Acute pancreatitis is among the most common gastrointestinal causes for hospitalization in the U.S. Roughly one in five patients with acute pancreatitis will have recurrent bouts. Recurrent acute pancreatitis (RAP) is a strong risk factor for progression to chronic pancreatitis, an irreversible fibroinflammatory disease that greatly impacts quality of life, and is also a risk factor for pancreatic cancer. Increased intraductal pressure is an accepted cause for precipitating an episode of acute pancreatitis. Pancreas divisum, seen in 7-10% of the general population, occurs when the dorsal and ventral pancreatic ducts have incomplete or nonexistent fusion during early embryologic development. Using this rationale, endoscopists often perform endoscopic retrograde cholangiopancreatography (ERCP) with minor papilla sphincterotomy (miES) in patients who have idiopathic RAP (iRAP) and pancreas divisum with a goal to reduce subsequent attack(s). This practice remains highly controversial, due to major limitations in the available data which are derived almost exclusively from small, retrospective cohort studies with inconsistent and subjective outcomes. This is one of the highest risk indications for ERCP, having post-ERCP pancreatitis rates of 10-20%. The SpHincterotomy for Acute Recurrent Pancreatitis (SHARP) trial is a sham-controlled, single blind with a blinded outcome assessment, randomized trial evaluating the impact of miES on the natural history of iRAP in patients with pancreas divisum. Eligibile participants were randomized using an equal (1:1) allocation to either EUS + sham or EUS + ERCP with miES and followed for up to 48 months. A biorepository was established for future exploratory studies of novel risk factors for RAP, progression to chronic pancreatitis and its sequelae, and factors associated with response to miES. Patients fulfilling the entry criteria but declining enrollment into the randomized trial were approached to enroll into an observational cohort.

To compare the incidence of acute pancreatitis > 30 days after treatment allocation using the next attack of acute pancreatitis during the follow up period.

The SHARP trial had three main secondary objectives:

• to compare the incidence rate ratio of acute pancreatitis between treatment groups defined as the incidence rate (episodes/time pre- and post-randomization; since baseline incidence rate is a probable predictor of post-randomization incidence rate, the investigators compare the incidence rate ratios between the two arms, keeping person-time equal between the pre/post periods);
• to compare changes in patient-centered outcomes between treatment groups; and,
• to compare progression rates to chronic pancreatitis.

The primary outcome of the next attack of acute pancreatitis is a time-to-event outcome that is assessed starting 30 days after treatment allocation through a maximum follow-up of 48 months.The secondary outcome measures are: the change in incidence rate of attacks, patient-centered outcomes, and progression to chronic pancreatitis.

• Patient must consent to be in the study and must have signed and dated an approved consent form.
• >18 years
• Two or more episodes of acute pancreatitis, with each episode meeting two of the following three criteria:
  • abdominal pain consistent with acute pancreatitis (acute onset of a persistent, severe, epigastric pain often radiating to the back);
  • serum lipase activity (or amylase activity) at least three times greater than the upper limit of normal;
  • characteristic findings of acute pancreatitis on CECT, MRI or transabdominal ultrasonography.
• At least one episode of acute pancreatitis within 24 months of enrollment
• Pancreas divisum confirmed by prior MRCP that is reviewed by an abdominal radiologist at the recruiting site.
• By physician assessment, there is no certain explanation for recurrent acute pancreatitis.
• Patients must be able to fully understand and participate in all aspects of the study, including completion of questionnaires and telephone interviews, in the opinion of the clinical investigator.

• Prior minor papilla therapy (endoscopic or surgical)
• Calcific chronic pancreatitis, defined as parenchymal or ductal calcifications identified on computed tomography or magnetic resonance imaging scan that is reviewed by an expert radiologist at the recruiting site.
• Main pancreatic duct stricture*
• Presence of a structural etiology for acute pancreatitis, such as anomalous pancreatobiliary union, periampullary mass, or pancreatic mass lesion on imaging*
• Presence of a local complication from acute pancreatitis which requires pancreatogram
• Regular use of opioid medication for abdominal pain for the past three months
• Medication as the etiology for acute pancreatitis by physician assessment
• TWEAK score ≥ 4
• Hypertriglyceridemia, defined as a serum triglyceride level > 500mg/dL during a prior episode of acute pancreatitis
• Hypercalcemia, defined as a corrected serum calcium level > 10.5mg/dL associated with a prior episode of acute pancreatitis
• Clinical presentation consistent with type I or type II autoimmune pancreatitis
• Pregnancy (urine test)
• Low probability of follow-up on a regular basis to achieve study objectives
• Life expectancy < 6 months based on the opinion of the physician investigator

In this randomized trial including 148 individuals with unexplained acute recurrent pancreatitis and pancreas divisum followed up for a median of 34 months, ERCP with minor papillotomy did not significantly reduce the rate of acute pancreatitis during follow-up (34.7% vs 43.8% for sham ERCP; adjusted hazard ratio, 0.83 [95% CI, 0.49-1.41]). There was no between-group difference in acute pancreatitis episode frequency and development of chronic calcific pancreatitis, diabetes, or exocrine pancreatic dysfunction.