PrEveNtion of Biliary Events After Acute Pancreatitis in NonSUrgicaL PAtients: PENINSULA Trial

Our working hypothesis is that endoscopic treatment with biliary sphincterotomy will reduce the number of biliopancreatic events compared to conservative treatment in patients with non-operable biliary acute pancreatitis (AP) due to a high surgical risk or in those patients who refuse surgery.

The primary aim is to assess the recurrence of the combined variable of biliopancreatic events (BPE) (biliary colic, cholangitis, choledocholithiasis, acute cholecystitis or AP) of the endoscopic sphincterotomy strategy during the follow-up time after diagnosis of AP of biliary origin in inoperable patients with respect to conservative treatment.

This is a randomized, multicenter, open-label, nationwide, intention-to-treat clinical trial. Patients will be randomized 1:1 to the two treatment groups stratified by center and AP severity.

Centers considered to participate as collaborators centers will need to have an endoscopy unit with ERCP availability that perform more than 150 ERCPs/year, and endoscopists trained in this technique. Patient inclusion and exclusion criteria is specified in a specific section of the protocol.

For the inclusion of patients, after diagnosis of biliary AP (BAP), and having ruled cholecystectomy as a possibility for the patient because of high surgical risk (after evaluation by surgery or anesthesia) or patient's refusal to undergo cholecystectomy, the absence of choledocholithiasis will be confirmed by MRCP or EUS.

If the patient fulfills these requirements, in addition to all the previous inclusion criteria and none of the exclusion criteria, and agrees to participate in the study and signs the informed consent the patient will be included and randomized.

This randomization will be carried out in each of the collaborating centers and the patient will be assigned to a treatment group following the random assignment method.

The randomization of patients to each of the treatment groups will be carried out centrally by the REDCap software; REDCap is a program that offers an online electronic data collection notebook. It will be stratified by center and by severity of BAP (mild, moderate or severe according to the Revised Atlanta Classification).

Patients will be randomized to receive ERCP biliary sphincterotomy or conservative management. 63 patients will be allocated to each group. An interim safety analysis is proposed, which will be evaluated by an independent committee of 3 persons, with experience in complications associated with ERCP and knowledge of biliopancreatic pathology, once 50% of the sample reaches 6 months of follow-up. In the event that in this first analysis the risks of treatment outweigh the benefits, according to the decision of the safety committee, the study could be stopped. Also, in the event that at this point there are statistically significant differences in favor of treatment by biliary sphincterotomy with respect to the primary outcome, recruitment can be stopped and the study stopped early.

In the group assigned to receive endoscopic treatment, ERCP for biliary sphincterotomy will be performed during the index admission for acute pancreatitis, prior to discharge or up till one month from discharge.

The procedure will be performed after at least 6 hours of fasting during the index admission, by endoscopists in charge of performing ERCP as usual in the collaborating centers under sedation controlled by endoscopists or anesthesia according to the usual practice of the Endoscopy Unit of each collaborating center.

For ERCP biliary cannulation, the usual techniques available in each center will be used, including advanced cannulation techniques if necessary. The type of papilla, cannulation attempts, time to biliary cannulation and the technique(s) used will be recorded. Possible adverse effects will be recorded. If biliary cannulation is not possible, a new ERCP attempt will be performed within a maximum of one month. If biliary cannulation is still not achieved, it will be counted as a technical failure, maintaining the established clinical follow-up.

The inhospital management of patients with AP in the conservative treatment group, before and after randomization, will be under the care of their responsible physicians on the hospitalization wart at the corresponding collaboration center who will follow the management recommended by the clinical guidelines. Their discharge will be decided by their regular physician.

Periodic follow-up contacts will be made: at one month, at 6 months and at one year. Contacts may be made by face-to-face or telematic visits after consultation with the patient, especially if the patient is institutionalized or has severe mobility problems.

In these contacts, the following will be performed:

• Record of complications associated with the treatment received and record of BPE developed since the last visit (especially the presence of biliary colic that did not require admission or evaluation in the emergency department). An interview will be conducted aimed at collecting the presence of BPE that did not require admission (such as biliary colic or related pain), recording the type and date of onset. The digital medical record will also be reviewed to record admissions and assessments by the emergency department related or unrelated to BPE and also to assess mortality.
• EORTQ30 quality of life questionnaire will be conducted in every visit.