Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT05611840 |
| Other study ID # |
003kkcng/surg/cuhk |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
May 1, 2023 |
| Est. completion date |
December 31, 2025 |
Study information
| Verified date |
August 2023 |
| Source |
Chinese University of Hong Kong |
| Contact |
Kelvin Ng, PhD |
| Phone |
(852)35051496 |
| Email |
kelvinng[@]surgery.cuhk.edu.hk |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial 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.
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 260,000 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 2016.5 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 5.8 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 investigator's
center is over 700 per year in recent 3 years. From the prospectively collected database on
management of difficult choledocholithiasis in the principle investigator's 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 26.7%, including acute pancreatitis (14%), papillotomy
bleeding (9.1%) and bowel perforation (3.5%). There was no hospital mortality. Interval
cholecystectomy can be completed in 223 patients (61.6%). Among these patients undergone ERCP
plus interval cholecystectomy, the stone clearance rate was 78.4%. 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. 26.7%). 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 > 1.5cm, and/or multiple stones
> 3, and/or 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 1:1
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
investigator's 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 Calot's 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 1.5cm 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 5/0 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 manner.22
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 patient's
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 (i.e. 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 investigator's 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 0.1%
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 0.1%.
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 11.0 (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 Fisher's exact test. Other secondary
outcome measure will be compared using Chi-squared test or Fisher's 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 < 0.05 is considered statistically significant.
All clinical data including patients' demographics, endoscopic and operative details, and
clinical outcome measure will be collected in principle investigator's 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 investigator's center
is available for patients' diagnosis, recruitment, intervention and follow-up.
2. Principle investigator's center has endoscopy and operating facilities for robotic and
endo-laparoscopic interventions of difficult choledocholithiasis.
3. Principle investigator's 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
