Design
The EVL trial is a multi-centre, single-blind, randomized, and controlled trial projected to assess whether EPSP is a superior strategy in preventing PEP. Patients undergoing pancreatic guidewire-assisted technique are randomised into EPSP and LPSP groups.
This study strictly adhered to the SPIRIT 2013 guideline16 for clinical trials and obtained the necessary ethical clearance No. Quick-PJ 2023–14 − 12 (the First Affiliated Hospital Ethics Committee of Anhui Medical University).
Participants and recruitment
Patients with challenging biliary access using pancreatic guidewire-assisted method will be enrolled in the study. Recruitment will take place among individuals referred to the four participating centers for therapeutic biliary procedures. After obtaining signed consent forms, participants who meet all the inclusion criteria and have no exclusion criteria will be randomly grouped (with a 1:1 ratio) into EPSP and LPSP (Fig. 1).
Inclusion criteria
Participants who fulfill all the below criteria will be enrolled: 1. with naive papilla; 2. over 18 years; 3. undergoing ERCP with pancreatic guidewire-assisted technique for biliary access; 4. providing a signed, written informed consent.
Exclusion criteria
Participants who meet any of the following criteria will be excluded: 1. unreachable main papillae; 2. surgically altered gastrointestinal anatomy; 3. concurrent acute pancreatitis; 4. biliary cannulation over pancreatic duct stent after precut sphincterotomy or wire-guided method (native early attribute); 5. failed biliary cannulation; 6. severe active cardiopulmonary disease; 7. breastfeeding or pregnancy; 8. ampullary tumour.
Procedure and interventions
First, all potential individuals will be requested to afford written informed consent by the physicians overseeing this trial at each institution. Therapeutic ERCP procedures will adhere to standard protocols for participant preparation, sedation, and duodenum intubation. Patients will receive sedation using a combination of diazepam, pethidine hydrochloride, midazolam, and/or propofol. Patients will be kept blinded to their assigned treatment arm. To minimize potential confounding factors, rectal diclofenac or indomethacin were not included in the scheduled interventions. After the completion of ERC or EST, enrolled participants will be randomly assigned in a 1:1 ratio to EPSP and LPSP arms. Randomization was stratified by treatment center, ensuring that treatment allocation is balanced within each site. The random numbers and the arm assignment will be provided in sealed envelopes and will be exclusively handled by the central principal investigator. A set of 25 envelopes will be distributed and utilized at each site. Once the initial set of 25 envelopes is exhausted, an additional set of envelopes will be dispatched in blocks of 20 to ensure an adequate supply. These envelopes will be disclosed just after the ERC or EST completion.
In the EPSP group, a single pig-tail pancreatic stent (5Fr) will be inserted instantly after ERC or EST, and subsequent biliary procedures will proceed as planned. In contrast, in the LPSP group, while keeping the PD guidewire in place, a single pig-tail PD stent (5Fr) will be ultimately placed after all completion of therapeutic biliary procedures, e.g. biliary stone removal or drainage. The length of stent will be determined at the discretion of the endoscopist. The decision to remove the prosthesis depended on whether the disorder is benign or malignant. If benign, the PD stent will typically be removed endoscopically within 2 weeks after ERCP, and if malignant, it is usually not removed unless symptoms are present.
Due to the inherent nature of ERCP, it is not feasible to blind the practitioner(s) to the intervention. However, to maintain equal co-treatments between the trial arms, the timing of pancreatic stent placement will not be recorded in the endoscopy and medical record. Furthermore, for enhanced objectivity in data analysis, the project statisticians will be blinded to the arm allocation.
Data collection and follow-up
All participants are hospitalized and their relevant data are collected locally using standardized case record forms (CRFs) before ERCP procedure, intra-procedure, and within 24 h following the procedure. The completion of CRFs will be done by the study group personnel.
Pre-procedure demographics collection will include body mass indexage, sex, previous medical history, blood routine count, blood biochemistry, and the treatment indication.
Intra-procedure data will be documented at the following times: endoscope entry, reaching the papilla of Vater, contact of the sphincterotome with the papilla, successful biliary cannulation, ERC, EST, pancreatic stenting, and completion of endoscopy. Additionally, the endoscopist’s level, ampullary morphology, frequency of papillary contacts, numbers of unintentional PD cannulation, biliary access method, bile duct diameter, and any intraoperative complications will also be noted.
Post-procedure data will include the assessment for hyperamylasemia/ pancreatitis at 24 h following ERCP. Any AEs and readmissions within 30 days after surgery will be documented. The diagnosis and grading of post-ERCP pancreatitis were based on the revised Atlanta Classification17. Cholangitis was defined according to the Tokyo guidelines 201818. For other AEs, such as hemorrhage and perforation, the recommendations provided by the American Society for Gastrointestinal Endoscopy (ASGE)19 will be followed. (Table 1)
Table 1: Definition of ERCP-related AEs.
PEP
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when post-procedural abdominal pain occurs, associated with an elevation in serum pancreatic enzymes of at least three times the normal level occurring more than 24 hours after the procedure. Mild, no organ dysfunction or other adverse events; Moderate, transient organ failure for <48 h or local or systemic adverse events without persistent organ failure; and Severe, persistent single or multi-organ failure for >48 h or present or persistent systemic inflammatory response syndrome.
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Cholangitis
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A. systemic inflammation: body temperature ≥ 38°C, chills, WBC (× 109/L) < 4 or > 10, CRP ⩾ 1g/L; B. cholestasis: TBil ⩾ 34.2 μmol/L, abnormal liver function (ALP(U/L) > 1.5× ULN, γGTP(U/L) > 1.5× ULN, AST(U/L) > 1.5× ULN, ALT(U/L) > 1.5× ULN); C. Imaging: biliary dilatation, imaging findings. Definite diagnosis: 1 A+1 B+ 1 C.
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Hemorrhage
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clinical evidence of bleeding with a decrease in hemoglobin of at least 2 g/dL.
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Perforation
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suspected perforation was based on clinical findings and definite if leak of contrast was observed.
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ERCP: endoscopic retrograde cholangiopancreatography. PEP: post-ERCP pancreatitis. AEs: adverse events. WBC: white blood cell. CRP: C-reactive protein. TBil: total bilirubin. ALP: alkaline phosphatase. AST: aspartate transaminase. ALT: alanine transaminase. γGTP: γ-glutamyltranspeptidase. ULN: upper limit of normal.
Endpoint
The primary endpoint is the incidence and severity of PEP. The secondary endpoints are hyperamylasemia, the rate of stenting success, and other ERCP-related adverse events (AEs). Adjudicators will be blinded when assessing the endpoint.
Analyses
All analyses will be conducted according to the intention-to-treat principle, which means that all patients who are randomized will be included in the analysis based on their initially assigned study arm. Cases of failed stenting, inadvertent loss of PD guidewire, and stenting in advance due to the impact of the persistence of PD guidewire on subsequent biliary manipulations will not be excluded from the analyses, which because these scenarios can occur in the clinical setting and should be accounted for in the analysis. Multiple regression analysis will be performed where appropriate. We will also perform analyses depending on subgroups, such as age ⩽ 50years, sex, indication, duodenal diverticulum, history of pancreatitis, normal bilirubin levels, non-biliary dilation, and balloon dilatation of an intact biliary sphincter. Results of the EVL trials will be reported in accordance with the guidelines outlined in the Consolidated Standards of Reporting Trials (CONSORT) Statement (Fig. 2). Statistical significance was determined for two-tailed P-values less than 0.05.
Premature termination of the study
An interim analysis will be conducted by a blinded statistician once the follow-up of 384 patients, which corresponds to 50% of the total, is completed. The study will be halted if a significant difference (p < 0.001) is detected between the primary results of the two groups, and it will not be terminated for futility.
Clinical monitoring
Data will be stored and managed using a secure encrypted program to ensure confidentiality and security. A comprehensive site monitoring project is implemented to maintain that the trial is conducted in adherence to the registered protocol, regulatory standards, and good clinical practice. Verification of study and regulatory documents will be carried out remotely. Independent monitors, who are not blinded to the treatment assignments, will visit participating sites annually to perform source document verification on 10% of the case report forms (CRFs), which includes all components of the primary endpoint. In the event of any inconsistencies, a thorough inspection of all CRFs will be conducted.