Explanation for the choice of comparators

To evaluate whether 6-mm FCSEMS are as effective as 10-mm FCSEMS for the treatment of patients with unresectable malignant distal bile duct stricture, we will compare outcomes of patients who receive 6-mm diameter FCSEMS vs those who receive 10-mm diameter FCSEMS. Adverse events will also be compared.

Intervention description

Patients will be randomized to receive either the standard treatment (a HANAROSTENT® Biliary Full Cover NEO 10 mm Diameter Full Cover [Boston Scientific, Natick, MA, USA]) or the intervention (HANAROSTENT® Biliary Full Cover Benefit Full-Coverage 6 mm diameter [Boston Scientific, Natick, MA, USA]) (Fig. 1). The stent length will be long enough to cover ≥10 mm upstream from the stenosis and to allow the lower end of the stent to exit ≥5 mm toward the duodenum from the papilla. Patients should undergo the procedure within 14 days of enrollment; if a patient receives the treatment later than 15 days, the reason will be noted.

Criteria for discontinuing or modifying allocated interventions

Discontinuation can occur in the following situations: the patient requests withdrawal or withdraws consent; if it is found that eligibility is not satisfied after registration; inability to continue examinations for illness or other reasons; discovery of a pregnancy; failure to visit the hospital; or any other situation where the physician considers it appropriate to discontinue the study. Patients that meet any of the exclusion criteria will be identified and excluded prior to study entry. Thus, patients who do not meet the eligibility requirements will not be randomized.

Strategies to improve adherence to interventions

Not applicable, because the intervention is applied once during the ERCP procedure.

Relevant concomitant care permitted or prohibited during the trial

Patients can receive antispasmodics, sedatives, and analgesics during the procedure, as required. Patients may also receive the following concomitant and supportive therapies: diclofenac or other pancreatitis prophylaxis, prophylactic antibiotics, prophylactic hemostatic agents such as carbazochrome sodium sulfonate or tranexamic acid, pancreatic duct stenting for the prevention of pancreatitis, and endoscopic biliary drainage with guidewire-assisted insertion via a percutaneous transhepatic bile duct puncture route or with guidewire-assisted insertion via an ultrasound endoscopic puncture route.

Provisions for post-trial care

As medical care provided in this study will be covered by the patients’ insurance coverage, no additional compensation for medical expenses or other care post-trial will be provided.

Outcomes

The primary endpoint is TRBO, defined as the time (days) between the date of registration and the occurrence of recurrent biliary obstruction (RBO). RBO is defined as the coexistence of abnormal liver enzyme values from blood tests and the observation of dilation of the common bile duct and intrahepatic bile duct upstream of the stent on imaging tests (abdominal ultrasound, computer tomography scan, magnetic resonance imaging, or ERCP) [16]. Abnormal liver enzyme values are defined as total bilirubin (>1.5 mg/dL), AST (>100 IU/L), ALT (>100 IU/L), γ-GTP (>150 IU/L), or ALP levels (>600 IU/L). The date of RBO occurrence is defined as the date when the bile duct dilation is observed, not the time of symptom onset.

The secondary safety endpoint is the incidence of non-RBO events, including pancreatitis, non-stent obstructive cholangitis, cholecystitis, bleeding, perforation, and other events (for example, ulceration) [16].

Secondary efficacy endpoints are non-RBO rates (at 3, 6, and 12 months), overall survival, cause of RBO (stent obstruction [tumor ingrowth or mucosal hyperplasia, tumor overgrowth, biliary mud with or without concomitant stones], presence of food residue, biliary bleeding, bile duct kink, or other), and symptomatic stent deviation (liver side or papillary side).

The background information that will be collected are patient age, sex, ECOG-PS, type of primary disease (pancreatic cancer, cholangiocarcinoma, gallbladder cancer, papillary carcinoma, lymph node metastasis, or unknown), histological diagnosis, degree of progression (local/metastatic, TNM classification [17]), resectability classification (per the pancreatic cancer treatment protocol for pancreatic cancer [15]), presence/absence of duodenal invasion, presence/absence of gallbladder enlargement (per the Guidelines for the Treatment of Acute Cholangitis [18]), presence and type of immediate bile duct drainage, presence and severity of acute cholangitis (per the Guidelines for the Treatment of Acute Cholangitis [18]), peripheral blood count, and biochemical test results (white blood cell, platelet count, total bilirubin, AST, ALT, ALP, γ-GTP, C-reactive protein, and amylase).

Participant timeline

The schedule of enrollment, interventions, and assessments is shown in Table 2.

Table 2 Observation scheduleSample size

The target sample size is set at 250 patients (125 patients per group). A Japanese retrospective comparative study of stents for malignant distal bile duct stricture reported an RBO rate at 12 months of 52.4% and 43.5% in the 10-mm and 6-mm groups, respectively [6]. Thus, the median expected TRBO for the 10-mm group and the 6-mm group in this study is set at 9 months.

The non-inferiority margin is a hazard ratio (HR) of 1.33. With a one-sided α of 0.05 and a detection power of 80%, the target number of patients is set to 250, assuming that approximately 5% of patients will be ineligible.

The enrollment period is set to 36 months, and the observation period will be 24 months. Approximately one patient every 2 months in ≥20 participating institutions is expected over 36 months; therefore, over 360 eligible patients are expected to be enrolled. Assuming consent will be obtained from 80% of these patients, a target population of 250 patients is considered feasible.

Recruitment

Investigators at each institution will create a list of all patients presenting with unresectable malignant distal bile duct stricture regardless of their requirement for interventional treatment. Investigators will screen patients on the list for eligibility. The Principal Investigator will create a webpage to introduce the current trial to hospitals so as to increase referral rate.