preGallstep - A Clinical Pilot Trial

In Denmark, more than 7500 cholecystectomies are performed every year. Common bile duct gallstones (CBDS) are found in 3.4% to 18% of patients undergoing cholecystectomy. A two-step approach including endoscopic retrograde cholangiography (ERC) with stone extraction and papillotomy with subsequent laparoscopic cholecystectomy has become gold standard for treatment of CBDS in Denmark. However, ERC is associated with a high risk of complications and more than 50% of patients require multiple ERCs. Recent meta analyses find that a one-step approach might be superior in terms of safety, CBDS clearance rate, hospital stay, operative time, hospital cost and stone recurrence, but much more data is needed.

The preGallstep trial is an investigator-initiated multicentre randomised clinical pilot trial with blinded outcome assessment investigating a novel one-step laparoscopic cholecystectomy with common bile duct exploration and stone extraction versus conventional two-step endoscopic retrograde cholangiography with stone extraction plus a subsequent laparoscopic cholecystectomy for patients with CBDS. After enrolment, the participant will be randomised to one of the two treatment approaches. Adult patients with imaging confirmed CBDS are eligible for inclusion. Potential postoperative complications will be assessed within 90 days following the procedure.

The primary outcome is the proportion of serious adverse events (corresponding to a Clavien-Dindo score II or above) requiring re-intervention within 90 days of the initial procedure. This outcome will be used for a future sample size calculation. The sample size estimate, the inclusion rate and the estimated length of subsequent trial will be used to determine the feasibility of a large pragmatic and confirmatory trial.

We hypothesize that the one-step approach will significantly reduce the risk of complications and number of treatments needed thereby making a difference to hundreds of people in Denmark each year.

Purpose The preGallstep pilot trial is a pilot randomised clinical trial investigating two different surgical methods in patients with common bile duct stones: one-step laparoscopic cholecystectomy with common bile duct exploration (experimental intervention) versus two-step endoscopic retrograde cholangiography with stone extraction plus subsequent laparoscopic cholecystectomy (control intervention) for the removal of common bile duct stones.

The investigators alternative hypothesis is that both patient safety, assessed by serious adverse events, as well as the number of procedures needed to obtain stone clearance are better in the one-step approach than in the control approach. However, based on updated systematic review of previously conducted randomised clinical trials (RCTs) the investigators are not able to say which procedure is preferable. Further analysis of these previous RTCs show they are very far from obtaining a confirmatory sample size, thus illustrating the need for larger multicenter trials.

Prior to conducting a large pragmatic and confirmatory trial, the investigators propose this multicenter preGallstep pilot trial.

The purpose of preGallstep is to assess the proportion of participants in the control group with complications in order to conduct more precise sample size estimation for a future pragmatic randomised clinical trial. Furthermore, the investigators want to assess the feasibility of implementing randomisation between different surgical techniques in a daily complex clinical setting.

Background In the Nordic countries, 80 to 200 surgical removals of the gallbladder (cholecystectomies) per 100000 inhabitants are performed annually making it one of the most common surgical procedures. In Denmark, over 7500 cholecystectomies are performed every year. Cholecystectomy is most often performed due to symptomatic gallstones in the gallbladder. However, common bile duct gallstones (CBDS) are found in 3.4% to 18% of patients undergoing cholecystectomy, with highest proportions during acute surgery. However, the most efficient and safest procedure to remove CBDS has yet to be identified.

A two-step approach including endoscopic retrograde cholangiography (ERC) with stone extraction and papillotomy with subsequent laparoscopic cholecystectomy has become the gold standard treatment for CBDS in Denmark. However, as the gallbladder is left in situ following successful clearance of CBDS there are high risks of symptom recurrence and gallstone complications.

ERC is an advanced endoscopic procedure and multiple ERCs are required in as much as 59% of patients. Temporary stents are placed in patients with failed stone clearance during ERC. This delays stone extraction and requires repeat-ERC. Acute pancreatitis is a feared complication following ERC and is reported to occur in 4% of patients (range 2.6% to 18%). Acute pancreatitis causes high mortality and morbidity and is associated with low long-term quality of life. Other long-term complications of ERC papillotomy include recurrent bile duct stones, cholangitis, stenosis, and an unknown risk of malignant transformation.

The most comprehensive study on gallstone disease included 34,200 unselected patients undergoing laparoscopic cholecystectomy and reported CBDS in 11.6% of which 16% were left untreated. In these 16%, one out of four patients experienced unfavourable outcomes such as complicated gallstone disease (pancreatitis, cholangitis, jaundice) or the need of ERC within 90 days. All other treatment strategies to remove CBDS caused lower risk of adverse events when compared to leaving CBDS untreated.

The treatment of CBDS is, therefore, recommended to include both clearance of CBDS and a cholecystectomy.

This one-step approach including laparoscopic common bile duct exploration with gallstoneclearance (LCBDE) plus laparoscopic cholecystectomy is an emerging minimal-invasive approach for CBDS. The one-step LCBDE plus laparoscopic cholecystectomy approach seems to cause less postoperative pancreatitis although no significant associations have been published yet.

A Cochrane review of five RCTs of the one-step versus the two-step approach with ERC first including 621 patients concluded that the two approaches were comparable regarding stone clearance, morbidity, and mortality. Newer RCTs have shown comparable stone clearance proportions and comparable occurrence of short-term postoperative complications and mortality between the two approaches.

The most recently published meta-analyses find that LCBDE versus ERC is superior in terms of safety (perioperative complications, conversion rate to other procedure), CBDS clearance rate, hospital stay, operative time, in hospital costs, and stones recurrence. Trial Sequential Analysis of the two approaches has been performed but due to the small sample sizes available, they were unable to make final conclusions on patient safety or CBDS removal efficiency. In order to explore what sample size was needed to make a final conclusion on patient safety, Trial Sequential Analysis including all known RCTs has been performed. The outcome of interest was adverse events defined by short-term postoperative complications as defined by the single studies. Intention-to-treat data were extracted where possible, however, some studies excluded randomised patients without CBDS at intraoperative cholangiography or patients that did not complete the protocolled treatments. Most trials randomised patients with only a clinical suspicion of CBDS and only few RCTs randomised patients with CBDS proven by MRCP or EUL. Through meta-analysis, the total proportion of adverse events was found to be 16% (102/649) in the two-step approach. Based on Trial Sequential Analyses, with a relative risk reduction 20%, α at 0.05, β at 0.10, a diversity of 0%, and when a two-sided test was used, the total sample size required was 5060 participants for adverse events. Previous trials already included 1302 participants and the trial sequential monitoring boundaries for superiority, inferiority, or futility have not been reached. The literature has, thereby, not yet identified the safest procedure or which treatment the patients prefer to remove CBDS. More research on patient safety, stone clearance, and patient-centred outcomes is needed.

Methods Trial design The preGallstep pilot is an investigator-initiated multicentre randomised parallel group, clinical, pilot trial with blinded outcome assessment at 90 days.

Randomisation Participants will be randomised at the allocation ratio 1:1. Web-based randomisation will be handled centrally at the Copenhagen Trial Unit (CTU) using a concealed computer-generated allocation sequence with a varying block size concealed from investigators. The allocation sequence will be stratified for trial site. A trial nurse will enroll and allocate participants.

Participant timeline Both acute and non-acute patients may enter. The physician in charge will offer enrolment to eligible patients. After enrolment, the participant will be randomised to one of the two treatment approaches.

Baseline data including quality of life survey will be established by the trial nurse.

The patient will receive the trial intervention or control intervention no later than one week after randomisation. Follow-up for immediate complications within first 24 postoperative hours will be performed by the trial nurse (follow-up day 1).

Blood samples including amylase will be drawn following the procedure. If no immediate complications occur, the patients will be discharged within 24 hours following the procedure. A 90-day clinical follow-up will be performed to assess outcomes. Registration of lost to follow-up and reasons will also be assessed here.

Blinding Blinding of participants and surgeons is not possible. Most of the outcomes are dependent on physician assessment. To have blinded outcome assessment, the trial nurse who has not been part of the surgical team and who is blinded to treatment allocation will perform the follow-up visits. Outcome will be assessed by a blinded outcome committee of three experts not associated with the trial or the participating departments.

Statistical plan and data analysis As this is a pilot trial, a formal sample size calculation is not necessary. A sample size of 150 participants is deemed feasible to include and randomised within 18 months, and it should be sufficient to base a formal size calculation on for the planning of a large pragmatic trial.

Statistical analysis will be performed according to the intention-to-treat principle. All patient included in the trial have CBDS according to the inclusion criteria and according to the best diagnostic modalities used in the clinic today (see above) and, therefore, the intention-to-treat principle can be used without any post-randomisation exclusions as done in some previous studies. Thereby, all patients with spontaneously passed stones at intra-operative cholangiography, lost-to follow up at 90 days, or patients not undergoing the full two-step procedures will be included in the statistical analyses. Analyses of the primary outcome will be performed for differences between intervention and control group after 90 days of follow-up. Dichotomous outcomes will be analysed using logistic regression. Continuous outcomes will be analysed using linear regression or van Eltern test. Analyses will be adjusted for the stratification variable. Odds ratios or mean differences will be reported with 95% confidence intervals and P-values. As this is a pilot trial, any significant result can be due to random errors and lack of power. It is therefore purely hypothesis generating.

Publications The investigators plan to publish a design article and an article describing the results of the preGallstep pilot trial. Furthermore, the results will be added to an updated meta-analysis. Authorship will be determined by the guidelines by the International Committee for Medical Journal Editors. Members of the trial steering committee as well as the principle investigator from each trial site will be invited as coauthors.

Collaborations The preGallstep trial is in collaboration between five major surgical departments in Denmark.

Investigators of each department have reached expert level of LC+LCBDE and have given consent of participation in the trial.

Protocol development, randomisation, data management, and surveillance of the trial are in collaboration with the Copenhagen Trial Unit (CTU). CTU is a non-specialty oriented clinical intervention research unit consisting of experienced trialists, clinicians, epidemiologists, statisticians, information-technology engineers, and information specialists.

Significance of the project There has not been a significant improvement to the treatment of bile stone disease since the introduction of laparoscopic surgery and ERC more than twenty years ago. Each year more than 750 new patients are diagnosed with CBDS in Denmark alone. ERC combined with LC is the treatment of choice but is affected by a high rate of severe complications and the risk of extended course of treatment.

The investigators propose a new method of treatment that might significantly reduce risk of complications, number of treatments needed, cost to society and improve patient satisfaction and make a difference to hundreds of people in Denmark alone each year.

Since this is a poorly researched area and large RCTs is needed it is important to make the necessary preparations by conducting a large pilot RCT

Eligibility Criteria:
Inclusion Criteria:

* Common bile duct stones identified by magnetic resonance cholangiopancreatography (MRCP).
* Age 18 years or older.
* Both interventions must be possible to perform within a clinically reasonable timeframe, as assessed by the investigator.
* Informed consent.

Exclusion Criteria:

Patients with acute cholangitis corresponding to a grade III (elevated serum bilirubin, fever, and/or elevated white blood cell count and signs of severe organ failure) according to Tokyo guidelines 2018 including severe organ failure.

* Common bile duct cysts shown by magnetic resonance cholangiopancreatography (MRCP), ultrasonography, computer tomography (CT), or cholangiography.
* Pancreatic/biliary/hepatic malignancies.
* Prior cholecystectomy or sphincterotomy.
* Chronic pancreatitis.
* If assessed by investigator that laparoscopic cholecystectomy is not possible, e.g. due to prior surgery or patient condition.
* Gastric bypass.
* Pregnancy confirmed by elevated choriogonadotropin (hCG) in women below 60 years.
* No informed consent.