Rectal Indomethacin in the Prevention of Post-ERCP Pancreatitis in High Risk Patients: Searching for the Optimal Dose. A Prospective, Randomized Trial
Phase: PHASE2
Conditions: Post-ERCP Pancreatitis
Sponsor: Indiana University

Version date 07-13-2017 
 
E-mail Correspondence with the Food and Drug Administration (FDA) regarding 
an exemption for an Investigational New Drug (IND) Application  
 
 
From: xxx 
Sent: Friday, April 05, 2013 8:23 AM 
To: xxx 
Cc:  
Subject: FW: Rectal Indomethacin for Patients Undergoing ERCP 
 
Dear xxx: 
 
We have received, on March 19, 2013, your e-mail dated March 19, 2013, for 
Indocin Suppositories. This submission contains a protocol titled, "Rectal 
Indomethacin in the Prevention of Post-ERCP Pancreatitis in High Risk Patients: 
Searching for the Optimal Dose. A Prospective, Randomized Trial" and a request 
for exemption from the requirement to conduct the study under an Investigational 
New Drug Application. 
 
After reviewing the information contained in your submission, we have concluded that 
your study meets all of the requirements for exemption from the IND regulations and, 
therefore, an IND is not required to conduct your investigation. 
 
 
 
 

Version date 07-13-2017 
 
 
Rectal Indomethacin in the Prevention of  
Post- ERCP Pancreatitis in High Risk Patients:  
Searching for the Optimal Dose. 
A Prospective, Randomized Trial 
 
 
Protocol Version 8.0 
 
 
 
 
Evan L. Fogel, MD 
Professor of Medicine 
Indiana University 
 
 
 
Richard S. Kwon, MD  
 
 
 
Glen Lehman, MD 
Assistant Professor of Medicine 
 
 
Professor of Medicine 
University of Michigan 
 
 
 
Indiana University 
 
James Scheiman, MD 
 
 
 
Stuart Sherman, MD 
Professor of Medicine  
 
 
 
Professor of Medicine 
University of Michigan 
 
 
 
Indiana University 
 
Grace Elta, MD 
 
 
 
 
Paul Tarnasky, MD 
Professor of Medicine  
 
 
 
Clinical Associate Professor of Medicine 
University of Michigan 
 
 
 
University of Texas Southwestern 
 
Nalini Guda, MD 
 
 
 
 
B. Joseph Elmunzer, MD 
Clinical Associate Professor of Medicine 
 
Associate Professor of Internal Medicine 
University of Wisconsin 
 
 
 
Medical University of South Carolina 
 

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A. Objective:  To compare the efficacy of two different dose regimens of prophylactic rectally-administered 
indomethacin on the incidence on post-endoscopic retrograde pancreatography (ERCP) pancreatitis (PEP) 
in high-risk patients. 
 
B. Hypotheses and Specific Aims 
 
H1 (primary):  A higher peri-procedure dose of rectal indomethacin at ERCP will reduce the incidence of 
PEP in high risk patients, compared with standard dosing. 
 
H2 (secondary): A higher peri-procedure dose of rectal indomethacin at ERCP will reduce the incidence of 
moderate to severe PEP in high risk patients, compared with standard dosing. 
 
SA1 (primary): To perform a prospective, randomized, double-blind clinical trial comparing a higher dose 
indomethacin regimen to standard dosing in preventing PEP in high-risk patients. 
 
SA2 (secondary): In the same format as SA1, to compare a higher dose indomethacin regimen to standard 
dosing in preventing moderate to severe PEP in high-risk patients. 
 
C. Background, preliminary data, and significance 
 
Pancreatitis is the most frequent complication of endoscopic retrograde cholangiopancreatography (ERCP), 
accounting for substantial morbidity, occasional mortality, and increased health care expenditures (1-3). 
Multiple pharmacologic agents have been evaluated in the prevention of post-ERCP pancreatitis (PEP) (4). 
Recently, interest has developed in the study of non-steroidal anti-inflammatory drugs (NSAIDs) for the 
prevention of PEP.  Mechanistically, NSAIDs are potent inhibitors of phospholipase A2, prostaglandins, and 
neutrophil/endothelial interaction, all believed to play an important role in the pathogenesis of acute 
pancreatitis (5-7). Animal models have demonstrated that NSAIDs can reduce mortality associated with 
pancreatitis (8-10) and a small human trial of indomethacin in non-ERCP acute pancreatitis showed 
improvement in clinical outcomes (11). 
 
NSAIDs are attractive in the pharmacologic prevention of PEP because they are widely available, 
inexpensive, and easily administered. In addition, they appear to have a favorable risk profile when given 
as a one-time dose to appropriately selected patients. Prospective clinical trials evaluating the use of 
NSAIDS in ERCP have shown that the incidence of adverse events attributable to NSAIDs, including post-
procedure hemorrhage, is equivalent in the NSAIDs and placebo groups (12-17). This observation is 
congruent with previously published data suggesting that NSAIDs in standard doses do not increase the 
risk of significant bleeding after biliary sphincterotomy (3,18). 
 
Several prospective clinical trials have evaluated rectal NSAIDs in the prevention of PEP (12-15,17). Murray 
et al. (12) demonstrated a statistically significant benefit of rectal diclofenac in 220 patients who either 
underwent pancreatography or had manometrically documented sphincter of Oddi dysfunction (SOD). 
Conversely, Sotoudehmanesh et al. (13) failed to show prophylactic benefit of rectal indomethacin in 442 
mostly low-risk patients. A post hoc subgroup analysis of this study, however, did reveal a protective effect 
in patients undergoing pancreatic duct injection, although the power of this subgroup was insufficient to 
draw concrete clinical conclusions. Khoshbaten et al. (14) showed a statistically significant benefit of rectal 
diclofenac in 100 patients undergoing pancreatography and Montano Loza et al. (15) also demonstrated a 
benefit in 150 patients at low-risk for PEP receiving rectal indomethacin or placebo. A meta-analysis of 
these four studies evaluating rectal NSAIDs in preventing post-ERCP pancreatitis revealed a statistically 
significant 64% reduction in PEP, with a number needed to treat to prevent one episode of pancreatitis of 
15 patients (19). Although the results of this meta-analysis were encouraging, several limitations were 
noted. First, the component studies enrolled patients at variable risk for PEP. As such, it remained unclear 
from these data whether rectal NSAIDs were effective in both high and low risk patients, and if so, which 
group derived the most favorable risk & cost-benefit ratios. Second, the meta-analysis included outcomes 
from studies evaluating either diclofenac or indomethacin. While these drugs demonstrate similar 

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phospholipase A2 inhibition in vivo, it remains unclear if both drugs are independently clinically effective 
(20,21). Moreover, prior positive meta-analyses of prophylactic agents in preventing PEP have 
subsequently been disproved by additional rigorous clinical investigation (22,23). Therefore, a definitive 
clinical trial evaluating rectal indomethacin in the prevention of PEP was needed to confirm the results of 
the meta-analysis (19) and establish a concrete role for prophylactic rectal NSAIDs in clinical practice. 
 
In order to specifically address this issue, Elmunzer and colleagues recently evaluated the role of rectal 
indomethacin in the prevention of PEP in high-risk patients (17). This multicenter, randomized, placebo-
controlled, double-blind clinical trial assigned high-risk patients (82% had suspected or confirmed SOD) to 
receive a single dose (100mg) of rectal indomethacin or placebo (a glycerin suppository) immediately after 
ERCP. Post-ERCP pancreatitis developed in 27/295 patients (9.2%) in the indomethacin group compared 
with 52/307 (16.9%) in the placebo group (p=0.005). This beneficial effect of indomethacin was seen across 
all subgroups analyzed. Furthermore, moderate-to-severe pancreatitis rates were significantly lower in the 
indomethacin group (4.4% vs 8.8%, p=0.03). Adverse events were uncommon, as clinically significant 
bleeding occurred in 4 patients in the indomethacin group and 7 patients in the placebo group (p=0.72). 
Two cases of acute renal failure occurred, both in the placebo group. While confirmatory data would be of 
interest, indomethacin appears to be the first unequivocally effective pharmacologic agent in the prevention 
of PEP in high-risk patients. Indeed, anecdotal data currently suggest that indomethacin is being 
increasingly adopted into widespread clinical use for the prophylaxis of PEP. 
 
While the beneficial effect of indomethacin as demonstrated by Elmunzer et al. (17) represents a major 
advancement in PEP prevention, pancreatitis rates remain unacceptably high in high-risk patients  --  nearly 
10% in this study which took place in academic centers with experienced endoscopists. When used as an 
analgesic or anti-inflammatory agent in the management of patients with arthritis (gout, rheumatoid, 
ankylosing spondylitis), the recommended maximal daily dose of indomethacin is 200 mg per day, in divided 
doses (product insert, Merck & Co.). The half-life of this agent is approximately 4.5 hours. Potentially, a 
higher dose of indomethacin, perhaps leading to a higher peak serum concentration, might further lower 
PEP rates in high-risk patients.  Alternatively, a second dose of the drug might lead to a more sustained 
effect. We acknowledge that there are no pharmacokinetic data to confirm or substantiate these 
hypotheses. If either of these phenomena is important in pancreatitis prevention, then a regimen consisting 
of a higher initial dose followed by a second dose may be hypothesized to be superior.  
 
While all patients undergoing ERCP may benefit from the protective effect of indomethacin, the incidence 
of pancreatitis in high-risk patients is such that prevention of PEP in this patient population would lead to 
the most substantial reduction in morbidity and health care costs. Moreover, the elevated baseline risk of 
PEP in high-risk patients makes clinical trials in this group more feasible due to more manageable sample 
sizes. 
 
Our objective is to perform a prospective, randomized, double-blind trial evaluating two different dose 
regimens of rectal indomethacin in the prevention of PEP. While a single 100 mg dose (the “standard” dose) 
is effective in high-risk patients (17), the ideal or most efficacious dose regimen is unknown. This study will 
determine which dose regimen of rectal indomethacin is more effective in preventing post-ERCP 
pancreatitis. The results will help the research team determine whether there is reason to continue this line 
of research or whether it would be better to focus on a different area (perhaps use of another class of drugs 
or a device). 
 
D. Sample size calculation: 
 
An internal audit of high-risk ERCPs at the four tertiary referral centers involved in this clinical trial reveals 
a PEP rate of approximately 10%, despite the routine use of prophylactic pancreatic duct stent placement 
(24-26) in appropriate patients and selective use of indomethacin. It is anticipated that the patient 
characteristics/demographics in this study will be very similar to that of Elmunzer et al. (17), as inclusion 
and exclusion criteria will be the same (see below). In that study (17), the PEP rate in patients who received 
indomethacin 100 mg was 9.2%. To achieve a 50% reduction in the rate of PEP (i.e. to 4.6%), with two-
sided α=0.05 and a power of 0.8, the necessary sample size is 1036. This absolute reduction in incidence 

Version date 07-13-2017 
is felt to be clinically relevant and substantial enough to change existing clinical practice. 
 
E. Methodology- Design and procedures 
 
This study is designed as a prospective, randomized, double-blind clinical trial. We plan on enrolling 1036 
high-risk patients undergoing ERCP. These patients will be enrolled at six tertiary care hospitals in the 
United States: Indiana University Hospital (Indianapolis, IN), University of Michigan Medical Center (Ann 
Arbor, MI), Methodist Dallas Medical Center (Dallas, TX), Aurora St. Luke’s Medical Center (Milwaukee, 
WI), the Medical University of South Carolina (Charleston, SC), and Beth Israel Deaconess Medical Center 
(Boston, MA). The study will be conducted after approval from the internal review committees of all 
participating institutions.  We have been granted an IND exemption from the Food and Drug Administration 
for this protocol (see attached). 
 
Patients, study personnel, and treating physicians will be blinded to study group assignment. The 
randomization schedule, which is stratified according to study center, will be generated centrally at the 
University of Michigan and distributed to the other study sites. The randomization schedule will be kept by 
personnel not directly involved with the study. This same personnel will be responsible for packaging the 
drug and placebo.  Based on current annual procedure volume, it is assumed that 700 patients will be 
recruited by the Indiana University site, with 336 patients recruited by the other sites. These estimates are 
not binding, as all sites will be allowed to continue recruiting patients until the recruitment goal is met, or 
interim analyses suggest early study termination. The individual sites will order the indomethacin 
suppositories as necessary through the research coordinator at Indiana University, as determined by their 
recruitment rate. The exception to this is MUSC will be ordering indomethacin suppositories on their own, 
which will come from the same manufacturer, G and W laboratories, that all other sites are using.  The 
glycerin suppositories will be obtained either by each institution’s standard ordering procedure, or by 
ordering from Indiana University. If ordering from Indiana University, the suppositories will be shipped 
directly to each individual site.   
 
Inclusion criteria: 
 
The inclusion criteria are intended to select a group of patients at high-risk (approximately 10%) for post- 
ERCP pancreatitis. These criteria are based on patient and procedure-related risk factors that have been 
previously shown in multivariable analyses to confer a significantly increased risk of PEP. 
------------------------------------------------------------------------------------------------- 
 
Included patients are those undergoing ERCP and have: 
 
one of the following: 
 
1) Suspected sphincter of Oddi dysfunction, type I or type II 
2) History of post-ERCP pancreatitis (at least one episode) 
3) Pancreatic sphincterotomy 
4) Pre-cut (access) sphincterotomy 
5) > 8 cannulation attempts of any sphincter 
6) Pneumatic dilation of intact biliary sphincter 
7) Ampullectomy 
8) Assessment for post-sphincterotomy stenosis 
 
or at least 2 of the following: 
 
1)   Age < 50 years old and female gender 
2)   History of recurrent pancreatitis (at least 2 episodes) 
3)   ≥3 pancreatic injections, with at least one injection to tail 
4)   Pancreatic acinarization (excluding ventral pancreas of pancreas divisum) 

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5)   Pancreatic brush cytology. 
 
Exclusion criteria: 
------------------------------------------------------------------------------------------------ 
 
1)   Unwillingness or inability to consent for the study 
2)   Age < 18 years 
3)   Intrauterine pregnancy 
4)   Breastfeeding mother 
5)   Standard contraindications to ERCP 
6)   Allergy / hypersensitivity to aspirin or NSAIDs 
7)   Received NSAIDS in prior 7 days (aspirin 325 mg or less OK) 
8)   Renal failure (Cr > 1.4) 
9)   Active or recent (within 4 weeks) gastrointestinal hemorrhage 
10) Acute pancreatitis (lipase peak) within 72 hours 
11) Known chronic calcific pancreatitis 
12) Pancreatic head mass 
13) Procedure performed on major papilla/ventral pancreatic duct in a patient with pancreas divisum 
(dorsal duct not attempted or injected) 
14) ERCP for biliary stent removal or exchange without anticipated pancreatogram 
15) Subject with prior biliary sphincterotomy now scheduled for repeat biliary therapy without anticipated 
pancreatogram 
16) Anticipated inability to follow protocol 
17) Known active cardiovascular or cerebrovascular disease 
 
 
Protocol:  
 
Subjects who do not meet any exclusion criteria may be consented for the trial by a clinical research 
coordinator or one of the investigators. The consent process will occur prior to ERCP in the procedure 
preparation area. At this time, the objectives of the study as well as the risks and benefits of enrolling will 
be explained in detail to potential subjects. 
 
After obtaining informed consent, subjects will undergo ERCP per clinical protocol. All procedure-related 
clinical decisions and interventions will be dictated by the performing physician as he or she sees fit. At the 
end of the procedure, it will be determined by the endoscopist and research coordinator whether the patient 
meets inclusion criteria. If inclusion criteria are met, subjects will be randomized by concealed allocation to 
receive either 100 mg or 150 mg indomethacin, in the form of two or three 50 mg   identical-appearing rectal 
suppositories. Those patients who are randomized to receive the 100 mg dose will receive an additional 
glycerin suppository. The suppositories will be placed while the patient is still sedated in the ERCP suite, 
prior to transfer to the recovery area. Four hours later (+/- 20 minutes), those patients who were randomized 
to the high-dose group (already received 150 mg dose) will then receive an additional 50 mg suppository 
while in the recovery area. At this same time point, subjects who were randomized to the standard-dose 
group (already received 100 mg dose) will receive a glycerin suppository in the recovery area. All 
participating patients, therefore, will receive a total of 4 suppositories, as summarized below: 
 
 
 
 
      Immediately post-ERCP 
 
 
   4 hours post-ERCP 
 
High dose 
 
Indomethacin 150 mg (50 mg x 3) 
 
Indomethacin 50 mg x 1 
 
Standard dose  
Indomethacin 100 mg (50 mg x 2) 
 
        glycerin x 1 
 
 
 
 
+ glycerin x1 
 
 
 

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There will be one source of indomethacin suppositories for all six participating sites. G and W Laboratories, 
Inc., South Plainfield, NJ  07080 will manufacture the indomethacin suppositories.  The suppositories will 
then be distributed by IROKO Pharmaceuticals, LLC, Philadelphia, PA  19112.  
 
Indomethacin and glycerin suppositories will be packaged according to the randomization schedule by 
personnel not directly involved in the conduct or interpretation of the study. The study package for each 
subject will be an opaque envelope or bottle. High-dose packages will contain 2 small plastic bags: bag #1 
containing 3 indomethacin suppositories and bag #2 containing 1 indomethacin suppository. Standard dose 
packages will contain 2 small plastic bags: bag #1 containing 2 indomethacin suppositories and 1 glycerin 
suppository and bag #2 containing 1 glycerin suppository. The package will be fully opaque such that the 
contents of cannot be discerned without opening the envelope or bottle.  
 
Since there are differences in the appearance of the indomethacin and glycerin suppositories, they will only 
be administered by clinical nurses not involved in the study. Immediately after ERCP, the clinical nurse will 
be instructed to deliver contents of bag #1 and the sealed package will be returned to the study coordinator, 
who will instruct a clinical nurse to deliver the contents of bag #2 approximately four hours after the 
procedure.  
 
The packages will be stored in a clinical refrigerator prior to administration of bag #1 and between 
administration of bags #1 and #2.  
 
Pancreatic duct stent placement will be at the discretion of the endoscopist on a case-by-case basis, as 
patients enrolled in this study will be considered to be at high-risk for PEP. The manufacturer, length, and 
caliber of prophylactic pancreatic stents will also be left to the discretion of the endoscopist, reflecting the 
variability in clinical practices in this area.  
 
At our institutions, subjects are observed in the recovery area for approximately 4 hours after the termination 
of the procedure. Patients who develop abdominal pain (or worsening of their baseline abdominal pain) 
during this observation period are generally admitted to the hospital (for current inpatients, kept in the 
hospital) in order to exclude procedural complications, including pancreatitis and perforation. The decision 
to admit the patient or prolong existing hospitalization will be left to the discretion of the endoscopist and 
clinical service, respectively. Those patients who are hospitalized will have serum amylase and lipase drawn 
at least once 24 hours after the procedure and subsequently at the discretion of the clinical service. Patients 
who are discharged uneventfully after ERCP will be contacted by telephone or email within 5 ± 2 days of 
the procedure by a study team member to evaluate for the development of post-ERCP pancreatitis and 
other related or unrelated complications. All subjects will also be contacted 30 ± 5 days by telephone or 
email after the procedure to verify that information about complications has been captured, particularly 
bleeding which can be delayed after ERCP. Definitions: PEP will be defined per consensus guidelines (27): 
1) New or increased abdominal pain that is clinically consistent with a syndrome of acute pancreatitis and 
2) amylase or lipase ≥ 3x the upper limit of normal 24 hours after the procedure and 3) Hospitalization (or 
prolongation of existing hospitalization) for at least 2 days (at least night of ERCP & next night). Mild PEP 
will be defined as pancreatitis that results in hospitalization (or prolongation of existing hospitalization) for 
≤3 days. Moderate PEP will be defined as pancreatitis that results in hospitalization (or prolongation of 
existing hospitalization) for 4-10 days. Severe PEP will be defined as pancreatitis that results in 
hospitalization (or prolongation of existing hospitalization) for > 10 days, or leads to the development of 
pancreatic necrosis or pseudocyst, or requires additional endoscopic, percutaneous, or surgical 
intervention. 
 
 
 
 
 
Data management: 
 
Patient demographics, risk factors, the procedural elements of the ERCP, and follow-up data will be 

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recorded on a standardized data collection form at the time of the procedure and within 5 days and 30 days 
after the procedure. This information will be recorded by a research coordinator.  All completed data 
collection forms from the University of Michigan Medical Center, Methodist Dallas Medical Center, Aurora 
St. Luke’s Medical Center,the Medical University of South Carolina, and Beth Israel Deaconess Medical 
Center will be faxed, emailed, or uploaded into MiShare and sent to IU.  The data will be transferred by the 
IU study coordinator to a master excel database, housed on a password protected desktop computer in a 
locked research office. A second research team member from IU will perform data entry confirmation. 
 
F. Statistical analysis 
 
For the analysis of the primary endpoint, the difference in the proportion of patients developing post-ERCP 
pancreatitis between the two groups will be analyzed using a two-tailed Fisher's exact test, with a two-sided 
p < 0.05 indicating statistical significance. 
 
After enrolling 400 patients (37.7% of total enrollment) a BLINDED interim analysis will be conducted by 
the independent DSMB as follows.  For each subject the DSMB will be provided with 1) the subject ID 
number, 2) whether or not the primary endpoint (post-ERCP pancreatitis) occurred, 3) whether or not a 
bleeding event occurred, and 4) in which group (high-dose or standard dose regimen) the patient belonged. 
If > 66% of the pancreatitis cases or bleeding cases are in a particular group (high-dose or standard dose 
regimen), the DSMB will break the code to determine whether these events are in the standard 100 mg 
indomethacin group or high-dose indomethacin group. This value was selected because it represents a 
2:1 (double) frequency of an endpoint outcome in one group or another. If either of these events has 
occurred at this high frequency in one group or another, then the DSMB will decide that the study should 
be stopped. Even if the DSMB is required to break the code for this above listed purpose, the investigators 
will never be aware of this information. The DSMB will simply tell the investigators whether or not to 
continue the study. If during this blinded interim analysis, the DSMB finds that the proportion of the patients 
with pancreatitis in the higher dose indomethacin group is significantly lower, a formal statistical analysis 
will be performed and statistical significance will only be declared (and the study terminated) if the two-
sided p value is less than 0.005. In this unlikely circumstance, the DSMB will inform the investigators that 
the study should be terminated for ethical reasons (i.e., it would be unethical to withhold this from high-risk 
patients). 
 
After enrolling 600 subjects (56.6% of total enrollment) a BLINDED interim analysis will be conducted by 
the independent DSMB as follows.  For each subject the DSMB will be provided with 1) the subject ID 
number, 2) whether or not the primary endpoint (post-ERCP pancreatitis) occurred, 3) whether or not a 
bleeding event occurred, and 4) in which group (high-dose or standard dose regimen) the patient belonged. 
This analysis will be performed because it was a specific request of the DSMB that it be performed to ensure 
the safety of subjects. Analysis and criteria for stopping the study at this second interim analysis will be the 
same as those noted above, for the first interim analysis. 
 
For the analysis of the secondary endpoint, the difference in the proportion of patients developing moderate-
severe PEP between the two groups will be analyzed using a two-tailed Fisher's exact test. 
 
An additional secondary analysis will include the multivariate evaluation of the prediction of PEP by 
treatment arm while controlling for covariates, which we expect may contribute to the variance in PEP 
incidence. These covariates will include: 
 
Clinical suspicion of sphincter of Oddi dysfunction 
Age 
Gender 
Race 
Body mass index 
History of recurrent pancreatitis (at least 2 episodes)  
History of post-ERCP pancreatitis (at least one episode)  

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Pancreatic sphincterotomy 
Pre-cut (access) sphincterotomy  
Number of cannulation attempts  
Number of pancreatic injections 
Pneumatic dilation of intact biliary sphincter 
Ampullectomy  
Pancreatic brush cytology 
Pancreatic acinarization 
Cardioprotective aspirin use 
Pancreatic duct stent placement 
Use of double wire cannulation technique 
Trainee involvement in procedure 
Biliary sphincterotomy 
Prophylactic pancreatic stent characteristics (manufacturer/length/caliber) 
Type of sphincter of Oddi dysfunction (suspicion, pre-manometry) 
Inpatient vs. outpatient status 
Participating medical center 
 
 
We realize that the event rate may be too low to include more than a few variables in the multivariate model. 
Based on univariate analysis of each variable in predicting PEP, we will include no more than one variable 
per 10 PEP events in the final multivariate model predicting PEP.  
 
Exploratory subgroup analyses will also be performed on the following pre-specified characteristics: age, 
gender, race, body mass index, suspicion of sphincter of Oddi dysfunction, prior post-ERCP pancreatitis, 
history of recurrent pancreatitis, manometrically documented sphincter of Oddi dysfunction, difficult 
cannulation, pre-cut (access) sphincterotomy, pancreatic sphincterotomy, pancreatic acinarization, biliary 
sphincterotomy, double wire cannulation technique pancreatic stent placement, trainee involvement, 
cardioprotective aspirin use, prophylactic pancreatic stent characteristics, type of sphincter of Oddi 
dysfunction, inpatient vs. outpatient status, and participating medical center. These subgroup analyses 
will allow the development of hypotheses regarding which subgroups of patients, if any, may particularly 
benefit from a more intensive indomethacin regimen.  
Further, we will perform a heterogeneity in treatment effects analysis on enrolled subjects according to 
their pre-treatment risk of post-ERCP pancreatitis, functionally assessing whether the relative treatment 
effect is consistent across the spectrum of study subjects’ risk of post-ERCP pancreatitis. Individual 
subject risk scores will be calculated by assigning one point for each major inclusion criterion and 0.5 
points for each minor inclusion criterion, as previously reported (17).  
It is recognized that some patients may have difficulty holding their suppositories, and expulsion of the 
suppositories may or may not be witnessed by study personnel. All patients will be analyzed on an intent-
to-treat basis, in the group to which they were randomized. However, we anticipate that this point will have 
little impact on study outcome, as indomethacin suppositories dissolve quickly (rather than melt slowly) and 
are seldom recovered in recognizable form if the patient retains the suppository for more than a few minutes 
(product insert, Merck & Co.). If a suppository is recovered in visible and intact form, it may be re-inserted. 
 
G. Budget  
 
Funding for this study has been obtained from the American College of Gastroenterology.  The Clinical 
Research Award amount is $34,975 which will be used for medication costs for all sites, as well as 
coordinator support at Indiana University. 
 
 
 

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References: 
 
1. La Ferla G, Gordon S, Archibald M, et al. Hyperamylasaemia and acute pancreatitis following endoscopic 
retrograde cholangiopancreatography. Pancreas 1986;1(2):160-163. 
 
2. Sherman S, Lehman GA. ERCP and endoscopic sphincterotomy-induced pancreatitis. Pancreas 
1991;6:350-67. 
 
3. Freeman ML, Nelson DB, Sherman S, et al. Complications of endoscopic biliary sphincterotomy. N Engl 
J Med 1996;335:909-18. 
 
4. Frank CD, Adler DG. Post-ERCP pancreatitis and its prevention. Nat Clin Pract 
Gastroenterol Hepatol. 2006;3:680-8 
 
5. Gross V, Leser HG, Heinisch A, at al. Inflammatory mediators and cytokines-new aspects of the 
pathophysiology and assessment of severity of acute pancreatitis? Hepatogastroenterol 1993;40:522-530. 
 
6. Makela A, Kuusi T, Schroeder T. Inhibition of serum phospholipase A2 in acute pancreatitis by 
pharamacologic agents in vitro. Scand J Clin Lab Invest 1997;57:401-408. 
 
7. Davies NM, Anderson KE. Clinical phamacokinetics of diclofenac. Therapeutic insights and pitfalls. Clin 
Pharamakokinet 1997; 33:184-213. 
 
8. Lankisch PG, Koop H, Winckler K et al. Indomethacin treatment of acute experimental pancreatitis in the 
rat. Scand J Gastroenterol 1978;13:629-633. 
 
9. Wildenhain PM, Melhem MF, Birsic WI, et al. Acute hemorrhagic pancreatitis in mice: improved survival 
after indomethacin administration. Digestion 1989;44:41-51. 
 
10. Cosen-Binker LI, Binker MG, Cosen R, et al. Influence of nitric oxide-donating 
nonsteroidal anti-inflammatory drugs on the evolution of acute pancreatitis. Shock 2006;25:190- 
203. 
 
11. Ebbehøj N, Friis J, Svendsen LB, et al. Indomethacin treatment of acute pancreatitis. A controlled 
double-blind trial. Scand J Gastroenterol 1985;20:798-800. 
 
12. Murray B, Carter R, Imrie C, et al. Diclofenac reduces the incidence of acute pancreatitis after 
endoscopic retrograde cholangiopancreatography. Gastroenterology 
2003;124:1786-1791. 
 
13. Sotousdehmanesh R, Khatibian M, Kolahdoozan S, et al. Indomethacin may reduce the incidence and 
severity of acute pancreatitis after ERCP. Am J Gastroenterol 2007; 
102:978-983. 
 
14. Khoshbaten M, Khorram H, Mamad L, et al. Role of diclofenac in reducing postendoscopic retrograde 
cholangiopancreatography pancreatitis. J Gastroenetrol Hepatol 
2007; epub ahead of print. 
 
15. Montaño Loza A, Rodriguez Lomeli X, Garcia Correa J, et al. Effect of rectal administration of 
indomethacin on amylase serum levels after endoscopic retrograde cholangiopancreatography, and its 
impact on the development of secondary pancreatitis episodes. Rev Esp Enferm Dig 2007;99:330-336. 
 

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16. Cheon Y, Cho K, Watkins J, et al. Efficacy of diclofenac in the prevention of post- ERCP pancreatitis in 
predominantly high risk patients: a randomized double-blind prospective trial. Gastrointest Endosc 
2007;66:1126-1132. 
 
17. Elmunzer BJ, Scheiman JM, Lehman GA, et al. A randomized trial of rectal indomethacin to prevent 
post-ERCP pancreatitis. N Engl J Med 2012;366:1414-22.   
 
18. Nelson DB, Freeman ML. Major hemorrhage from endoscopic sphincterotomy: risk factor analysis. J 
Clin Gastroenterol 1994;19:283-287. 
 
19. Elmunzer B, Waljee A, Elta G, et al. A meta-analysis of rectal NSAIDs in the prevention of post-ERCP 
pancreatitis. Gut 2008; epub ahead of print. 
 
20. Van Der Marel C, Anderson BJ, Romsing J, et al. Diclofenac and metabolite pharmacokinetics in 
children. Paediatr Anesth 2004;14:443-451. 
 
21. Gross V, Leser HG, Heinisch A, at al. Inflammatory mediators and cytokines - new aspects of 
pathophysiology and assessment of severity of acute pancreatitis? Hepatogastroenterol 1993;40:522-530. 
 
22. Andriulli A, Leandro G, Niro G, et al. Pharmacologic treatment can prevent pancreatic injury after ERCP: 
a meta-analysis. Gastrointest Endosc 2000;51:1-7. 
 
23. Andriulli A, Leandro G, Federici T, at al. Prophylactic administration of somatostatin or gabexate does 
not prevent pancreatitis after ERCP: an updated meta-analysis. Gastrointest Endosc 2007;65: 624-632. 
 
24. Tarnasky P, Palesch Y, Cunningham JT, et al. Pancreatic stenting prevents pancreatitis after biliary 
sphincterotomy in patients with sphincter of Oddi dysfunction. Gastroenterology 
1998;115:1518-24. 
 
25. Fazel A, Quadri A, Catalano MF, et al. Does a pancreatic duct stent prevent post-ERCP 
pancreatitis? A prospective randomized study. Gastrointest Endosc 2003;57:291-4. 
 
26. Singh P, Das A, Isenberg G, et al. Does prophylactic pancreatic stent placement reduce the risk of post-
ERCP pancreatitis? A meta-analysis of controlled trials. Gastrointest Endosc 2004; 60: 544-550. 
 
27. Cotton PB, Lehman G, Vennes J, et al. Endoscopic sphincterotomy complications and their 
management: an attempt at consensus. Gastrointest Endosc 1991;37:383-393.