T-tube drainage versus choledochojejunostomy in hepatolithiasis patients with sphincter of Oddi laxity: study protocol for a randomized controlled trial

This prospective, single-centre, randomized and interventional clinical trial is being conducted at the First Affiliated Hospital of Anhui Medical University, which began in February 2020 and is expected to end in 2026. Patients with diagnosed HL who meet the 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. The full protocol and the datasets analysed during the current study are available on request from the corresponding author.

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.

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.

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.

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. Laboratory tests mainly include routine blood, liver and kidney function, electrolytes, procalcitonin, C-reaction protein, carcinoembryonic antigen, carbohydrate antigen 199 (CA199) and alpha-fetoprotein (AFP).

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 (shown in Additional file 2: Table S1) [8]. Long-term quality of life will be assessed by clinical grading according to Terblanche et al. [9]. Grades I and II constituted excellent or good results, grade III fair and grade IV poor (shown in Additional file 2: Table S2).

Laboratory examination routinely collects 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. The specific time laboratory examination and abdominal ultrasonography are shown in Fig. 2, and the perioperative laboratory examination time is the first day, the third day, and the seventh day after the operation.

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.

The operations will be performed by two senior surgeons (XP Geng and FB Liu) 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 a 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 are 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.

There is no anticipated harm and compensation for trial participation

The principal investigators and data analysts will have access to the final cleaned dataset. All paper forms will be scanned and stored at the password cabinet in the First Affiliated Hospital of Anhui Medical University office of clinical trials. All electronic data will be coded and stored separately without the personal data in on a password-protected computer. The files of the participants will be stored for a minimum of 10 years after the end of the study. 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 principal 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 accordingly 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. The results will be submitted for publication in peer-reviewed journals.

To ensure the safety and validity of the trial, the data will be overseen by an independent Data Safety Monitoring Board (DSMB) for efficacy outcomes and safety, which consists of surgical experts, statistics experts and ethics experts. It is independent from the sponsor and competing interests. During the trial, the DSMB is charged with providing advice recommendations that include (a) continuation of the study, (b) continuation with modification and (c) termination of the study.

All data will be treated as confidential. The data will be acquired only by researchers, research institutions and ethics committees who have signed a confidential disclosure agreement. The study will not release the individual identities of the participants without consent, except in special circumstances as required by law.

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 non-parametric 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.