The purpose of the SVI study was to determine whether rectal indomethacin had no important loss of efficacy compared to the combination of rectal indomethacin and prophylactic pancreatic stent placement in patients undergoing high-risk endoscopic retrograde cholangiopancreatography (ERCP) who required pancreatic stent placement (PSP) for the sole purpose of pancreatitis prevention. The primary efficacy endpoint was defined as post-ERCP pancreatitis defined per consensus (Atlanta) criteria.

This was a blinded, two-armed, non-inferiority trial where eligible patients were randomized to either the combination treatment or indomethacin alone. Participants were randomized during the ERCP procedure after eligibility was confirmed and received indomethacin at the time of randomization. The primary efficacy endpoint of post-ERCP pancreatitis within 2 days from randomization was assessed by an independent adjudication panel. The participant follow-up period was 30 days from randomization.

Primary Objective: To assess whether rectal indomethacin alone was non-inferior to the combination of rectal indomethacin and prophylactic pancreatic stent placement (PSP) for preventing post-ERCP pancreatitis (PEP) in high-risk cases.

Secondary Objective: To establish a repository of whole blood, serum, plasma, urine, duodenal fluid, and stool from study participants to allow future translational research elucidating the molecular and genetic mechanisms of PEP, as well as the mechanisms by which non-steroidal anti-inflammatory drugs prevent this complication.

The primary outcome measure was post-ERCP pancreatitis, based on a widely validated consensus definition that was applied as a diagnostic framework. In this consensus definition, post-ERCP pancreatitis was diagnosed if there was new onset (or increase) of pain in the upper abdomen, elevation in pancreatic enzymes of at least three times the upper limit of normal 24 hours after the procedure, and hospitalization for at least two nights. The outcome was independently adjudicated by three ERCP experts at non-enrolling centers based on review of the medical records for study participants who were hospitalized with any adverse event within 2 days of the ERCP. To ensure unbiased assessment of the primary outcome, medical records were redacted of all information that could potentially reveal study group assignment, including radiology reports. The consensus definition was applied as a diagnostic framework (rather than a strict definition) so that adjudicators could use their best judgment in cases that did not strictly satisfy the criteria (e.g., pancreatic enzymes not collected until 2 days after ERCP). The secondary outcome measure was moderate or severe post-ERCP pancreatitis, also based on the consensus definition as a diagnostic framework. For the severity assessment, radiographic information was made available to the adjudicators.

Inclusion criteria:

• Any patient undergoing ERCP in whom pancreatic stent placement is planned for post-ERCP pancreatitis prevention, is ≥ 18 years old, who provides informed consent, AND has one of the following:
• Clinical suspicion of or known sphincter of Oddi dysfunction
• History of post-ERCP pancreatitis (at least one prior episode of pancreatitis after ERCP)
• Pancreatic sphincterotomy
• Pre-cut (access) sphincterotomy (including septotomy)
• Difficult cannulation: cannulation duration ≥ 6 minutes (starting at time of initial papillary engagement with at least 25% of the time in contact with the papilla) AND/OR ≥ 6 cannulation attempts (defined as sustained contact with papilla lasting at least 1 second)
• Short-duration (≤ 1 minute) balloon dilation of an intact biliary sphincter Or has at least two of the following:
• Age < 50 years old and female gender
• History of recurrent pancreatitis (at least 2 episodes)
• ≥ 3 pancreatic injections
• Pancreatic acinarization
• Pancreatic brush cytology

Exclusion criteria:

• Ampullectomy
• Cases in which a pancreatic stent must be placed for therapeutic intent
• Unwillingness or inability to consent for the study
• Pregnancy
• Breast feeding mother
• Standard contraindication to ERCP
• Allergy to Aspirin or NSAIDs
• Ongoing or recent (within 1 week) hospitalization for acute pancreatitis, or known ongoing biochemical or anatomic evidence of unresolved pancreatic injury
• Known chronic calcific pancreatitis

Between September 17, 2015, and January 25, 2023, a total of 1,950 participants were randomly assigned. Post-ERCP pancreatitis occurred in 145 (14.9%) of 975 participants in the indomethacin alone group and in 110 (11.3%) of 975 participants in the indomethacin plus stent group (risk difference 3.6%; 95% CI: 0.6-6.6; p=0.18 for non-inferiority). A post-hoc intention-to-treat analysis of the risk difference between groups showed that indomethacin alone was inferior to the combination of indomethacin plus prophylactic stent (p=0.011). The relative benefit of stent placement was generally consistent across study subgroups but appeared more prominent among participants at highest risk for pancreatitis. Safety outcomes (serious adverse events, intensive care unit admission, and hospital length of stay) did not differ between groups.