Short-term prophylactic biliary stenting after complete common bile duct stone removal to prevent post-ERCP cholangitis in Japan (STEP-ERCP study): study protocol for a confirmatory multicentre randomised controlled trial

Abstract

Introduction

Endoscopic retrograde cholangiopancreatography (ERCP) is the standard treatment for common bile duct stones. Although complete stone removal can be achieved in most cases, post-ERCP cholangitis still occurs in a subset of patients, even in the absence of preprocedural cholangitis. Temporary prophylactic biliary stenting after complete stone extraction may reduce post-ERCP cholangitis by preventing transient biliary obstruction caused by papillary oedema, impaired bile drainage or residual biliary sludge. However, evidence supporting this strategy is currently limited to retrospective studies. The STEP-ERCP study is designed to test the hypothesis that short-term prophylactic biliary stenting after complete removal of common bile duct stones reduces the incidence of post-ERCP cholangitis compared with no biliary stenting.

Methods and analysis

The STEP-ERCP study is a multicentre, prospective, open-label, randomised controlled superiority trial. Adult patients undergoing ERCP for common bile duct stones without evidence of acute cholangitis at the time of ERCP and achieving complete stone clearance will be enrolled. Participants will be randomly assigned in a 1:1 ratio to prophylactic biliary stenting using a spontaneous dislodgement biliary stent or no stenting. Randomisation will be stratified by participating institution and maximum stone diameter (<10 mm vs ≥10 mm). The primary endpoint is the incidence of post-ERCP cholangitis within 7 days after ERCP, diagnosed using modified Tokyo Guidelines 2018 criteria adapted for post-ERCP conditions. Secondary endpoints include cholangitis severity, time to cholangitis onset, therapeutic antibiotic use, repeat ERCP or biliary drainage, ERCP-related adverse events and revisit or readmission within 30 days after ERCP. A total of 186 participants will be enrolled.

Ethics and dissemination

The study will be conducted in accordance with the Declaration of Helsinki and the Ethical Guidelines for Medical and Health Research Involving Human Subjects in Japan.

The study protocol was approved by the Institutional Review Board of Yokohama City University Hospital on 11 May 2026. Additional approval will be obtained from participating institutions before study initiation.

Written informed consent will be obtained from all participants.

Study findings will be disseminated through peer-reviewed publications and scientific conferences.

Trial registration number

jRCT1032260128

STRENGTHS AND LIMITATIONS OF THIS STUDY.

• This is a multicentre, prospective, open-label, parallel-group randomised controlled trial.

• Randomisation is centrally performed and stratified by participating institution and maximum stone diameter.

• Eligibility criteria are restricted to patients without suspected or definite acute cholangitis immediately before endoscopic retrograde cholangiopancreatography (ERCP).

• The primary endpoint is assessed using predefined modified Tokyo Guidelines 2018 criteria adapted for post-ERCP conditions.

• Routine laboratory testing during the Day 3–7 follow-up window is not mandatory and is performed when clinically indicated.

Introduction

Endoscopic retrograde cholangiopancreatography (ERCP) is widely performed as the standard treatment for common bile duct stones.^1–5 Advances in endoscopic sphincterotomy and papillary balloon dilation techniques have enabled successful complete stone removal in most patients. Despite complete stone clearance, post-ERCP cholangitis remains an important clinical problem.

Previous studies have reported that post-ERCP cholangitis occurs in approximately 5%–30% of patients depending on patient selection, procedural complexity and perioperative management.^6–9 Even in patients without cholangitis before ERCP, transient papillary oedema, temporary impairment of bile drainage, increased biliary pressure or residual sludge may contribute to infectious complications after the procedure.^{10 11}

In clinical practice, prophylactic biliary stenting after complete stone extraction is occasionally performed to maintain temporary bile drainage and prevent post-ERCP cholangitis.^12–14 Retrospective studies, including a single-centre analysis from our institution, have suggested that prophylactic biliary stenting after complete stone extraction may reduce post-ERCP cholangitis.^12–14 However, these findings were derived exclusively from retrospective analyses and remain susceptible to selection bias and procedural heterogeneity. No prospective randomised trial has yet evaluated this strategy.

The diagnosis of post-ERCP cholangitis is also challenging. Although Tokyo Guidelines 2018 (TG18) are widely used for the diagnosis and severity grading of acute cholangitis, these criteria were originally developed for spontaneous acute cholangitis rather than post-ERCP conditions.^{15 16} Following ERCP, transient inflammatory responses and temporary hepatobiliary enzyme abnormalities frequently occur and may reduce the specificity of standard TG18 criteria for clinically meaningful post-ERCP cholangitis.⁸ Therefore, this study employs modified TG18 criteria adapted specifically for post-ERCP conditions.

The aim of this multicentre randomised controlled trial is to test the hypothesis that prophylactic temporary biliary stenting reduces the incidence of post-ERCP cholangitis after complete common bile duct stone removal compared with no stenting.

Methods and analysis

Study design

The short-term prophylactic biliary stenting after complete common bile duct stone removal to prevent post-ERCP cholangitis (STEP-ERCP) study is a multicentre, prospective, open-label, parallel-group, superiority randomised controlled trial conducted in Japan. The study period is from 11 May 2026 to 31 March 2031, with participant recruitment planned from institutional approval at each participating site to 31 March 2030.

Study setting

The study will be conducted at approximately 11 tertiary referral centres specialising in pancreatobiliary endoscopy. All ERCP procedures will be performed or supervised by experienced pancreatobiliary endoscopists at participating centres according to local institutional standards. Participating centres are tertiary referral centres with established experience in ERCP and pancreatobiliary endoscopy. Because this is a pragmatic multicentre trial, no additional minimum operator-level eligibility criteria, central certification process or routine collection of operator-level experience data will be imposed beyond each centre’s routine credentialing and supervision system.

Eligibility criteria

Inclusion criteria

Participants must meet all of the following criteria:

1. Age ≥20 years.

2. Diagnosis of common bile duct stones by imaging studies and scheduled ERCP for stone extraction.

3. No suspected or definite acute cholangitis according to TG18 immediately before ERCP.

4. Hepatobiliary enzyme levels, including AST, ALT, ALP and γ-GTP, within three times the upper limit of normal at each participating institution.

5. Body temperature <38.0°C, white blood cell count 4.0–10.0×10^∧9/L, and C-reactive protein <1.0 mg/dL immediately before ERCP.

6. Provision of written informed consent after receiving sufficient explanation of the study.

Exclusion criteria

Participants meeting any of the following criteria will be excluded:

1. Suspected or definite acute cholangitis according to TG18 at the time of ERCP or within 2 weeks before ERCP.

2. Malignant biliary stricture, ampullary tumour or surgically altered anatomy other than Billroth-I reconstruction, including Roux-en-Y or Billroth-II reconstruction, making standard ERCP difficult or non-standard.

3. Serious safety concerns, such as biliary perforation, severe infection or markedly poor general condition.

4. Severe cardiopulmonary disease or renal failure that precludes endoscopic treatment under general anaesthesia or sedation.

5. Deemed inappropriate for study participation by the principal investigator or sub-investigator for medical reasons.

Randomisation and allocation

After confirmation of complete stone removal, eligible patients will be randomly assigned in a 1:1 ratio to either the prophylactic biliary stenting group or the no-stenting group using a central web-based randomisation system, the University hospital Medical Information Network Internet Data and Information Center for Medical Research (UMIN INDICE). Allocation concealment will be ensured through the secure central web-based randomisation system.

Randomisation will be stratified by:

• Participating institution

• Maximum stone diameter (<10 mm vs ≥10 mm)

A stratified permuted block randomisation method will be used. Due to the nature of the intervention, blinding of endoscopists and participants is not feasible. However, outcome assessment will be performed using predefined objective criteria. The overall study design is shown in figure 1.

Figure 1. Study flow of the STEP-ERCP trial. Patients with common bile duct stones undergoing ERCP are assessed for eligibility. After confirmation of complete stone removal and fulfilment of all inclusion criteria, eligible participants are randomly assigned in a 1:1 ratio to prophylactic biliary stenting or no stenting. Participants are followed for assessment of post-ERCP cholangitis and other ERCP-related adverse events. ERCP, endoscopic retrograde cholangiopancreatography; STEP-ERCP, short-term prophylactic biliary stenting after complete common bile duct stone removal to prevent post-ERCP cholangitis.

Interventions

Prophylactic biliary stenting group

After complete stone extraction, a spontaneous dislodgement plastic biliary stent (BIT stent; 6 Fr/4 cm) will be placed during the same ERCP session. Scheduled endoscopic removal will not be performed. Routine endoscopic or radiological confirmation of spontaneous stent dislodgement will not be required during the 7-day follow-up period. However, if stent-related symptoms, suspected stent retention, migration, biliary obstruction, cholangitis or other adverse events occur, additional evaluation, including imaging or endoscopy, will be performed at the discretion of the treating physician.

No-stenting group

After complete stone extraction, ERCP will be completed without prophylactic biliary stenting.

Periprocedural management, including antibiotic administration and use of non-steroidal anti-inflammatory drugs, will follow local institutional practice.

Outcomes

Primary outcome

The primary endpoint is the incidence of post-ERCP cholangitis within 7 days after ERCP.

Post-ERCP cholangitis will be diagnosed using modified TG18 criteria adapted for post-ERCP conditions.¹⁶ The modified criteria require:

1. Evidence of systemic inflammation (fever ≥38°C, elevated white blood cell count, or elevated C-reactive protein level).

2. Evidence of cholestasis or re-elevation of hepatobiliary enzymes after ERCP.

3. Exclusion of alternative infectious sources.

ERCP-related adverse events will additionally be evaluated according to established consensus definitions.^{8 17 18} Because some patients may be discharged shortly after ERCP, routine laboratory testing during the Day 3–7 follow-up window will not be mandatory. Laboratory tests will be performed during this period when post-ERCP cholangitis or other adverse events are clinically suspected.

Secondary outcomes

Secondary endpoints include the severity of post-ERCP cholangitis, time to onset of post-ERCP cholangitis, proportion of patients requiring therapeutic antibiotics after ERCP, proportion of patients requiring repeat ERCP or biliary drainage after ERCP, incidence of ERCP-related adverse events and revisit or readmission within 30 days after ERCP. The schedule of enrolment, interventions, assessments and follow-up procedures is summarised in table 1.

Table 1. Schedule of enrolment, interventions and assessments.

Study period	Screening	ERCP	Day 1	Day 3–7 follow-up
Eligibility assessment	✓
Written informed consent	✓
Demographics and baseline characteristics	✓
Laboratory tests	✓	✓	✓	If clinically indicated
Randomisation		✓
Complete stone removal confirmation		✓
Prophylactic biliary stenting		✓
Assessment of post-ERCP cholangitis			✓	✓
Assessment of adverse events		✓	✓	✓
Reintervention assessment				✓
Readmission assessment				✓

ERCP, endoscopic retrograde cholangiopancreatography.

Sample size calculation

Based on retrospective data from our institution, the incidence of post-ERCP cholangitis was estimated to be approximately 30% in the no-stenting group and 6% in the prophylactic stenting group.¹² Because these estimates were derived from a single-centre retrospective study, we assumed a lower event rate of 20% in the no-stenting group for the present multicentre prospective trial, considering potential selection bias, inter-centre differences in periprocedural management and the possibility that prospective follow-up may reduce the event rate compared with historical data. This estimate is within the range of previously reported post-ERCP cholangitis rates, while remaining lower than the event rate observed in our retrospective cohort. The expected event rate in the prophylactic stenting group was set at 6%, resulting in assumed event rates of 20% and 6%, respectively. Assuming a two-sided significance level of 0.05, 80% power and a 1:1 allocation ratio, 90 patients per group were required to compare two proportions. Allowing for an approximately 3% rate of withdrawal or unevaluable primary endpoint data, the target sample size was set at 186 patients, with 93 patients per group.

Statistical analysis

Analysis populations

The primary analysis will be performed in the full analysis set (FAS). The FAS will include all patients who provide informed consent and are randomly assigned. Patients with no available data for the primary endpoint, and those found to have no valid written informed consent or a serious registration-related protocol violation, will be excluded from the FAS.

The per-protocol set (PPS) will be used for supplementary analysis. The PPS will include patients in the FAS who receive the allocated treatment and complete the required follow-up without major protocol deviations that could materially affect the efficacy assessment.

The safety analysis set (SAS) will include all randomly assigned patients who undergo ERCP according to the allocated treatment strategy and will be analysed according to the treatment actually received.

Analysis of the primary endpoint

The primary analysis will be performed in the FAS. The risk ratio will be estimated using a modified Poisson regression model with a log link and robust variance estimation. The model will include treatment group and maximum stone diameter as explanatory variables. Participating institution will not be included as a fixed effect in the primary analysis model because the expected number of primary endpoint events is limited and inclusion of multiple centre effects may lead to model instability. Centre effects will be evaluated in prespecified supplementary analyses using cluster-robust variance estimation and adjustment for participating institution. The risk ratio, two-sided p value and 95% CI will be reported. The risk difference and its 95% CI will also be reported as a supplementary effect measure.

The following supplementary analysis will be performed. First, the same analysis as the primary analysis will be conducted in the PPS. Second, the primary analysis model will be fitted in the FAS using robust variance estimation clustered by participating institution. Third, a modified Poisson regression model including treatment group, maximum stone diameter and participating institution as explanatory variables will be fitted in the FAS. Fourth, an unadjusted modified Poisson regression model including only treatment group as an explanatory variable will be fitted in the FAS.

Exploratory subgroup analyses will be performed according to age, bile duct diameter and papillary status at enrolment. For each subgroup factor, a modified Poisson regression model based on the primary analysis model will be fitted with the addition of the subgroup factor and the treatment-by-subgroup interaction term. These subgroup analyses will be interpreted exploratorily based on effect estimates and 95% CIs.

Analysis of secondary endpoints and safety outcomes

Secondary endpoints will be analysed in the FAS. For binary endpoints, risk ratios or risk differences with corresponding 95% CIs will be calculated. For continuous endpoints, means or medians with corresponding 95% CIs will be calculated, depending on the distribution of the data.

Safety outcomes will be analysed in the SAS. Adverse events will be evaluated descriptively according to treatment group, type and severity. Adverse events considered to have a reasonable causal relationship with the allocated intervention will be evaluated in the same manner.

General statistical considerations

Categorical variables will be summarised as frequencies and percentages, and continuous variables will be summarised using appropriate descriptive statistics by treatment group. All statistical tests will be two-sided, and a p value <0.05 will be considered statistically significant for the primary analysis. No formal adjustment for multiplicity will be applied to secondary, safety, sensitivity or subgroup analyses. Missing data will not be imputed in the primary analysis, and analyses will be based on available data. The number and reasons for missing primary endpoint data will be summarised by treatment group. Because the follow-up period is limited to 7 days after ERCP, the proportion of missing primary endpoint data is expected to be low. If primary endpoint data are missing, a sensitivity analysis will be considered using conservative assumptions to assess the robustness of the primary analysis. No separate statistical analysis plan is currently planned, as the main statistical analyses are described in this protocol. If further detailed specifications are considered necessary, a statistical analysis plan will be documented before the database lock.

Data collection and management

Clinical data will be collected through the UMIN INDICE electronic data capture system and entered by investigators at each participating site. Data required for outcome assessment will be obtained from medical records and study-specific case report forms. Study data will be stored in a secure electronic database accessible only to authorised study personnel. Participant confidentiality will be protected through anonymisation of study data.

Data monitoring

Given the low-risk nature of the intervention and the short follow-up period, a formal independent data monitoring committee will not be established. Trial conduct and data collection will be periodically reviewed by the coordinating study office.

Interim analysis

No interim analysis is planned.

Ethics and dissemination

The study will be conducted in accordance with the Declaration of Helsinki¹⁹ and the Ethical Guidelines for Medical and Health Research Involving Human Subjects in Japan. Ethical approval has been obtained from the institutional review board of Yokohama City University Hospital (approval number: F260507001). Additional approval will be obtained from participating institutions before study initiation.

Written informed consent will be obtained from all participants using the approved participant information sheet and consent form, an example of which is provided as online supplemental material. Personal information and study data will be handled in accordance with applicable data protection regulations.

Study results will be published in peer-reviewed journals and presented at scientific meetings.

Important protocol modifications will be communicated to participating institutions and updated in the trial registry as appropriate.

Discussion

Although ERCP is highly effective for common bile duct stone removal, post-ERCP cholangitis remains a clinically relevant complication. Current guidelines do not recommend routine prophylactic biliary drainage after complete stone extraction in patients without cholangitis, largely because prospective evidence is lacking.

This study will provide the first multicentre randomised evidence evaluating prophylactic short-term biliary stenting after complete stone removal. If effective, this strategy may reduce post-ERCP cholangitis, reintervention and healthcare burden. Conversely, if no benefit is demonstrated, the study may support avoidance of unnecessary biliary stenting.

The use of modified TG18 criteria is another important feature of this trial. Standard TG18 criteria may overestimate cholangitis after ERCP due to transient postprocedural inflammatory changes. The modified criteria aim to improve diagnostic specificity and better reflect clinically meaningful events.

Several limitations should be acknowledged. First, this trial focuses on early post-ERCP events within 7 days after complete stone removal, and routine confirmation of spontaneous stent dislodgement will not be performed in all patients. Therefore, late stent-related events, including delayed migration, persistent stent retention or delayed biliary obstruction, may not be fully captured. However, clinically suspected stent-related adverse events will be evaluated and managed according to routine clinical practice. Second, patient-reported outcomes, quality-of-life measures and formal cost-effectiveness analyses are not included in this trial. Therefore, the broader patient-centred and economic impact of prophylactic biliary stenting, including symptom burden, patient satisfaction and healthcare costs, will not be directly assessed. Third, operator-level experience, annual ERCP volume and individual endoscopist-level outcomes will not be collected. Although all procedures will be performed or supervised by experienced pancreatobiliary endoscopists at tertiary referral centres, residual variability in procedural expertise may affect ERCP-related outcomes. These aspects should be considered in future studies if the clinical efficacy of this strategy is demonstrated.

In conclusion, the STEP-ERCP study will address an important evidence gap regarding post-ERCP management after complete common bile duct stone removal.

Trial status

Protocol version 1.0 dated 11 May 2026. Recruitment has not yet started at the time of manuscript preparation.