Study design
This prospective, single-centre, randomized and interventional clinical trial conducted at the First Affiliated Hospital of Anhui Medical University began in February 2020 and is expected to end in 2026. Patients with diagnosed HL who meet entry criteria will be recruited and randomly assigned to undergo either T-tube drainage or Roux-en-Y HJ. The flowchart according to the Consolidated Standards of Reporting Trials (CONSORT) statement is shown in Fig 1, and the schedule of enrolment, interventions and assessments are summarized in Fig 2. The Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guidelines are provided in Additional file 1.
Number of patients needed
The sample size is based on a two-sided t-test for differences with respect to the primary parameter and the primary analysis. In a retrospective analysis of our own series, the incidence of biliary complications was 30% in patients with HL with SOL undergoing T-tube drainage. The calculated sample size was 186 (93 per group), with 80% statistical power to detect a difference in the supposed incidence of biliary complications of 15% (30% in the T-tube drainage group vs. 15% in the Roux-en-Y HJ group). Given an estimated withdrawal rate of 10%, the minimum required sample size would be 204 patients. We plan to enrol a total of 210 patients (105 per group).
Eligibility criteria
Inclusion criteria
- Aged between 18 and 70 years
- Diagnosed with HL with SOL during the operation
- Underwent foci removal, stone extraction and stricture correction during the operation
- Provided written informed consent
- Was willing to complete a 3-year follow-up.
Exclusion criteria
- Participation in concurrent intervention trials that would interfere with the outcomes of this study
- Associated tumour
- Complete loss of function or normal sphincter of Oddi (SO)
- Previous choledochojejunostomy
- Lack of compliance
Withdrawal
An informed consent form, which describes the detailed study procedures and illustrates the potential benefits and risks, will be provided to all participants so that they can decide whether to volunteer. All the participants are freely informed to participate in the study and can withdraw from the trial at their own request at any time. If the patient withdraws, the information will not be used in this study. However, the research team can still record the outcome data in clinical report forms.
Ethics, study registration and consent
The final protocol was approved by the Ethics Committee of the First Affiliated Hospital of Anhui Medical University (PJ2019-17-12). The trial protocol was registered at the ClinicalTrials.gov protocol registration system (NCT04218669). Patients with HL who are scheduled for common bile duct exploration at the Department of General Surgery, Anhui Medical University, will be screened for eligibility and informed about the trial. The study procedure, benefits, risks and data management will be clarified in detail during the conversation.
Trial interventions
All patients with SOL underwent common bile duct exploration and complete stone extraction. The surgical procedures of the T-tube drainage arm and Roux-en-Y HJ arm are as follows.
Group A: T-tube drainage
A T-tube was placed for biliary drainage, and the common bile duct was intermittently sutured with 4-0 Vicryl sutures.
Group B: Roux-en-Y HJ
The common hepatic duct was cut, and the duodenal side was closed with sutures. The small intestine was cut off 15 cm below the ligament of Treitz. The distal end was lifted, and a 1-2 cm incision was made at the jejunal wall 4-5 cm from the jejunal stump. The anastomosis used 5-0 PDS II with double-armed inside-out sutures in the jejunum and outside-in sutures in the hepatic duct. One side of the needle was used to continuously penetrate and suture the whole layer of the posterior-lateral wall of the jejunum and the posterior-lateral wall of the biliary duct, and the other side of the needle was used to continuously suture the anterior part of the anastomosis. Mucosa-to-mucosa contact should be ensured with every stitch. The anastomotic stomas were then checked for leakage. Enteric-enteric anastomosis was performed 60 cm below the site of the hepaticojejunal anastomosis.
Primary and secondary endpoints
All participants will be followed up regularly according to the schedule shown in Fig 2 at the stated intervals after surgery for at least 3 years. At the follow-up visits, patients will undergo laboratory tests and abdominal ultrasonography as described in Fig 2. CT or MRI will be performed in cases of suspected stone recurrence or cholangitis.
The primary efficacy endpoint of the trial will be the incidence of biliary complications (stone recurrence, biliary stricture, cholangitis). Stone recurrence will include any bile duct stones detected with any imaging modality during follow-up. Biliary stricture will be defined as clinically evident stenosis and subclinical stenosis proven by endoscopic examination or reoperation. The diagnosis of cholangitis will be based on clinical evidence (abdominal discomfort/pain, jaundice or fever associated with hepatolithiasis).
The secondary outcomes will be the surgical, perioperative and long-term follow-up outcomes. The surgical outcomes will include operative duration, intraoperative blood loss, intraoperative blood transfusions, stone distribution and SO function. The perioperative events occurring within 90 days after surgery will be recorded, including biliary leakage, wound infection, pulmonary infection, reoperation, hepatic injury, haemorrhage, bowel function recovery, intra-abdominal fluid collection or abscess, mortality, duration of postoperative hospital stay and total hospitalization expenditure. The indices of long-term follow-up outcomes will be hepatic injury, stone recurrence, biliary stricture, rate of unplanned readmission for HL, incidence of cholangitis and quality of life. Postoperative complications will be graded based on severity according to the Clavien-Dindo definition. Long-term quality of life will be assessed by clinical grading according to Terblanche et al[7]. Grades I and II constituted excellent or good results, grade III fair, and grade IV poor (shown in Additional file 2: Tables S1).
Laboratory examination routinely collect patient blood samples in the ward or clinic. The blood samples store at room temperature, and test in the laboratory of our hospital that day
Randomization and blinding
To achieve comparable groups of known and unknown risk factors, randomization will be performed. Patients meeting the eligibility criteria will be randomly assigned (1:1) to the T-tube drainage arm or Roux-en-Y HJ arm by computer-generated allocation based on the envelope method and the hierarchical block randomization method. The envelopes will be opened after common bile duct exploration.
Blinding of the surgeons and patients is not feasible due to the obviously different characteristics of the two types of biliary drainage. However, the statisticians will be blinded to the treatment allocation during data collection and analysis.
Standardization of perioperative care
The operations will be performed by two senior surgeons (XP Geng and FB Liuo) who are equally skilled in T-tube drainage and Roux-en-Y HJ. Intraoperative flexible choledochoscopy (CHF-P20, external diameter, 4.9 mm; Olympus, Tokyo, Japan) will be routinely performed to explore the biliary ducts, identify the function of the SO and remove residual stones. All patients included in the study should successfully undergo cleaning of all ductal stones, removal of all strictures and elimination of the non-functioning liver segments that harbour bacteria and serve as foci of infection. For the patients with T-tubes, cholangiography will be performed to ensure that all the stones are clean before the T-tubes are removed. If there are residual stones, they could be cleaned through postoperative choledochoscopy. Indications for liver lobe resection will include liver segment or lobe filled with stones that were inaccessible by other approaches for treatment, strictures associated with stones, atrophy of the affected liver segments or lobe, presence of liver abscess, or suspected cholangiocarcinoma. The selection criteria for hepatectomy will require patients to have Child’s A grade liver function and no evidence of portal hypertension. The grading criteria for SO function is as follows: normal: the shape of the SO is circular (Fig 3A) or comma-like (Fig 3B) with normal rhythmic contractions, a flexible choledochoscope cannot enter the duodenum, and the SO can completely close without gaps during closure; SOL (shown in Additional file 3: Video S1-Grading criteria for the SO function laxity): the shape of the SO is oval (Fig 3C) or irregular (Fig 3D), a flexible choledochoscope can enter the duodenum with some resistance, the SO cannot completely close during closure, or reflux of food or methylene blue can be seen in the common bile duct during flexible choledochoscopy; and loss of function: the flexible choledochoscope can directly enter the duodenum, and no contractions are observed after the morphine-neostigmine test.
Data management and quality assurance
All relevant information for each subject should be recorded in the Case Report Form (CRF) and inputted into the Microsoft Access database in a timely, truthful and precise manner by trained research staff. An explanation should be given for all missing data. Complete CRF pages will be checked by the principle investigator and the responsible monitor with respect to completeness and plausibility. The patients will also be informed of the outpatient follow-up interviews by telephone, and all items will be regularly according assessed to the schedule shown in Fig 2. Changes to the database can only be made with joint written consent from the data managers, statisticians and clinical research leaders.
To ensure the safety and validity of the trial, the data will be overseen by an independent Data Safety Monitoring Board, which consists of clinicians and statisticians, during the study period.
Statistical analysis
The two-sided null hypothesis for the primary outcome measure states that both study interventions lead to a similar rate of stone recurrence; the alternative hypothesis is that one intervention will perform better than the other. The continuous variables will be recorded as the mean ± SD (for normally distributed variables) or medians and interquartile ranges (for skewed parameters) and will be statistically analysed with Student’s t-test and the nonparametric Mann–Whitney U test, respectively.
Categorical data will be presented as frequencies and group percentages and compared with Fisher’s exact test. Graded data, including age, quality of life, and Clavien-Dindo classification, will be compared with the Wilcoxon signed-rank test.
The odds ratio for having biliary complications will be determined with a logistic regression model. The homogeneity of the two groups will be described by comparing the demographic data and the baseline values.
All analyses will be performed on an intention-to-treat (ITT) basis. Statistical Package for the Social Sciences (SPSS) 10.0 (SPSS Inc., Chicago, IL, USA) will be used for statistical analysis. Statistical significance will be defined as P < 0.05.