Ignite Creation Date:
2024-05-06 @ 6:17 PM
Last Modification Date:
2024-10-26 @ 2:45 PM
Study NCT ID:
NCT05611840
Status:
RECRUITING
Last Update Posted:
2023-08-31
First Post:
2022-10-30
Brief Title:
RCT on Robotic vs Endo-laparoscopic Approach for Difficult Choledocholithiasis
Sponsor:
Chinese University of Hong Kong
Organization:
Chinese University of Hong Kong
Study Overview
Official Title:
Randomized Trial Comparing One-stage Robotic Approach Versus Two-stage Endo-laparoscopic Approach for Difficult Choledocholithiasis REAL Trial
Status:
RECRUITING
Status Verified Date:
2023-08
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Gallstone disease is a very common disease identity in the world Migration of stones from gallbladder to common bile duct CBD causing CBD stones choledocholithiasis occurs in up to 22 of cases Traditionally choledocholithiasis can be managed by therapeutic endoscopic retrograde cholangiopancreatography ERCP with interval cholecystectomy in 85 of patients In around 15 of the patients the clearance of choledocholithiasis cannot be effectively achieved with standard ERCP difficult choledocholithiasis
As recommended by European Society of Gastrointestinal Endoscopy guideline difficult choledocholithiasis can be managed by either endoscopic or surgical approaches Clinical evidences by meta-analyses comparing endoscopic with surgical approaches are conflicting Considering the timing of cholecystectomy to eliminate the pathological source of CBD stone one-stage laparoscopic CBD exploration LCBDE plus laparoscopic cholecystectomy LC is an attractive approach Although one-stage laparoscopic approach is associated with higher stone clearance rate up to 96 than traditional two-stage endo-laparoscopic approach preoperative ERCP and LC postoperative complication rate is substantial up to 17 Among those complications postoperative bile leak is likely related to laparoscopic instrumental limitations in LCBDE
With advancement of da Vinci robotic system there are 3-dimensional dual cameras providing high-quality intraoperative view and 7-degree of freedom of robotic instruments The system is able to cope with complex hepatobiliary surgical procedure including robotic CBD exploration RCBDE Theoretically postoperative bile leak following RCBDE is lower than that of LCBDE Hence one-stage RCBDE plus robotic cholecystectomy RC could become a new standard of treatment for difficult choledocholithiasis
Up till now only case series have reported the safety and efficacy of RCBDE There is however no prospective randomized trial comparing one-stage RCBDE and RC with traditional two-stage endo-laparoscopic approach preoperative ERCP and interval LC for difficult choledocholithiasis in terms of stone clearance rate and procedure-related complications The investigators thus propose a single-center randomized trial on this issue 90 patients 45 patients in each arm with difficult choledocholithiasis will be randomized to definitive treatment by either one-stage robotic approach or two-stage endo-laparoscopic approach The primary outcome is the stone clearance rate The secondary outcomes include treatment related morbidity hospital mortality and hospital stay This will be the first randomized trial in the world evaluating the efficacy of the novel one-stage robotic approach for difficult choledocholithiasis and it will certainly add level 1 evidence to change the management algorithm for choledochothiliasis
As recommended by European Society of Gastrointestinal Endoscopy guideline difficult choledocholithiasis can be managed by either endoscopic or surgical approaches Clinical evidences by meta-analyses comparing endoscopic with surgical approaches are conflicting Considering the timing of cholecystectomy to eliminate the pathological source of CBD stone one-stage laparoscopic CBD exploration LCBDE plus laparoscopic cholecystectomy LC is an attractive approach Although one-stage laparoscopic approach is associated with higher stone clearance rate up to 96 than traditional two-stage endo-laparoscopic approach preoperative ERCP and LC postoperative complication rate is substantial up to 17 Among those complications postoperative bile leak is likely related to laparoscopic instrumental limitations in LCBDE
With advancement of da Vinci robotic system there are 3-dimensional dual cameras providing high-quality intraoperative view and 7-degree of freedom of robotic instruments The system is able to cope with complex hepatobiliary surgical procedure including robotic CBD exploration RCBDE Theoretically postoperative bile leak following RCBDE is lower than that of LCBDE Hence one-stage RCBDE plus robotic cholecystectomy RC could become a new standard of treatment for difficult choledocholithiasis
Up till now only case series have reported the safety and efficacy of RCBDE There is however no prospective randomized trial comparing one-stage RCBDE and RC with traditional two-stage endo-laparoscopic approach preoperative ERCP and interval LC for difficult choledocholithiasis in terms of stone clearance rate and procedure-related complications The investigators thus propose a single-center randomized trial on this issue 90 patients 45 patients in each arm with difficult choledocholithiasis will be randomized to definitive treatment by either one-stage robotic approach or two-stage endo-laparoscopic approach The primary outcome is the stone clearance rate The secondary outcomes include treatment related morbidity hospital mortality and hospital stay This will be the first randomized trial in the world evaluating the efficacy of the novel one-stage robotic approach for difficult choledocholithiasis and it will certainly add level 1 evidence to change the management algorithm for choledochothiliasis
Detailed Description:
Background
i Background information
Gallstone disease is a very common disease identity in developed countries causing a major health burden There is an estimate of 20 - 25 million adults diagnosed to have gallstone disease annually resulting in more than 260000 hospitalization for cholecystitis in the year 2000 in US In Asia the prevalence rate ranges from 5 to 20 of population Common bile duct CBD stone choledocholithiasis occurs when there is migration of stone from gallbladder to CBD in up to 22 of cases The resulting acute cholangitis and acute biliary pancreatitis leads to substantial morbidity and mortality to patients Traditionally choledocholithiasis can be managed successfully by therapeutic endoscopic retrograde cholangiopancreatography ERCP with interval cholecystectomy in 85 of patients However standard ERCP fails to clear choledocholithiasis in around 15 of the patients and these cases are referred as difficult choledocholithiasis
According to European Society of Gastrointestinal Endoscopy guideline difficult choledocholithiasis can be managed by either two-stage endo-laparoscopic approach or one-stage surgical approaches The two-stage endo-laparoscopic approach involves ERCP using advanced endoscopic stone-clearing techniques with interval laparoscopic cholecystectomy LC in two weeks time On the other hand the one-stage surgical approach is carried out by performing CBD exploration with simultaneous cholecystectomy using minimally invasive or open method Potentially the latter holds the advantage of treating two disease identities choledocholithiasis and gallstone by single operation under general anaesthesia From the guideline whether to proceed to two-stage endo-laparoscopic or one-stage surgical approach still requires high-level evidence
ii Research gap
By far most centers adapt sequential two-stage endo-laparoscopic approach for difficult choledocholithiasis and reserving one-stage LCBDE plus LC for selected patient A Cochrane review on 16 randomized clinical trials comparing endoscopic and surgical approaches for treatment of choledochothiliasis in 1758 patients was published in 20165 There was no difference in mortality morbidity and stone clearance rate between one-stage laparoscopic approach and two-stage endo-laparoscopic approach More recently another meta-analysis on studies comparing these two approaches has shown different findings The two-stage endo-laparoscopic approach had higher CBD stone clearance rate lower postoperative bile leakage rate and higher rate of pancreatitis than one-stage laparoscopic approach which might help to shorten the hospital stay One major critic is that the nature of choledocholithiasis whether it was difficult choledocholithiasis or not was poorly defined in all of those randomized studies The resulting heterogeneity in patient selection makes the results from these studies difficult to compare and convincing conclusion is hard to generate Thus a well-designed randomized clinical trial comparing the two-stage endo-laparoscopic with one-stage minimally invasive approach for difficult choledocholithiasis with clear-cut stone clearance rate as primary outcome measure is needed
With advancement of da Vinci robotic system there are 3-dimensional dual cameras providing high-quality intraoperative view and 7-degree of freedom of robotic instruments The system is able to cope with complex hepatobiliary surgical procedure especially those procedure involving intra-corporeal suturing techniques To tackle difficult choledocholithiasis one-stage robotic common bile duct exploration RCBDE and robotic cholecystectomy RC could be an effective method with high successful rate and low complication Ji et al published the first series of one-stage RCBDE plus RC in 5 patients There was no conversion to laparoscopic or open surgery One patient developed chest complication The average hospital stay was 58 days and the stone clearance rate was 100 Alkhamesi et al compared RCBDE with open surgery in a retrospective study The robotic approach posed an advantage of shorter hospital stay when compared with open approach From European Association of Endoscopic Surgeons consensus statement robotic assistance may facilitate complex biliary surgery including RCBDE Theoretically one-stage RCBDE plus RC is superior than traditional two-stage endo-laparoscopic approach for difficult choledocholithiasis because of the following two reasons
1 One-stage robotic approach can achieve much higher stone clearance rate than two-stage endo-laparoscopic approach Potentially one-stage procedure can have nearly 100 stone clearance rate since it eliminates both gallstone and choledocholithiasis in one surgery In contrast two-stage approach may have time lag between initial therapeutic ERCP and interval LC There is always a chance of stone migration into CBD during waiting period for LC
2 With an aid of robotic instruments closure of CBD opening can be safely performed without the risk of postoperative bile leak which happens in around 5 of LCBDE
iii Novelty of proposed study So far there is no prospective clinical trial from the registry of clinical trials provided by the US National Library of Medicine to test the hypothesis that one-stage robotic approach is superior than two-stage endo-laparoscopic approach for difficult choledocholithiasis The principle investigator thus propose a single-center randomized trial REAL trial with the primary objective of testing the superiority of one-stage robotic approach over two-stage endo-laparoscopic approach for difficult choledocholithiasis with primary outcome measure of stone clearance rate
iv Preliminary data The average number of ERCP performed in the principle investigators center is over 700 per year in recent 3 years From the prospectively collected database on management of difficult choledocholithiasis in the principle investigators center from 2018 - 2020 there were 362 patients with difficult choledocholithiasis treated by therapeutic ERCP endoscopic papillary large balloon dilatation and or mechanical lithotripsy and or cholangioscopy-assisted lithotripsy The median number of sessions was 3 ranged 2 - 8 Post-ERCP complication rate was 267 including acute pancreatitis 14 papillotomy bleeding 91 and bowel perforation 35 There was no hospital mortality Interval cholecystectomy can be completed in 223 patients 616 Among these patients undergone ERCP plus interval cholecystectomy the stone clearance rate was 784 During the same study period there were 20 patients receiving one-stage RCBDE plus RC There was no hospital mortality The postoperative complication rate was much lower than that of two-stage endo-laparoscopic approach 5 vs 267 The stone clearance rate was 100 which was much higher than two-stage approach The median hospital stay was 4 days ranged 3 - 7 days Unpublished data From these preliminary results it is obvious that one-stage robotic approach is superior to two-stage endo-laparoscopic approach in terms of higher stone clearance and lower procedure-related complications
Research Plan and Methodology
Study design Single-center randomized trial
Center involved Department of Surgery The Chinese University of Hong Kong
Inclusion and Exclusion Criteria
Consecutive patients with newly diagnosed difficult choledocholithiasis by diagnostic radiological studies ultrasonography or CT scan or MRI cholangiography will be recruited into the trial Initial endoscopic retrograde cholangiopancreatography ERCP will be performed to confirm the diagnosis of difficult choledocholithiasis and temporarily plastic biliary stent will be inserted to bypass biliary obstruction The followings are inclusion criteria
1 Definition of difficult choledocholithiasis stone size 15cm andor multiple stones 3 andor narrow and angled distal common bile duct CBD 135o
2 Diagnostic ERCP with successful CBD deep cannulation and temporarily CBD stenting
3 No history of cholecystectomy with provisional diagnosis of choledocholithiasis originating from gallstone disease
4 General condition fit for anaesthesia for both advanced therapeutic ERCP or robotic surgery
The following patients will be excluded
1 History of recurrent pyogenic cholangitis
2 Failed endoscopic biliary stenting by initial ERCP
3 Complications acute pancreatitis papillotomy bleeding or bowel perforation from initial ERCP
4 Previous upper abdominal surgery including gastrectomy
5 General condition unfit for anesthesia
Randomization
Patients with their consent will be recruited to participate by investigators after considering the inclusion and exclusion criteria Treatment allocation to the eligible patients will follow a randomization schedule A total of 90 patients will be randomized 11 to one of the two treatment arms
1 Robotic group Patients receive one-stage robotic common bile duct exploration and simultaneous robotic cholecystectomy
2 Endo-laparoscopic group Patients receive two-stage therapeutic ERCP and interval laparoscopic cholecystectomy
The randomization schedule will be generated by the Clinical Trials Centre CTC of principle investigators center prior to the start of the study Block randomization is used to maintain good balance to each treatment group The randomization list will be kept in a set of tamper-evident envelopes The envelopes will be identical and sealed The trial identifier with a sequential number will be printed on each envelope and the inside will contain the treatment allocation Envelopes will be unsealed to reveal the allocation treatment one day prior to the surgery
Pre-treatment Investigations and Assessments
All patients undergo the following pre-treatment investigations and assessments
1 Blood tests complete blood count liver and renal function tests coagulation profile serum carcinoembryonic antigen
2 Radiological imaging CT scan or MRI of abdomen to exclude the possibility of recurrent pyogenic cholangitis and malignant cause of biliary obstruction
3 ECG and or other cardiac assessment as requested by anesthetist for general anesthesia assessment
Treatment Procedures
Robotic group
Under general anesthesia four robotic 8-mm trocars and one 5-mm laparoscopic assistant trocar will be inserted and pneumoperitoneum is created A conventional approach of robotic cholecystectomy is first performed with dissection of Calots triangle and the removal of gallbladder from liver bed The cystic duct is then retracted laterally to facilitate the exposure of anterior wall of common bile duct CBD CBD is subsequently opened longitudinally for about 15cm using robotic scissors If choledocholithiasis CBD stone is encountered over the choledochotomy site it will be removed directly by robotic forceps If not a 5-mm flexible choledochoscope will be inserted into CBD through choledochotomy site to identify the stone which will be removed by sterile saline flushing stone basket or electrohydraulic lithotripsy Ductal clearance will be confirmed by choledochoscopic examination from lower CBD up to left and right intrahepatic ducts The intraluminal plastic biliary stent which was inserted before the procedure will be left in-situ The cystic duct is divided and the gallbladder is delivered The choledochotomy site will be closed by interrupted resorbable sutures preferably 50 PDS A Fr 21 abdominal drain will be placed at right subhepatic space to observe for postoperative bile leakage
Endo-laparoscopic group
The treatment process commenced with the first stage therapeutic endoscopic retrograde cholangiopancreatography ERCP under general anesthesia or monitored anaesthetic control With patient in prone position ERCP is performed using side-view scope Endoscopic sphincterotomy is performed via needle knife sphincterotome which cuts papilla alongside the previous plastic biliary stent The plastic biliary stent is then removed and the sphincterotomy side is enlarged using endoscopic papillary large balloon dilatation The choledocholithiasis will then be removed by means of mechanical lithotripsy and or cholangioscopy-assisted lithotripsy If necessary serial sessions of therapeutic ERCP will be arranged until ductal clearance of CBD is confirmed by balloon occlusion cholangiogram Temporary plastic biliary stent will be inserted to ensure biliary drainage while waiting for cholecystectomy
Laparoscopic cholecystectomy will be arranged as second stage procedure in 2-4 weeks interval after first stage ERCP The procedure will be performed in a standard manner22
Perioperative management The perioperative management of all recruited patient is standardized All patients receive broad-spectrum antibiotics during postoperative period For robotic group attention is to observe for postoperative bile leakage by examining the content of abdominal drain which will be removed if there is no evidence of bile leak in 2-3 days after surgery Routine monitoring of liver function is carried out till patients discharge For endo-laparoscopic group attention is to look for complications of therapeutic ERCP including acute pancreatitis elevated serum amylase papillotomy bleeding evidence of tarry stool or hematemesis and drop in hemoglobin level and bowel perforation acute peritonitis Post-ERCP complications will be treated accordingly Following second stage laparoscopic cholecystectomy patients will be observed routinely
Postoperative assessments
1 Liver function Liver biochemistry and coagulation profile at days 1 3 and 7 after surgery to evaluate changes in liver function
2 Postoperative morbidities according to Clavien-Dindo classification23
1 Robotic group postoperative bile leak pulmonary complication
2 Endo-laparoscopic group post-ERCP complications acute pancreatitis post-papillotomy bleeding and bowel perforation
3 Operative mortality 30-day mortality and hospital mortality any death within the same admission for surgery
4 In both groups post-procedure ERCP will be arranged in 4 weeks interval to assess the possibility of residual choledocholithiasis ie stone clearance rate and to remove biliary plastic stent
5 MRI cholangiography MRCP will be arranged 3 months after index procedure for the assessment of biliary system After completion of funding period MRCP will be arranged in 6 months interval up to 2 years for long-term assessment of the possibility of common bile duct stone recurrence
Outcome Measures
The primary study end point outcome measure is stone clearance rate as assessed by post-procedure ERCP It is used for sample size calculation The secondary outcome measures include bile leak rate post-ERCP complications and othergrade IIIA or above complication according to Clavien-Dindo classification23 30-day mortality hospital mortality and total hospital stay
Number of Patients to be Recruited and Expected Duration of Study
Based on a previous reported stone rate of 84 after two-stage endo-laparoscopic approach for choledocholithiasis and assumed 95 after one-stage robotic approach for the same situation an one-sided non-inferiority study is designed with a non-inferior margin of 10 allowed for robotic approach With 80 power at the 5 Type I error alpha 45 patients need to be recruited to each arm total 90 patients in the study allowing 15 drop-out rate The principle investigators unit is a major referral center for management of biliary stone disease in Hong Kong with more than 700 cases of choledocholithiasis managed by ERCP each year It is therefore expected that recruitment can be completed in about 33 months The last recruited patient will be observed for at least 3 months after procedure Hence the total period of study including follow-up is 3 years which is also the funding period for the grant application After completion of funding period the recruited patients will be followed up to 2 years with interval investigations of biliary system to look for common bile duct stone recurrence
Foreseeable risks of the study
This study involves two different approaches for management of difficult choledocholithiasis which are associated with different degree of morbidity and mortality The one-stage robotic common bile duct exploration and cholecystectomy has potential surgical risks of 01 mortality and 5 - 10 complication rate intra-abdominal sepsis chest complications and wound complications Meanwhile the two-stage endo-laparoscopic approach might carry potential complications related to ERCP 5 and interval laparoscopic cholecystectomy 5 The post-ERCP complications include acute pancreatitis post-papillotomy gastrointestinal bleeding and bowel perforation whereas the post-cholecystectomy complications include intra-abdominal sepsis chest complications and wound complications The overall mortality risk following two-stage endo-laparoscopic approach would be 01
Blinding of the study
After randomization the recruited patient will be allocated either robotic or endo-laparoscopic group There will be no blinding of the randomization result to the recruited patients the operating surgeons and clinician-in-charge
Statistical plan and data monitoring
Statistical analysis will be performed using SPSS version 110 SPSS Inc Chicago Ill on an intention-to-treat basis The stone clearance rate primary outcome will be calculated and compared between groups by Chi-squared test or Fishers exact test Other secondary outcome measure will be compared using Chi-squared test or Fishers exact test for categorical variables and Mann-Whitney U test for continuous variables Univariate and multivariate analyses using logistic regression are performed to identify potential risk factors influencing the stone clearance rate All tests of significance will be two-tailed and a P value 005 is considered statistically significant
All clinical data including patients demographics endoscopic and operative details and clinical outcome measure will be collected in principle investigators center Any missing data will be documented with reasons Continuous clinical data monitoring and interim and final analyses will be performed by principle investigator and co-investigators with the help of a research assistance
Potential problems anticipated The patient recruitment will be reviewed every 4 months If the accrual rate is slower than expected investigator meeting will be carried out to review the underlying reasons and the ways to improve recruitment rate
Existing Facilities
This study is supported by the following existing facilities
1 Multidisciplinary team hepatobiliary and pancreatic surgeons endoscopists gastrointestinal physicians and research assistance of principle investigators center is available for patients diagnosis recruitment intervention and follow-up
2 Principle investigators center has endoscopy and operating facilities for robotic and endo-laparoscopic interventions of difficult choledocholithiasis
3 Principle investigators center has laboratory and radiological facilities for follow-up assessment of recruited patient
Justification of Requirements
This study receives general research grant from the government of Hong Kong Special Administrative region for the following financial support
1 Recruitment of one research assistant for assistance of patient recruitment process coordination of randomization clinical data collection and maintenance
2 Conference cost for conference registration and travel expenses for presentation in international conferences
3 Publication cost for one to two publication in international peer-reviewed journal
i Background information
Gallstone disease is a very common disease identity in developed countries causing a major health burden There is an estimate of 20 - 25 million adults diagnosed to have gallstone disease annually resulting in more than 260000 hospitalization for cholecystitis in the year 2000 in US In Asia the prevalence rate ranges from 5 to 20 of population Common bile duct CBD stone choledocholithiasis occurs when there is migration of stone from gallbladder to CBD in up to 22 of cases The resulting acute cholangitis and acute biliary pancreatitis leads to substantial morbidity and mortality to patients Traditionally choledocholithiasis can be managed successfully by therapeutic endoscopic retrograde cholangiopancreatography ERCP with interval cholecystectomy in 85 of patients However standard ERCP fails to clear choledocholithiasis in around 15 of the patients and these cases are referred as difficult choledocholithiasis
According to European Society of Gastrointestinal Endoscopy guideline difficult choledocholithiasis can be managed by either two-stage endo-laparoscopic approach or one-stage surgical approaches The two-stage endo-laparoscopic approach involves ERCP using advanced endoscopic stone-clearing techniques with interval laparoscopic cholecystectomy LC in two weeks time On the other hand the one-stage surgical approach is carried out by performing CBD exploration with simultaneous cholecystectomy using minimally invasive or open method Potentially the latter holds the advantage of treating two disease identities choledocholithiasis and gallstone by single operation under general anaesthesia From the guideline whether to proceed to two-stage endo-laparoscopic or one-stage surgical approach still requires high-level evidence
ii Research gap
By far most centers adapt sequential two-stage endo-laparoscopic approach for difficult choledocholithiasis and reserving one-stage LCBDE plus LC for selected patient A Cochrane review on 16 randomized clinical trials comparing endoscopic and surgical approaches for treatment of choledochothiliasis in 1758 patients was published in 20165 There was no difference in mortality morbidity and stone clearance rate between one-stage laparoscopic approach and two-stage endo-laparoscopic approach More recently another meta-analysis on studies comparing these two approaches has shown different findings The two-stage endo-laparoscopic approach had higher CBD stone clearance rate lower postoperative bile leakage rate and higher rate of pancreatitis than one-stage laparoscopic approach which might help to shorten the hospital stay One major critic is that the nature of choledocholithiasis whether it was difficult choledocholithiasis or not was poorly defined in all of those randomized studies The resulting heterogeneity in patient selection makes the results from these studies difficult to compare and convincing conclusion is hard to generate Thus a well-designed randomized clinical trial comparing the two-stage endo-laparoscopic with one-stage minimally invasive approach for difficult choledocholithiasis with clear-cut stone clearance rate as primary outcome measure is needed
With advancement of da Vinci robotic system there are 3-dimensional dual cameras providing high-quality intraoperative view and 7-degree of freedom of robotic instruments The system is able to cope with complex hepatobiliary surgical procedure especially those procedure involving intra-corporeal suturing techniques To tackle difficult choledocholithiasis one-stage robotic common bile duct exploration RCBDE and robotic cholecystectomy RC could be an effective method with high successful rate and low complication Ji et al published the first series of one-stage RCBDE plus RC in 5 patients There was no conversion to laparoscopic or open surgery One patient developed chest complication The average hospital stay was 58 days and the stone clearance rate was 100 Alkhamesi et al compared RCBDE with open surgery in a retrospective study The robotic approach posed an advantage of shorter hospital stay when compared with open approach From European Association of Endoscopic Surgeons consensus statement robotic assistance may facilitate complex biliary surgery including RCBDE Theoretically one-stage RCBDE plus RC is superior than traditional two-stage endo-laparoscopic approach for difficult choledocholithiasis because of the following two reasons
1 One-stage robotic approach can achieve much higher stone clearance rate than two-stage endo-laparoscopic approach Potentially one-stage procedure can have nearly 100 stone clearance rate since it eliminates both gallstone and choledocholithiasis in one surgery In contrast two-stage approach may have time lag between initial therapeutic ERCP and interval LC There is always a chance of stone migration into CBD during waiting period for LC
2 With an aid of robotic instruments closure of CBD opening can be safely performed without the risk of postoperative bile leak which happens in around 5 of LCBDE
iii Novelty of proposed study So far there is no prospective clinical trial from the registry of clinical trials provided by the US National Library of Medicine to test the hypothesis that one-stage robotic approach is superior than two-stage endo-laparoscopic approach for difficult choledocholithiasis The principle investigator thus propose a single-center randomized trial REAL trial with the primary objective of testing the superiority of one-stage robotic approach over two-stage endo-laparoscopic approach for difficult choledocholithiasis with primary outcome measure of stone clearance rate
iv Preliminary data The average number of ERCP performed in the principle investigators center is over 700 per year in recent 3 years From the prospectively collected database on management of difficult choledocholithiasis in the principle investigators center from 2018 - 2020 there were 362 patients with difficult choledocholithiasis treated by therapeutic ERCP endoscopic papillary large balloon dilatation and or mechanical lithotripsy and or cholangioscopy-assisted lithotripsy The median number of sessions was 3 ranged 2 - 8 Post-ERCP complication rate was 267 including acute pancreatitis 14 papillotomy bleeding 91 and bowel perforation 35 There was no hospital mortality Interval cholecystectomy can be completed in 223 patients 616 Among these patients undergone ERCP plus interval cholecystectomy the stone clearance rate was 784 During the same study period there were 20 patients receiving one-stage RCBDE plus RC There was no hospital mortality The postoperative complication rate was much lower than that of two-stage endo-laparoscopic approach 5 vs 267 The stone clearance rate was 100 which was much higher than two-stage approach The median hospital stay was 4 days ranged 3 - 7 days Unpublished data From these preliminary results it is obvious that one-stage robotic approach is superior to two-stage endo-laparoscopic approach in terms of higher stone clearance and lower procedure-related complications
Research Plan and Methodology
Study design Single-center randomized trial
Center involved Department of Surgery The Chinese University of Hong Kong
Inclusion and Exclusion Criteria
Consecutive patients with newly diagnosed difficult choledocholithiasis by diagnostic radiological studies ultrasonography or CT scan or MRI cholangiography will be recruited into the trial Initial endoscopic retrograde cholangiopancreatography ERCP will be performed to confirm the diagnosis of difficult choledocholithiasis and temporarily plastic biliary stent will be inserted to bypass biliary obstruction The followings are inclusion criteria
1 Definition of difficult choledocholithiasis stone size 15cm andor multiple stones 3 andor narrow and angled distal common bile duct CBD 135o
2 Diagnostic ERCP with successful CBD deep cannulation and temporarily CBD stenting
3 No history of cholecystectomy with provisional diagnosis of choledocholithiasis originating from gallstone disease
4 General condition fit for anaesthesia for both advanced therapeutic ERCP or robotic surgery
The following patients will be excluded
1 History of recurrent pyogenic cholangitis
2 Failed endoscopic biliary stenting by initial ERCP
3 Complications acute pancreatitis papillotomy bleeding or bowel perforation from initial ERCP
4 Previous upper abdominal surgery including gastrectomy
5 General condition unfit for anesthesia
Randomization
Patients with their consent will be recruited to participate by investigators after considering the inclusion and exclusion criteria Treatment allocation to the eligible patients will follow a randomization schedule A total of 90 patients will be randomized 11 to one of the two treatment arms
1 Robotic group Patients receive one-stage robotic common bile duct exploration and simultaneous robotic cholecystectomy
2 Endo-laparoscopic group Patients receive two-stage therapeutic ERCP and interval laparoscopic cholecystectomy
The randomization schedule will be generated by the Clinical Trials Centre CTC of principle investigators center prior to the start of the study Block randomization is used to maintain good balance to each treatment group The randomization list will be kept in a set of tamper-evident envelopes The envelopes will be identical and sealed The trial identifier with a sequential number will be printed on each envelope and the inside will contain the treatment allocation Envelopes will be unsealed to reveal the allocation treatment one day prior to the surgery
Pre-treatment Investigations and Assessments
All patients undergo the following pre-treatment investigations and assessments
1 Blood tests complete blood count liver and renal function tests coagulation profile serum carcinoembryonic antigen
2 Radiological imaging CT scan or MRI of abdomen to exclude the possibility of recurrent pyogenic cholangitis and malignant cause of biliary obstruction
3 ECG and or other cardiac assessment as requested by anesthetist for general anesthesia assessment
Treatment Procedures
Robotic group
Under general anesthesia four robotic 8-mm trocars and one 5-mm laparoscopic assistant trocar will be inserted and pneumoperitoneum is created A conventional approach of robotic cholecystectomy is first performed with dissection of Calots triangle and the removal of gallbladder from liver bed The cystic duct is then retracted laterally to facilitate the exposure of anterior wall of common bile duct CBD CBD is subsequently opened longitudinally for about 15cm using robotic scissors If choledocholithiasis CBD stone is encountered over the choledochotomy site it will be removed directly by robotic forceps If not a 5-mm flexible choledochoscope will be inserted into CBD through choledochotomy site to identify the stone which will be removed by sterile saline flushing stone basket or electrohydraulic lithotripsy Ductal clearance will be confirmed by choledochoscopic examination from lower CBD up to left and right intrahepatic ducts The intraluminal plastic biliary stent which was inserted before the procedure will be left in-situ The cystic duct is divided and the gallbladder is delivered The choledochotomy site will be closed by interrupted resorbable sutures preferably 50 PDS A Fr 21 abdominal drain will be placed at right subhepatic space to observe for postoperative bile leakage
Endo-laparoscopic group
The treatment process commenced with the first stage therapeutic endoscopic retrograde cholangiopancreatography ERCP under general anesthesia or monitored anaesthetic control With patient in prone position ERCP is performed using side-view scope Endoscopic sphincterotomy is performed via needle knife sphincterotome which cuts papilla alongside the previous plastic biliary stent The plastic biliary stent is then removed and the sphincterotomy side is enlarged using endoscopic papillary large balloon dilatation The choledocholithiasis will then be removed by means of mechanical lithotripsy and or cholangioscopy-assisted lithotripsy If necessary serial sessions of therapeutic ERCP will be arranged until ductal clearance of CBD is confirmed by balloon occlusion cholangiogram Temporary plastic biliary stent will be inserted to ensure biliary drainage while waiting for cholecystectomy
Laparoscopic cholecystectomy will be arranged as second stage procedure in 2-4 weeks interval after first stage ERCP The procedure will be performed in a standard manner22
Perioperative management The perioperative management of all recruited patient is standardized All patients receive broad-spectrum antibiotics during postoperative period For robotic group attention is to observe for postoperative bile leakage by examining the content of abdominal drain which will be removed if there is no evidence of bile leak in 2-3 days after surgery Routine monitoring of liver function is carried out till patients discharge For endo-laparoscopic group attention is to look for complications of therapeutic ERCP including acute pancreatitis elevated serum amylase papillotomy bleeding evidence of tarry stool or hematemesis and drop in hemoglobin level and bowel perforation acute peritonitis Post-ERCP complications will be treated accordingly Following second stage laparoscopic cholecystectomy patients will be observed routinely
Postoperative assessments
1 Liver function Liver biochemistry and coagulation profile at days 1 3 and 7 after surgery to evaluate changes in liver function
2 Postoperative morbidities according to Clavien-Dindo classification23
1 Robotic group postoperative bile leak pulmonary complication
2 Endo-laparoscopic group post-ERCP complications acute pancreatitis post-papillotomy bleeding and bowel perforation
3 Operative mortality 30-day mortality and hospital mortality any death within the same admission for surgery
4 In both groups post-procedure ERCP will be arranged in 4 weeks interval to assess the possibility of residual choledocholithiasis ie stone clearance rate and to remove biliary plastic stent
5 MRI cholangiography MRCP will be arranged 3 months after index procedure for the assessment of biliary system After completion of funding period MRCP will be arranged in 6 months interval up to 2 years for long-term assessment of the possibility of common bile duct stone recurrence
Outcome Measures
The primary study end point outcome measure is stone clearance rate as assessed by post-procedure ERCP It is used for sample size calculation The secondary outcome measures include bile leak rate post-ERCP complications and othergrade IIIA or above complication according to Clavien-Dindo classification23 30-day mortality hospital mortality and total hospital stay
Number of Patients to be Recruited and Expected Duration of Study
Based on a previous reported stone rate of 84 after two-stage endo-laparoscopic approach for choledocholithiasis and assumed 95 after one-stage robotic approach for the same situation an one-sided non-inferiority study is designed with a non-inferior margin of 10 allowed for robotic approach With 80 power at the 5 Type I error alpha 45 patients need to be recruited to each arm total 90 patients in the study allowing 15 drop-out rate The principle investigators unit is a major referral center for management of biliary stone disease in Hong Kong with more than 700 cases of choledocholithiasis managed by ERCP each year It is therefore expected that recruitment can be completed in about 33 months The last recruited patient will be observed for at least 3 months after procedure Hence the total period of study including follow-up is 3 years which is also the funding period for the grant application After completion of funding period the recruited patients will be followed up to 2 years with interval investigations of biliary system to look for common bile duct stone recurrence
Foreseeable risks of the study
This study involves two different approaches for management of difficult choledocholithiasis which are associated with different degree of morbidity and mortality The one-stage robotic common bile duct exploration and cholecystectomy has potential surgical risks of 01 mortality and 5 - 10 complication rate intra-abdominal sepsis chest complications and wound complications Meanwhile the two-stage endo-laparoscopic approach might carry potential complications related to ERCP 5 and interval laparoscopic cholecystectomy 5 The post-ERCP complications include acute pancreatitis post-papillotomy gastrointestinal bleeding and bowel perforation whereas the post-cholecystectomy complications include intra-abdominal sepsis chest complications and wound complications The overall mortality risk following two-stage endo-laparoscopic approach would be 01
Blinding of the study
After randomization the recruited patient will be allocated either robotic or endo-laparoscopic group There will be no blinding of the randomization result to the recruited patients the operating surgeons and clinician-in-charge
Statistical plan and data monitoring
Statistical analysis will be performed using SPSS version 110 SPSS Inc Chicago Ill on an intention-to-treat basis The stone clearance rate primary outcome will be calculated and compared between groups by Chi-squared test or Fishers exact test Other secondary outcome measure will be compared using Chi-squared test or Fishers exact test for categorical variables and Mann-Whitney U test for continuous variables Univariate and multivariate analyses using logistic regression are performed to identify potential risk factors influencing the stone clearance rate All tests of significance will be two-tailed and a P value 005 is considered statistically significant
All clinical data including patients demographics endoscopic and operative details and clinical outcome measure will be collected in principle investigators center Any missing data will be documented with reasons Continuous clinical data monitoring and interim and final analyses will be performed by principle investigator and co-investigators with the help of a research assistance
Potential problems anticipated The patient recruitment will be reviewed every 4 months If the accrual rate is slower than expected investigator meeting will be carried out to review the underlying reasons and the ways to improve recruitment rate
Existing Facilities
This study is supported by the following existing facilities
1 Multidisciplinary team hepatobiliary and pancreatic surgeons endoscopists gastrointestinal physicians and research assistance of principle investigators center is available for patients diagnosis recruitment intervention and follow-up
2 Principle investigators center has endoscopy and operating facilities for robotic and endo-laparoscopic interventions of difficult choledocholithiasis
3 Principle investigators center has laboratory and radiological facilities for follow-up assessment of recruited patient
Justification of Requirements
This study receives general research grant from the government of Hong Kong Special Administrative region for the following financial support
1 Recruitment of one research assistant for assistance of patient recruitment process coordination of randomization clinical data collection and maintenance
2 Conference cost for conference registration and travel expenses for presentation in international conferences
3 Publication cost for one to two publication in international peer-reviewed journal
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None