Efficacy and safety of aggressive hydration for preventing post-endoscopic retrograde cholangiopancreatography pancreatitis: study protocol for a phase 3, multicenter, open-label, randomized controlled study

Efficacy and safety of aggressive hydration for preventing post-endoscopic retrograde cholangiopancreatography pancreatitis: study protocol for a phase 3, multicenter, open-label, randomized controlled study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Study protocol Efficacy and safety of aggressive hydration for preventing post-endoscopic retrograde cholangiopancreatography pancreatitis: study protocol for a phase 3, multicenter, open-label, randomized controlled study Reiko Yamada, Kenji Nose, Takamitsu Tanaka, Tetsuro Miwata, Yasuaki Shimada, and 37 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8469484/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 5 You are reading this latest preprint version Abstract Background Endoscopic retrograde cholangiopancreatography (ERCP), a procedure to treat pancreaticobiliary disorders, is generally safe. However, adverse events (AEs) of post-ERCP pancreatitis (PEP) can occur, which can be fatal. Physicians performing ERCP can take measures to prevent PEP, including endoscopic pancreatic duct stents and pharmacological prophylaxis. Periprocedural aggressive hydration has been investigated for its potential for reducing PEP risk. This study aims to evaluate the efficacy and safety of periprocedural aggressive hydration plus intrarectal diclofenac versus standard hydration therapy plus intrarectal diclofenac in preventing PEP onset in Japanese patients. Methods This phase 3, multicenter, open-label, randomized controlled study is being conducted at an anticipated 27 sites in Japan. The study plans to enroll 780 adults (aged ≥ 18 years) who are scheduled to receive an ERCP procedure. Patients will be randomized 1:1 to the aggressive hydration or standard hydration group. Approximately 8 h prior to the ERCP procedure, patients in both groups will be administered the main infusion (≤ 1.5 mL/kg/h). The aggressive hydration group will receive a bolus of 500 mL Ringer’s solution at the start of the ERCP procedure (500 mL/h) followed by Ringer’s solution administered at 3mL/kg/h for 8 h. The standard hydration group will be administered Ringer’s solution at 1.5 mL/kg/h initiated at the start of the ERCP procedure and continuing for 9 h. Within 30 min of completing the ERCP procedure, patients in both groups will receive intrarectal diclofenac sodium (standard, 50 mg; patients weighing < 50 kg or aged ≥ 80 years, 25 mg). The primary endpoint is the incidence of PEP (serum amylase ≥ 400 U/I after ERCP completion and persistent abdominal pain for ≥ 24 h). Secondary endpoints include the incidence of PEP by severity, the incidence of hyperamylasemia (increase in amylase ≥ 400 U/I), and the incidence of infusion-related AEs. AEs will be monitored throughout the study. Discussion This study aims to clarify whether aggressive hydration reduces PEP incidence versus standard hydration, and to compare PEP incidence by severity, and the incidence of hyperamylasemia and infusion-related AEs. Safety will be determined in both groups. Trial registration: Japan Registry of Clinical Trials (jRCT: s041230145; registered February 6, 2024; https://jrct.mhlw.go.jp/latest-detail/jRCTs041230145 ) Aggressive hydration endoscopic retrograde cholangiopancreatography post-endoscopic retrograde cholangiopancreatography pancreatitis Figures Figure 1 Administrative Information Note: the numbers in curly brackets in this protocol refer to SPIRIT checklist item numbers. The order of the items has been modified to group similar items (see http://www.equator-network.org/reporting-guidelines/spirit-2013-statement-defining-standard-protocol-items-for-clinical-trials/). Title {1} Efficacy and safety of aggressive hydration for preventing post-endoscopic retrograde cholangiopancreatography pancreatitis: study protocol for a phase 3, multicenter, open-label, randomized controlled study Trial registration {2a and 2b}. Japan Registry of Clinical Trials (jRCT: s041230145; registered February 6, 2024; https://jrct.mhlw.go.jp/latest-detail/jRCTs041230145) Protocol version {3} Version 1.4, April 24, 2025 Funding {4} Mie University Hospital Specified Clinical Trial Promotion Grant (S2023-002) Author details {5a} Reiko Yamada 1 , Kenji Nose 1 , Takamitsu Tanaka 1 , Tetsuro Miwata 1 , Yasuaki Shimada 1 , Minako Urata 1 , Atsushi Kanno 2 , Eriko Ikeda 2 , Hiroyuki Isayama 3 , Ichiro Yasuda 4 , Nobuhiko Hayashi 4 , Takuji Iwashita 5 , Shinya Uemura 6 , Keisuke Iwata 7 , Yuhei Iwasa 7 , Fumihiro Okumura 8 , Kensaku Yoshida 9 , Ken Sugimoto 10 , Yasushi Hamaya 10 , Tadahisa Inoue 11 , Yasuki Hori 12 , Kazuki Hayashi 13 , Eizaburo Ohno 14 , Senju Hashimoto 15 , Yoshihiko Tachi 16 , Hideki Kamada 17 , Motohiro Yoshinari 18 , Shunpei Hashigo 19 , Yumi Oya 20 , Tomoki Nakaji 20 , Ryohei Sakaguchi 21 , Isao Moritani 22 , Shunsuke Tano 23 , Hiroaki Naota 24 , Hajime Imai 25 , Toshitaka Fukui 25 , Shinya Kawaguchi 26 , Mitsuru Okuno 27 , Yasuto Imai 28 , Toru Ogura 28 , Satoshi Tamaru 28 , Hayato Nakagawa 1 1 Department of Gastroenterology and Hepatology, Mie University Hospital, Mie University School of Medicine, Mie, Japan 2 Department of Gastroenterology and Hepatology, Jichi Medical University Hospital, Tochigi, Japan 3 Department of Gastroenterology, Juntendo University Hospital, Juntendo University School of Medicine, Tokyo, Japan 4 Department of Gastroenterology, University of Toyama Hospital, Toyama, Japan 5 Department of Gastroenterology, Shiga University of Medical Science Hospital, Shiga, Japan 6 First Department of Internal Medicine, Gifu University Hospital, Gifu, Japan 7 Department of Gastroenterology, Gifu Municipal Hospital, Gifu, Japan 8 Department of Gastroenterology, Gifu Prefectural Tajimi Hospital, Gifu, Japan 9 Department of Gastroenterology, Gifu Prefectural General Medical Center, Gifu, Japan 10 Department of Gastroenterology, Hamamatsu University School of Medicine, Hamamatsu, Japan 11 Department of Gastroenterology, Aichi Medical University, Nagakute, Aichi, Japan 12 Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan 13 Department of Gastroenterology, Nagoya City University East Medical Center, Nagoya, Japan 14 Department of Gastroenterology, Fujita Health University Hospital, Aichi, Japan 15 Department of Gastroenterology, Fujita Health University Bantane Hospital, Aichi, Japan 16 Department of Gastroenterology, Fujita Health University Okazaki Medical Center, Aichi, Japan 17 Department of Gastroenterology, Kagawa University Hospital, Kagawa, Japan 18 Department of Gastroenterology, Kumamoto University Hospital, Kumamoto, Japan 19 Department of Gastroenterology, Kumamoto City Hospital, Kumamoto, Japan 20 Department of Gastroenterology, Kuwana City Medical Center, Mie, Japan 21 Department of Gastroenterology, Yokkaichi Hazu Medical Center, Mie, Japan 22 Department of Gastroenterology, Mie Prefectural General Medical Center, Mie, Japan 23 Department of Gastroenterology, Suzuka Kaisei Hospital, Mie, Japan 24 Department of Gastroenterology, Matsusaka Chuo General Hospital, Mie, Japan 25 Department of Gastroenterology, Okanami General Hospital, Mie, Japan 26 Department of Gastroenterology and Hepato-Biliary-Pancreatic Medicine, Shizuoka General Hospital, Shizuoka, Japan 27 Department of Gastroenterology and Pancreato-Biliary Medicine, Matsunami General Hospital, Gifu, Japan 28 Clinical Research Support Center, Mie University Hospital, Mie, Japan Name and contact information for the trial sponsor {5b} Mie University Hospital Special Clinical Research Incentive Fund Operational Grants from the Department of Gastroenterology and Hepatology, Mie University Hospital Role of sponsor {5c} The sponsor is responsible for the overall design, management, and conduct of the study. Mie University Hospital oversees study coordination, data management, and quality assurance. The sponsor will have no role in patient recruitment or data analysis and will not influence the interpretation of study results. Introduction Background and rationale {6a} Endoscopic retrograde cholangiopancreatography (ERCP) is an important procedure that is mainly used to treat pancreaticobiliary disorders [ 1 ]. Although the procedure is considered generally safe, several adverse events (AEs) are associated with ERCP, including post-ERCP pancreatitis (PEP), bleeding, cholangitis, cholecystitis, and perforation [ 2 ]. Among these, PEP is the most common. A meta-analysis of randomized controlled trials reported that PEP occurs at a cumulative incidence of 10.2% overall, with 0.5% of patients experiencing severe PEP and 0.2% of patients experiencing fatal PEP [ 3 ]. There are several measures that clinicians can use to prevent PEP. For example, endoscopic pancreatic duct stents have been shown to reduce the incidence of PEP in high-risk patients [ 4 ]. As such, Japanese, European, and American guidelines recommend pancreatic duct stents for patients at high risk of PEP [ 5 – 7 ]. Of note, the non-therapeutic use of pancreatic duct stents is not reimbursed by the national insurance system in Japan. Pharmacological prophylaxis for PEP is also available. Randomized clinical trials have demonstrated that rectal administration of nonsteroidal anti-inflammatory drugs (NSAIDs) either immediately before or after ERCP significantly lowers the incidence of PEP [ 8 , 9 ], and guidelines support routine prophylactic rectal administration of NSAIDs for patients undergoing ERCP [ 5 – 7 ]. Periprocedural aggressive hydration is a measure that has been gaining attention for its potential to reduce the risk of PEP. Both a pilot study (N = 62) and a randomized, double-blind study (N = 150) that used the same protocol for aggressive hydration (intravenous [IV] lactated Ringer’s solution 3 mL/kg/h during the procedure, IV bolus 20 mL/kg immediately after the procedure, IV 3 mL/kg/h for 8 h after the procedure) found that this method significantly reduced the incidence of PEP compared with standard hydration [ 10 , 11 ]. A meta-analysis of randomized controlled trials found that periprocedural aggressive hydration reduced the incidence of PEP by 56% compared with standard hydration (5.1% vs 11.1%; odds ratio 0.44; p = 0.0004), with no significant difference in the incidence of fluid overload-related AEs between the two approaches [ 12 ]. Although this is promising, a standard protocol for aggressive hydration has yet to be established. The Department of Gastroenterology and Hepatology at Mei University Hospital in Japan conducted a single-arm study, RESOLUTION-PEP, in 231 patients to evaluate the efficacy and safety of aggressive hydration with lactated Ringer’s solution combined with intrarectal diclofenac sodium (diclofenac) for PEP prevention [ 13 ]. The study used an IV bolus administration of lactated Ringer’s solution (5 mL/kg) at the start of the ERCP procedure, with a continuous IV infusion of 3 mL/kg/h for 8 h after the procedure. The PEP incidence rate was 5.6%, which was similar to that reported in the meta-analysis (5.1%) [ 12 ]. No severe AEs due to aggressive hydration were reported. Objectives {7} This randomized, controlled study is being conducted to further evaluate the efficacy and safety of periprocedural aggressive hydration plus intrarectal diclofenac versus standard hydration plus intrarectal diclofenac in preventing the onset of PEP in Japanese patients. Trial design {8} This is a phase 3, multicenter, open-label, randomized (1:1) controlled study ( Fig. 1 ). Methods: Participants, interventions, and outcomes Study setting {9} The study is being conducted in Japan between 6 February 2024 and 31 March 2028 and is expected to include 27 study sites ( Table 1 ) and 780 patients. [Place Table 1 here] Eligibility criteria {10} This study will include patients aged ≥ 18 years who are scheduled to receive an ERCP procedure. Patients with any of the following will be excluded from the study: previous ERCP with a history of papillary procedures, reduced cardiac function (New York Heart Association grade ≥ 2 cardiac function, left ventricular ejection fraction < 40%, or a serum brain natriuretic peptide [BNP] ≥ 100 pg/mL or serum N-terminal pro-BNP ≥ 400 pg/mL), reduced renal function (estimated glomerular filtration rate < 60 mL/min/1.73m 2 ), respiratory failure (peripheral oxygen saturation 147 mEq/L), Eastern Cooperative Oncology Group performance status ≥ 3, a colostomy rendering it impossible to rectally administer diclofenac, contraindications to diclofenac, history of allergy to iodine contrast media, postoperative reconstructed intestinal tract, organic stenosis of the gastrointestinal tract that makes papillary access impossible, scheduled from the outset to undergo transpapillary cannulation of the bile duct or pancreatic duct via percutaneous transhepatic biliary drainage-assisted rendezvous or endoscopic ultrasonography-guided rendezvous, or who are pregnant or may become pregnant. Who will take informed consent? {26a} Potential study participants will be given a thorough explanation of the study in writing and orally by the principal investigator or an assistant investigator, and written informed consent will be obtained. Additional consent provisions for collection and use of participant data and biological specimens {26b} Not applicable. There is no collection of data or biological specimens for ancillary studies. Interventions Explanation for the choice of comparators {6b} Normal hydration was selected as the comparator because it reflects the current standard clinical practice during ERCP procedures. At present, patients undergoing ERCP typically receive routine intravenous hydration, and this approach is widely accepted as the standard of care. Therefore, comparing the loading infusion strategy against normal hydration will allow us to evaluate the additional benefit of fluid loading over the established standard treatment. Intervention description {11a} The infusion protocol for each group is described below and the study observation schedule is shown in Table 2 . For both groups, during the 8 h prior to the ERCP procedure, the main infusion will be administered at a rate of ≤ 1.5 mL/kg/h. Side-tube infusions may be administered with a total volume of ≤ 100 mL up to two times, separately from the main infusion. Patients in the aggressive hydration group will receive a bolus of 500 mL Ringer’s solution (adjusted to 10 mL/kg for patients weighing < 50 kg) at the start of the ERCP procedure. The infusion will be administered at 500 mL/h using an infusion pump, and the bolus will be terminated after 1 h even if the entire volume has not been administered. At the end of the bolus administration, patients will receive Ringer’s solution at 3 mL/kg/h for 8 h. Patients in the standard hydration group will receive Ringer’s solution at 1.5 mL/kg/h, which will be initiated at the start of the ERCP procedure and continued for 9 h. Within 30 min of completing the ERCP procedure, patients in both groups will receive intrarectal diclofenac 50 mg (adjusted to 25 mg for patients weighing < 50 kg or aged ≥ 80 years). Additionally, at the conclusion of the infusion specified for each treatment group, until the blood test for determining the onset of PEP is performed (when blood sampling is conducted 9–24 h after ERCP), any ongoing infusion, if administered, will be given at a rate not exceeding 1.5 mL/kg/h for the main infusion, regardless of the type of fluid. Side-tube infusions may be administered with a total volume of ≤ 100 mL up to three times, separately from the main infusion. Patients should undergo the ERCP procedure within 14 days of enrollment in the study. [Place Table 2 here] Criteria for discontinuing or modifying allocated interventions {11b} During the treatment period, a change in the infusion load will be implemented if considered necessary due to the onset of acute pancreatitis, hypotension (systolic blood pressure 180 mmHg) or excessive circulating plasma volume, or in the case of serum electrolyte values outside of the normal range (normal range: sodium 135–147 mEq/L; potassium 3.6–5.0 mEq/L; chloride 98–108 mEq/L; calcium 8.8–10.2 mg/dL). Strategies to improve adherence to interventions {11c} Adherence to the intervention will be ensured by verifying the residual volume after each infusion to confirm whether the prescribed volume has been fully administered. Relevant concomitant care permitted or prohibited during the trial {11d} Temporary pancreatic ductal stenting for PEP prophylaxis should not be performed unless one or more of the following are true: suspected or confirmed papillary insufficiency, history of post-ERCP pancreatitis or acute pancreatitis, difficulty in cannulation, pancreatic duct insertion or pancreatic duct angiography, pre-cut sphincterotomy of the major duodenal papilla during ERCP, pancreatic duct stent placement before or during endoscopic papillary resection, or when the purpose of the ERCP is pancreatic duct stenting. The following concomitant medications are prohibited: protease inhibitors, nitrates, and nafamostat mesylate. Provisions for post-trial care {30} No post-treatment is specified. Outcomes {12} The primary endpoint is the incidence of PEP, defined as serum amylase ≥ 400 U/I after the completion of the ERCP (whether or not the patient had an elevated level prior to ERCP) and persistent abdominal pain (≥ 24 h) according to the criteria of the American Society for Gastrointestinal Endoscopy (ASGE) [ 14 ], with the blood sampling timing modified to facilitate blood sampling in real-world clinical practice (16 h ± 8 h after ERCP completion). Abdominal pain is defined as the occurrence of epigastric pain with a score of ≥ 3 on an integer visual analogue scale (VAS; 0–10) within 48 h after the start of ERCP, or an increase of ≥ 3 points compared with the pre-ERCP score, which persists for at least 24 h. The secondary endpoints are the incidence of PEP by severity, the incidence of hyperamylasemia (increase in amylase ≥ 400 U/I), and the incidence of infusion-related AEs. The severity of PEP will be assessed using the 2012 Atlanta Classification [ 15 ]. AEs will be monitored throughout the study and will be classified per the Japanese translation of the Common Terminology Criteria for Adverse Events version 5.0 (Japan Clinical Oncology Group Shared Criteria Scope) [ 16 ]. Participant timeline {13} Table 2 provides procedures at each timepoint. Sample size {14} The sample size was calculated as follows. Under the assumption that the incidence of PEP in the aggressive hydration group and the standard hydration group will be the same as reported in a 2019 meta-analysis (5.1% and 11.1%, respectively) [ 12 ], and assuming a two-sided α significance level of 0.05 and a power of 1-β = 0.8, the number of patients required to detect a significant difference between the two groups was 714 total, with 357 patients in each group. Considering that some patients will be ineligible, withdraw from the study, or be lost to follow-up, the expected number of enrolled patients was set at 780. Recruitment {15} Eligible patients scheduled for ERCP will be identified during outpatient visits or upon hospital admission, and will be approached for study participation after providing informed consent. Assignment of interventions: allocation Sequence generation {16a} The Nagoya University Registration and Randomization System will be employed to perform randomization using a minimization method with the following stratification factors to ensure balance between the treatment groups: age (< 50 years, ≥ 50 years), sex (male, female), purpose of ERCP (with or without the intent of pancreatic duct cannulation), and study site. Concealment mechanism {16b} The allocation will not be concealed, as this is an open-label study. The details of the random assignment procedure will not be made available to the principal investigator or assistant investigators. Implementation {16c} Patients will be registered by physicians at each participating study site using the Nagoya University Registration and Randomization System, which will randomly allocate patients 1:1 to the aggressive hydration group or standard hydration group. The randomization process will be independently monitored and overseen by the Mei University Data Center. Assignment of interventions: Blinding Who will be blinded {17a} No blinding will be performed. Procedure for unblinding if needed {17b} Not applicable. This was an open-label study. Data collection and management Plans for assessment and collection of outcomes {18a} During the observation period, patients will be monitored for the presence and severity of PEP, post-ERCP AEs other than PEP (hyperamylasemia, acute cholangitis, gastrointestinal bleeding, and gastrointestinal perforation according to the ASGE) [ 14 ], and infusion-related AEs (cerebral edema, respiratory failure, peripheral edema, and hypernatremia). Data collection will be performed using electronic case report forms (eCRF) implemented in the study’s electronic data capture (EDC) system, which is managed by the Mie University Data Center. Plans to promote participant retention and complete follow-up {18b} This study will be completed within the index hospitalization, and all outcomes will be assessed until discharge. Therefore, no long-term follow-up is required. For patients who discontinue or deviate from the intervention protocol, outcome data including the occurrence and severity of PEP, post-ERCP AEs, and infusion-related AEs will still be collected until discharge to ensure completeness of outcome assessment. Data management {19} All study data will be entered directly into eCRFs within the EDC system. Data entry will be performed by the investigators or designated research staff at each participating site. The EDC system incorporates automatic range and consistency checks to minimize entry errors and ensure data quality. Additional data validation and query management will be conducted by the Mie University Data Center, which is responsible for overseeing data management. Detailed procedures for data handling and quality control are described in the data management standard operating procedures maintained by the Mie University Data Center. Confidentiality {27} The principal investigator will be responsible for data management. Paper information other than medical records will be stored in lockable cabinets at each study site. Electronic data will be stored on personal computers, password protected, and stored in a lockable cabinet at each study site. Information will be stored for at least five years from the date of study completion and will be disposed of in a way that prevents identification of specific individuals. Plans for collection, laboratory evaluation and storage of biological specimens for genetic or molecular analysis in this trial/future use {33} Blood samples will be disposed of in the usual manner after the laboratory measurements have been obtained. Statistical methods Statistical methods for primary and secondary outcomes {20a} The primary and secondary endpoints will be analyzed using the full analysis set, which will comprise all patients who underwent ERCP and for whom the primary endpoint can be evaluated. Categorial variables will be summarized using frequency and proportion and continuous variables will be summarized using descriptive statistics. Fisher’s exact test will be used to compare the primary, secondary, and safety outcomes between the two treatment groups. A two-sided significance level of 5% will be used. The statistical analyses will be conducted according to the statistical methods outlined in the study protocol. The full statistical methods are provided in Additional file 1 . Interim analyses {21b} No interim analysis is planned. Methods for additional analyses (e.g. subgroup analyses) {20b} Not applicable. No subgroup analysis will be performed in this study. Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c} Patients with missing data related to determining the primary or secondary endpoints will be excluded from the analysis. Missing AE data will be entered as “unspecified”. Plans to give access to the full protocol, participant-level data and statistical code {31c} The full study protocol will be made available upon reasonable request to the corresponding author. Participant-level data and statistical code will not be shared owing to privacy and institutional restrictions. Oversight and monitoring Composition of the coordinating center and trial steering committee {5d} The coordinating center for this trial is the Mie University Data Center, which is responsible for patient registration, data management, and overall coordination of the study. Day-to-day operational support, including patient enrollment, completion of case report forms, and data entry, will be carried out by physicians and research staff at each participating site under the supervision of the coordinating center. Although no independent trial steering committee has been established, oversight of study conduct and data integrity will be ensured by the coordinating center. In the event of any serious issues or concerns regarding study conduct, an independent audit will be arranged in accordance with institutional and regulatory requirements. Composition of the data monitoring committee, its role and reporting structure {21a} The Data Monitoring Committee will consist of persons not directly involved in the conduct of the trial. The committee will monitor the study to ensure that it is being conducted safely, in compliance with the study protocol, and that data are collected accurately. An independent Efficacy and Safety Assessment Committee will periodically review safety and efficacy information during the study and will make recommendations to the principal investigator regarding the continuation, modification, or discontinuation of the study. The committee is independent from the sponsor and has no competing interests. Adverse event reporting and harms {22} All serious AEs will be immediately reported to the principal investigator, who will then notify the drug provider and report to the Efficacy and Safety Evaluation Committee as necessary. Frequency and plans for auditing trial conduct {23} If a serious violation of relevant laws or regulations, or deviation from the study protocol is identified during monitoring, an audit will be conducted. Plans for communicating important protocol amendments to relevant parties (e.g. trial participants, ethical committees) {25} Any modifications to the protocol that may impact the conduct, safety, design, population, or procedures of the study will require a formal modification to the protocol. Any modification must be approved by the relevant authorities before being implemented in the study. Dissemination plans {31a} The trial results will be disseminated through presentations at national and international scientific meetings and publication in peer-reviewed journals. Summaries of the study results will also be provided to the participating investigators. There are no restrictions on publication, and results will be reported in accordance with applicable guidelines for clinical trial registration and reporting. Discussion This study aims to address whether the use of aggressive hydration reduces the incidence of PEP compared with standard hydration. The study also aims to compare the incidence of PEP by severity, the incidence of hyperamylasemia, and the incidence of infusion-related AEs between patients who receive aggressive hydration versus standard hydration. The study will also determine overall safety in both groups. At the end of the study, the study data will be presented at conferences and/or journal articles. The study is expected to determine whether aggressive hydration plus intrarectal diclofenac effectively and safely reduces the incidence of PEP. PEP is the most common and serious AE of ERCP [ 2 ]. Thus, it is of interest to evaluate prophylactic and perioperative interventions to reduce the incidence of PEP. A meta-analysis supports a reduced incidence of PEP when patients receive aggressive hydration versus standard hydration in randomized controlled trials [ 12 ]. This multicenter study is expected to provide further evidence regarding the efficacy and safety of perioperative aggressive hydration in Japanese patients. A major strength of this study is its broad participation of both university and community hospitals across Japan, which enhances the generalizability of the findings. Randomization will be performed using a minimization method with stratification by age, sex, purpose of ERCP (pancreatic duct cannulation or not), and study site to minimize imbalance between groups. In addition, several important PEP-related factors have been carefully standardized to reduce potential confounding. Intrarectal diclofenac will be administered to all patients, and the indications for prophylactic pancreatic stent placement are clearly defined to prevent discretionary use. Furthermore, trainee endoscopists will be excluded, ensuring that all procedures are performed by experienced endoscopists. Procedure-related details such as difficulty of cannulation, cannulation time, type of papillary intervention, pancreatic duct injection, modified Schutz classification, and the presence or absence of transpapillary self-expandable metallic stent placement will also be recorded, allowing for detailed subgroup analyses. The study will also document whether the assigned study infusion was completed as per protocol. For the assessment of post-ERCP pain, the VAS will be used to provide an objective and standardized endpoint rather than a subjective evaluation. Taken together, this study has been designed to enable an accurate comparison of the pure effect of aggressive hydration on the incidence of PEP, under rigorously controlled and clearly defined clinical conditions. Although this multicenter study is being conducted only at study sites in Japan, which may limit the generalizability of the findings to other populations, the participation of diverse institutions across a wide geographic area is expected to mitigate this limitation. In conclusion, this study aims to clarify whether aggressive hydration is effective for reducing the incidence of PEP compared with standard hydration and will evaluate the safety of this intervention. Trial status Study Protocol version 1.1 (April 24, 2025) will be used to conduct the trial. Recruitment began on 20 May 2024 and is expected to be completed on 31 March 2028. Abbreviations eCRF Electronic case report form ERCP Endoscopic retrograde cholangiopancreatography AE Adverse event PEP Post-endoscopic retrograde cholangiopancreatography pancreatitis NSAID Nonsteroidal anti-inflammatory drug IV Intravenous BNP Brain natriuretic peptide jRCT Japan Registry of Clinical Trials ASGE American Society for Gastrointestinal Endoscopy ECOG PS Eastern Cooperative Oncology Group performance status EUS Endoscopic ultrasonography ERCP Endoscopic retrograde cholangiopancreatography GI Gastrointestinal PRBD Percutaneous transhepatic biliary drainage EDC Electronic data capture NT-proBNP N-terminal pro-B-type natriuretic peptide VAS Visual analogue scale Declarations Acknowledgements The authors would like to thank the physicians, nurses, and research staff at all participating institutions for their valuable contributions to this study. We also express our sincere gratitude to the patients and their families for their cooperation and participation. The authors thank Sarah Bubeck, PhD, of Edanz (www.edanz.com) for providing medical writing support, which was funded by Mie University Hospital Specified Clinical Trial Promotion Grant S2023-002, in accordance with Good Publication Practice (GPP3) guidelines (http://www.ismpp.org/gpp3). Authors’ contributions {31b} RY and KN conceived and designed the study. YI provided guidance on the electronic data capture (EDC) system for conducting a multicenter study, and ST advised on the development of the study protocol in compliance with regulatory requirements. All authors contributed to patient enrollment and data collection. KN and TO performed the statistical analysis. RY drafted the manuscript and critically revised it for important intellectual content. All authors contributed to the interpretation of the data and approved the final version of the manuscript. Funding {4} This study was supported by Mie University Hospital Specified Clinical Trial Promotion Grant S2023-002. The funding body is responsible for the overall design, management, and conduct of the study and will have no role in patient recruitment or data analysis, and will not influence the interpretation of the study results. Availability of data and materials {29} The final trial dataset will be accessible only to the principal investigator and authorized members of the Mie University Data Center responsible for data management. Participating investigators will have access to the data pertaining to their own patients. There are no contractual agreements that limit access to the dataset for investigators beyond these restrictions. Ethics approval and consent to participate {24} All patients must provide written informed consent prior to study enrollment, which will be collected by the study investigator or research assistant at each study site. This study will comply with the principles outlined in the Declaration of Helsinki. The study protocol was approved by the Clinical Research Review Board at Mei University Hospital (CRB4180006). The responsible regional bureau of health and welfare was the Takai–Hokuriku Regional Bureau of Health and Welfare. The study was prospectively registered with the Japan Registry of Clinical Trials (jRCT: s041230145; registered February 6, 2024; https://jrct.mhlw.go.jp/latest-detail/jRCTs041230145). Consent for publication {32} Not applicable, as no patient data are presented in this manuscript. Competing interests {28} The authors have no competing interests to declare. References Azimaraghi O, Bilal M, Amornyotin S, et al. Consensus guidelines for the perioperative management of patients undergoing endoscopic retrograde cholangiopancreatography. Br J Anaesth. 2023;130:763–72. doi: 10.1016/j.bja.2023.03.012 . Bishay K, Meng ZW, Khan R, et al. Adverse events associated with endoscopic retrograde cholangiopancreatography: Systematic review and meta-analysis. Gastroenterology. 2025;168:568–86. doi: 10.1053/j.gastro.2024.10.033 . Akshintala VS, Kanthasamy K, Bhullar FA, et al. Incidence, severity, and mortality of post-ERCP pancreatitis: an updated systematic review and meta-analysis of 145 randomized controlled trials. Gastrointest Endosc. 2023;98:1–6.e12. doi: 10.1016/j.gie.2023.03.023 . Sofuni A, Maguchi H, Mukai T, et al. Endoscopic pancreatic duct stents reduce the incidence of post-endoscopic retrograde cholangiopancreatography pancreatitis in high-risk patients. Clin Gastroenterol Hepatol. 2011;9:851–8; quiz e110. doi: 10.1016/j.cgh.2011.06.033 . Takada T, Isaji S, Mayumi T, et al. JPN clinical practice guidelines 2021 with easy-to-understand explanations for the management of acute pancreatitis. J Hepatobiliary Pancreat Sci. 2022;29:1057–83. doi: 10.1002/jhbp.1146 . Dumonceau JM, Kapral C, Aabakken L, et al. ERCP-related adverse events: European Society of Gastrointestinal Endoscopy (ESGE) Guideline. Endoscopy. 2020;52:127–49. doi: 10.1055/a-1075-4080 . ASGE Standards of Practice Committee; Chandrasekhara V, Khashab MA, Muthusamy VR, et al. Adverse events associated with ERCP. Gastrointest Endosc. 2017;85:32–47. doi: 10.1016/j.gie.2016.06.051 . Elmunzer BJ, Scheiman JM, Lehman GA, et al; U.S. Cooperative for Outcomes Research in Endoscopy (USCORE). A randomized trial of rectal indomethacin to prevent post-ERCP pancreatitis. N Engl J Med. 2012;366:1414–22. doi: 10.1056/NEJMoa1111103 . Otsuka T, Kawazoe S, Nakashita S, et al. Low-dose rectal diclofenac for prevention of post-endoscopic retrograde cholangiopancreatography pancreatitis: a randomized controlled trial. J Gastroenterol. 2012;47:912–7. doi: 10.1007/s00535-012-0554-7 . Buxbaum J, Yan A, Yeh K, Lane C, Nguyen N, Laine L. Aggressive hydration with lactated Ringer's solution reduces pancreatitis after endoscopic retrograde cholangiopancreatography. Clin Gastroenterol Hepatol. 2014;12:303- 7.e1 . doi: 10.1016/j.cgh.2013.07.026. Shaygan-Nejad A, Masjedizadeh AR, Ghavidel A, Ghojazadeh M, Khoshbaten M. Aggressive hydration with Lactated Ringer's solution as the prophylactic intervention for postendoscopic retrograde cholangiopancreatography pancreatitis: A randomized controlled double-blind clinical trial. J Res Med Sci. 2015;20:838–43. doi: 10.4103/1735-1995.170597 . Radadiya D, Devani K, Arora S, et al. Peri-procedural aggressive hydration for post endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis prophylaxsis: Meta-analysis of randomized controlled trials. Pancreatology. 2019;19:819–27. doi: 10.1016/j.pan.2019.07.046 . Hattori A, Yamada R, Murabayashi T, et al. The safety and efficacy of Ringer's solution loading with rectal diclofenac for prevention of post-endoscopic retrograde cholangiopancreatography pancreatitis: The RESOLUTION-PEP study. DEN Open. 2023;3:e236. doi: 10.1002/deo2.236 . Cotton PB, Eisen GM, Aabakken L, et al. A lexicon for endoscopic adverse events: report of an ASGE workshop. Gastrointest Endosc. 2010;71:446–54. doi: 10.1016/j.gie.2009.10.027 . Banks PA, Bollen TL, Dervenis C, et al; Acute Pancreatitis Classification Working Group. Classification of acute pancreatitis—2012: revision of the Atlanta classification and definitions by international consensus. Gut. 2013;62:102–11. doi: 10.1136/gutjnl-2012-302779 . Japan Clinical Oncology Group. Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. https://jcog.jp/doctor/tool/ctcaev5/ . Accessed 25 September 2025. Tables Table 1. List of study sites and investigators Study site Principal investigator Jichi Medical University Hospital Atsushi Kanno Juntendo Hospital, Juntendo Medical School, Juntendo University Hiroyuki Isayama University of Toyama Hospital Ichiro Yasuda Gifu University Hospital Shinya Uemura Gifu Municipal Hospital Keisuke Iwata Gifu Prefectural Tajimi Hospital Fumihiro Okumura Gifu Prefectural General Medical Center Kensaku Yoshida Hamamatsu University Hospital Ken Sugimoto Aichi Medical University Tadahisa Inoue Nagoya City University Hospital Graduate School of Medical Sciences Yasuki Hori Nagoya City University Eastern Medical Center Kazuki Hayashi Fujita Medical College Hospital Eizaburo Ohno Fujita Medical College Bantane Hospital Senju Hashimoto Fujita Medical College Okazaki Medical Center Yoshihiko Tachi Mie University Hospital Reiko Yamada Kagawa University Hospital Hideki Kamada Kumamoto University Hospital Motohiro Yoshinari Kumamoto City Hospital Shunpei Hashigo Kuwana City General Medical Center Yumi Oya Yokkaichi Hazu Medical Center Ryohei Sakaguchi Mie Prefectural General Medical Center Isao Moritani Suzuka Kaisei Hospital Shunsuke Tano Matsusaka Central General Hospital Hiroaki Naota Okanami General Hospital Hajime Imai Shizuoka Prefectural General Hospital Shinya Kawaguchi Matsunami General Hospital Mitsuru Okuno Shiga University Hospital, Shiga University of Medical Science Takuji Iwashita Table 2. Study observation schedule STUDY PERIOD Enrollment/Allocation Post-allocation Enrollment Day before ERCP (Day 1) a Day 2 Day 3 through discharge date Obtain consent, registration, and allocation ○ Disease requiring ERCP, pre-existing conditions, antithrombotic medications ○ Confirmation of PEP risk factors ○ Self-reported and other symptoms ○ Physical examination findings Δ Physical findings ○ ○ Δ Blood and biochemical tests b ○ BNP or NT-pro-BNP Δ BNP or NT-proBNP ○ Chest X-ray Δ Δ Imaging tests Δ Δ Electrocardiogram Δ Echocardiography (only when performed to evaluate cardiac function) Diclofenac administration ○ Infusion with therapeutic prescription ○ ○ ERCP ○ Availability of PEP ○ AE evaluation ○ Outcome ○ Length of hospital stay ○ a The period from registration to the first ERCP should not exceed 14 days. If pancreatitis or other incidental changes in the patient's condition occur after the ERCP, and the patient is not enrolled in the study treatment period, the ERCP must be performed within 14 days of the initial ERCP. If a change in the main infusion is necessary during the infusion period (up to 9 hours before the start of ERCP for both groups), the study treatment should be stopped immediately, and the infusion should be changed to a clinically appropriate intravenous fluid at the discretion of the treating physician. b If PEP or other AEs occur, blood samples should be collected from day 3 to the day of discharge, and the highest amylase value during that time should be reported. ○ = mandatory (to be collected as part of the EDC). Δ = items that are not collected in the EDC but should be implemented to ensure safety, or depending on the course of events. AE, adverse event; BNP, brain natriuretic peptide; EDC, electronic data capture; ERCP, endoscopic retrograde cholangiopancreatography; NT-proBNP, N-terminal pro-B-type natriuretic peptide; PEP, post-ERCP pancreatitis Additional Declarations No competing interests reported. Supplementary Files SupplementaryInformation.docx Supplementary Information Additional file 1. Statistical analysis (.doc) Describes the full statistical analysis plan. Cite Share Download PDF Status: Under Review Version 1 posted Reviewers agreed at journal 09 May, 2026 Reviewers invited by journal 04 May, 2026 Editor assigned by journal 08 Apr, 2026 Submission checks completed at journal 22 Jan, 2026 First submitted to journal 19 Jan, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8469484","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Study protocol","associatedPublications":[],"authors":[{"id":637482092,"identity":"47e1e177-a51d-4cec-99af-59ac90b53967","order_by":0,"name":"Reiko Yamada","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA90lEQVRIiWNgGAWjYFACxmYQKQfEBmAEATwEtRgYk6KFgRmkOrEBST1+YN7e3GzwgeFP+tr25g1MNwpsGAwOMD/8wCBzB6cWmTMHmxNnMBjkbjtzrIA5xyANqIXNWIKB5xlOLRISic2Hef8BtdzIMQBqOVy/4QCDGdAvh3FrkX/YfJiHwSDd7P4bkJb/QFvYv+HXIsHYnAzUkmB2gwek5QBQCw8BW3gSmw1nMBgbbjuTVnA4xyCZQfIwT7FEAj6/sB9/LPGBQU7e7PjhjY9z/tgx8B1v3/jhYw/uEEMBB8AkKJ4Sew4QpwUJ/CBdyygYBaNgFAxbAAALj03KQwR48gAAAABJRU5ErkJggg==","orcid":"","institution":"Mie University Hospital, Mie University School of Medicine","correspondingAuthor":true,"prefix":"","firstName":"Reiko","middleName":"","lastName":"Yamada","suffix":""},{"id":637482093,"identity":"c0864335-22fe-4df3-9c50-d252c34713f3","order_by":1,"name":"Kenji Nose","email":"","orcid":"","institution":"Mie University Hospital, Mie University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Kenji","middleName":"","lastName":"Nose","suffix":""},{"id":637482095,"identity":"e30cd11d-f063-45ff-a51f-62aad924eb01","order_by":2,"name":"Takamitsu Tanaka","email":"","orcid":"","institution":"Mie University Hospital, Mie University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Takamitsu","middleName":"","lastName":"Tanaka","suffix":""},{"id":637482098,"identity":"bd344c23-0415-4ff8-98dc-fca20fe41616","order_by":3,"name":"Tetsuro Miwata","email":"","orcid":"","institution":"Mie University Hospital, Mie University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Tetsuro","middleName":"","lastName":"Miwata","suffix":""},{"id":637482101,"identity":"c166a06d-201c-41a4-a43a-003d388234ff","order_by":4,"name":"Yasuaki Shimada","email":"","orcid":"","institution":"Mie University Hospital, Mie University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Yasuaki","middleName":"","lastName":"Shimada","suffix":""},{"id":637482104,"identity":"2faf6207-23df-49cb-b59a-ec9e48c749ca","order_by":5,"name":"Minako Urata","email":"","orcid":"","institution":"Mie University Hospital, Mie University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Minako","middleName":"","lastName":"Urata","suffix":""},{"id":637482105,"identity":"a259f0dc-5fac-41a9-a5bf-b114c6571b8d","order_by":6,"name":"Atsushi Kanno","email":"","orcid":"","institution":"Jichi Medical University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Atsushi","middleName":"","lastName":"Kanno","suffix":""},{"id":637482106,"identity":"b1e62aef-514f-4693-b43f-bbabc37af76d","order_by":7,"name":"Eriko Ikeda","email":"","orcid":"","institution":"Jichi Medical University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Eriko","middleName":"","lastName":"Ikeda","suffix":""},{"id":637482107,"identity":"21bab557-7cf2-4cf9-9ea0-5e45874d7ee1","order_by":8,"name":"Hiroyuki Isayama","email":"","orcid":"","institution":"Juntendo University Hospital, Juntendo University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Hiroyuki","middleName":"","lastName":"Isayama","suffix":""},{"id":637482108,"identity":"6e991917-c4a3-4746-b936-9df5ea5d0b20","order_by":9,"name":"Ichiro Yasuda","email":"","orcid":"","institution":"University of Toyama Hospital","correspondingAuthor":false,"prefix":"","firstName":"Ichiro","middleName":"","lastName":"Yasuda","suffix":""},{"id":637482109,"identity":"686afa3c-6b08-4ca2-be8d-edde1ccf1fa8","order_by":10,"name":"Nobuhiko Hayashi","email":"","orcid":"","institution":"University of Toyama Hospital","correspondingAuthor":false,"prefix":"","firstName":"Nobuhiko","middleName":"","lastName":"Hayashi","suffix":""},{"id":637482110,"identity":"cc2d621e-ad10-4c04-a482-49fda8ac7b28","order_by":11,"name":"Takuji Iwashita","email":"","orcid":"","institution":"Shiga University of Medical Science Hospital","correspondingAuthor":false,"prefix":"","firstName":"Takuji","middleName":"","lastName":"Iwashita","suffix":""},{"id":637482111,"identity":"b1d852e7-29c3-4284-9666-73acea9adf67","order_by":12,"name":"Shinya Uemura","email":"","orcid":"","institution":"Gifu University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Shinya","middleName":"","lastName":"Uemura","suffix":""},{"id":637482113,"identity":"e6715ca3-2bd0-44ae-93bb-88bad996ca52","order_by":13,"name":"Keisuke Iwata","email":"","orcid":"","institution":"Gifu Municipal Hospital","correspondingAuthor":false,"prefix":"","firstName":"Keisuke","middleName":"","lastName":"Iwata","suffix":""},{"id":637482114,"identity":"6adb0390-1450-4909-bdc0-dd1f613af4e9","order_by":14,"name":"Yuhei Iwasa","email":"","orcid":"","institution":"Gifu Municipal Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yuhei","middleName":"","lastName":"Iwasa","suffix":""},{"id":637482116,"identity":"07a41eb7-a560-4112-bddf-bb2aa7f5b3a6","order_by":15,"name":"Fumihiro Okumura","email":"","orcid":"","institution":"Gifu Prefectural Tajimi Hospital","correspondingAuthor":false,"prefix":"","firstName":"Fumihiro","middleName":"","lastName":"Okumura","suffix":""},{"id":637482119,"identity":"4f17730b-4482-4284-80ac-9a57ba33c011","order_by":16,"name":"Kensaku Yoshida","email":"","orcid":"","institution":"Gifu Prefectural General Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Kensaku","middleName":"","lastName":"Yoshida","suffix":""},{"id":637482120,"identity":"11d42c48-8dec-4655-acbc-a30e544e0749","order_by":17,"name":"Ken Sugimoto","email":"","orcid":"","institution":"Hamamatsu University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Ken","middleName":"","lastName":"Sugimoto","suffix":""},{"id":637482122,"identity":"eff35f12-eb03-44a6-b056-4a7e06b4b0a6","order_by":18,"name":"Yasushi Hamaya","email":"","orcid":"","institution":"Hamamatsu University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Yasushi","middleName":"","lastName":"Hamaya","suffix":""},{"id":637482123,"identity":"d1f4a0c1-9085-469f-8806-303dba6343e3","order_by":19,"name":"Tadahisa Inoue","email":"","orcid":"","institution":"Aichi Medical University","correspondingAuthor":false,"prefix":"","firstName":"Tadahisa","middleName":"","lastName":"Inoue","suffix":""},{"id":637482125,"identity":"319e48c0-8f70-4a90-8a13-f6f00f901040","order_by":20,"name":"Yasuki Hori","email":"","orcid":"","institution":"Nagoya City University Graduate School of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Yasuki","middleName":"","lastName":"Hori","suffix":""},{"id":637482127,"identity":"2904f565-8f8f-47ef-a547-1e95a5fb9363","order_by":21,"name":"Kazuki Hayashi","email":"","orcid":"","institution":"Nagoya City University East Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Kazuki","middleName":"","lastName":"Hayashi","suffix":""},{"id":637482128,"identity":"4d0c4129-0c83-42af-978f-a9b16a4c2645","order_by":22,"name":"Eizaburo Ohno","email":"","orcid":"","institution":"Fujita Health University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Eizaburo","middleName":"","lastName":"Ohno","suffix":""},{"id":637482129,"identity":"d2fbdb35-e1b8-4558-8af1-8df97eddb781","order_by":23,"name":"Senju Hashimoto","email":"","orcid":"","institution":"Fujita Health University Bantane Hospital","correspondingAuthor":false,"prefix":"","firstName":"Senju","middleName":"","lastName":"Hashimoto","suffix":""},{"id":637482130,"identity":"095548d3-efbf-40eb-a046-cb7cd1c2c6a2","order_by":24,"name":"Yoshihiko Tachi","email":"","orcid":"","institution":"Fujita Health University Okazaki Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Yoshihiko","middleName":"","lastName":"Tachi","suffix":""},{"id":637482131,"identity":"17ba9bb9-a2d1-40a7-aca7-cf5d24ddc86c","order_by":25,"name":"Hideki Kamada","email":"","orcid":"","institution":"Kagawa University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Hideki","middleName":"","lastName":"Kamada","suffix":""},{"id":637482132,"identity":"cbe73d41-b93a-4b7c-8460-35cc1d0bbd86","order_by":26,"name":"Motohiro Yoshinari","email":"","orcid":"","institution":"Kumamoto University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Motohiro","middleName":"","lastName":"Yoshinari","suffix":""},{"id":637482133,"identity":"7d5b410d-7275-4033-97cf-677a8bd64438","order_by":27,"name":"Shunpei Hashigo","email":"","orcid":"","institution":"Kumamoto City Hospital","correspondingAuthor":false,"prefix":"","firstName":"Shunpei","middleName":"","lastName":"Hashigo","suffix":""},{"id":637482134,"identity":"c044ee81-540a-4c46-8649-506f1eec4343","order_by":28,"name":"Yumi Oya","email":"","orcid":"","institution":"Kuwana City Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Yumi","middleName":"","lastName":"Oya","suffix":""},{"id":637482135,"identity":"44904b46-83f9-4dd6-9072-753081e43b85","order_by":29,"name":"Tomoki Nakaji","email":"","orcid":"","institution":"Kuwana City Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Tomoki","middleName":"","lastName":"Nakaji","suffix":""},{"id":637482136,"identity":"35e43dec-d094-42d5-9e81-21150691038d","order_by":30,"name":"Ryohei Sakaguchi","email":"","orcid":"","institution":"Yokkaichi Hazu Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Ryohei","middleName":"","lastName":"Sakaguchi","suffix":""},{"id":637482137,"identity":"985b5073-3e5c-4b6b-9c71-1a8c600847f9","order_by":31,"name":"Isao Moritani","email":"","orcid":"","institution":"Mie Prefectural General Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Isao","middleName":"","lastName":"Moritani","suffix":""},{"id":637482138,"identity":"e8ca1aec-e791-45b8-b659-654ef4667a4b","order_by":32,"name":"Shunsuke Tano","email":"","orcid":"","institution":"Suzuka Kaisei Hospital","correspondingAuthor":false,"prefix":"","firstName":"Shunsuke","middleName":"","lastName":"Tano","suffix":""},{"id":637482140,"identity":"2731bf94-2782-4571-a65d-7d4b69079827","order_by":33,"name":"Hiroaki Naota","email":"","orcid":"","institution":"Matsusaka Chuo General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Hiroaki","middleName":"","lastName":"Naota","suffix":""},{"id":637482141,"identity":"6b284f2a-c1ec-44c5-80ec-90c3bc5e0b75","order_by":34,"name":"Hajime Imai","email":"","orcid":"","institution":"Okanami General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Hajime","middleName":"","lastName":"Imai","suffix":""},{"id":637482143,"identity":"220b4f54-0fba-430f-b0f9-52517c71ee51","order_by":35,"name":"Toshitaka Fukui","email":"","orcid":"","institution":"Okanami General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Toshitaka","middleName":"","lastName":"Fukui","suffix":""},{"id":637482146,"identity":"2243f8b2-9f59-448d-8116-a52c84ee3858","order_by":36,"name":"Shinya Kawaguchi","email":"","orcid":"","institution":"Shizuoka General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Shinya","middleName":"","lastName":"Kawaguchi","suffix":""},{"id":637482152,"identity":"e3da776b-da39-4f16-8c20-a6e89be3adcd","order_by":37,"name":"Mitsuru Okuno","email":"","orcid":"","institution":"Matsunami General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Mitsuru","middleName":"","lastName":"Okuno","suffix":""},{"id":637482153,"identity":"3efac512-57ab-4280-98ea-9f717cc77f5a","order_by":38,"name":"Yasuto Imai","email":"","orcid":"","institution":"Mie University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yasuto","middleName":"","lastName":"Imai","suffix":""},{"id":637482155,"identity":"2d468e3a-2f54-4295-894f-d6e6afb4072a","order_by":39,"name":"Toru Ogura","email":"","orcid":"","institution":"Mie University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Toru","middleName":"","lastName":"Ogura","suffix":""},{"id":637482156,"identity":"8530b1c3-0981-4110-93bf-455422eccf07","order_by":40,"name":"Satoshi Tamaru","email":"","orcid":"","institution":"Mie University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Satoshi","middleName":"","lastName":"Tamaru","suffix":""},{"id":637482157,"identity":"d58e027c-c9dd-4673-9835-c6183aa76d30","order_by":41,"name":"Hayato Nakagawa","email":"","orcid":"","institution":"Mie University Hospital, Mie University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Hayato","middleName":"","lastName":"Nakagawa","suffix":""}],"badges":[],"createdAt":"2025-12-29 05:53:16","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8469484/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8469484/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":109169962,"identity":"5c67dbca-75c7-446e-b1cd-dfa06f353f96","added_by":"auto","created_at":"2026-05-13 08:45:10","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":93505,"visible":true,"origin":"","legend":"\u003cp\u003eStudy flow diagram\u003c/p\u003e\n\u003cp\u003e\u003csup\u003ea\u003c/sup\u003eAdjusted to 10 mL/kg for patients weighing \u0026lt;50 kg.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003eb\u003c/sup\u003eAdministered at 500 mL/h, to be terminated after 1 h even if the entire volume has not been administered.\u003c/p\u003e\n\u003cp\u003eECOG PS, Eastern Cooperative Oncology Group performance status; ERCP, endoscopic retrograde cholangiopancreatography; EUS, endoscopic ultrasonography; GI, gastrointestinal; PRBD, percutaneous transhepatic biliary drainage\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-8469484/v1/0af6dc62af8e396f250a5579.png"},{"id":109170209,"identity":"a13cc252-ab0e-4c12-b1b7-63df21b8f564","added_by":"auto","created_at":"2026-05-13 08:46:21","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":458051,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8469484/v1/32b63a7b-a131-4f23-bea2-8e2ac84f8008.pdf"},{"id":109169907,"identity":"7f278ad4-8c35-4868-b789-cd73a2fad346","added_by":"auto","created_at":"2026-05-13 08:44:56","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":17295,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSupplementary Information\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAdditional file 1. Statistical analysis (.doc)\u003c/p\u003e\n\u003cp\u003eDescribes the full statistical analysis plan.\u003c/p\u003e","description":"","filename":"SupplementaryInformation.docx","url":"https://assets-eu.researchsquare.com/files/rs-8469484/v1/afd94fd94329c42229e10dc2.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Efficacy and safety of aggressive hydration for preventing post-endoscopic retrograde cholangiopancreatography pancreatitis: study protocol for a phase 3, multicenter, open-label, randomized controlled study","fulltext":[{"header":"Administrative Information","content":"\u003cp\u003eNote: the numbers in curly brackets in this protocol refer to SPIRIT checklist item numbers. The order of the items has been modified to group similar items (see http://www.equator-network.org/reporting-guidelines/spirit-2013-statement-defining-standard-protocol-items-for-clinical-trials/).\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"639\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 34.1158%;\"\u003e\n \u003cp\u003eTitle {1}\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 65.8842%;\"\u003e\n \u003cp\u003eEfficacy and safety of aggressive hydration for preventing post-endoscopic retrograde cholangiopancreatography pancreatitis: study protocol for a phase 3, multicenter, open-label, randomized controlled study\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 34.1158%;\"\u003e\n \u003cp\u003eTrial registration {2a and 2b}.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 65.8842%;\"\u003e\n \u003cp\u003eJapan Registry of Clinical Trials (jRCT: s041230145; registered February 6, 2024; https://jrct.mhlw.go.jp/latest-detail/jRCTs041230145)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 34.1158%;\"\u003e\n \u003cp\u003eProtocol version {3}\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65.8842%;\"\u003e\n \u003cp\u003eVersion 1.4, April 24, 2025\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 34.1158%;\"\u003e\n \u003cp\u003eFunding {4}\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 65.8842%;\"\u003e\n \u003cp\u003eMie University Hospital Specified Clinical Trial Promotion Grant (S2023-002)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 34.1158%;\"\u003e\n \u003cp\u003eAuthor details {5a}\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 65.8842%;\"\u003e\n \u003cp\u003eReiko Yamada\u003csup\u003e1\u003c/sup\u003e, Kenji Nose\u003csup\u003e1\u003c/sup\u003e,\u0026nbsp;Takamitsu Tanaka\u003csup\u003e1\u003c/sup\u003e,\u0026nbsp;Tetsuro Miwata\u003csup\u003e1\u003c/sup\u003e, Yasuaki Shimada\u003csup\u003e1\u003c/sup\u003e,\u0026nbsp;Minako Urata\u003csup\u003e1\u003c/sup\u003e, Atsushi Kanno\u003csup\u003e2\u003c/sup\u003e, Eriko Ikeda\u003csup\u003e2\u003c/sup\u003e, Hiroyuki Isayama\u003csup\u003e3\u003c/sup\u003e, Ichiro Yasuda\u003csup\u003e4\u003c/sup\u003e, Nobuhiko Hayashi\u003csup\u003e4\u003c/sup\u003e, Takuji Iwashita\u003csup\u003e5\u003c/sup\u003e, Shinya Uemura\u003csup\u003e6\u003c/sup\u003e, Keisuke Iwata\u003csup\u003e7\u003c/sup\u003e, Yuhei Iwasa\u003csup\u003e7\u003c/sup\u003e, Fumihiro Okumura\u003csup\u003e8\u003c/sup\u003e, Kensaku Yoshida\u003csup\u003e9\u003c/sup\u003e, Ken Sugimoto\u003csup\u003e10\u003c/sup\u003e, Yasushi Hamaya\u003csup\u003e10\u003c/sup\u003e, Tadahisa Inoue\u003csup\u003e11\u003c/sup\u003e, Yasuki Hori\u003csup\u003e12\u003c/sup\u003e, Kazuki Hayashi\u003csup\u003e13\u003c/sup\u003e, Eizaburo Ohno\u003csup\u003e14\u003c/sup\u003e, Senju Hashimoto\u003csup\u003e15\u003c/sup\u003e, Yoshihiko Tachi\u003csup\u003e16\u003c/sup\u003e, Hideki Kamada\u003csup\u003e17\u003c/sup\u003e, Motohiro Yoshinari\u003csup\u003e18\u003c/sup\u003e, Shunpei Hashigo\u003csup\u003e19\u003c/sup\u003e, Yumi Oya\u003csup\u003e20\u003c/sup\u003e, Tomoki\u0026nbsp;Nakaji\u003csup\u003e20\u003c/sup\u003e, Ryohei Sakaguchi\u003csup\u003e21\u003c/sup\u003e, Isao Moritani\u003csup\u003e22\u003c/sup\u003e, Shunsuke Tano\u003csup\u003e23\u003c/sup\u003e, Hiroaki Naota\u003csup\u003e24\u003c/sup\u003e, Hajime Imai\u003csup\u003e25\u003c/sup\u003e, Toshitaka Fukui\u003csup\u003e25\u003c/sup\u003e, Shinya Kawaguchi\u003csup\u003e26\u003c/sup\u003e, Mitsuru Okuno\u003csup\u003e27\u003c/sup\u003e, Yasuto Imai\u003csup\u003e\u0026nbsp;28\u003c/sup\u003e, Toru Ogura\u003csup\u003e28\u003c/sup\u003e, Satoshi Tamaru\u003csup\u003e28\u003c/sup\u003e, Hayato Nakagawa\u003csup\u003e1\u003c/sup\u003e\u003c/p\u003e\n \u003cp\u003e\u003csup\u003e1\u003c/sup\u003eDepartment of Gastroenterology and Hepatology, Mie University Hospital, Mie University School of Medicine, Mie, Japan\u003c/p\u003e\n \u003cp\u003e\u003csup\u003e2\u003c/sup\u003eDepartment of Gastroenterology and Hepatology, Jichi Medical University Hospital, Tochigi, Japan\u003c/p\u003e\n \u003cp\u003e\u003csup\u003e3\u003c/sup\u003eDepartment of Gastroenterology, Juntendo University Hospital, Juntendo University School of Medicine, Tokyo, Japan\u003c/p\u003e\n \u003cp\u003e\u003csup\u003e4\u003c/sup\u003eDepartment of Gastroenterology, University of Toyama Hospital, Toyama, Japan\u003c/p\u003e\n \u003cp\u003e\u003csup\u003e5\u003c/sup\u003eDepartment of Gastroenterology, Shiga University of Medical Science Hospital, Shiga, Japan\u003c/p\u003e\n \u003cp\u003e\u003csup\u003e6\u003c/sup\u003eFirst Department of Internal Medicine, Gifu University Hospital, Gifu, Japan\u003c/p\u003e\n \u003cp\u003e\u003csup\u003e7\u003c/sup\u003eDepartment of Gastroenterology, Gifu Municipal Hospital, Gifu, Japan\u003c/p\u003e\n \u003cp\u003e\u003csup\u003e8\u003c/sup\u003eDepartment of Gastroenterology, Gifu Prefectural Tajimi Hospital, Gifu, Japan\u003c/p\u003e\n \u003cp\u003e\u003csup\u003e9\u003c/sup\u003eDepartment of Gastroenterology, Gifu Prefectural General Medical Center, Gifu, Japan\u003c/p\u003e\n \u003cp\u003e\u003csup\u003e10\u003c/sup\u003eDepartment of Gastroenterology, Hamamatsu University School of Medicine, Hamamatsu, Japan\u003c/p\u003e\n \u003cp\u003e\u003csup\u003e11\u003c/sup\u003eDepartment of Gastroenterology, Aichi Medical University, Nagakute, Aichi, Japan\u003c/p\u003e\n \u003cp\u003e\u003csup\u003e12\u003c/sup\u003e Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan\u003c/p\u003e\n \u003cp\u003e\u003csup\u003e13\u003c/sup\u003eDepartment of Gastroenterology, Nagoya City University East Medical Center, Nagoya, Japan\u003c/p\u003e\n \u003cp\u003e\u003csup\u003e14\u003c/sup\u003eDepartment of Gastroenterology, Fujita Health University Hospital, Aichi, Japan\u003c/p\u003e\n \u003cp\u003e\u003csup\u003e15\u003c/sup\u003eDepartment of Gastroenterology, Fujita Health University Bantane Hospital, Aichi, Japan\u003c/p\u003e\n \u003cp\u003e\u003csup\u003e16\u003c/sup\u003eDepartment of Gastroenterology, Fujita Health University Okazaki Medical Center, Aichi, Japan\u003c/p\u003e\n \u003cp\u003e\u003csup\u003e17\u003c/sup\u003eDepartment of Gastroenterology, Kagawa University Hospital, Kagawa, Japan\u003c/p\u003e\n \u003cp\u003e\u003csup\u003e18\u003c/sup\u003eDepartment of Gastroenterology, Kumamoto University Hospital, Kumamoto, Japan\u003c/p\u003e\n \u003cp\u003e\u003csup\u003e19\u003c/sup\u003eDepartment of Gastroenterology, Kumamoto City Hospital, Kumamoto, Japan\u003c/p\u003e\n \u003cp\u003e\u003csup\u003e20\u003c/sup\u003eDepartment of Gastroenterology, Kuwana City Medical Center, Mie, Japan\u003c/p\u003e\n \u003cp\u003e\u003csup\u003e21\u003c/sup\u003eDepartment of Gastroenterology, Yokkaichi Hazu Medical Center, Mie, Japan\u003c/p\u003e\n \u003cp\u003e\u003csup\u003e22\u003c/sup\u003eDepartment of Gastroenterology, Mie Prefectural General Medical Center, Mie, Japan\u003c/p\u003e\n \u003cp\u003e\u003csup\u003e23\u003c/sup\u003eDepartment of Gastroenterology, Suzuka Kaisei Hospital, Mie, Japan\u003c/p\u003e\n \u003cp\u003e\u003csup\u003e24\u003c/sup\u003eDepartment of Gastroenterology, Matsusaka Chuo General Hospital, Mie, Japan\u003c/p\u003e\n \u003cp\u003e\u003csup\u003e25\u003c/sup\u003eDepartment of Gastroenterology, Okanami General Hospital, Mie, Japan\u003c/p\u003e\n \u003cp\u003e\u003csup\u003e26\u003c/sup\u003eDepartment of Gastroenterology and Hepato-Biliary-Pancreatic Medicine, Shizuoka General Hospital, Shizuoka, Japan\u003c/p\u003e\n \u003cp\u003e\u003csup\u003e27\u003c/sup\u003eDepartment of Gastroenterology and Pancreato-Biliary Medicine, Matsunami General Hospital, Gifu, Japan\u003c/p\u003e\n \u003cp\u003e\u003csup\u003e28\u003c/sup\u003eClinical Research Support Center, Mie University Hospital, Mie, Japan\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 34.1158%;\"\u003e\n \u003cp\u003eName and contact information for the trial sponsor {5b}\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 65.8842%;\"\u003e\n \u003cp\u003eMie University Hospital Special Clinical Research Incentive Fund Operational Grants from the Department of Gastroenterology and Hepatology, Mie University Hospital\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 34.1158%;\"\u003e\n \u003cp\u003eRole of sponsor {5c}\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 65.8842%;\"\u003e\n \u003cp\u003eThe sponsor is responsible for the overall design, management, and conduct of the study.\u003cbr\u003e\u0026nbsp;Mie University Hospital oversees study coordination, data management, and quality assurance.\u003cbr\u003e\u0026nbsp;The sponsor will have no role in patient recruitment or data analysis and will not influence the interpretation of study results.\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"},{"header":"Introduction","content":"\n\u003ch3\u003eBackground and rationale {6a}\u003c/h3\u003e\n\u003cp\u003eEndoscopic retrograde cholangiopancreatography (ERCP) is an important procedure that is mainly used to treat pancreaticobiliary disorders [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Although the procedure is considered generally safe, several adverse events (AEs) are associated with ERCP, including post-ERCP pancreatitis (PEP), bleeding, cholangitis, cholecystitis, and perforation [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Among these, PEP is the most common. A meta-analysis of randomized controlled trials reported that PEP occurs at a cumulative incidence of 10.2% overall, with 0.5% of patients experiencing severe PEP and 0.2% of patients experiencing fatal PEP [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThere are several measures that clinicians can use to prevent PEP. For example, endoscopic pancreatic duct stents have been shown to reduce the incidence of PEP in high-risk patients [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. As such, Japanese, European, and American guidelines recommend pancreatic duct stents for patients at high risk of PEP [\u003cspan additionalcitationids=\"CR6\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Of note, the non-therapeutic use of pancreatic duct stents is not reimbursed by the national insurance system in Japan. Pharmacological prophylaxis for PEP is also available. Randomized clinical trials have demonstrated that rectal administration of nonsteroidal anti-inflammatory drugs (NSAIDs) either immediately before or after ERCP significantly lowers the incidence of PEP [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e], and guidelines support routine prophylactic rectal administration of NSAIDs for patients undergoing ERCP [\u003cspan additionalcitationids=\"CR6\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e \u003cp\u003ePeriprocedural aggressive hydration is a measure that has been gaining attention for its potential to reduce the risk of PEP. Both a pilot study (N\u0026thinsp;=\u0026thinsp;62) and a randomized, double-blind study (N\u0026thinsp;=\u0026thinsp;150) that used the same protocol for aggressive hydration (intravenous [IV] lactated Ringer\u0026rsquo;s solution 3 mL/kg/h during the procedure, IV bolus 20 mL/kg immediately after the procedure, IV 3 mL/kg/h for 8 h after the procedure) found that this method significantly reduced the incidence of PEP compared with standard hydration [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. A meta-analysis of randomized controlled trials found that periprocedural aggressive hydration reduced the incidence of PEP by 56% compared with standard hydration (5.1% vs 11.1%; odds ratio 0.44; p\u0026thinsp;=\u0026thinsp;0.0004), with no significant difference in the incidence of fluid overload-related AEs between the two approaches [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Although this is promising, a standard protocol for aggressive hydration has yet to be established. The Department of Gastroenterology and Hepatology at Mei University Hospital in Japan conducted a single-arm study, RESOLUTION-PEP, in 231 patients to evaluate the efficacy and safety of aggressive hydration with lactated Ringer\u0026rsquo;s solution combined with intrarectal diclofenac sodium (diclofenac) for PEP prevention [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. The study used an IV bolus administration of lactated Ringer\u0026rsquo;s solution (5 mL/kg) at the start of the ERCP procedure, with a continuous IV infusion of 3 mL/kg/h for 8 h after the procedure. The PEP incidence rate was 5.6%, which was similar to that reported in the meta-analysis (5.1%) [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. No severe AEs due to aggressive hydration were reported.\u003c/p\u003e\n\u003ch3\u003eObjectives {7}\u003c/h3\u003e\n\u003cp\u003eThis randomized, controlled study is being conducted to further evaluate the efficacy and safety of periprocedural aggressive hydration plus intrarectal diclofenac versus standard hydration plus intrarectal diclofenac in preventing the onset of PEP in Japanese patients.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eTrial design {8}\u003c/h2\u003e \u003cp\u003eThis is a phase 3, multicenter, open-label, randomized (1:1) controlled study (\u003cb\u003eFig.\u0026nbsp;1\u003c/b\u003e).\u003c/p\u003e \u003c/div\u003e"},{"header":"Methods: Participants, interventions, and outcomes","content":"\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eStudy setting {9}\u003c/h2\u003e \u003cp\u003eThe study is being conducted in Japan between 6 February 2024 and 31 March 2028 and is expected to include 27 study sites (\u003cb\u003eTable\u0026nbsp;1\u003c/b\u003e) and 780 patients.\u003c/p\u003e \u003cp\u003e[Place Table\u0026nbsp;1 here]\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eEligibility criteria {10}\u003c/h3\u003e\n\u003cp\u003eThis study will include patients aged\u0026thinsp;\u0026ge;\u0026thinsp;18 years who are scheduled to receive an ERCP procedure. Patients with any of the following will be excluded from the study: previous ERCP with a history of papillary procedures, reduced cardiac function (New York Heart Association grade\u0026thinsp;\u0026ge;\u0026thinsp;2 cardiac function, left ventricular ejection fraction\u0026thinsp;\u0026lt;\u0026thinsp;40%, or a serum brain natriuretic peptide [BNP]\u0026thinsp;\u0026ge;\u0026thinsp;100 pg/mL or serum N-terminal pro-BNP\u0026thinsp;\u0026ge;\u0026thinsp;400 pg/mL), reduced renal function (estimated glomerular filtration rate\u0026thinsp;\u0026lt;\u0026thinsp;60 mL/min/1.73m\u003csup\u003e2\u003c/sup\u003e), respiratory failure (peripheral oxygen saturation\u0026thinsp;\u0026lt;\u0026thinsp;90% in room air), concomitant pancreatitis, suspected dehydration or shock, hypernatremia (serum sodium\u0026thinsp;\u0026gt;\u0026thinsp;147 mEq/L), Eastern Cooperative Oncology Group performance status\u0026thinsp;\u0026ge;\u0026thinsp;3, a colostomy rendering it impossible to rectally administer diclofenac, contraindications to diclofenac, history of allergy to iodine contrast media, postoperative reconstructed intestinal tract, organic stenosis of the gastrointestinal tract that makes papillary access impossible, scheduled from the outset to undergo transpapillary cannulation of the bile duct or pancreatic duct via percutaneous transhepatic biliary drainage-assisted rendezvous or endoscopic ultrasonography-guided rendezvous, or who are pregnant or may become pregnant.\u003c/p\u003e\n\u003ch3\u003eWho will take informed consent? {26a}\u003c/h3\u003e\n\u003cp\u003ePotential study participants will be given a thorough explanation of the study in writing and orally by the principal investigator or an assistant investigator, and written informed consent will be obtained.\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eAdditional consent provisions for collection and use of participant data and biological specimens {26b}\u003c/h2\u003e \u003cp\u003eNot applicable. There is no collection of data or biological specimens for ancillary studies.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eInterventions\u003c/h3\u003e\n\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eExplanation for the choice of comparators {6b}\u003c/h2\u003e \u003cp\u003eNormal hydration was selected as the comparator because it reflects the current standard clinical practice during ERCP procedures. At present, patients undergoing ERCP typically receive routine intravenous hydration, and this approach is widely accepted as the standard of care. Therefore, comparing the\u003c/p\u003e \u003cp\u003eloading infusion strategy against normal hydration will allow us to evaluate the additional benefit of fluid loading over the established standard treatment.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eIntervention description {11a}\u003c/h2\u003e \u003cp\u003eThe infusion protocol for each group is described below and the study observation schedule is shown in \u003cb\u003eTable\u0026nbsp;2\u003c/b\u003e. For both groups, during the 8 h prior to the ERCP procedure, the main infusion will be administered at a rate of \u0026le;\u0026thinsp;1.5 mL/kg/h. Side-tube infusions may be administered with a total volume of \u0026le;\u0026thinsp;100 mL up to two times, separately from the main infusion. Patients in the aggressive hydration group will receive a bolus of 500 mL Ringer\u0026rsquo;s solution (adjusted to 10 mL/kg for patients weighing\u0026thinsp;\u0026lt;\u0026thinsp;50 kg) at the start of the ERCP procedure. The infusion will be administered at 500 mL/h using an infusion pump, and the bolus will be terminated after 1 h even if the entire volume has not been administered. At the end of the bolus administration, patients will receive Ringer\u0026rsquo;s solution at 3 mL/kg/h for 8 h. Patients in the standard hydration group will receive Ringer\u0026rsquo;s solution at 1.5 mL/kg/h, which will be initiated at the start of the ERCP procedure and continued for 9 h. Within 30 min of completing the ERCP procedure, patients in both groups will receive intrarectal diclofenac 50 mg (adjusted to 25 mg for patients weighing\u0026thinsp;\u0026lt;\u0026thinsp;50 kg or aged\u0026thinsp;\u0026ge;\u0026thinsp;80 years). Additionally, at the conclusion of the infusion specified for each treatment group, until the blood test for determining the onset of PEP is performed (when blood sampling is conducted 9\u0026ndash;24 h after ERCP), any ongoing infusion, if administered, will be given at a rate not exceeding 1.5 mL/kg/h for the main infusion, regardless of the type of fluid. Side-tube infusions may be administered with a total volume of \u0026le;\u0026thinsp;100 mL up to three times, separately from the main infusion. Patients should undergo the ERCP procedure within 14 days of enrollment in the study.\u003c/p\u003e \u003cp\u003e[Place Table\u0026nbsp;2 here]\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eCriteria for discontinuing or modifying allocated interventions {11b}\u003c/h2\u003e \u003cp\u003eDuring the treatment period, a change in the infusion load will be implemented if considered necessary due to the onset of acute pancreatitis, hypotension (systolic blood pressure\u0026thinsp;\u0026lt;\u0026thinsp;90 mmHg) or insufficient circulating plasma volume, hypertension (systolic blood pressure\u0026thinsp;\u0026gt;\u0026thinsp;180 mmHg) or excessive circulating plasma volume, or in the case of serum electrolyte values outside of the normal range (normal range: sodium 135\u0026ndash;147 mEq/L; potassium 3.6\u0026ndash;5.0 mEq/L; chloride 98\u0026ndash;108 mEq/L; calcium 8.8\u0026ndash;10.2 mg/dL).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eStrategies to improve adherence to interventions {11c}\u003c/h2\u003e \u003cp\u003eAdherence to the intervention will be ensured by verifying the residual volume after each infusion to confirm whether the prescribed volume has been fully administered.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eRelevant concomitant care permitted or prohibited during the trial {11d}\u003c/h2\u003e \u003cp\u003eTemporary pancreatic ductal stenting for PEP prophylaxis should not be performed unless one or more of the following are true: suspected or confirmed papillary insufficiency, history of post-ERCP pancreatitis or acute pancreatitis, difficulty in cannulation, pancreatic duct insertion or pancreatic duct angiography, pre-cut sphincterotomy of the major duodenal papilla during ERCP, pancreatic duct stent placement before or during endoscopic papillary resection, or when the purpose of the ERCP is pancreatic duct stenting. The following concomitant medications are prohibited: protease inhibitors, nitrates, and nafamostat mesylate.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eProvisions for post-trial care {30}\u003c/h2\u003e \u003cp\u003eNo post-treatment is specified.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003eOutcomes {12}\u003c/h2\u003e \u003cp\u003eThe primary endpoint is the incidence of PEP, defined as serum amylase\u0026thinsp;\u0026ge;\u0026thinsp;400 U/I after the completion of the ERCP (whether or not the patient had an elevated level prior to ERCP) and persistent abdominal pain (\u0026ge;\u0026thinsp;24 h) according to the criteria of the American Society for Gastrointestinal Endoscopy (ASGE) [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e], with the blood sampling timing modified to facilitate blood sampling in real-world clinical practice (16 h\u0026thinsp;\u0026plusmn;\u0026thinsp;8 h after ERCP completion). Abdominal pain is defined as the occurrence of epigastric pain with a score of \u0026ge;\u0026thinsp;3 on an integer visual analogue scale (VAS; 0\u0026ndash;10) within 48 h after the start of ERCP, or an increase of \u0026ge;\u0026thinsp;3 points compared with the pre-ERCP score, which persists for at least 24 h.\u003c/p\u003e \u003cp\u003eThe secondary endpoints are the incidence of PEP by severity, the incidence of hyperamylasemia (increase in amylase\u0026thinsp;\u0026ge;\u0026thinsp;400 U/I), and the incidence of infusion-related AEs. The severity of PEP will be assessed using the 2012 Atlanta Classification [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. AEs will be monitored throughout the study and will be classified per the Japanese translation of the Common Terminology Criteria for Adverse Events version 5.0 (Japan Clinical Oncology Group Shared Criteria Scope) [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003eParticipant timeline {13}\u003c/h2\u003e \u003cp\u003e \u003cb\u003eTable\u0026nbsp;2\u003c/b\u003e provides procedures at each timepoint.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec18\" class=\"Section2\"\u003e \u003ch2\u003eSample size {14}\u003c/h2\u003e \u003cp\u003eThe sample size was calculated as follows. Under the assumption that the incidence of PEP in the aggressive hydration group and the standard hydration group will be the same as reported in a 2019 meta-analysis (5.1% and 11.1%, respectively) [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e], and assuming a two-sided α significance level of 0.05 and a power of 1-β\u0026thinsp;=\u0026thinsp;0.8, the number of patients required to detect a significant difference between the two groups was 714 total, with 357 patients in each group. Considering that some patients will be ineligible, withdraw from the study, or be lost to follow-up, the expected number of enrolled patients was set at 780.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec19\" class=\"Section2\"\u003e \u003ch2\u003eRecruitment {15}\u003c/h2\u003e \u003cp\u003eEligible patients scheduled for ERCP will be identified during outpatient visits or upon hospital admission, and will be approached for study participation after providing informed consent.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec20\" class=\"Section2\"\u003e \u003ch2\u003eAssignment of interventions: allocation\u003c/h2\u003e \u003cdiv id=\"Sec21\" class=\"Section3\"\u003e \u003ch2\u003eSequence generation {16a}\u003c/h2\u003e \u003cp\u003eThe Nagoya University Registration and Randomization System will be employed to perform randomization using a minimization method with the following stratification factors to ensure balance between the treatment groups: age (\u0026lt;\u0026thinsp;50 years, \u0026ge;\u0026thinsp;50 years), sex (male, female), purpose of ERCP (with or without the intent of pancreatic duct cannulation), and study site.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec22\" class=\"Section2\"\u003e \u003ch2\u003eConcealment mechanism {16b}\u003c/h2\u003e \u003cp\u003eThe allocation will not be concealed, as this is an open-label study. The details of the random assignment procedure will not be made available to the principal investigator or assistant investigators.\u003c/p\u003e \u003cdiv id=\"Sec23\" class=\"Section3\"\u003e \u003ch2\u003eImplementation {16c}\u003c/h2\u003e \u003cp\u003ePatients will be registered by physicians at each participating study site using the Nagoya University Registration and Randomization System, which will randomly allocate patients 1:1 to the aggressive hydration group or standard hydration group. The randomization process will be independently monitored and overseen by the Mei University Data Center.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec24\" class=\"Section2\"\u003e \u003ch2\u003eAssignment of interventions: Blinding\u003c/h2\u003e \u003cdiv id=\"Sec25\" class=\"Section3\"\u003e \u003ch2\u003eWho will be blinded {17a}\u003c/h2\u003e \u003cp\u003eNo blinding will be performed.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec26\" class=\"Section3\"\u003e \u003ch2\u003eProcedure for unblinding if needed {17b}\u003c/h2\u003e \u003cp\u003eNot applicable. This was an open-label study.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec27\" class=\"Section3\"\u003e \u003ch2\u003eData collection and management\u003c/h2\u003e \u003cdiv id=\"Sec28\" class=\"Section4\"\u003e \u003ch2\u003ePlans for assessment and collection of outcomes {18a}\u003c/h2\u003e \u003cp\u003eDuring the observation period, patients will be monitored for the presence and severity of PEP, post-ERCP AEs other than PEP (hyperamylasemia, acute cholangitis, gastrointestinal bleeding, and gastrointestinal perforation according to the ASGE) [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e], and infusion-related AEs (cerebral edema, respiratory failure, peripheral edema, and hypernatremia). Data collection will be performed using electronic case report forms (eCRF) implemented in the study\u0026rsquo;s electronic data capture (EDC) system, which is managed by the Mie University Data Center.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec29\" class=\"Section2\"\u003e \u003ch2\u003ePlans to promote participant retention and complete follow-up {18b}\u003c/h2\u003e \u003cp\u003eThis study will be completed within the index hospitalization, and all outcomes will be assessed until discharge. Therefore, no long-term follow-up is required. For patients who discontinue or deviate from the intervention protocol, outcome data including the occurrence and severity of PEP, post-ERCP AEs, and infusion-related AEs will still be collected until discharge to ensure completeness of outcome assessment.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eData management {19}\u003c/h3\u003e\n\u003cp\u003eAll study data will be entered directly into eCRFs within the EDC system. Data entry will be performed by the investigators or designated research staff at each participating site. The EDC system incorporates automatic range and consistency checks to minimize entry errors and ensure data quality. Additional data validation and query management will be conducted by the Mie University Data Center, which is responsible for overseeing data management. Detailed procedures for data handling and quality control are described in the data management standard operating procedures maintained by the Mie University Data Center.\u003c/p\u003e \u003cdiv id=\"Sec31\" class=\"Section2\"\u003e \u003ch2\u003eConfidentiality {27}\u003c/h2\u003e \u003cp\u003eThe principal investigator will be responsible for data management. Paper information other than medical records will be stored in lockable cabinets at each study site. Electronic data will be stored on personal computers, password protected, and stored in a lockable cabinet at each study site. Information will be stored for at least five years from the date of study completion and will be disposed of in a way that prevents identification of specific individuals.\u003c/p\u003e \u003cp\u003e \u003cb\u003ePlans for collection, laboratory evaluation and storage of biological specimens for genetic or molecular analysis in this trial/future use {33}\u003c/b\u003e \u003c/p\u003e \u003cp\u003eBlood samples will be disposed of in the usual manner after the laboratory measurements have been obtained.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec32\" class=\"Section2\"\u003e \u003ch2\u003eStatistical methods\u003c/h2\u003e \u003cdiv id=\"Sec33\" class=\"Section3\"\u003e \u003ch2\u003eStatistical methods for primary and secondary outcomes {20a}\u003c/h2\u003e \u003cp\u003eThe primary and secondary endpoints will be analyzed using the full analysis set, which will comprise all patients who underwent ERCP and for whom the primary endpoint can be evaluated. Categorial variables will be summarized using frequency and proportion and continuous variables will be summarized using descriptive statistics. Fisher\u0026rsquo;s exact test will be used to compare the primary, secondary, and safety outcomes between the two treatment groups. A two-sided significance level of 5% will be used. The statistical analyses will be conducted according to the statistical methods outlined in the study protocol. The full statistical methods are provided in \u003cb\u003eAdditional file 1\u003c/b\u003e.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec34\" class=\"Section3\"\u003e \u003ch2\u003eInterim analyses {21b}\u003c/h2\u003e \u003cp\u003eNo interim analysis is planned.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e\n\u003ch3\u003eMethods for additional analyses (e.g. subgroup analyses) {20b}\u003c/h3\u003e\n\u003cp\u003eNot applicable. No subgroup analysis will be performed in this study.\u003c/p\u003e \u003cp\u003e \u003cb\u003eMethods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c}\u003c/b\u003e \u003c/p\u003e \u003cp\u003ePatients with missing data related to determining the primary or secondary endpoints will be excluded from the analysis. Missing AE data will be entered as \u0026ldquo;unspecified\u0026rdquo;.\u003c/p\u003e\n\u003ch3\u003ePlans to give access to the full protocol, participant-level data and statistical code {31c}\u003c/h3\u003e\n\u003cp\u003eThe full study protocol will be made available upon reasonable request to the corresponding author. Participant-level data and statistical code will not be shared owing to privacy and institutional restrictions.\u003c/p\u003e \u003cdiv id=\"Sec37\" class=\"Section2\"\u003e \u003ch2\u003eOversight and monitoring\u003c/h2\u003e \u003cdiv id=\"Sec38\" class=\"Section3\"\u003e \u003ch2\u003eComposition of the coordinating center and trial steering committee {5d}\u003c/h2\u003e \u003cp\u003eThe coordinating center for this trial is the Mie University Data Center, which is responsible for patient registration, data management, and overall coordination of the study. Day-to-day operational support, including patient enrollment, completion of case report forms, and data entry, will be carried out by physicians and research staff at each participating site under the supervision of the coordinating center. Although no independent trial steering committee has been established, oversight of study conduct and data integrity will be ensured by the coordinating center. In the event of any serious issues or concerns regarding study conduct, an independent audit will be arranged in accordance with institutional and regulatory requirements.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec39\" class=\"Section2\"\u003e \u003ch2\u003eComposition of the data monitoring committee, its role and reporting structure {21a}\u003c/h2\u003e \u003cp\u003eThe Data Monitoring Committee will consist of persons not directly involved in the conduct of the trial. The committee will monitor the study to ensure that it is being conducted safely, in compliance with the study protocol, and that data are collected accurately. An independent Efficacy and Safety Assessment Committee will periodically review safety and efficacy information during the study and will make recommendations to the principal investigator regarding the continuation, modification, or discontinuation of the study. The committee is independent from the sponsor and has no competing interests.\u003c/p\u003e \u003cdiv id=\"Sec40\" class=\"Section3\"\u003e \u003ch2\u003eAdverse event reporting and harms {22}\u003c/h2\u003e \u003cp\u003eAll serious AEs will be immediately reported to the principal investigator, who will then notify the drug provider and report to the Efficacy and Safety Evaluation Committee as necessary.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e\n\u003ch3\u003eFrequency and plans for auditing trial conduct {23}\u003c/h3\u003e\n\u003cp\u003eIf a serious violation of relevant laws or regulations, or deviation from the study protocol is identified during monitoring, an audit will be conducted.\u003c/p\u003e\n\u003ch3\u003ePlans for communicating important protocol amendments to relevant parties (e.g. trial participants, ethical committees) {25}\u003c/h3\u003e\n\u003cp\u003eAny modifications to the protocol that may impact the conduct, safety, design, population, or procedures of the study will require a formal modification to the protocol. Any modification must be approved by the relevant authorities before being implemented in the study.\u003c/p\u003e \u003cp\u003e \u003cb\u003eDissemination plans {31a}\u003c/b\u003e \u003c/p\u003e \u003cp\u003eThe trial results will be disseminated through presentations at national and international scientific meetings and publication in peer-reviewed journals. Summaries of the study results will also be provided to the participating investigators. There are no restrictions on publication, and results will be reported in accordance with applicable guidelines for clinical trial registration and reporting.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study aims to address whether the use of aggressive hydration reduces the incidence of PEP compared with standard hydration. The study also aims to compare the incidence of PEP by severity, the incidence of hyperamylasemia, and the incidence of infusion-related AEs between patients who receive aggressive hydration versus standard hydration. The study will also determine overall safety in both groups. At the end of the study, the study data will be presented at conferences and/or journal articles.\u003c/p\u003e \u003cp\u003eThe study is expected to determine whether aggressive hydration plus intrarectal diclofenac effectively and safely reduces the incidence of PEP. PEP is the most common and serious AE of ERCP [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Thus, it is of interest to evaluate prophylactic and perioperative interventions to reduce the incidence of PEP. A meta-analysis supports a reduced incidence of PEP when patients receive aggressive hydration versus standard hydration in randomized controlled trials [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. This multicenter study is expected to provide further evidence regarding the efficacy and safety of perioperative aggressive hydration in Japanese patients. A major strength of this study is its broad participation of both university and community hospitals across Japan, which enhances the generalizability of the findings. Randomization will be performed using a minimization method with stratification by age, sex, purpose of ERCP (pancreatic duct cannulation or not), and study site to minimize imbalance between groups. In addition, several important PEP-related factors have been carefully standardized to reduce potential confounding. Intrarectal diclofenac will be administered to all patients, and the indications for prophylactic pancreatic stent placement are clearly defined to prevent discretionary use. Furthermore, trainee endoscopists will be excluded, ensuring that all procedures are performed by experienced endoscopists. Procedure-related details such as difficulty of cannulation, cannulation time, type of papillary intervention, pancreatic duct injection, modified Schutz classification, and the presence or absence of transpapillary self-expandable metallic stent placement will also be recorded, allowing for detailed subgroup analyses. The study will also document whether the assigned study infusion was completed as per protocol. For the assessment of post-ERCP pain, the VAS will be used to provide an objective and standardized endpoint rather than a subjective evaluation. Taken together, this study has been designed to enable an accurate comparison of the pure effect of aggressive hydration on the incidence of PEP, under rigorously controlled and clearly defined clinical conditions.\u003c/p\u003e \u003cp\u003eAlthough this multicenter study is being conducted only at study sites in Japan, which may limit the generalizability of the findings to other populations, the participation of diverse institutions across a wide geographic area is expected to mitigate this limitation. In conclusion, this study aims to clarify whether aggressive hydration is effective for reducing the incidence of PEP compared with standard hydration and will evaluate the safety of this intervention.\u003c/p\u003e \u003cp\u003e \u003cb\u003eTrial status\u003c/b\u003e \u003c/p\u003e \u003cp\u003eStudy Protocol version 1.1 (April 24, 2025) will be used to conduct the trial. Recruitment began on 20 May 2024 and is expected to be completed on 31 March 2028.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eeCRF\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eElectronic case report form\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eERCP\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eEndoscopic retrograde cholangiopancreatography\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eAE\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eAdverse event\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePEP\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ePost-endoscopic retrograde cholangiopancreatography pancreatitis\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eNSAID\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eNonsteroidal anti-inflammatory drug\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eIV\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eIntravenous\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eBNP\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eBrain natriuretic peptide\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ejRCT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eJapan Registry of Clinical Trials\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eASGE\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eAmerican Society for Gastrointestinal Endoscopy\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eECOG PS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eEastern Cooperative Oncology Group performance status\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eEUS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eEndoscopic ultrasonography\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eERCP\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eEndoscopic retrograde cholangiopancreatography\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eGI\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eGastrointestinal\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePRBD\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ePercutaneous transhepatic biliary drainage\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eEDC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eElectronic data capture\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eNT-proBNP\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eN-terminal pro-B-type natriuretic peptide\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eVAS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eVisual analogue scale\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors would like to thank the physicians, nurses, and research staff at all participating institutions for their valuable contributions to this study. We also express our sincere gratitude to the patients and their families for their cooperation and participation. The authors thank Sarah Bubeck, PhD, of Edanz (www.edanz.com) for providing medical writing support, which was funded by Mie University Hospital Specified Clinical Trial Promotion Grant S2023-002, in accordance with Good Publication Practice (GPP3) guidelines (http://www.ismpp.org/gpp3).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors’ contributions {31b}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eRY and KN conceived and designed the study. YI provided guidance on the electronic data capture (EDC) system for conducting a multicenter study, and ST advised on the development of the study protocol in compliance with regulatory requirements. All authors contributed to patient enrollment and data collection. KN and TO performed the statistical analysis. RY drafted the manuscript and critically revised it for important intellectual content. All authors contributed to the interpretation of the data and approved the final version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding {4}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was supported by Mie University Hospital Specified Clinical Trial Promotion Grant S2023-002. The funding body is responsible for the overall design, management, and conduct of the study and will have no role in patient recruitment or data analysis, and will not influence the interpretation of the study results.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials {29}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe final trial dataset will be accessible only to the principal investigator and authorized members of the Mie University Data Center responsible for data management. Participating investigators will have access to the data pertaining to their own patients. There are no contractual agreements that limit access to the dataset for investigators beyond these restrictions.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate {24}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll patients must provide written informed consent prior to study enrollment, which will be collected by the study investigator or research assistant at each study site. This study will comply with the principles outlined in the Declaration of Helsinki. The study protocol was approved by the\u0026nbsp;Clinical Research Review Board at Mei University Hospital (CRB4180006). The responsible regional bureau of health and welfare was the Takai–Hokuriku Regional Bureau of Health and Welfare. The study was prospectively registered with the Japan Registry of Clinical Trials (jRCT: s041230145; registered February 6, 2024; https://jrct.mhlw.go.jp/latest-detail/jRCTs041230145).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication {32}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable, as no patient data are presented in this manuscript.\u003cbr\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests {28}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors have no competing interests to declare.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eAzimaraghi O, Bilal M, Amornyotin S, et al. Consensus guidelines for the perioperative management of patients undergoing endoscopic retrograde cholangiopancreatography. Br J Anaesth. 2023;130:763\u0026ndash;72. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.bja.2023.03.012\u003c/span\u003e\u003cspan address=\"10.1016/j.bja.2023.03.012\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBishay K, Meng ZW, Khan R, et al. Adverse events associated with endoscopic retrograde cholangiopancreatography: Systematic review and meta-analysis. Gastroenterology. 2025;168:568\u0026ndash;86. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1053/j.gastro.2024.10.033\u003c/span\u003e\u003cspan address=\"10.1053/j.gastro.2024.10.033\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAkshintala VS, Kanthasamy K, Bhullar FA, et al. Incidence, severity, and mortality of post-ERCP pancreatitis: an updated systematic review and meta-analysis of 145 randomized controlled trials. Gastrointest Endosc. 2023;98:1\u0026ndash;6.e12. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.gie.2023.03.023\u003c/span\u003e\u003cspan address=\"10.1016/j.gie.2023.03.023\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSofuni A, Maguchi H, Mukai T, et al. Endoscopic pancreatic duct stents reduce the incidence of post-endoscopic retrograde cholangiopancreatography pancreatitis in high-risk patients. Clin Gastroenterol Hepatol. 2011;9:851\u0026ndash;8; quiz e110. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.cgh.2011.06.033\u003c/span\u003e\u003cspan address=\"10.1016/j.cgh.2011.06.033\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTakada T, Isaji S, Mayumi T, et al. JPN clinical practice guidelines 2021 with easy-to-understand explanations for the management of acute pancreatitis. J Hepatobiliary Pancreat Sci. 2022;29:1057\u0026ndash;83. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1002/jhbp.1146\u003c/span\u003e\u003cspan address=\"10.1002/jhbp.1146\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDumonceau JM, Kapral C, Aabakken L, et al. ERCP-related adverse events: European Society of Gastrointestinal Endoscopy (ESGE) Guideline. Endoscopy. 2020;52:127\u0026ndash;49. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1055/a-1075-4080\u003c/span\u003e\u003cspan address=\"10.1055/a-1075-4080\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eASGE Standards of Practice Committee; Chandrasekhara V, Khashab MA, Muthusamy VR, et al. Adverse events associated with ERCP. Gastrointest Endosc. 2017;85:32\u0026ndash;47. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.gie.2016.06.051\u003c/span\u003e\u003cspan address=\"10.1016/j.gie.2016.06.051\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eElmunzer BJ, Scheiman JM, Lehman GA, et al; U.S. Cooperative for Outcomes Research in Endoscopy (USCORE). A randomized trial of rectal indomethacin to prevent post-ERCP pancreatitis. N Engl J Med. 2012;366:1414\u0026ndash;22. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1056/NEJMoa1111103\u003c/span\u003e\u003cspan address=\"10.1056/NEJMoa1111103\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOtsuka T, Kawazoe S, Nakashita S, et al. Low-dose rectal diclofenac for prevention of post-endoscopic retrograde cholangiopancreatography pancreatitis: a randomized controlled trial. J Gastroenterol. 2012;47:912\u0026ndash;7. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s00535-012-0554-7\u003c/span\u003e\u003cspan address=\"10.1007/s00535-012-0554-7\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBuxbaum J, Yan A, Yeh K, Lane C, Nguyen N, Laine L. Aggressive hydration with lactated Ringer's solution reduces pancreatitis after endoscopic retrograde cholangiopancreatography. Clin Gastroenterol Hepatol. 2014;12:303-\u003cdiv class=\"ExternalRefDOI\"\u003e7.e1\u003c/div\u003e. doi: 10.1016/j.cgh.2013.07.026.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShaygan-Nejad A, Masjedizadeh AR, Ghavidel A, Ghojazadeh M, Khoshbaten M. Aggressive hydration with Lactated Ringer's solution as the prophylactic intervention for postendoscopic retrograde cholangiopancreatography pancreatitis: A randomized controlled double-blind clinical trial. J Res Med Sci. 2015;20:838\u0026ndash;43. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.4103/1735-1995.170597\u003c/span\u003e\u003cspan address=\"10.4103/1735-1995.170597\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRadadiya D, Devani K, Arora S, et al. Peri-procedural aggressive hydration for post endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis prophylaxsis: Meta-analysis of randomized controlled trials. Pancreatology. 2019;19:819\u0026ndash;27. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.pan.2019.07.046\u003c/span\u003e\u003cspan address=\"10.1016/j.pan.2019.07.046\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHattori A, Yamada R, Murabayashi T, et al. The safety and efficacy of Ringer's solution loading with rectal diclofenac for prevention of post-endoscopic retrograde cholangiopancreatography pancreatitis: The RESOLUTION-PEP study. DEN Open. 2023;3:e236. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1002/deo2.236\u003c/span\u003e\u003cspan address=\"10.1002/deo2.236\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCotton PB, Eisen GM, Aabakken L, et al. A lexicon for endoscopic adverse events: report of an ASGE workshop. Gastrointest Endosc. 2010;71:446\u0026ndash;54. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.gie.2009.10.027\u003c/span\u003e\u003cspan address=\"10.1016/j.gie.2009.10.027\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBanks PA, Bollen TL, Dervenis C, et al; Acute Pancreatitis Classification Working Group. Classification of acute pancreatitis\u0026mdash;2012: revision of the Atlanta classification and definitions by international consensus. Gut. 2013;62:102\u0026ndash;11. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1136/gutjnl-2012-302779\u003c/span\u003e\u003cspan address=\"10.1136/gutjnl-2012-302779\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJapan Clinical Oncology Group. Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://jcog.jp/doctor/tool/ctcaev5/\u003c/span\u003e\u003cspan address=\"https://jcog.jp/doctor/tool/ctcaev5/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. Accessed 25 September 2025.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1.\u0026nbsp;\u003c/strong\u003eList of study sites and investigators\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 64.5503%;\"\u003e\n \u003cp\u003eStudy site\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 35.4497%;\"\u003e\n \u003cp\u003ePrincipal investigator\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 64.5503%;\"\u003e\n \u003cp\u003eJichi Medical University Hospital\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 35.4497%;\"\u003e\n \u003cp\u003eAtsushi Kanno\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 64.5503%;\"\u003e\n \u003cp\u003eJuntendo Hospital, Juntendo Medical School, Juntendo University\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 35.4497%;\"\u003e\n \u003cp\u003eHiroyuki Isayama\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 64.5503%;\"\u003e\n \u003cp\u003eUniversity of Toyama Hospital\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 35.4497%;\"\u003e\n \u003cp\u003eIchiro Yasuda\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 64.5503%;\"\u003e\n \u003cp\u003eGifu University Hospital\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 35.4497%;\"\u003e\n \u003cp\u003eShinya Uemura\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 64.5503%;\"\u003e\n \u003cp\u003eGifu Municipal Hospital\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 35.4497%;\"\u003e\n \u003cp\u003eKeisuke Iwata\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 64.5503%;\"\u003e\n \u003cp\u003eGifu Prefectural Tajimi Hospital\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 35.4497%;\"\u003e\n \u003cp\u003eFumihiro Okumura\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 64.5503%;\"\u003e\n \u003cp\u003eGifu Prefectural General Medical Center\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 35.4497%;\"\u003e\n \u003cp\u003eKensaku Yoshida\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 64.5503%;\"\u003e\n \u003cp\u003eHamamatsu University Hospital\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 35.4497%;\"\u003e\n \u003cp\u003eKen Sugimoto\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 64.5503%;\"\u003e\n \u003cp\u003eAichi Medical University\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 35.4497%;\"\u003e\n \u003cp\u003eTadahisa Inoue\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 64.5503%;\"\u003e\n \u003cp\u003eNagoya City University Hospital\u0026nbsp;Graduate School of Medical Sciences\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 35.4497%;\"\u003e\n \u003cp\u003eYasuki Hori\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 64.5503%;\"\u003e\n \u003cp\u003eNagoya City University Eastern Medical Center\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 35.4497%;\"\u003e\n \u003cp\u003eKazuki Hayashi\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 64.5503%;\"\u003e\n \u003cp\u003eFujita Medical College Hospital\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 35.4497%;\"\u003e\n \u003cp\u003eEizaburo Ohno\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 64.5503%;\"\u003e\n \u003cp\u003eFujita Medical College Bantane Hospital\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 35.4497%;\"\u003e\n \u003cp\u003eSenju Hashimoto\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 64.5503%;\"\u003e\n \u003cp\u003eFujita Medical College Okazaki Medical Center\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 35.4497%;\"\u003e\n \u003cp\u003eYoshihiko Tachi\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 64.5503%;\"\u003e\n \u003cp\u003eMie University Hospital\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 35.4497%;\"\u003e\n \u003cp\u003eReiko Yamada\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 64.5503%;\"\u003e\n \u003cp\u003eKagawa University Hospital\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 35.4497%;\"\u003e\n \u003cp\u003eHideki Kamada\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 64.5503%;\"\u003e\n \u003cp\u003eKumamoto University Hospital\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 35.4497%;\"\u003e\n \u003cp\u003eMotohiro Yoshinari\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 64.5503%;\"\u003e\n \u003cp\u003eKumamoto City Hospital\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 35.4497%;\"\u003e\n \u003cp\u003eShunpei Hashigo\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 64.5503%;\"\u003e\n \u003cp\u003eKuwana City General Medical Center\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 35.4497%;\"\u003e\n \u003cp\u003eYumi Oya\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 64.5503%;\"\u003e\n \u003cp\u003eYokkaichi Hazu Medical Center\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 35.4497%;\"\u003e\n \u003cp\u003eRyohei Sakaguchi\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 64.5503%;\"\u003e\n \u003cp\u003eMie Prefectural General Medical Center\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 35.4497%;\"\u003e\n \u003cp\u003eIsao Moritani\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 64.5503%;\"\u003e\n \u003cp\u003eSuzuka Kaisei Hospital\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 35.4497%;\"\u003e\n \u003cp\u003eShunsuke Tano\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 64.5503%;\"\u003e\n \u003cp\u003eMatsusaka Central General Hospital\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 35.4497%;\"\u003e\n \u003cp\u003eHiroaki Naota\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 64.5503%;\"\u003e\n \u003cp\u003eOkanami General Hospital\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 35.4497%;\"\u003e\n \u003cp\u003eHajime Imai\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 64.5503%;\"\u003e\n \u003cp\u003eShizuoka Prefectural General Hospital\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 35.4497%;\"\u003e\n \u003cp\u003eShinya Kawaguchi\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 64.5503%;\"\u003e\n \u003cp\u003eMatsunami General Hospital\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 35.4497%;\"\u003e\n \u003cp\u003eMitsuru Okuno\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 64.5503%;\"\u003e\n \u003cp\u003eShiga University Hospital, Shiga University of Medical Science\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 35.4497%;\"\u003e\n \u003cp\u003eTakuji Iwashita\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003e\u003c/strong\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2.\u0026nbsp;\u003c/strong\u003eStudy observation schedule\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" class=\"fr-table-selection-hover\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 157px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"4\" valign=\"top\" style=\"width: 409px;\"\u003e\n \u003cp\u003eSTUDY PERIOD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 157px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 203px;\"\u003e\n \u003cp\u003eEnrollment/Allocation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 207px;\"\u003e\n \u003cp\u003ePost-allocation\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 157px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 101px;\"\u003e\n \u003cp\u003eEnrollment\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 102px;\"\u003e\n \u003cp\u003eDay before ERCP\u003c/p\u003e\n \u003cp\u003e(Day 1)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 102px;\"\u003e\n \u003cp\u003eDay 2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 105px;\"\u003e\n \u003cp\u003eDay 3 through discharge date\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 157px;\"\u003e\n \u003cp\u003eObtain consent, registration, and allocation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 203px;\"\u003e\n \u003cp\u003e○\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 102px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 105px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 157px;\"\u003e\n \u003cp\u003eDisease requiring ERCP, pre-existing conditions, antithrombotic medications\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 203px;\"\u003e\n \u003cp\u003e○\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 102px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 105px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 157px;\"\u003e\n \u003cp\u003eConfirmation of PEP risk factors\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 203px;\"\u003e\n \u003cp\u003e○\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 102px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 105px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 157px;\"\u003e\n \u003cp\u003eSelf-reported and other symptoms\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 101px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 102px;\"\u003e\n \u003cp\u003e○\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 102px;\"\u003e\n \u003cp\u003ePhysical examination findings\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 105px;\"\u003e\n \u003cp\u003e\u0026Delta;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 157px;\"\u003e\n \u003cp\u003ePhysical findings\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 203px;\"\u003e\n \u003cp\u003e○\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 102px;\"\u003e\n \u003cp\u003e○\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 105px;\"\u003e\n \u003cp\u003e\u0026Delta;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 157px;\"\u003e\n \u003cp\u003eBlood and biochemical tests\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 203px;\"\u003e\n \u003cp\u003e○\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 102px;\"\u003e\n \u003cp\u003eBNP or NT-pro-BNP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 105px;\"\u003e\n \u003cp\u003e\u0026Delta;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 157px;\"\u003e\n \u003cp\u003eBNP or NT-proBNP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 203px;\"\u003e\n \u003cp\u003e○\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 102px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 105px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 157px;\"\u003e\n \u003cp\u003eChest X-ray\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 203px;\"\u003e\n \u003cp\u003e\u0026Delta;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 207px;\"\u003e\n \u003cp\u003e\u0026Delta;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 157px;\"\u003e\n \u003cp\u003eImaging tests\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 203px;\"\u003e\n \u003cp\u003e\u0026Delta;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 207px;\"\u003e\n \u003cp\u003e\u0026Delta;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 157px;\"\u003e\n \u003cp\u003eElectrocardiogram\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 203px;\"\u003e\n \u003cp\u003e\u0026Delta;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 102px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 105px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 157px;\"\u003e\n \u003cp\u003eEchocardiography\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 203px;\"\u003e\n \u003cp\u003e(only when performed to evaluate cardiac function)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 102px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 105px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 157px;\"\u003e\n \u003cp\u003eDiclofenac administration\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 101px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 102px;\"\u003e\n \u003cp\u003e○\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 102px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 105px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 157px;\"\u003e\n \u003cp\u003eInfusion with therapeutic prescription\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 101px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 102px;\"\u003e\n \u003cp\u003e○\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 102px;\"\u003e\n \u003cp\u003e○\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 105px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 157px;\"\u003e\n \u003cp\u003eERCP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 101px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 102px;\"\u003e\n \u003cp\u003e○\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 102px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 105px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 157px;\"\u003e\n \u003cp\u003eAvailability of PEP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 101px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 309px;\"\u003e\n \u003cp\u003e○\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 157px;\"\u003e\n \u003cp\u003eAE evaluation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 101px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 309px;\"\u003e\n \u003cp\u003e○\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 157px;\"\u003e\n \u003cp\u003eOutcome\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 101px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 102px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 102px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 105px;\"\u003e\n \u003cp\u003e○\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 157px;\"\u003e\n \u003cp\u003eLength of hospital stay\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 101px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 102px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 102px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 105px;\"\u003e\n \u003cp\u003e○\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003csup\u003ea\u003c/sup\u003eThe period from registration to the first ERCP should not exceed 14 days. If pancreatitis or other incidental changes in the patient\u0026apos;s condition occur after the ERCP, and the patient is not enrolled in the study treatment period, the ERCP must be performed within 14 days of the initial ERCP. If a change in the main infusion is necessary during the infusion period (up to 9 hours before the start of ERCP\u0026nbsp;for both groups), the study treatment should be stopped immediately, and the infusion should be changed to a clinically appropriate intravenous fluid at the discretion of the treating physician.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003eb\u003c/sup\u003eIf PEP or other AEs occur, blood samples should be collected from day 3 to the day of discharge, and the highest amylase value during that time should be reported.\u003c/p\u003e\n\u003cp\u003e○ = mandatory (to be collected as part of the EDC).\u003c/p\u003e\n\u003cp\u003e\u0026Delta; = items that are not collected in the EDC but should be implemented to ensure safety, or depending on the course of events.\u003c/p\u003e\n\u003cp\u003eAE, adverse event; BNP, brain natriuretic peptide; EDC, electronic data capture; ERCP, endoscopic retrograde cholangiopancreatography; NT-proBNP, N-terminal pro-B-type natriuretic peptide; PEP, post-ERCP pancreatitis\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"trials","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"trls","sideBox":"Learn more about [Trials](http://trialsjournal.biomedcentral.com/)","snPcode":"13063","submissionUrl":"https://www.editorialmanager.com/trls","title":"Trials","twitterHandle":"MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Aggressive hydration, endoscopic retrograde cholangiopancreatography, post-endoscopic retrograde cholangiopancreatography pancreatitis","lastPublishedDoi":"10.21203/rs.3.rs-8469484/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8469484/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eEndoscopic retrograde cholangiopancreatography (ERCP), a procedure to treat pancreaticobiliary disorders, is generally safe. However, adverse events (AEs) of post-ERCP pancreatitis (PEP) can occur, which can be fatal. Physicians performing ERCP can take measures to prevent PEP, including endoscopic pancreatic duct stents and pharmacological prophylaxis. Periprocedural aggressive hydration has been investigated for its potential for reducing PEP risk. This study aims to evaluate the efficacy and safety of periprocedural aggressive hydration plus intrarectal diclofenac versus standard hydration therapy plus intrarectal diclofenac in preventing PEP onset in Japanese patients.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThis phase 3, multicenter, open-label, randomized controlled study is being conducted at an anticipated 27 sites in Japan. The study plans to enroll 780 adults (aged\u0026thinsp;\u0026ge;\u0026thinsp;18 years) who are scheduled to receive an ERCP procedure. Patients will be randomized 1:1 to the aggressive hydration or standard hydration group. Approximately 8 h prior to the ERCP procedure, patients in both groups will be administered the main infusion (\u0026le;\u0026thinsp;1.5 mL/kg/h). The aggressive hydration group will receive a bolus of 500 mL Ringer\u0026rsquo;s solution at the start of the ERCP procedure (500 mL/h) followed by Ringer\u0026rsquo;s solution administered at 3mL/kg/h for 8 h. The standard hydration group will be administered Ringer\u0026rsquo;s solution at 1.5 mL/kg/h initiated at the start of the ERCP procedure and continuing for 9 h. Within 30 min of completing the ERCP procedure, patients in both groups will receive intrarectal diclofenac sodium (standard, 50 mg; patients weighing\u0026thinsp;\u0026lt;\u0026thinsp;50 kg or aged\u0026thinsp;\u0026ge;\u0026thinsp;80 years, 25 mg). The primary endpoint is the incidence of PEP (serum amylase\u0026thinsp;\u0026ge;\u0026thinsp;400 U/I after ERCP completion and persistent abdominal pain for \u0026ge;\u0026thinsp;24 h). Secondary endpoints include the incidence of PEP by severity, the incidence of hyperamylasemia (increase in amylase\u0026thinsp;\u0026ge;\u0026thinsp;400 U/I), and the incidence of infusion-related AEs. AEs will be monitored throughout the study.\u003c/p\u003e\u003ch2\u003eDiscussion\u003c/h2\u003e \u003cp\u003eThis study aims to clarify whether aggressive hydration reduces PEP incidence versus standard hydration, and to compare PEP incidence by severity, and the incidence of hyperamylasemia and infusion-related AEs. Safety will be determined in both groups.\u003c/p\u003e\u003ch2\u003eTrial registration:\u003c/h2\u003e \u003cp\u003eJapan Registry of Clinical Trials (jRCT: s041230145; registered February 6, 2024; \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://jrct.mhlw.go.jp/latest-detail/jRCTs041230145\u003c/span\u003e\u003cspan address=\"https://jrct.mhlw.go.jp/latest-detail/jRCTs041230145\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e)\u003c/p\u003e","manuscriptTitle":"Efficacy and safety of aggressive hydration for preventing post-endoscopic retrograde cholangiopancreatography pancreatitis: study protocol for a phase 3, multicenter, open-label, randomized controlled study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-05-13 08:41:13","doi":"10.21203/rs.3.rs-8469484/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"237568029402770115532442784712256147734","date":"2026-05-09T19:42:18+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-05-04T18:30:50+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-04-08T06:07:24+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-01-22T11:43:04+00:00","index":"","fulltext":""},{"type":"submitted","content":"Trials","date":"2026-01-20T01:49:14+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"trials","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"trls","sideBox":"Learn more about [Trials](http://trialsjournal.biomedcentral.com/)","snPcode":"13063","submissionUrl":"https://www.editorialmanager.com/trls","title":"Trials","twitterHandle":"MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"1b5908ae-bdcc-4222-8001-b4379a0cf275","owner":[],"postedDate":"May 13th, 2026","published":true,"recentEditorialEvents":[{"type":"reviewerAgreed","content":"237568029402770115532442784712256147734","date":"2026-05-09T19:42:18+00:00","index":10,"fulltext":""},{"type":"reviewersInvited","content":"1","date":"2026-05-04T18:30:50+00:00","index":"","fulltext":""}],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-05-13T08:41:19+00:00","versionOfRecord":[],"versionCreatedAt":"2026-05-13 08:41:13","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8469484","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8469484","identity":"rs-8469484","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}