A Double-Blind Study to Determine if Intraduodenal Indomethacin Can Decrease the Incidence of Post-ERCP Pancreatitis

Post-ERCP pancreatitis is likely due to the patient's inflammatory response to duct
instrumentation during the procedure and severity is based on the magnitude of this
response. Phospholipase A2 (PLA2) plays a pivotal role in inflammation since it regulates
many pro-inflammatory mediators, including prostaglandins, leukotrienes, and platelet
activating factor. NSAIDs inhibit PLA2, and indomethacin is the most potent clinically
available PLA2 inhibitor. Our study hypothesis is that treatment with indomethacin will
reduce the inflammatory response to ERCP, and therefore lessen the incidence and severity of
post-ERCP pancreatitis.

Aim: We plan to conduct a prospective, multicenter, randomized, placebo-controlled trial to
determine if a single dose of 100 mg indomethacin suspension instilled into the duodenum by
the endoscope immediately following ERCP can reduce the incidence and severity of post-ERCP
pancreatitis.

Patients scheduled to undergo diagnostic or therapeutic ERCP would be serially enrolled.
Standard indications for ERCP will include the following: evaluation of obstructive
jaundice, unexplained pancreatitis, recurrent pancreaticobiliary pain and abnormal liver
tests. Those patients who are deemed to be at increased risk of pancreatitis (suspected
sphincter of oddi dysfunction, age < 40 yrs, normal bilirubin, prior post ERCP pancreatitis,
difficult cannulation, pancreatic duct injection, pancreatic duct sphincterotomy, undergoing
pre-cut sphincterotomy and balloon dilation of the biliary sphincter) would undergo
placement of a 3 French pancreatic stent at the time of ERCP. Prospective randomized studies
have demonstrated a marked decrease in post-ERCP pancreatitis rates in high risk patients
who have undergone pancreatic stenting. Following ERCP and therapy (if required), they would
be randomized to receive a dose of indomethacin or placebo instilled into the duodenum via
the biopsy channel of the duodenoscope. Patients as well as physicians and nurses performing
the procedure and overseeing the study will be unaware of treatment assignments.

All of the endoscopic and clinical practices will follow the current standard of care of the
Yale interventional endoscopy department. Participation in the study will not alter this in
any way. The experimental intervention is limited to the administration of a single dose of
indomethacin, injected into the endoscope channel prior to removal of the scope at the
conclusion of the ERCP and subsequent monitoring for signs and symptoms of post-ERCP
pancreatitis, much of which is also part of routine clinical practice.

At the end of the procedure the details of the endoscopic maneuver are recorded, including
ease/difficulty of cannulation, sphincterotomy (biliary and/or pancreatic) performed, number
of cannulations, number of pancreatic duct injections, technique of sphincterotomy (Needle
Knife/Stent vs pull-type) and duct diameters.

All patients will be observed for 4 hours following ERCP which is part of the routine
clinical practice following ERCP. Patients with minimal pain will be discharged after a
4-hour period of observation. All patients will have baseline serum amylase levels which
will be repeated 4 hours after the ERCP has been completed. Patients with significant
abdominal pain following ERCP will be hospitalized overnight and evaluated for post-ERCP
pancreatitis with monitoring of vital signs, urinary output and serum amylase levels the
following morning. Patients with ongoing symptoms at 48 hours and later will undergo imaging
with either abdominal ultrasonography or CT scanning. This also represents current standard
clinical practice.

Patients discharged home will be contacted by telephone the following day to assess for
complications including post-ERCP pancreatitis.

Inclusion Criteria:

- Patients undergoing ERCP as part of their clinical care.

Exclusion Criteria:

- Pancreatitis within 60 days of ERCP

- Age less than 18 years

- Pregnant patients

- Patients who have received NSAIDs within the past 7 days

- Patients with a previous allergy to NSAIDs

- Patients who were previously enrolled in the study

- Patients with a history of peptic ulcers, gastrointestinal bleeding, on
anticoagulants and/or with a bleeding diathesis.