Randomized Trial of Rectal Indomethacin and Papillary Spray of Epinephrine Versus Rectal Indomethacin to Prevent Post-ERCP Pancreatitis

Background: Post-ERCP pancreatitis (PEP) is the most common complication of endoscopic
retrograde cholangiopancreatography (ERCP) with an estimated incidence of 3-7% among average
risk patients and 15-20% among patients at high risk for developing PEP. Around 500,000 -
700,000 ERCPs are performed annually in U.S. Even with a modest incidence of 5%, PEP results
in approximately $150 million in healthcare costs in the US alone.

A recent landmark controlled trial demonstrated the superiority of rectal nonsteroidal
antiinflammatory drug - NSAIDs (indomethacin) over placebo in preventing PEP among patients
at high risk for PEP. Also, epinephrine sprayed on the major duodenal papilla was shown to
reduce the incidence of PEP in multiple studies. Our group performed a network meta-analysis
(NMA) which simultaneously compared 16 drugs evaluated in 99 randomized controlled trials
with 25,313 patients, to determine their relative efficacy using direct and indirect
comparisons. Interestingly, the NMA ranked epinephrine as the best performing drug, followed
by rectal NSAIDs and nafamostat.

Indomethacin acts on pancreatic inflammation while epinephrine sprayed on duodenal papilla
keeps the pancreatic duct open by reducing papillary edema. The use of these drugs in
combination may potentially synergistically reduce or further reduce the incidence of PEP.

Hypothesis: A combination of papillary spray of epinephrine and rectal indomethacin is
superior to the use of rectal indomethacin alone, for PEP prophylaxis among patients at high
risk for PEP.

Sample size justification: Based on the information from earlier controlled trials, the
Investigators assume that PEP incidence will be 10% in the rectal NSAID arm (Group A) and it
will be reduced to 5% by the additional use of papillary spray of epinephrine (Group B).
Therefore, a total of 474 patients in each arm, or 948 patients in total, will be required to
see a 50% difference between the groups with a power of 0.8 and two sided alpha of 0.05.

Recruitment and Consenting: Patients scheduled to undergo ERCP will be screened for patient
based inclusion / exclusion criteria and will be consented, in the private waiting area of
the endoscopy units.

Randomization procedures and delivery of drugs: During ERCP performed according to standard
clinical care, if the endoscopist determines that the patient meets the criteria for
'high-risk', the study coordinator will randomize the patient to either group A or B in a 1:1
fashion using a web-based central randomization system. Randomization will be stratified by
each center and a randomly varying block size will be used. The patients will be randomized
to either Group A - Patients will receive 20 ml of normal saline sprayed on the duodenal
papilla and surrounding regions of edema, over a period of 1 minute using any ERCP
cannulation catheter, at the end of procedure, just before the withdrawal of endoscope;
followed by 100 mg of rectal indomethacin OR Group B - Patients will receive 20 ml of 0.02%
epinephrine sprayed on the duodenal papilla and surrounding regions of edema, over a period
of 1 minute using any ERCP cannulation catheter, at the end of procedure, just before the
withdrawal of endoscope; followed by 100 mg of rectal indomethacin.

Statistical Plan: For the statistical analysis of primary end point, the difference in
proportion of PEP among the two groups will be calculated by stratifying the site and by
combining patients from all sites, as separate analyses. A two sided p-value of <0.05 will be
considered statistically significant. The severity of PEP, mortality and other complications
related to PEP will also be compared among the two groups. The data on the risk factors of
PEP, incidence of PEP will be used for the development of PEP risk

Data and safety monitoring board (DSMB) charter: An Independent DSMB, clinical trial monitor
(safety officer) will be formed consisting of five endoscopists from India and U.S., with
expertise in biostatistics and clinical trial methodology. DSMB will review study related
documentation including and not limited to, protocol, standard operating procedures, consent
form, data entry forms; monitor study performance, will ensure adherence to good clinical
practice guidelines and regulatory requirements; and will make appropriate recommendations to
the investigators. All adverse events, will be reported to the safety officer by the study
coordinators at each center. Blinded interim analysis will be performed at 33% and 66% of the
sample size. If the PEP incidence or complication rate is >25% in any of the treatment
groups, DSMB will break randomization code and will terminate the study. During interim
analysis, if a statistically significant difference is found between the two groups
(p<0.001), the study will be terminated for ethical considerations.

Inclusion Criteria:

- Major inclusion criteria (If patients meet at least 1 of the criteria):

1. History of PEP

2. Pancreatic sphincterotomy

3. Pre-cut sphincterotomy

4. Difficult cannulation (>5 attempts / 10 minutes to cannulate)

5. Failed cannulation

6. Pneumatic dilation of an intact sphincter

7. Sphincter of Oddi dysfunction of Type I or Type II

- Minor inclusion criteria (If patients meet at least 2 of the criteria):

1. Age < 50 & Female gender

2. History of acute pancreatitis (at least 2 episodes)

3. >/= 3 pancreatic injections (with at least 1 injection in tail)

4. Pancreatic acinarization

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 or epinephrine

7. Chronic renal disease (Cr > 1.4)

8. Active or recent (within 4 weeks) gastrointestinal hemorrhage

9. Acute pancreatitis (lipase peak) within 72 hours

10. Known chronic calcific pancreatitis

11. Pancreatic head mass

12. Receiving pancreatic duct stent placement for any indication

13. Procedure performed on major papilla/ventral pancreatic duct in patients with pancreas
divisum

14. ERCP for pancreatic/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. Sphincter of Oddi dysfunction of Type III