
Kicking, or legs drawn up 
Activity 
Lying quietly, normal 
position, moves easily 
Squirming, shifting, back and forth, 
tense 
Arched, rigid or jerking 
Cry 
No cry (awake or asleep) 
Moans or whimpers; occasional 
complaint 
Crying steadily, screams or 
sobs, frequent complaints 
Consolability 
Content, relaxed 
Reassured by occasional touching, 
hugging or being talked to, distractible 
Difficult to console or comfort 
 
5. Numeric Rating Scale (NRS) Pain scale for patients 6 years old and above [6] 
 
a. Mild- 0 to 3 
 
b. Moderate- 4 to 6 
 
c. Severe- 7 to 10 
6. Acute Kidney Injury: 
Per Kidney Disease: Improving Global Outcomes (KDIGO) 
a. Increase in serum creatinine > 0.3 mg/dL from baseline within 48 hours 

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b. Increase in serum creatinine to > 1.5 tune baseline within the prior 7 days 
c. Urine volume <0.5 mL/kg/hour for 6 hours 
7. Chronic Kidney Disease per KDIGO: 
 
a. Glomerular filtration rate (GFR) less than 60 mL/min per 1.73 m2 for greater than 3 months 
 
b. GFR greater than 60 mL/min per 1.73 m2 accompanied by evidence of structural damage or 
other markers of functional kidney abnormalities 
8. GFR calculations: 
 
a. Children less than 18 years old- Creatinine Based “Bedside Schwartz” Equation: 
 
GFR = 0.413 x (height in cm/serum creatinine) 
 
b. Patients 18-25 years old- Creatinine Cystatin C (cysC) Based Chronic Kidney Disease in 
Children (CKID) equation: 
 
Estimated GFR = 39.8 x [Height/Serum Creatinine]0.456 x [1.8/cysC]0.418 x [30/BUN]0.079 x 
[1.076male] [1.00female] x [Height/1.4]0.179 
 
9. Organ dysfunction table per International pediatric sepsis consensus conference[7].  
We will use the organ dysfunction table below per the International Pediatric Sepsis Consensus 
Conference to assess organ dysfunction and SIRS (Table 2) [7]. Any patients that meet criteria for organ 
dysfunction or SIRS will be exempt from the study except for patients with elevated bilirubin or liver 
enzymes (ALT or AST) as these may be elevated due to choledocholithiasis and other biliary pathology 
requiring ERCP intervention. 
 
 
 
2.0 Objectives 

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1. Evaluate the efficacy of IV Ketorolac and rectal Indomethacin in preventing PEP in patients 
undergoing ERCP.  
2. To compare efficacy of IV ketorolac, as compared to rectal indomethacin, to reduce rates of PEP 
3. To determine if the use of IV ketorolac, as compared to rectal indomethacin, reduces PEP 
sequelae 
4. To identify possible biomarkers to predict PEP 
 
 
2.1 Endpoints 
1. Primary endpoint: Post-ERCP Pancreatitis (Time Frame: 2 weeks) 
 
 
a. Number of patient who develop PEP 
2. Secondary endpoints: 
a. Increased pain after ERCP 
b. Next day post-ERCP pain score 
c. Laboratory markers associated PEP (Amylase and Lipase) 
d. Length of stay 
e. Severity of pancreatitis (mild, moderately severe, severe) 
f. Inflammatory markers 
g. Post-ERCP bleeding 
 
3.0 Study Design 
This will be a prospective study where patients will be randomized via a static sheet of randomization 
scheme into either rectal indomethacin (>=50 kg, 100 mg; 30-49 kg, 50 mg; 10-29 kg, 25 mg) or IV 
ketorolac 0.5 mg/kg (maximum: 15 mg).  
 
After the procedure, patients will be started on D5 Lactated Ringers (D5LR) at 1.5 maintenance rate as 
per the ERCP order set and a clear liquid diet to be advanced as tolerated within 6 hours. 
 
A minimum of 3 pain assessments are to be completed by nursing staff/anesthesia during admission: 
Anesthesia/ PACU- initial pain assessment  
Evening-2100- pain assessment by RN  
Morning –0800- pain assessment by RN  
 
If pain (worse than on admission) based on FLACC or NRS scoring or nausea occurs this will trigger a best 
practice order set for the primary provider to obtain a standard set of lab work. The lab work to be 
obtained is standard of care including: CRP, CBC w/ differential, Amylase, and Lipase. If patient meets 
criteria for PEP, they will remain on D5LR and diet to be returned to a clear liquid diet.  
 
4.0 Study Procedures 
Either medication will be administered upon endoscope insertion. For planned procedures, after 
consent is obtained patients will be directly placed into our static randomization sheet to determine 
which treatment arm he or she receives. This document will be available electronically to endoscopists, 
CRCs, and other pertinent team members via our medically secured REDCap database. 
 
Data Collection in REDCap: 

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Data collected may include patient name, age, date of birth, sex, height, weight, relevant lab values, 
results of imaging modalities (MRCP, CT, US, or ERCP, EUS), genetic testing, family history, pancreatic 
function testing results (such as fecal fat, fecal elastase), medications, pain scores, hospital stay, 
complications, clinical course and progression, and interventions or surgical procedures. Relevant data 
from any Cincinnati Children’s Hospital Medical Center (CCHMC) admission or clinic visit may be utilized.  
Data will be collected on specific case report forms (CRFs) that will be entered into a Research Electronic 
Data Capture (REDCap) database. REDCap is a CTSA sponsored, widely used, secure, web-based 
application designed for data management. REDCap satisfies all good clinical practices guidelines. Each 
participant will be identified with a study ID number, and the key will be maintained in a separate 
password protected file. Only authorized study personnel will have access to this key. Computer files will 
also be password protected and data will be entered into the secure web-based database. 
Specimen Collection:  
Optional blood specimens for this study will be obtained for research purposes only. 
When possible we will obtain research blood at the time of a clinical blood draw or when a patient is 
anesthetized for a procedure. Blood collection for this protocol will follow the blood collection 
guidelines for children - the lesser of 3 ml/kg of blood or a maximum of 10 ml per sample will be 
collected for research purposes. A single blood draw will not exceed 3 ml/kg, and no more than 4 ml/kg 
(5% of total blood volume) will be drawn over a one month period. This protocol allows for up to three 
blood samples per ERCP-related appointment or admission for up to 24 months following enrollment. 
 
Repeat ERCPs: 
Some subjects will have more than one clinically indicated ERCP. Subjects will be eligible for 
randomization of IV ketorolac versus rectal indomethacin for each clinically indicated ERCP for the 
duration of the study.  
 
5.0 Subject Population 
 
The subject population will include patients 6 months to 21 years of age requiring ERCP. This pediatric 
population has not yet been evaluated in a randomized trial to compare IV ketorolac versus rectal 
indomethacin for PEP prophylaxis; both treatments are current standard of care for acute pancreatitis.  
 
Inclusion criteria-  
• 
Any patient undergoing ERCP (diagnostic or therapeutic with cannulation of the major or minor 
papilla)  
• 
Age 6 month- 21 years old  
• 
Does not meet exclusion criteria  
 
Exclusion criteria-  
• 
< 10 kg 
• 
Low risk subgroup: Biliary indication with history of prior biliary sphincterotomy.   
• 
High risk for bleeding (Example: Planned liver biopsy)  
• 
Gastrointestinal bleeding in previous 3 days 
• 
Acute pancreatitis (within 3 days) at the time of ERCP 
• 
Use of NSAIDs in the previous 5 days  
• 
Peptic ulcer disease  
• 
Acute kidney Injury or Known Chronic Kidney Disease per KDIGO 

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• 
Pregnancy (Pregnancy tests are administered prior to ERCP as standard of care) 
• 
Lithium therapy  
• 
Allergy to ketorolac or indomethacin  
• 
Organ Dysfunction or SIRS 
 
6.0 Selection and Recruitment of Study Participants 
Subject Recruitment:  
Recruited subjects will be identified through review of patients presenting for ERCP for clinical 
care.   Following screening, patients will be enrolled by the research staff after informed consent is 
obtained through the informed consent process mentioned below.  
 
Process of obtaining Consent (including eConsent):  
Consent, parental permission and/or assent will be obtained from all patients before any study-related 
procedures are performed. Written assent will be obtained from participants 11 years of age and older. 
The investigator will be available to answer any questions that the participant or parent may have 
regarding procedures, risks, and alternatives. The consent process will be documented on the informed 
consent process note.  
 
Consent may take place by several methods: in-person paper consent, in-person electronic consent 
(using REDCap for the eConsent) or over the phone (via paper or REDCap for eConsent). Signatures of 
the subject and study staff may not always occur on the same date depending on how and when the 
subject returns the signed consent. No matter the consenting process, study procedures will not occur 
prior to a fully executed consent form.  Consent will be obtained following the CCHMC consenting SOP. 
REDCap eConsent will not replace the consenting method, it will be used as an additional resource for 
signing the consent form. A copy of the consent form will either be given to the subject in paper form or 
emailed to them via REDCap depending on how the consent is completed. In all cases, the consent 
process will be documented on the informed consent process note and a copy of the signed consent(s) 
will be kept in the patient’s medical record.  
Staff will make sure that the eConsent database is updated as soon as possible after a new version of 
the paper consent is approved. Staff will also make sure paper consents are used to consent eligible 
subjects in the event that the eConsent database is not updated prior to eligible subjects being available 
for consent approach by a member of the study staff. For the reasons described, the eConsent will not 
be submitted to the IRB for approval.  
 
Subjects will be reminded that participation in research is completely voluntary. Coercion is eliminated 
by having the subjects sign an assent document and the parent/guardian signs the consent document. 
We will give potential subjects time to read the consent form, consent them in a private setting, and 
answer any questions they may have. Potential subjects (or parents) will be told that the subject's 
(parent's) decision to participate will not affect the clinical care received.  
 
Subjects will be informed that signing the informed consent form will provide consent for randomization 
to receive Rectal Indomethacin or IV Ketorolac for all repeat ERCP procedures. Re-consent will not be 
required at each procedure. However, the family will be reminded of their participation prior to any 
future procedures and be given the opportunity to opt out if requested. 
 

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If patients do not want to participate, at any time, they are instructed to call the Research Coordinator 
to opt out. The study consent process will ensure that potential subjects will be adequately informed 
about the study and will have an opportunity to ask questions.    
  
7.0 Data Management & Analysis 
1. Data will be stored in REDCap. Study data will be restricted to study personnel only after all 
research training is complete.  
2. Once data is collected, a code will be created. The identifying information will be removed from 
the data file and replaced with the code. Codes will be stored in a separate file. Only research 
personnel will have access to the data. 
3. Research blood samples (stored for extraction of plasma and DNA) will be obtained and banked 
during the subject’s ERCP. All samples will be collected and processed from specimen tubes 
containing the subject’s unique study identification code. Specimens will be stored in the 
Pancreatitis Registry biorepository (IRB 2012-4050) identified only by their study ID code. The 
password protected bio-specimen database which associates unique study codes with personal 
identifiers will be accessible only to essential staff members designated by the PI. Leftover 
specimens will be banked for future IRB approved research. 
4. Once the study is complete, data will be retained in a coded state for potential future currently 
unspecified research.  Future research will require IRB approval prior to utilizing this dataset.  
 
7.1 Statistical Analysis Plan 
Descriptive analysis of the data using means ± standard deviations, medians and interquartile ranges 
(25th-75th percentiles), ranges, confidence intervals, proportions and frequencies will be 
performed.  We will examine the distribution of all variables to identify outliers and if continuous 
variables are normally distributed or skewed. Additional statistical analysis of the data may include t-
tests or Mann-Whitney Wilcoxon tests, Chi-square or Fischer’s exact tests, ANOVA, and/or regressions 
to test for differences in those developing PEP between the medication groups as well as identify risk 
factors for developing PEP.  We will control for confounders of therapy by standardizing time of 
medications intra-operatively, the type and rate of IV fluids, and advancement of diet through our ERCP 
order set. Statistical analyses will be performed using SAS®, version 9.4 (SAS Institute, Cary, North 
Carolina, USA). A p-value <0.05 will be considered statistically significant. Two-sided tests will be used 
for group comparisons in order to assess any differences between the medication groups. If one 
medication has a significantly (p<0.05) lower proportion of PEP and significantly decreased odds ratio of 
developing PEP then that medication would be deemed preferable over the other after assessing and 
controlling for any confounding factors.  
 
Multiple samplings of the same patient would be important for potential drug-drug comparison as well 
as the overall proportion of PEP for generalizability purposes in order to have the most procedures/data 
for this study. We will report on the number of patients that had single and multiple procedures. In 
order to address the multiple sampling from the same participant issue (to avoid overweighting certain 
patients that could influence the results) we will do a sensitivity analysis and use the first procedure for 
each patient and compare the outcomes of the single procedures to the overall outcomes in order to 
make sure the findings are consistent. If there would be any differences in results or conclusions drawn 
using the first procedure vs overall data, we will report on these differences and then use the first 
procedure performed.  

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Per internal power calculation for 80% power the study will require 96 patients in each treatment 
group (96 IV ketorolac and 96 rectal indomethacin) - 192 patients total. For 90% power, would 
need 128 patients in each treatment group (128 IV ketorolac, 128 rectal indomethacin) - 256 total 
patients.  
  
8.0 Potential Risks and Benefits to Subjects 
 
8.1 Potential Risks 
The level of risk for the participants is minimal. Both indomethacin and ketorolac are standard of care 
treatments. However, the risks associated with each medication are listed below:  
  
Ketorolac adverse reactions: Abdominal pain, dyspepsia, and nausea (>10%); increased liver enzymes (< 
15%), and headache (>10%). All other adverse reactions are less than 10%. 
 
Indomethacin adverse reactions: Vomiting (< 12%), postoperative hemorrhage (< 11%), and headache 
(12-16%). All other adverse reactions are less than 10%. 
  
Risks associated with a breach of confidentiality: There is a risk that someone not authorized to view 
participant information, including identifiable information, will gain access to this information. We will 
take measures to prevent this from happening and will comply with local regulations. To protect patient 
information, research records and source documents will be maintained in a research file and stored in 
the investigators locked office or in password protected electronic files. No primary data or patient 
identifiers will be published.   
 
8.2 Data Safety Monitoring Plan:    
This study is a minimal risk study. Therefore, no formal data safety monitoring board will be 
appointed.  Adverse events related to the study procedures will be monitored by the study coordinator 
and reported to the PI.  The PI will then report any adverse events in writing to the CCHMC IRB within 
the time frame specified in the IRB guidelines. These procedures should be highly effective in minimizing 
risk to study participants.  
  
8.3 Potential Benefits:  
There is no direct benefit to the study subject.  However, future patients may benefit due to the 
knowledge gained from this study that may direct future patient care.  
 
8.4 Privacy & Confidentiality:  
Access to original data and study materials will be limited to the investigative team. Every effort will be 
made to protect each research participant’s identity. Each participant will be identified with a study ID 
number, and the key will be maintained in a password protected file. Only authorized site personnel will 
have access to this key. Computer files will also be password protected. 
 
Research subjects will be informed that agencies that make rules and policies about how research is 
done have the right to review these records, as well as agencies that pay for the study. Only study staff, 
Institutional Review Board, OHRP, and NIH representatives will have access to study records. 
 
 

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9. 0 Timeline/ Budget  
Study recruitment will begin at CCHMC in October 2022. Per internal power calculation for 80% power 
the study will require 96 patients in each treatment group (96 IV ketorolac and 96 rectal indomethacin) - 
192 patients total. For 90% power, it would require 128 patients in each treatment group (128 IV 
ketorolac, 128 rectal indomethacin) - 256 total patients. We hope to enroll 96 patients in each 
treatment arm to reach 80% power for the study. 
 
At our tertiary care center, 180 to 190 ERCP cases are completed per year. We should be able to 
complete recruitment by spring 2024, although we may need to extend the recruitment period to 
acquire sufficient power to complete the study. We anticipate data analysis to be completed in the 
spring to summer of 2024. 
 
We anticipate that the cost will be minimal, as the labs will be standard of care. All treatment charges 
will be billed to the patient and/or the patient’s insurance company because they are the standard of 
care for acute pancreatitis. We will have access to a modest amount of funding via the NIH T32 training 
grant to cover any ancillary costs of the study. Any labs that are not obtained by the primary team, will 
be obtained at the research cost and will be entered into research EPIC. The patients will be entered 
into EPIC as a mixed inpatient/research encounter.  
 
10.0 Bibliography: 
1. 
Mark, J.A. and R.E. Kramer, Ketorolac Is Safe and Associated With Lower Rate of Post-Endoscopic 
Retrograde Cholangiopancreatography Pancreatitis in Children With Pancreatic Duct 
Manipulation. J Pediatr Gastroenterol Nutr, 2021. 73(4): p. 542-547. 
2. 
Geraci, G., et al., Rectal Diclofenac administration for prevention of post-Endoscopic Retrograde 
Cholangio-Pancreatography (ERCP) acute pancreatitis. Randomized prospective study. Clin Ter, 
2019. 170(5): p. e332-e336. 
3. 
Abu-El-Haija, M., et al., Classification of Acute Pancreatitis in the Pediatric Population: Clinical 
Report From the NASPGHAN Pancreas Committee. J Pediatr Gastroenterol Nutr, 2017. 64(6): p. 
984-990. 
4. 
Committee, A.S.o.P., et al., Complications of ERCP. Gastrointest Endosc, 2012. 75(3): p. 467-73. 
5. 
Merkel, S.I., et al., The FLACC: a behavioral scale for scoring postoperative pain in young 
children. Pediatr Nurs, 1997. 23(3): p. 293-7. 
6. 
Ferreira-Valente, M.A., J.L. Pais-Ribeiro, and M.P. Jensen, Validity of four pain intensity rating 
scales. Pain, 2011. 152(10): p. 2399-2404. 
7. 
Goldstein, B., et al., International pediatric sepsis consensus conference: definitions for sepsis 
and organ dysfunction in pediatrics. Pediatr Crit Care Med, 2005. 6(1): p. 2-8.