Aggressive hydration with lactated Ringers solution versus plasma solution for the prevention of post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (ALPS study): protocol for a multicentre, double-blind, randomised controlled trial

Background

Endoscopic retrograde cholangiopancreatography (ERCP) is of fundamental importance in the diagnosis and treatment of pancreaticobiliary diseases. It should be noted that ERCP tends to have a higher rate of adverse events (AEs) compared with other types of gastrointestinal endoscopic procedures; post-ERCP pancreatitis (PEP) occurs in 2%–15% of all ERCP patients.1–4 PEP occurs in 15%–42% of patients with high risk factors, such as female sex, a history of PEP and sphincter of Oddi dysfunction. Moreover, PEP is treated conservatively with fluid resuscitation and bowel rest, and most PEP patients improve within a few days without complications. However, severe pancreatitis can occur in some PEP patients, in which case the mortality rate is 0.1%–0.7%.1 2 5 In the USA, where around 700 000 ERCPs are performed every year, the financial burden placed on healthcare by PEP is substantial, with an estimated annual cost of around 200 million dollars.6 South Korea also bears an economic burden of PEP, with around 50 000 ERCPs performed every year.7 Assuming an average incidence of PEP of 5%, around 35 000 and 2500 patients are expected to develop PEP in the USA and South Korea, respectively, requiring additional healthcare expenditure. Therefore, the implementation of effective preventive strategies against PEP is of paramount clinical importance.

Despite advances in PEP prevention, its complete eradication remains an unsolved challenge. A crucial aspect of PEP prophylaxis is the meticulous identification and optimisation of preventive strategies. In particular, a substantial study emphasised the effectiveness of rectal non-steroidal anti-inflammatory drugs (NSAIDs) in reducing the risk of PEP, leading to the approval of preprocedural rectal NSAID administration in the guidelines provided by the American Society for Gastrointestinal Endoscopy (ASGE) and the European Society for Gastrointestinal Endoscopy (ESGE).1 2 8 However, the search for other prophylaxis strategies remains fundamental, especially for high-risk patient groups, including those with peptic ulcer disease or renal insufficiency, as well as in locations where rectal NSAIDs are not easily accessible. In addition, the results of a survey indicate that rectal NSAIDs are used in about 40% of average-risk patients in the USA, in contrast to fluid therapy, which is used in more than 80% of these cases.9 Intravenous hydration is a well-known critical strategy, evidencing cost-effectiveness even in high-risk patients and a tendency towards milder manifestations of PEP.1 2 Numerous pivotal studies have evaluated the efficacy of aggressive intravenous hydration with lactated Ringer’s solution in preventing PEP.10–12 This is a universally accessible and simple measure in the prevention of PEP; however, endoscopists are actively involved in discussions about the potential for its refinement and improvement. A recent study introduced a critical perspective, questioning whether excessive fluid therapy could potentially increase adverse effects.13 This underlines the need for a thorough evaluation of hydration methods using lactated Ringer’s solution, which is currently considered the standard therapy, to determine whether there are opportunities for improvement and optimisation.

In real practice, it is crucial to consider not just the type of fluid utilised, but also the most effective fluid volume for preventing PEP, along with the optimal timing for administering the fluid. Given that a significant number of ERCPs are performed in outpatient settings in the USA and other countries, the current protocol allowing outpatients to occupy recovery areas for extended periods, such as 8 hours post-ERCP, seems challenging to implement in real clinical practice.1 These considerations highlight the necessity for a re-evaluation of existing guidelines. Therefore, the present reassessment aims, not only to optimise efficiency and patient flow in medical settings but also to evaluate the effectiveness of the protocol in preventing PEP considering practical duration of intravenous fluid infusion, such as 4 hours postprocedure.1

Objectives

In previous comparative studies related to PEP prevention, research bias may have been introduced because of insufficient blinding of the treatment strategies, as well as instances where the evaluating investigator did not perform blinding. We are therefore conducting a multicentre, randomised comparative study double-blinded as to the two types of fluid (lactated Ringer’s solution or plasma solution), and in which the endoscopists, outcome assessors and patients are blinded to the randomisation allocation.

Study design and context

The study is a multicentre, double-blind, randomised, controlled trial (RCT), initiated by the investigator-sponsor, on post-ERCP hydration. Patients with naïve papilla scheduled for ERCP will be prospectively included and randomised to receive either lactated Ringer’s solution or plasma solution in a ratio of 1: 1.

The study will be carried out in three tertiary centres in Seoul, Korea. These centres have sufficient experience in performing ERCP and treating patients with pancreatitis. The duration of the trial is 18 months after institutional review board (IRB) approval.

This research protocol was written following the Standard Protocol Items: Recommendations for Interventional Trials reporting guidelines.14

Participants and eligibility criteria

Among patients with a naïve major duodenal papilla, we will include those with a medium to high risk of PEP. Once the eligibility of the subjects who voluntarily agree to enrol in this clinical trial has been confirmed, informed consent (online supplemental material 1) will be obtained and the screening phase will proceed.

If one or more of the following inclusion criteria apply, the subject is considered to be in the medium to high risk group for PEP and enrolled in this study: aged ≤40 years; (suspected) Oddi sphincter dysfunction; normal serum total bilirubin level; history of recurrent pancreatitis; need for injection of a contrast agent into the pancreatic duct; need for endoscopic biliary or pancreatic sphincterotomy, need for precut sphincterotomy (including infundibulotomy) or pancreatic ductal sphincterotomy; in need of endoscopic papillary balloon dilatation; planned endoscopic papillectomy; diagnosed with a periampullary tumour and planned for insertion of a self-expanding metal stent, which is associated with a high risk of pancreatitis. Because enrolled patients are expected to undergo therapeutic ERCP with endoscopic biliary or pancreatic sphincterotomy, which carry moderate risk of PEP,15 enrolled patients may have at least one moderate risk of PEP as technical aspects before ERCP.

Participants will be excluded if any of the following conditions are met: they have not consented to take part in the study; aged ≤18 years; serious comorbidities (eg, end-stage renal disease, end-stage chronic obstructive pulmonary disease, hypoglycaemic dysregulation and decompensated liver cirrhosis); sepsis (defined as the fulfilment of two or more of the following: body temperature>38.3°C or <36°C, heart rate>90 beats/min, tachypnoea (respiratory rate>20 breaths/min), leucocytosis (leucocytes>12.000 ^microL-1) or leucopenia (leucocytes<4000 ^microL-1)); acute pancreatitis; chronic pancreatitis; heart failure (New York Heart Association class 2 or higher); clinical signs of fluid overload; hypernatraemia (>150 mEq/L) or hyponatraemia (<130 mEq/L); history of endoscopic papillary sphincterotomy; history of endoscopic papillary dilatation (balloon); hypercalcaemia or alkalaemia; scheduling of regular endoscopic biliary stent exchange; patients with pancreatic head tumours and presumed low risk of PEP; lack of access to the main duodenal papilla owing to surgical deformity.

Description of the intervention

For subjects who have signed the research consent form, the researcher will check the inclusion criteria and the exclusion criteria. If the subjects are suitable for the study, fluids are prescribed. Lactated Ringer’s solution or plasma solution should be supplied double-blind. The assigned fluid is administered intravenously to the ERCP subject. Plasma solution (HK inno.N Corp., Seoul, Republic of Korea) is a balanced crystalloid solution that contains the same ingredients as Plasma-Lyte A (Baxter International, Deer field, Ill) (table 1).

Preprocedure hydration begins 30–90 min before ERCP with an infusion rate of 10 mL/kg. All the ERCP procedures are performed under sedation with balanced propofol sedation (incremental dose of propofol in combination with fixed doses of fentanyl and midazolam), without general anaesthesia. The infusion rate during ERCP and 30–60 min after ERCP is 3 mL/kg/hour and 10 mL/kg, respectively (in the case of a 10 mL/kg injection after the procedure, the injection should be stopped at the point where it is necessary to move from the endoscopy room to the ward after the procedure, and the injection rate can be changed to 3 mL/kg/hour). The insertion of a prophylactic pancreatic duct stent for high risk of PEP is allowed at the discretion of the endoscopist. Postprocedure hydration is then maintained at an infusion rate of 3 mL/kg/hour for up to 4 hours after ERCP. If patients experienced postprocedural abdominal pain Numerical Rating Scale (NRS score>3) or a worsening of abdominal pain compared with the pain before ERCP, the administration of study fluid continues until 8 hours after ERCP because serum amylase/lipase within 4 hours after ERCP may have a result approximately 1–2 hours after blood sampling (figure 1). In this study, the conventional protocol involving a single 20 mL/kg bolus injection has been revised, with the dosage now divided into two separate 10 mL/kg injections administered before and after ERCP. This modification was implemented to mitigate the risk of volume overload. A participant must be removed from the trial at any time:

• If the participant withdraws their consent to take part in the trial.

• If the investigator decides that it is necessary to discontinue this trial for the patient.

• If a serious adverse event (SAE) occurs, the blinding and treatment allocation will be interrupted by the discretion of an investigator.

Figure 1

Schematic diagram of the study. ERCP, endoscopic retrograde cholangiopancreatography; NRS, Numeric pain Rating Scale.

Strategies to improve adherence to interventions

A designated investigator, such as a clinical research nurse, is assigned to each subject for the duration of the study. This researcher monitors the infusion rate from the start of preprocedure hydration to the end of hydration and ensures that appropriate care is taken during the procedure and the patient’s journey. In addition, this person ensures that the abdominal pain assessment and laboratory tests are carried out properly.

Relevant concomitant care permitted or prohibited during the trial

All procedures carried out during ERCP for the diagnosis and treatment of the patient are permitted. The use of prophylactic antibiotics, analgesics for adequate pain control and imaging tests to identify AEs are also permitted. However, the administration of medicines aimed at preventing PEP, such as NSAIDs and protease inhibitors, is prohibited.

Post-trial care provisions

At the end of the study period or after discontinuation, the subjects will receive routine care to treat the disease that caused the ERCP or the AEs that occurred after the ERCP in their respective tertiary hospitals. In the event of AEs, follow-up visits should continue until the AEs are resolved or considered stable by the investigators responsible for the treatment. All participants will be covered by the patient’s insurance at the respective venue.

Study objectives

The primary objective of this study is the occurrence of PEP. We define PEP as the development of abdominal pain (NRS score>3) or worsening of abdominal pain compared with the pain before ERCP, and a threefold or greater rise in serum lipase and/or amylase in the 24 hours (or the following morning) after the procedure. We will assess abdominal pain at 4 and 24 hours after ERCP. If the level of pancreatic enzymes is elevated>3 times the upper limit of normal level 24 hours after ERCP and upper abdominal pain is not uncertain, abdominal CT without enhancement will be performed at the discretion of the investigator. Patients with >3 times the upper limit of normal level 24 hours after ERCP and with a finding of acute pancreatitis abdominal CT, without typical upper abdominal pain (NRS score>3), are defined as having PEP.

Secondary parameters are the occurrence of presumed PEP 4 hours after ERCP, clinical signs of fluid overload, hyperamylasemia, occurrence or worsening of upper abdominal pain and duration of ERCP-related hospital stay, defined as the days from ERCP to the end of observation owing to the absence or disappearance of upper abdominal pain after ERCP.

Other parameters

Risk factors for PEP (age, sex, body mass index, alcohol consumption, history of smoking, history of pancreatitis prior to the procedure, indications for the procedure, method of intubation at the time of ERCP, difficult intubation (>5 times of papillary contact, >5 min of cannulation time and ≥1 inadvertent pancreatic duct or pancreatic opacification) at the time of ERCP,2 number of pancreatic duct intubations at the time of ERCP, other skills performed at the time of ERCP), type of biliary stent (plastic stents vs metal stents), American Society of Anesthesiologists (ASA) class on admission, clinical signs of excess fluid (pulmonary oedema, distal oedema, decreased cardiac function and hypernatraemia) and complications related to ERCP (inflammation of the biliary tract, haemorrhage,and perforation) will also be investigated. Delayed development (>48 hours after ERCP) or not-recognised PEP may occur after 24 hours of ERCP. To address this issue, patients with elevation of pancreatic enzymes to >3 times the upper limit of normal 24 hours after ERCP will be followed until the elevated level decreases, and we will monitor any ICU admission and 30-day and 180-day mortality during 6 month follow-up in all enrolled patients.

Sample size calculation

This is an evaluation of the superiority of PEP prevention between plasma solution (group 1) and lactated Ringer’s solution (group 2). Recently, Weiland and colleagues reported an open-label RCT, noting an 8% incidence of PEP in the group receiving aggressive fluid hydration with Ringer’s lactate solution.16 Consequently, we presume an 8% occurrence of PEP in group 2. However, PEP prevention with plasma solution is a novel approach that has not been previously studied. Therefore, so in this study, we assume a 60% risk reduction in PEP in group 1 compared with group 2, resulting in an assumed PEP incidence rate of 3.2%.16 These assumptions were validated after a thorough review by the statistical team and the IRB of Asan Medical Centre, the host institution of this study. To determine a 60% reduction in PEP rates in group 1 with 80% power and an alpha level of 0.05, 400 patients in each group are required. The proportion in group 1 is assumed to be 0.032 in the alternative hypothesis and 0.08 in the null hypothesis, with group 2 maintaining a rate of 0.08. The two-sided Fisher’s exact test will be used as the test statistic at a significance level of 0.05. A total of 844 patients will be recruited, considering a 5% dropout rate, which results in 422 patients per group.

Recruitment

Patients receiving their first ERCP are given leaflets introducing the study. Patients interested in taking part in the study can contact the designated doctors for more information. Furthermore, in order to identify the patients eligible for this study, the doctors and nurses authorised to access the medical records thoroughly analysed the clinical history and previous treatment records of all the patients who are going to undergo ERCP. Potentially eligible patients identified in the review process can be contacted by the researcher, with the authorisation of the doctor in charge. The actual study start date was 19 June 2023, and the estimated primary completion date and estimated study completion date is 30 September 2024.

Allocation of intervention

The randomisation code for this trial is generated using SAS (V.9.4, SAS Institute, Cary, NC, USA) by an independent statistician not directly related to this trial; patients are assigned to the lactated Ringer’s solution group or the plasma solution group in a 1:1 ratio using the stratified block randomisation method. The randomisation is stratified by treatment centre. Block size is a mixture of four and eight with a random order within each stratum. The suppliers of investigational medicinal products package and deliver the investigational medicinal products to the trial centre’s randomisation code. The clinical trial subjects who meet the inclusion/exclusion criteria are then assigned to each group in the order in which they are enrolled in the clinical trial, according to the randomisation code.

During this clinical trial, the lactated Ringer’s solution and the plasma solution must have the same formulation and appearance in order to maintain double-blinding, and participants are randomised to receive the experimental drug. This ensures that neither the researcher, the clinical trial subject, nor the monitor can distinguish which group the clinical trial participant is assigned to.

If a subject has a medical emergency and it is important to know which experimental drug has been administered, the subject’s blinding can be removed. Researchers should determine whether the information about the experimental drug administered is important for making decisions about the subject’s treatment before releasing that information. If the blinding needs to be removed, the clinical trial director can make the decision and only the subject can be blinded. For this purpose, an independent statistician responsible for clinical trials will provide the randomisation code table to the CRO’s independent security personnel who are not directly involved in the clinical trial. Prior to the start of the clinical trial, the CRO’s security personnel will create a blinded emergency randomisation code book for each subject and provide it to the clinical trial investigator. The clinical trial investigator is responsible for storing the blinded emergency randomisation code book confidentially and for maintaining blinding during the clinical trial.

If it is necessary to open the blind, the principal investigator should use the emergency randomisation codebook provided in advance to release the randomisation information of the subject to be opened and immediately notify the sponsor of this release. The facts and reasons for the removal of sales must be recorded and kept in the evidence register. Individuals whose randomisation code is revealed cannot continue with the trial.

Data management and confidentiality

The names of participants in clinical trials are kept confidential and recorded using a number assigned for identification purposes. Participants are informed that all clinical trial data are stored on a computer and treated strictly confidentially. In the electronic case report form (online supplemental material 2), no records will be collected that could identify the name or identity of the clinical trial subject, and anonymised information will be collected using a subject identification code. All documents related to the clinical trial will be kept in a secure storage facility with restricted access, and access to the computer for the electronic collection of clinical data and to the electronic case report form will be restricted by means of a password.

A signed copy of the consent form will be kept by the principal investigator and another copy will be given to the participant. The principal investigator will keep a record of the clinical trial number and the participant’s name and will store the relevant information securely. Monitors, clinical trial review committees and the director of the Agency for Food and Drug Safety can access the registers to check the reliability of the data, as required by the regulations, while maintaining the confidentiality of the participants. The informed consent form and the list of participants in the clinical trial will be kept for 3 years from the date of completion of the clinical trial and will be disposed of immediately when the retention period expires. The identity of the clinical trial subjects will be kept confidential even after the trial results have been published.

Statistical methods

The efficacy analysis is carried out on the ‘Full Analysis Set (FAS)’ and the ‘Per Protocol Set’ (PPS); however, the interpretation of the results for the final validity variables is based only on the FAS analysis group. The FAS analysis is carried out according to the ITT (intention-to-treat) principle, which means that all individuals who have been randomised to receive the experimental drug are included in the analysis. The following individuals are excluded from the FAS:

• Individuals who violated the inclusion/exclusion criteria.

• Individuals who have not received the experimental drug since randomisation.

• Individuals for whom primary efficacy outcome data have not been collected after administration of the drug.

All statistical analyses will be carried out using SAS, and the test of significance between groups will be based on a two-sided test and set at a level of 5%. As usual, continuous variables will be analysed using a t-test or Wilcoxon rank sum test to present descriptive statistics and test for differences between groups. Categorical variables will be presented as frequencies and proportions and analysed using a χ² test or Fisher’s exact test to determine the differences between the groups. If the data are skewed because of its nature, the values of the vital, haematological and haematochemical tests will be analysed using the Wilcoxon signed rank test within groups and the Wilcoxon rank sum test between groups. If the deviation in the data from the test value is not serious, it is analysed using the paired t-test or the t-test. In addition, statistically significant items between test values and categorical data, such as physical examination and urinalysis, are classified as normal or abnormal, and the frequency and ratio are presented. The proportion of individuals who change from normal to abnormal will be shown in a scrolling table.

Complementary analyses

The PPS analysis will only be carried out on those who completed the trial without serious protocol violations among the FAS analysis group. Significant violations of the protocol include violations of the inclusion/exclusion criteria, the taking of contraindicated drugs that could affect the safety and efficacy of the experimental drug during the trial, and other important violations that will be determined through a blind meeting before the database is blocked.

Safety analyses are carried out on all individuals who have received at least one dose of an investigational drug. People who took part in the trial but dropped out before receiving the experimental drug are excluded from the safety assessment group. The safety analysis only includes those who have received and been analysed for the experimental drug.

Interim analyses

There will be no formal interim analysis of effectiveness.

Handling missing values

If there are missing values in the effectiveness parameter for individuals in the FAS analysis, the Last Observation Carried Forward method will be applied. Efficacy parameters measured only once after the baseline will be analysed using only the observed data. Safety data and other data will be analysed as observed without correction.

Monitoring and data management plan

In this study, data are collected through case records. The investigator must ensure that all data entered into the case records are accurate, complete, easily understandable and consistent with the supporting data. The controller checks the case record against the supporting documents, notifies the investigator of any discrepancies and requests the necessary corrections. Only authorised personnel, such as the investigator or a person in charge of the task, can enter and modify the case record and supporting documents.

At 2 week intervals, the investigator-sponsor (professor, DHP) and two principal investigators from the centre (professor JKP and professor WHP) will monitor the safety data including incidence of PEP and SAEs by independent contract research organisation).

Monitoring is carried out to protect the rights and well-being of clinical trial participants, verify the accuracy of trial data and ensure that the trial is conducted in accordance with approved clinical trial protocols, Good Clinical Practice (GCP) and standardised practices. The monitoring staff of the clinical trial consignment institution regularly visits the trial site and makes phone calls to monitor the progress of the trial and confirm compliance with the protocol and related regulations. During the visits, the monitor will analyse the patient’s written consent forms, original records, case records, medication administration records, storage of research-related materials and basic documents and address any discrepancies or problems with the researcher and the person in charge.

Notification of adverse events and damage

AEs are defined as any undesirable medical events experienced by patients receiving investigational medicines. These events do not necessarily have a causal relationship with the investigational medicinal product, but may include symptoms, illnesses and abnormal laboratory results that are related to the time of use of the investigational medicinal product, regardless of their relevance to the investigational medicinal product. AEs that occur after consent has been obtained from clinical trial participants are monitored through medical examinations, such as questionnaires and blood tests. Information such as the date of onset and resolution, the severity and outcome of AEs, measures taken in relation to investigational medicinal products, potential causal links with the investigational medicinal product, treatment status and the content of AEs should be recorded in detail. All AEs must be recorded through supporting documents and the relevant information must be documented in the case record. The procedure for reporting adverse reactions follows the Korean GCP guidelines.

An AE is considered serious (SAE) for this trial if it meets one or more of the following criteria and is related to the treatment: results in death; life-threatening events; results in persistent or significant disability; requires prolonged hospitalisation; results in a congenital anomaly/birth defect or requires immediate medical or surgical intervention to prevent permanent disruption of a bodily function/structure or to alleviate an unforeseen temporary disruption or damage. All SAEs must be collected, regardless of their relevance to the treatment/control group and reported to the principal investigator or designee within 24 hours of the investigator becoming aware of them. In addition, the investigator will report any SAE to the IRB in accordance with IRB regulations or local regulations. To this end, all subjects must immediately contact the investigator or designated person when a SAE occurs, and all subjects must be trained at the time of enrolment to contact the investigator or designated person.

The investigator must complete the SAE report form for each SAE and communicate it to the IRB and the principal investigator or designee. The information provided must be sufficient to allow a medical assessment of the event. The designated security person can contact the investigator for more information if necessary. The investigator must provide additional information to the principal investigator or designee as soon as additional information is gathered about the SAE. All SAEs should be monitored until they are resolved or stabilised.

Patient and public involvement

None.

Trial status

Patient recruitment was initiated in June 2023 and the study is estimated to be finalised (last patient last visit) in September 2024.