Conditions: Post-ERCP Acute Pancreatitis
Keywords: post-ERCP pancreatitis pediatric ibuprofen
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 69
Healthy volunteers: no

Brief summary:
Endoscopic retrograde cholangiopancreatography (ERCP) is an advanced endoscopic technique utilized to diagnose and treat pathologic conditions involving the ducts draining the liver and pancreas. Post-ERCP pancreatitis (PEP) is the most common complication following ERCP and occurs in approximately 11% of children undergoing the procedure. By definition it leads to prolongation of hospital stay or delays in care and rarely can result in long-term morbidity or even death. Recent adult trials have demonstrated prevention of PEP with administration of rectal nonsteroidal anti-inflammatory drugs (NSAIDS). To date, no studies have been performed in children thus no "gold standard" or even commonly accepted method of preventing PEP in the pediatric population exist. Studying an IV NSAID such as ibuprofen has distinct advantages over rectally administered NSAIDs in the pediatric population in that it would allow for more consistent weight based dosing and would have more predictable absorption compared to suppository. Thus, this project proposes a pilot study evaluating the effectiveness of IV ibuprofen at preventing PEP in the pediatric population. The design of the proposed study is a prospective randomized double-blind trial comparing IV Ibuprofen to placebo controls (normal saline) at the time of procedure in patients undergoing ERCP at Children's Medical Center Dallas over a two-year period. The primary outcome measurement will be development of PEP. Post-ERCP bleeding and change in pre- and post- procedural pain scores will also be measured. The hypothesis is that IV Ibuprofen administered at the time of ERCP will decrease rates of post-ERCP pancreatitis in pediatric patients.

Detailed description:

Arms:
arm 1: Single dose IV Ibuprofen at a dose of 10mg/kg (max: 800mg). arm 2: Single dose IV normal saline

Interventions: intervention 1: Ibuprofen intervention 2: placebo
Intervention descriptions: intervention 1: None intervention 2: None

Protocol document:
Prot_SAP_000.pdf: 
The University of Texas Southwestern Medical Center at Dallas 
Institutional Review Board 
 
 
 
 
 
 
 
 
IV Ibuprofen for the Prevention of Post-ERCP Pancreatitis in Pediatric Patients: 
A Pilot Study 
Study #: STU 082014-033 
 
 
 
PI: David M. Troendle 
Co-investigator: Bradley A, Barth 
Version 1, 9.18.2014 
 
 
 
IND #: pending 
Clinicaltrials.gov Identifier: NCT02241512 
Funding Source: CCRAC W.W. Caruth Fellow Grant


 
1. Introduction and Purpose: 
Endoscopic retrograde cholangiopancreatography (ERCP) is an advanced endoscopic 
technique utilized to diagnose and treat a variety of pathology in the bile ducts and pancreas 
[1]. Post-ERCP pancreatitis (PEP) is the most common complication following ERCP 
occurring in approximately 11% of children undergoing the procedure [2]. By definition it 
leads to prolongation of hospital stay or delays in care and rarely can result in long-term 
morbidity or even death [3]. Recent adult trials have demonstrated prevention of PEP with 
administration of rectal nonsteroidal anti-inflammatory drugs (NSAIDS) [4]. To date, no 
studies have been performed in children thus no “gold standard” or even commonly accepted 
method of preventing PEP in the pediatric population exist. Studying an IV NSAID such as 
ibuprofen has distinct advantages over rectally administered NSAIDs in the pediatric 
population. It would allow for more consistent weight based dosing and provide more 
predictable absorption compared to suppository. Thus, this project proposes a pilot study 
evaluating the effectiveness and safety of IV ibuprofen at preventing PEP in the pediatric 
population. The hypothesis is that single dose IV ibuprofen at the time of ERCP will decrease 
the incidence of PEP after the procedure. The primary endpoint will be development of PEP 
which will be defined utilizing consensus criteria [5]. The secondary safety endpoint will be 
development of gastrointestinal bleeding which will also be defined utilizing consensus 
criteria [5]. The goal of the study is to gather preliminary data to allow sample size 
calculations for a future multi-center trial and evaluate the safety of administering IV 
Ibuprofen at the time of ERCP. While IV ibuprofen is not currently FDA approved for use in 
children, it has been shown to be safely and effectively used in pediatric patients across a 
large spectrum of ages and weights [6-8]. Thus, it is felt that the minimal risks that may be 
associated with its administration justify exploring the potential benefit associated with 
decreasing rates of PEP in the pediatric population. 
 
2. Background: 
Clinically significant pancreatitis is the most common complication following ERCP 
and leads to significant morbidity and rarely death [9]. Large prospective studies 
involving ERCPs performed in adult patients suggest that rates of PEP can be expected to be 
between 1-7% for most indications, although some series have reported much higher rates of 
PEP when ERCP is performed for high risk indications [10]. Most of these studies utilize the 
“Cotton Criteria” for defining episodes of PEP: typical pain and elevated pancreatic enzymes 
resulting in hospitalization or delays in care of at least 2 days [11]. To gauge the true impact 
of this entity on patients and the health care system, it would be more appropriate to utilize 
more inclusive criteria such as those proposed by the American Society of Gastrointestinal 
Endoscopists (ASGE): typical pain and elevated pancreatic enzymes resulting in any 
unexpected hospitalization or delay in clinical care [5]. When such criteria are utilized, it is 
likely that rates of PEP are slightly higher than that commonly reported in the literature. Rates 
of PEP in children remain poorly defined but are thought to occur at rates similar to adult 
populations [12-16], Our group recently reviewed data of 436 patients followed at Children’s 
Medical Center (CMC) Dallas who underwent ERCP between 2004-2013 and found that PEP 
occurred in 11% of patients [2]. Of the patients who developed PEP, 28% of them had a 
moderate to severe course, highlighting the importance of addressing this adverse event in 
this patient population. 
 
Currently, there is no standard of care for the prevention of PEP in the pediatric 
population and adopting adult based standards is problematic. Currently, pancreatic 
duct stenting is the most vigorously studied preventative measure in the adult literature and is 
considered by most endoscopist performing ERCP on adults to be the gold standard at 


preventing PEP. Pancreatic duct stenting is thought to prevent PEP by overcoming edema 
and inadequate drainage that may result following trauma associated with the papilla 
manipulation that occurs during ERCP. Several meta-analyses in adults have demonstrated 
that pancreatic stenting is effective at reducing rates of PEP [17, 18].  In the pediatric 
population large studies are lacking, but the only current pediatric specific study in the 
literature looking at PEP suggested that pancreatic stenting did not protect patients from PEP 
and actually increased the likelihood of developing PEP in patients with chronic pancreatitis 
[19]. In our review of patients treated at CMC Dallas, we found that pancreatic stenting 
significantly increased rates of PEP providing further evidence that it may actually be 
detrimental in the pediatric population [2]. This may not be surprising, as stenting has 
previously been suggested to be detrimental in certain adult patient populations as well, such 
as patients with smaller pancreatic ducts or more viscous pancreatic secretions at baseline 
[20].  Even in the adult literature, research continues to try and identify alternative measures 
at preventing PEP, mainly because placing such stents can be technically difficult and may 
necessitate additional procedures to remove them. While multiple pharmacological agents 
have been evaluated, none has been shown to unequivocally prevent PEP [3]. Recently, 
there has been gathering evidence that administration of rectal NSAIDS at the time of 
procedure does decrease the risk of PEP [21]. The mechanism of action appears to be 
inhibition of mediators of the inflammatory process (prostaglandins, phospholipase A2, and 
neutrophil/endothelial interactions) incited during ERCP as elucidated through in-vitro studies 
[22], animal studies [23], as well as in-vivo studies of non-ERCP pancreatitis [24]. While 
studies evaluating oral NSAID at time of ERCP have not consistently shown to be beneficial 
at preventing PEP, rectally administered NSAIDS have been shown to be consistently 
effective [25]. The most recent meta-analysis looking at the effectiveness of rectal NSAIDS 
(indomethacin or diclofenac) included 7 randomized control trials and 2133 patients showed 
that rectal NSAIDs decreased the incidence of PEP (RR 0.44; 95% CI 0.34-0.57, P<0.01) 
with a number needed to treat of 11 [21].  While these results are extremely encouraging, 
there are several considerations that limit their general applicability to the pediatric 
population. In addition, the fact remains that no single agent has specifically been studied to 
prevent PEP in the pediatric population. 
 
This study proposes a pilot study evaluating the ability of IV ibuprofen for the 
prevention of PEP in the pediatric population. While a rectal suppository provides a 
convenient relatively cheap form of drug administration in the adult population, it does not 
allow for the weight based dosing needed across the pediatric population. An IV formulation 
could overcome this limitations and allow for very predictable absorption [26]. While not 
currently FDA approved for use in patients <18 years of age, IV ibuprofen has been studied in 
a variety of pediatric conditions and found to be safe and effective. A large meta-analysis 
found IV ibuprofen to be as effective as indomethacin for the closure of a patent ductus 
arteriosus (PDA) in premature neonates with less side effects. The traditional dosing regimen 
for PDA closure is 10mg/kg followed by 5mg/kg at 24hr and 48hrs (10-5-5 mg/kg). More 
recently, a higher dose regimen (20-10-10 mg/kg) was found to be more effective at 
achieving PDA closure without increasing risk of side-effects [27]. IV ibuprofen has also been 
studied in older children and adolescents in the setting of post-tonsillectomy pain. A recent 
multicenter study of single dose IV ibuprofen at 10mg/kg given just prior to tonsillectomy, a 
procedure associated with a relatively high risk of bleeding, showed no increased risk of 
bleeding [8]. In a meta-analysis of all NSAIDS given during tonsillectomy which evaluated 
1101 children in 15 studies (not including the above study) a non-significant increase in the 
risk of bleeding requiring surgical intervention (OR 1.69, 95% CI 0.71-4.01) was seen. There 
was no increased risk of bleeding that required non-surgical intervention (OR 0.99, 95% CI 
0.41-2.40). When ketorolac was excluded from the analysis, the risk of bleeding requiring 


surgical intervention decreased (OR 0.89, 95% CI 0.28-2.83) and bleeding requiring non-
surgical intervention decreased as well (OR 0.30, 95% 0.04-3.46). To date there has been no 
study suggesting that there is a trend towards increased bleeding rates when IV ibuprofen is 
utilized during tonsillectomy. This is an important consideration, as 1-2% of patients 
undergoing ERCP may experience clinically significant bleeding as a result of the procedure 
[9].  
 
The proposed study is unique as it is the first to evaluate an IV NSAID for the 
prevention of PEP and it is the first to evaluate any pharmacologic intervention to 
prevent PEP in the pediatric population. In addition, previous studies have focused mainly 
on patient populations identified to be at “high risk” for developing PEP. This is possible 
because risk factors for the development of PEP have been well identified in the adult 
population [28]. This is problematic as even low risk adult patients can develop moderate to 
severe PEP, and a high-risk pediatric population has not been appropriately identified. We 
would argue that a PEP incidence of 11% justifies administration of a preventative 
intervention in all pediatric patients undergoing the procedure, particularly if the intervention 
can be shown to be safe and effective. Thus, this study proposes a randomized control trial to 
study single dose IV ibuprofen at a dose of 10mg/kg (max 800mg) at the time of ERCP for 
the prevention of PEP in pediatric patients undergoing ERCP.  
 
1. 
Barkay, O., et al., Endoscopic retrograde pancreatography. Clin Gastroenterol Hepatol, 2009. 
7(9): p. 931-43. 
2. 
Troendle D.M., A.O., Huang R., Barth B.A. Post-ERCP Pancreatitis in Children and 
Adolescents. in DDW. 2014. Chicago. 
3. 
Frank, C.D. and D.G. Adler, Post-ERCP pancreatitis and its prevention. Nat Clin Pract 
Gastroenterol Hepatol, 2006. 3(12): p. 680-8. 
4. 
Elmunzer, B.J., et al., A randomized trial of rectal indomethacin to prevent post-ERCP 
pancreatitis. N Engl J Med, 2012. 366(15): p. 1414-22. 
5. 
Cotton, P.B., et al., A lexicon for endoscopic adverse events: report of an ASGE workshop. 
Gastrointest Endosc, 2010. 71(3): p. 446-54. 
6. 
Ohlsson, A., R. Walia, and S.S. Shah, Ibuprofen for the treatment of patent ductus arteriosus 
in preterm and/or low birth weight infants. Cochrane Database Syst Rev, 2013. 4: p. 
CD003481. 
7. 
Lewis, S.R., et al., Nonsteroidal anti-inflammatory drugs and perioperative bleeding in 
paediatric tonsillectomy. Cochrane Database Syst Rev, 2013. 7: p. CD003591. 
8. 
Moss, J.R., et al., A multicenter, randomized, double-blind placebo-controlled, single dose trial 
of the safety and efficacy of intravenous ibuprofen for treatment of pain in pediatric patients 
undergoing tonsillectomy. Paediatr Anaesth, 2014. 
9. 
Committee, A.S.o.P., et al., Complications of ERCP. Gastrointest Endosc, 2012. 75(3): p. 467-
73. 
10. 
Baron, T.H., et al., Quality indicators for endoscopic retrograde cholangiopancreatography. Am 
J Gastroenterol, 2006. 101(4): p. 892-7. 
11. 
Cotton PB, L.G., Vennes J, Geenen JE, Russell RC, Meyers WC, Liguory C, Nickl N, 
Endoscopic sphincterotomy complications and their management: an attempt at consensus. 
Gastrointest Endosc, 1991. 37(3): p. 383-93. 
12. 
Enestvedt, B.K., et al., Endoscopic retrograde cholangiopancreatography in the pediatric 
population is safe and efficacious. J Pediatr Gastroenterol Nutr, 2013. 57(5): p. 649-54. 
13. 
Otto, A.K., et al., An appraisal of endoscopic retrograde cholangiopancreatography (ERCP) for 
pancreaticobiliary disease in children: our institutional experience in 231 cases. Surg Endosc, 
2011. 25(8): p. 2536-40. 
14. 
Durakbasa, C.U., et al., Diagnostic and therapeutic endoscopic retrograde 
cholangiopancreatography (ERCP) in children and adolescents: experience in a single 
institution. Eur J Pediatr Surg, 2008. 18(4): p. 241-4. 


15. 
Issa, H., A. Al-Haddad, and A.H. Al-Salem, Diagnostic and therapeutic ERCP in the pediatric 
age group. Pediatr Surg Int, 2007. 23(2): p. 111-6. 
16. 
Cheng, C.L., et al., Diagnostic and therapeutic endoscopic retrograde 
cholangiopancreatography in children: a large series report. J Pediatr Gastroenterol Nutr, 
2005. 41(4): p. 445-53. 
17. 
Choudhary, A., et al., Pancreatic stents for prophylaxis against post-ERCP pancreatitis: a 
meta-analysis and systematic review. Gastrointest Endosc, 2011. 73(2): p. 275-82. 
18. 
Mazaki, T., et al., Prophylactic pancreatic stent placement and post-ERCP pancreatitis: an 
updated meta-analysis. J Gastroenterol, 2014. 49(2): p. 343-55. 
19. 
Iqbal, C.W., et al., Post-ERCP pancreatitis in pediatric patients. J Pediatr Gastroenterol Nutr, 
2009. 49(4): p. 430-4. 
20. 
Harada, R., et al., Nonprevention of post-endoscopic retrograde cholangiopancreatographic 
pancreatitis by pancreatic stent after aspiration of pure pancreatic juice in patients with 
intraductal papillary mucinous neoplasms of the pancreas. Pancreas, 2010. 39(3): p. 340-4. 
21. 
Sethi, S., et al., A meta-analysis on the role of rectal diclofenac and indomethacin in the 
prevention of post-endoscopic retrograde cholangiopancreatography pancreatitis. Pancreas, 
2014. 43(2): p. 190-7. 
22. 
Makela, A., T. Kuusi, and T. Schroder, Inhibition of serum phospholipase-A2 in acute 
pancreatitis by pharmacological agents in vitro. Scand J Clin Lab Invest, 1997. 57(5): p. 401-7. 
23. 
Cosen-Binker, L.I., et al., Influence of nitric oxide-donating nonsteroidal anti-inflammatory 
drugs on the evolution of acute pancreatitis. Shock, 2006. 25(2): p. 190-203. 
24. 
Ebbehoj, N., et al., Indomethacin treatment of acute pancreatitis. A controlled double-blind 
trial. Scand J Gastroenterol, 1985. 20(7): p. 798-800. 
25. 
Puig, I., et al., How and When Should NSAIDs Be Used for Preventing Post-ERCP 
Pancreatitis? A Systematic Review and Meta-Analysis. PLoS One, 2014. 9(3): p. e92922. 
26. 
Smith, H.S. and B. Voss, Pharmacokinetics of intravenous ibuprofen: implications of time of 
infusion in the treatment of pain and fever. Drugs, 2012. 72(3): p. 327-37. 
27. 
Dani, C., et al., High-dose ibuprofen for patent ductus arteriosus in extremely preterm infants: 
a randomized controlled study. Clin Pharmacol Ther, 2012. 91(4): p. 590-6. 
28. 
Freeman, M.L., Complications of endoscopic retrograde cholangiopancreatography: avoidance 
and management. Gastrointest Endosc Clin N Am, 2012. 22(3): p. 567-86. 
 
 
3. Concise Summary of Project: 
This project proposes a pilot study evaluating the effectiveness of IV ibuprofen at preventing 
PEP in the pediatric population. The goal of the study is to gather preliminary data to allow 
sample size calculations for a future multi-center trial and evaluate the safety of administering 
IV Ibuprofen at the time of ERCP. The design of the proposed study is a prospective 
randomized double-blind control trial comparing IV Ibuprofen to placebo (normal saline) at the 
time of procedure in all patients undergoing ERCP at Children’s Medical Center over a two 
year period. IV ibuprofen will be given as a single dose of 10mg/kg (max: 800mg) at the time 
of endoscopy. It will be drawn up from a single use vial and diluted with normal saline to a 
concentration of 4mg/ml and will be infused over a 15 minute time period. Those assigned to 
receive the placebo control will receive an equivalent amount of normal saline only over the 
same time period. 128 eligible patients are expected to be encountered over the two-year 
study period. A total of 120 patients will be consented for this study (60 to receive placebo, 60 
to receive IV ibuprofen). The main outcome measurement will be development of PEP. Rates 
of post-ERCP bleeding will also be measured as a secondary safety endpoint. The results of 
this study will be utilized for the developing a larger multicenter study. 
 
4. Study Procedures: 
This study is designed as a prospective, randomized, double-blinded, clinical trial. We plan to 
enroll 120 consecutive patients undergoing ERCP at CMC Dallas over a two year study 


period. All patients will be enrolled at CMC Dallas by study team members. Figure 1 displays 
approximate timing of all study procedures. 
 
 
 
 
 
 
 
 
 
After a decision is made that a patient will undergo ERCP and before the procedure is 
performed, a member of the study team will approach the patient and their family for 
participation and consent. All providers who perform ERCP at CMC Dallas are members of 
the study team, which should allow for efficient screening of all potential subjects.  After 
consent is obtained, a study team member will fill out the pre-procedural form to collect 
demographic information as well as clinical information to quantify anticipated disposition and 
risk for developing AEs (Appendix A). All study patients will also undergo a pre-procedural 
pain assessment. Communicative patients will be asked to mark their level of pain on a Likert 
scale. Non-communicative patients will have the pain assessment completed by a legal 
guardian (Appendix E). Consenting patients will be randomly assigned to receive a single 
dose of either 10mg/kg (not to exceed 800mg) IV-ibuprofen or IV-normal saline at the time of 
scope insertion and patients will subsequently undergo ERCP as planned. The patient, study 
team, and endoscopist will be blinded to the intervention. Upon completion of the procedure a 
study team member will fill out the procedural form to document any intra-operative AEs as 
well as techniques performed during the procedure that may predispose to the development 
of AEs (Appendix B). 
 
Subsequent management will be dictated by routine clinical care practices. Patients 
undergoing a planned outpatient procedure will be monitored after the procedure for at least 
60 minutes per routine post-op protocol after which they may be discharged at the discretion 
of the care team. Decisions for unplanned admissions to manage abdominal pain, bleeding or 
any other adverse event will be made at the discretion of the care team. Patients who are 
unexpectedly admitted because of post-operative pain will have amylase and lipase drawn 
the morning following the procedure to determine if PEP is present per routine clinical 
practice. For those who experience clinical signs of bleeding, a CBC will be drawn at least 
once during the course of the admission after gastrointestinal bleeding is identified 
(hematemesis, hematochesia, or melena) to evaluate for development of post-ERCP 
bleeding. Subsequent lab draws and clinical management will be at the discretion of the 
clinical service caring for the patient. The patient will be followed until management of the 
adverse event is complete after which a study team member will fill out an adverse event 
form (Appendix C). 
 
Patients undergoing an inpatient procedure, or who will have a planned admission after 
ERCP will have amylase/lipase drawn the following day if abdominal pain concerning for 
pancreatitis develops that is likely to lead to delayed discharge or further delays in clinical 
care, which would constitute routine clinical care. Similarly, a CBC will be drawn on any 
inpatient who demonstrates clinical evidence of gastrointestinal bleeding (hematemesis, 
hematochezia, or melena). Subsequent lab draws and clinical management will be at the 
discretion of the clinical service caring for the patient. The patient will be followed until 
Figure 1: Study Procedures 
* Patient Consent 
* Pre-ERCP form 
* Pre-ERCP pain 
assessment 
* Procedure 
form 
days
0 
1 
14 
*Post-ERCP pain 
assessment 
*2 week 
f/u form 
*adverse 
event 
form 
*Intervention* 


management of the adverse event is complete after which a study team member will fill out 
an adverse event form (Appendix C).  
 
All enrolled patients will undergo a post-operative pain assessment which will be conducted 
by a member of the study team 24 hours (defined as between 20-28 hours) after the ERCP. 
For current inpatients, the patient or a legal guardian will be asked to describe their level of 
pain on a Likert scale in a fashion analogous to the pre-procedural assessment. They will 
have a copy of their pre-procedural pain assessment for reference. For discharged patients, a 
phone assessment will be made where they will be asked to rate their pain on a scale of 1-
10. They will have been given a copy of their pre-procedural pain assessment for reference. 
The post-procedure pain score will be recorded by a study team member (Appendix E). An 
amylase and lipase will be drain on all patients who have a pain score which increases 
between the pre-operative and post-operative evaluation as would be a part of routine clinical 
care. This information will be made available to both study team members and the primary 
care team for the patient to aid with clinical decision making. 
 
Two weeks after the procedure, a follow-up phone call or clinic visit will occur as is routine 
clinical practice for all patients undergoing ERCP at CMC Dallas. The information gathered 
from this two week follow-up communication will be filled out into the 2-week f/u form 
(Appendix D). The purpose of this interaction will be to identify patients who experienced an 
adverse event that might otherwise have been missed. For those patients in whom an AE is 
identified during this interaction, the AE will be followed to completion and then the adverse 
event form will be filled out by a study team member. For those patients who are unable to be 
reached at the two-week time point, three additional attempts will be made to reach the 
participant by phone. If after these attempts no contact is made, this will be noted on the 
follow-up form and the information available in the medical record will be utilized to determine 
if an AE occurred. This communication will not occur before 14 days following the procedure 
and all additional attempts to reach the family will be completed by 30 days following the 
procedure. 
 
The subject will not be responsible for any research-related costs and will not be 
compensated for participating. Patient’s participation will be completed upon completion of 
the two week follow-up interaction or upon completion of the management of any AEs, 
whichever is longer. For study purposes, no patient is anticipated to be followed for more 
than two months time. For patient’s whom require ongoing management of their AEs beyond 
two months time will have their AEs characterized according to the information available up 
until that time point utilizing the standardized criteria previously mentioned.  
 
 
Defining AEs: 
This study will monitor for both procedure related AEs as well as potential drug related AEs. 
Procedure related AEs will be systematically characterized utilizing the American Society of 
Gastrointestinal Endoscopy (ASGE) lexicon for AEs.  Accordingly, a procedure relate AE will 
be defined as any event that prevents completion of the planned procedure and/or results in 
admission to hospital, prolongation of existing hospital stay, another procedure, or 
subsequent medical consultation. A listing of all procedure related AEs that will be specifically 
monitored for during this study, along with their associated definition can be found in Table 1 
below. 
 
Procedural Related AEs 
Definition 
Pancreatitis 
Typical pain, amylase/lipase>3xULN 


(primary endpoint) 
Bleeding 
(secondary endpoint) 
Hematemesis and/or melena or hemoglobin drop>2grams 
Pain 
New or increased abdominal pain not related to pancreatitis or 
other AE. 
Cholangitis 
Fever >38C, >24 hours after procedure AND new or 
worsening cholestasis 
Fever without a source 
Fever >38C, >24 hours after procedure AND without an 
obvious source 
Perforation 
Evidence of air or luminal contents outside the GI tract 
Other (specify) 
 
Other procedure related adverse event not captured by 
definitions listed above 
 
Each procedure related AE will be characterized in terms of timing (pre-procedural, 
intraprocedural, <14 days post procedural, or >=14 days post procedural), likelihood of 
attribution (definite, probable, possible, unlikely) and severity (see Table 2 below). While all 
procedural related AEs will be recorded, only probable or definite cases of PEP or post-
ERCP related bleeding will be included in the final analysis of the primary and secondary 
endpoints. 
 
Consequence 
Mild 
Moderate Severe 
Fatal 
Procedure aborted because of AE 
X 
 
 
 
Post-procedure medical 
consultation 
X 
 
 
 
Unplanned anesthesia support 
 
X 
 
 
Unplanned admission or 
prolongation of hospital stay for 
<=3 nights 
X 
 
 
 
Unplanned admission or 
prolongation for 4-10 nights 
 
X 
 
 
Unplanned admission or 
prolongation for >10 nights 
 
 
X 
 
ICU admission for 1 night 
 
X 
 
 
ICU admission for >1 night  
 
 
X 
 
Transfusion 
 
X 
 
 
Repeat endoscopy for AE 
 
X 
 
 
Interventional radiology for AE 
 
X 
 
 
Interventional treatment for 
integument injuries 
 
X 
 
 
Surgery for AE 
 
 
X 
 
Permanent disability (specify) 
 
 
X 
 
Death 
 
 
 
X 
Table 2: Severity grading for AEs. 
 
Drug related AEs will be monitored throughout the study until the 2 week follow-up interaction 
is completed.  They will be defined as any untoward or unfavorable medical occurrence 
including any abnormal sign (e.g. abnormal physical exam or laboratory finding), symptom, or 
disease, temporally associated with the participants’ involvement in the research, whether or 
not considered related to participation in the research and will be elicited through direct 
patient interaction at 24 hours and 2 weeks after the procedure as well as review of the 


medical record up to 2 weeks following the procedure. Table 3 shows the definitions that will 
be utilized to define potential drug related AEs. The ASGE lexicon definitions outlined above 
will be utilized to categorize these AEs in terms of timing, attribution, and severity. 
 
Drug Related AE 
Definition 
Infection 
Any infection (ex: bacteremia, pneumonia, 
cholangitis) which is documented or 
presumptively treated during the course of study 
involvement. 
Bronchospasm 
Any new or increased use of any bronchodilator 
during the course of study involvement. 
Hypoxia 
Any new or increased oxygen requirement 
during the course of study involvement. 
Hematemesis 
Any visible blood in emesis during the course of 
study involvement. 
Hematochesia 
Any visible blood in stool during the course of 
study involvement. 
Skin reaction 
Any new rash during the course of study 
involvement. 
Elevated creatinine  
Creatinine increase above baseline and 
elevated for age during the course of study 
involvement. 
Allergic Reaction 
Any clinical condition felt to be a reaction to a 
medication or product as determined by their 
provider during the course of study involvement. 
Cardiovascular 
thrombotic event 
Any documented myocardial infarction or stroke 
during the course of study involvement. 
Other (specify) 
Any untoward or unfavorable medical 
occurrence including any abnormal sign (e.g. 
abnormal physical exam or laboratory finding), 
symptom, or disease, temporally associated with 
the participants’ involvement in the research, 
whether or not considered related to 
participation in the research not captured by 
definitions above 
Table 3: Study lexicon for potential drug related AEs which will be specifically monitored for in 
this study 
 
5. Sub-Study Procedures: 
Not applicable 
 
6. Criteria for Inclusion of Subjects: 
Age<=18 years 
Undergoing ERCP (defined as cannulation of the major or minor papilla) for any indication 
 
7. Criteria for Exclusion of Subjects: 
Age>18 
Pancreatitis within the 72 hours preceding ERCP 
Allergy or hypersensitivity to Aspirin or NSAID medications 
Pregnancy or breastfeeding mother 


Cr >1.4 
Gastrointestinal hemorrhage in preceding 72 hours 
Heart disease reliant upon a patient ductus arteriosis  
History of sickle cell disease 
 
8. Sources of Research Material: 
The laboratory data that will be collected and utilized during this study is data that will be 
generated as part of routine clinical care. No data will be specifically collected for research 
purposes only. All data will be obtained from the medical records at CMC Dallas.  
 
9. Recruitment Methods and Consenting Process: 
All potential subjects will be patients of the investigators as they perform all ERCPs at CMC 
Dallas. Potential subjects will be approached for inclusion after the decision is made that an 
ERCP will be performed and before the procedure is performed.  Patient of all ages and 
ethnicities will be approached for consent. For those patients between the age of 12 and 18, 
parental consent and patient assent will be obtained. For Spanish speaking patients, a short 
form Spanish consent will be obtained after the study is fully explained to them in their native 
language. Every effort will be made to minimize the potential for undue influence or coercion. 
It will be emphasized that patients will receive the same care whether they participate in the 
study or not. In addition the potential benefits of participating in the study will not be overly 
exaggerated. 
 
10. Potential Risks: 
Since its introduction as a possible PEP preventative measure, the fear is that NSAIDS may 
increase risks of bleeding associated with ERCP.  Multiple studies suggest that the standard 
risk of clinically significant bleeding after ERCP is in the range of 1-2% [9]. While IV ibuprofen 
has not been studied in the setting of ERCP, there is now a fair amount of surgical literature 
to suggest that NSAIDS, and ibuprofen in particular, do not increase risks of bleeding in 
general. A recent meta-analysis of NSAIDs (indomethacin and diclofinac) during ERCP 
showed no increased risk of clinically significant bleeding compared to placebo [21]. A recent 
multicenter study of single dose IV ibuprofen at 10mg/kg given just prior to tonsillectomy, 
another procedure associated with a relatively high risk of bleeding, showed no increased risk 
of bleeding [8]. In a meta-analysis of NSAIDS given during tonsillectomy which evaluated 
1101 children in 15 studies, a non-significant increase in the risk of bleeding requiring 
surgical intervention (OR 1.69, 95% CI 0.71-4.01) was seen. There was no increased risk of 
bleeding that required non-surgical intervention (OR 0.99, 95% CI 0.41-2.40). When ketorolac 
was excluded from the analysis, the risk of bleeding requiring surgical intervention decreased 
(OR 0.89, 95% CI 0.28-2.83) and bleeding requiring non-surgical intervention decreased as 
well (OR 0.30, 95% 0.04-3.46) [7].To date there has been no study suggesting that there is a 
trend towards increased bleeding rates when IV ibuprofen is utilized during tonsillectomy. 
Thus, based on the available literature, we feel that there is unlikely to be increased risk of 
bleeding with a single dose of IV ibuprofen given at the time of ERCP. That being said, 
because this procedure is associated with a relatively high rate of bleeding complications and 
IV ibuprofen has not been specifically evaluated for this indication, it is a secondary outcome 
that will be monitored. 
 
In this study we will be utilizing placebo (normal saline) controls. In the adult population, 
placing a pancreatic stent has been shown to reduce rates of PEP and is considered by 
many to be “the gold standard” [17, 18]. Pancreatic stenting to prevent PEP has not been 
specifically evaluated in the pediatric population. In reviewing our data at CMC Dallas since 
2004, we found that placing a pancreatic stent in patients who had their pancreatic duct 


injected during ERCP (a population we found to be at high risk for PEP on a multivariate 
analysis), rates of PEP actually increased significantly (20% vs 34%, p-value 0.041) [2]. 
Indeed, it has been suggested that certain adult populations (smaller pancreatic ducts, thicker 
secretions) may not benefit from pancreatic stent placement and that they may actually be 
detrimental [20]. Combining the fact that placing a pancreatic stent is technically difficult with 
the paucity of data behind pancreatic stenting to prevent PEP in children has lead many 
endoscopists performing endoscopy in children to abandon the practice.  Taking this into 
account, along with our personal experience with stenting outlined above, we conclude that it 
is both ethical and appropriate to utilize placebo as opposed to pancreatic stenting for our 
control patients.  
 
11. Subject Safety and Data Monitoring: 
Currently, IV ibuprofen is not FDA approved for the prevention of post-ERCP pancreatitis or 
in patients <18 years of age. Thus, this study will be filing an Investigational New Drug (IND) 
application with the FDA and await approval prior to enrollment. This study team will also 
adhere to the following Data Safety Monitoring Plan (DSMP). 
 
A blinded interim analysis by an independent reviewer (Dr. Lillienne Chan, a pediatric 
gastroenterologist at UT Southwestern Medical Center who is familiar with clinical research 
design and analysis) will be performed after 60 patients are enrolled (50% of the total study 
enrollment) or sooner if one of the following criteria are met: 
• 12 episodes of post-ERCP pancreatitis occur or  
• 3 episodes of post-ERCP bleeding occur  
These numbers were chosen because this would represent a doubling of the expected rate of 
post-ERCP pancreatitis and post-ERCP bleeding to be experienced in 60 patients.  
 
For each subject, the reviewer will be provided with the following: 
• Study identification number 
• Whether or not the primary endpoint occurred (PEP) 
• Whether or not the secondary endpoint occurred (post-ERCP bleeding) 
• In which group (A or B) the patient belonged 
 
If >66% of the post-ERCP pancreatitis or post-ERCP bleeding events occur in a particular 
group, the independent reviewer will break the code linking which intervention the patients 
received (IV Ibuprofen or placebo). This value was selected because it represents a 2:1 
(double) frequency of the endpoint outcomes. The study will be stopped if either endpoint 
occurs at this high rate in the IV Ibuprofen group. If the increased rate of pancreatitis is seen 
in the control group, then a formal statistical analysis will be performed and statistical 
significance will only be declared if the two-sided p value is less than 0.05 at which point the 
study will be terminated as it would be unethical to withhold IV Ibuprofen from future patients. 
If the independent reviewer is required to break the code, the study team members will not be 
aware of this fact unless the study must be terminated. The study team will only be told if they 
may continue the study or not. 
 
12. Procedures to Maintain Confidentiality: 
Patient, demographics, pre-procedural and procedural based risk factors, and follow-up data 
(Appendix A-D) will be entered into a REDCaps database in a de-identified fashion providing 
an encrypted mode of data storage that minimizes the risk of loss of confidentiality. Only 
study team members will be provided access to the REDCaps database. A separate 
password protected excel file linking patients MRN to their study identification number will be 


maintained by the primary investigator. This file will be located on the secure departmental 
drive only. No information will be disclosed to outside persons or entities. 
 
13. Potential Benefits: 
Research subjects who are randomized to the IV ibuprofen group may experience decrease 
rates of PEP (study primary outcome). Overall, this study is designed to identify a potential 
therapeutic means of preventing PEP in all pediatric patients who undergo ERCP. The data 
from this study will be utilized in the design of a larger multicenter clinical trial. It is the first 
study of its kind, designed to specifically evaluate the ability of a pharmacologic agent to 
prevent PEP in pediatric patients. 
 
14. Biostatistics:  
In 2013, 59 ERCPs were performed at CMC Dallas, 56 of whom would have met 
inclusion/exclusion criteria for this study. As we experience an approximate 10% increase in 
ERCP volume annually, it is reasonable to estimate that we will encounter 128 patients who 
will meet inclusion criteria over the two-year study period. 
 
The PEP incidence rate in the control group is estimated to be 11% based on CMC historical 
data. A recent meta-analysis suggests that NSAIDS at the time, or just after ERCP reduces 
the incidence of PEP by 51% [25]. Assuming a 50% reduction can be achieved with IV 
Ibuprofen, the incidence rate in the treatment group is estimated to be 5% over the same time 
period. With a sample size of 120 (60 in the treatment group and 60 in the control group), the 
power to detect a significant difference is 22.1%. Although it is underpowered, this pilot study 
will provide valuable information toward the design of a larger multicenter randomized clinical 
trial. 
 
The primary endpoint analysis will utilize the Fisher’s exact test or chi square test (depending 
on sample size) to analyze the difference in the proportion of patients with post-ERCP 
pancreatitis in the indomethacin group and the placebo group. A difference will be considered 
significant at p-value <0.05 (two-sided). Similarly, the secondary endpoint analysis will utilize 
the Fisher’s exact test or chi square test (depending on sample size) to analyze the 
difference in the proportion of patients with post-ERCP bleeding in the indomethacin group 
and the placebo group. A difference will be considered significant at p-value <0.05 (two-
sided). The incidence and severity of all adverse events throughout the study duration will be 
summarized using descriptive statistics.