preGallstep - A Clinical Pilot Trial
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
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.