Clinical trial NCT04863482: Safety of Laparoscopic ChOlecystectomy Performed by Trainee Surgeons With Different CHolangiographic Techniques
Official title: Safety of Laparoscopic ChOlecystectomy Performed by Trainee Surgeons With Different CHolangiographic Techniques
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: NA
Conditions: Cholecystitis; Gallstone
Lead sponsor: Università Politecnica delle Marche
Sponsor class: OTHER
First posted: 2021-04-28
Enrollment: 1500
Sex: ALL
Minimum age (years): 18
Maximum age (years): 99
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: Laparoscopic cholecystectomy (LC) gained popularity among general surgeons in 1990s and rapidly become one of the most commonly performed procedures in digestive surgery, with more than one million cholecystectomies being performed in the United States per year. LC remains also one of the most commonly performed procedure by general surgeons during the training period. Even if previous report LC cases performed by surgical trainees (ST) are not associated with higher operative morbidity, the length of operative time is significantly increased when compared with that of LC cases performed by attending surgeons, due, most of all, to difficulties in identifying the anatomical structure, and this sometimes leads to an attending surgeon taking away the case from the trainee. Furthermore, despite the fact that LC has proven to be a safe procedure, the rate of common bile duct (BDI) injury still remains unacceptably high even in the hands of minimally invasive trained surgeons ranging from 0.2 to 1.5% in individual reports, much higher than initial reports, associated with significant morbidity and mortality, lower quality of life and increased costs, related to additional health care measures, loss of work days, and insurance claims. The aim of this study is to address which of the techniques now available could be addressed as the best option in a training setting to enhance the learning curve, to ideally build a safe cholecystectomy training program and virtually eliminate the risk of BDI due to anatomic misinterpretation during the training period.

Detailed description: Study design The study will be a multicentre prospective observational study. Members of the Italian Society of Endoscopic Surgery \[SICE\] will be invited to participate. All participating centers will be required to register the study according to local regulations. Evidence of successful registration should be sent to your national network committee prior to beginning of data collection.

Rationale for Study Design Since to date there is no consensus on which is the best technique to correctly identify the anatomy of the Calot's triangle during LC performed by ST, this trial would aim to propose a standard technique to be used in this peculiar setting.

Potential Benefit for Patients In teaching hospitals and, more generally in a training setting, overcoming the problem of providing high surgical quality while educating ST can be challenging. This may change in the future if residents are able to better identify the anatomy with Intra-operative fluorescent cholangiography (IOIFC), shortening the learning curve and improving the safety profile of LC, that, in a clinical point of view, would translate into a shorter operative times and reduction of the potential risk of BDI.

Patient Risk There are no additional risks on the participation of this study as no additional procedures are being performed to clinical guidance. In accordance with standard care, patients shall receive written information regarding the index procedure.

Evaluated parameters i) Age ii) Sex iii) ASA scores iv) Preoperative work up v) Type of procedure (CVS-WL, NIFC, IOC) vi) Operative parameters (operative time, intraoperative complications) vii) BDI (according to the ATOM classification) viii) How the BDI was diagnosed intraoperatively ix) Duration of cholangiography x) Time needed to obtain a CVS xi) Post-operative outcomes (post-operative complications, late complications, need of readmission, length of hospital stay) xii) Surgeons' ease at performing the procedure (questionnaire on identification of anatomical structures, NASA task load test) xiii) Surgeons' satisfaction (visual analog scale)

Selection of Subjects Consecutive eligible patients will be recruited at the outpatient clinic in the participating center by the involved physician (surgeon). All patients fulfilling the above-mentioned criteria will be informed about the study by the physician. After consent is given, central data acquisition will take place web-based and patients will treated according to the study protocol.

Consent Potential participants will be counselled by a member of the research team directly involved with the study and who hold good clinical practice certification. Patients will be provided with written information and the consent form at the time of counselling with an opportunity to ask any questions. All patients participating in the study must hold capacity- this is an inclusion criteria and the absence of it an exclusion criteria.

Study procedures Critical view of Safety(CVS) The CVS has 3 requirements. First, the triangle of Calot must be cleared of fat and fibrous tissue. It does not require that the common bile duct be exposed. The second requirement is that the lowest part of the gallbladder be separated from the cystic plate, the flat fibrous surface to which the non peritonealized side of the gallbladder is attached. The cystic plate, which is sometimes referred to as the liver bed of the gallbladder, is part of the plate/sheath system of the liver. The third requirement is that 2 structures, and only 2, should be seen entering the gallbladder. Once these 3 criteria have been fulfilled, CVS has been attained). The rationale of CVS is based on a 2-step method for ductal identification that was and continues to be used in open cholecystectomy. First, by dissection in the triangle of Calot, the cystic duct and artery are putatively identified and looped with ligatures. Next, the gallbladder is completely dissected off the cystic plate, demonstrating that the 2 structures are the only structures still attached to the gallbladder. Time consumption and includes the period from the initial dissection and the obtaining of an acceptable view according to the previously described criteria in order to safely transect the cystic duct.

Intraoperative cholangiography (IOC)

IOC is performed after dissection of the cystic duct in a standardised manner, by cannulation of the cystic duct with a catheter using either a Kumar or Olsen grasper. Leakage is controlled by injecting saline prior to injection of iodine contrast means, according to the centre usual habits. A mobile X-ray C-arm system is used, and the monochrome X-ray image is shown on a separate screen. After satisfactory identification of the extra-hepatic biliary ducts, the intraoperative cholangiography is discontinued and the gallbladder is removed in a standardised manner. Time consumption includes the period from application of the Kumar/Olsen grasper until it is removed again after obtaining a satisfactory cholangiogram and the cystic duct is transected.

Near infrared cholangiography (NIR-C)

NIFC is performed injecting intravenously, 2.5-7.5 mg of indocyanine green (0.2 mg/kg) at the admission of the patients into the hospital, in patients admitted he same day of surgery, and at least 45 mins before the acquisition of the images. Indocyanine green rapidly binds to plasma proteins and is exclusively and entirely excreted by the hepatic parenchymal cells into the bile, starting within a few minutes after injection. During dissection, the fluorescence imaging mode is used when needed until critical view of safety is obtained. Before division of any tubular structure, the fluorescence imaging mode is routinely used again, and fluorescent angiography is performed by re-injecting the same dose of indocyanine green as initially used. After division of the cystic duct and artery, the fluorescence imaging mode is applied again to check for bile leakage. Time consumption and includes the period from the initial dissection and the obtaining of an acceptable CVS and transect the cystic duct.

Statistical analysis Descriptive statistics will be provided for all discrete variables in the form of rates and proportions with 95% confidence intervals. Continuous variables will be described by mean, standard deviation, median and range. Overall survival, disease free survival, local recurrence rate and metastasis rate will be estimated using the method of Kaplan Meier. Exploratory comparisons of discrete variables will be performed using a Chi-squared test, using continuity correction or Fisher's exact test. Continuous variables will be compared using a Student's t-test, or a non-parametric equivalent (Wilcoxon). All tests will be two sided with a p-value of less than 0.05 considered to indicate statistical significance. Data will be analysed according to intention-to treat principles.

Sample size Sample size was estimated using simulations for a superiority design. Assuming a success rate of 80% for the conventional intraoperative cholangiography, 90 % for the intraoperative fluorescent cholangiography and . This was done for a range of sample sizes. We then analysed each dataset to test whether intraoperative fluorescent cholangiography was no more than 10% inferior to conventional intraoperative cholangiography in a one-sided test applying a 5% level of significance. In conclusion, 60 patients in each group would yield a power of 90%.

Prior to data collection, assuming a baseline structure detection rate of 20%, 300 subjects per group was the estimated sample size needed to detect a 10% absolute increase (from 20 to 30%) in extrahepatic biliary structure visualization rates, with 95% confidence and 80% power. In addition to comparing structure detection rates between the 2 study arms, exploratory analysis was performed to identify potential effect modifiers like age, sex, body mass index (BMI), liver

Based on power calculations to demonstrate superiority of NBI over WLE for the endoscopic diagnosis of coeliac disease, 328 patients would be required in total (44 in each group): calculated using a significance level (alpha) 5%, power 1 (beta) 95%, %success in control (WLE) group 60% \[25\] and % success in experimental group (NBI) 91%.

The sample size has been considered with reference to (1) recruitment (2) adequately powered calculations to be conducted to address the outcomes including inter-observer variation.

Expected Duration of Trial The trial is expected to run for 6 months (time from first patient recruitment to last patient evaluation). Data analysis will take a maximum of 3 months after this time.

11. Ethics \& Regulatory Approvals The trial will be conducted in compliance with the principles of the Declaration of Helsinki (1996), the principles of GCP and in accordance with all applicable regulatory requirements including but not limited to the Research Governance Framework and the Medicines for Human Use (Clinical Trial) Regulations 2004, as amended in 2006 and any subsequent amendments.

This study protocol will be submitted for local REC review in addition with patient information leaflet and consent form. The protocol/ any amendments will follow the local REC process. The chief investigator shall provide annual REC reports as required and will notify the REC at the end of the study.

If the study is ended prematurely, the Chief Investigator will notify the REC, including the reasons for the premature termination.

Data Handling

The Chief Investigator will act as custodian for the trial data. The following guidelines will be strictly adhered to:

All study data will be:

* Stored in line with the Medicines for Human Use (Clinical Trials) Amended Regulations 2006 and the Data Protection Act.
* archived in line with the Medicines for Human Use (Clinical Trials) Amended Regulations 2006 as defined in the Joint Clinical Trials Office Archiving SOP

Eligibility criteria: Inclusion Criteria:

* Patient scheduled for elective laparoscopic cholecystectomy
* Patient age ≥ 18 years
* Patient able to give consent to the procedure

Exclusion Criteria:

* Open cholecystectomy
* Emergency laparoscopic cholecystectomy
* Allergy towards iodine or indocyanine green
* Liver or renal insufficiency
* Thyrotoxicosis
* Pregnancy or lactation
* Legally incompetent for any reason
* Withdrawal of inclusion consent at any time
* Age outside inclusion range

Primary outcomes:
measure: Time to obtain the CVS during laparoscopic cholecystectomy
timeFrame: operative period
Secondary outcomes:
measure: length of hospital stay
timeFrame: through study completion, an average of 1 year
measure: short term complications (reported with a descriptive name of scale and entered in an excel sheet)
timeFrame: up to 30 days from operation
measure: Operative time
timeFrame: operative period
measure: Intraoperative complications will be recorded namely as a descriptive variable and at the end of the study the frequency of each complication will be reported
timeFrame: operative period
measure: Need for conversion will be reported as a binomial variable and participants will be asked to feel the appropriate spaces with a 1 for yes and 0 for no, at the end the frequency of conversion occurrence will be provided
timeFrame: operative period
measure: Causes for conversion will be reported as a descriptive variable and at the end of the study frequencies will be reported
timeFrame: operative period
measure: Type of BDI
timeFrame: operative period
measure: rate of BDI
timeFrame: operative period
measure: Type of post-operative admission
timeFrame: immediate post-operative period
measure: Intensive care unit stay
timeFrame: up to 24 weeks
Other outcomes:
measure: Surgeon's satisfaction
timeFrame: operative period
measure: Surgeon's task load
timeFrame: operative period
Locations:
city: Ancona
country: Italy
facility: Università Politecnica delle Marche, Clinica Chirurgica
Study officials:
affiliation: Università Politecnica delle Marche
name: Monica Ortenzi, MD
role: PRINCIPAL_INVESTIGATOR
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