This international, multicenter, open-label randomized controlled trial evaluates whether repeated endobiliary radiofrequency ablation (EB-RFA) improves overall survival in patients with unresectable extrahepatic cholangiocarcinoma undergoing first-line systemic therapy with durvalumab plus gemcitabine and cisplatin (GCD). Eligible patients will be randomized 1:1 to EB-RFA with plastic stent placement or standard plastic stenting alone. A scheduled second endoscopic session will be performed at 3 months in both groups (repeat EB-RFA only in the EB-RFA arm). The primary endpoint is overall survival. Secondary endpoints include time to recurrent biliary obstruction, progression-free survival, adverse events, and technical/clinical success.
Extrahepatic cholangiocarcinoma (eCCA) frequently presents as unresectable disease with obstructive jaundice. Although gemcitabine, cisplatin plus durvalumab (GCD) is the global standard first-line regimen, median overall survival remains approximately one year. Endobiliary radiofrequency ablation (EB-RFA) is biologically plausible to enhance local tumor control by inducing coagulative necrosis at the biliary stricture. Retrospective studies, including a multicenter dataset from participating institutions, suggest a survival benefit of repeated EB-RFA, especially when combined with systemic therapy. However, prospective randomized evidence is lacking. This trial (BRAVE) randomizes eligible patients to EB-RFA plus standardized endoscopic stenting or endoscopic stenting alone, followed by GCD. A planned second endoscopic session is performed at Month 3 (window 2-4 months). Additional EB-RFA sessions (≥2-month intervals) are permitted in the EB-RFA arm if imaging shows potentially ablatable lesions and clinical benefit is expected. The study aims to determine whether repeated EB-RFA prolongs survival and improves biliary patency when integrated with modern systemic therapy.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
120
Endobiliary RFA performed using the ELRA® catheter (STARmed) with VIVA combo® generator. Recommended settings: 7-10 W, temperature control 80 °C, 120 seconds per application. Applied along the full stricture length. Repeat procedure at Month 3 (window 2-4 months). Additional sessions every ≥2 months permitted if imaging suggests ablatable residual lesion.
Placement of 7Fr or 8.5Fr plastic biliary stent from hepatic side of the stenosis to the duodenum. Bilateral preferred for hilar strictures; unilateral acceptable based on drainage.
Aichi Medical University
Aichi, Japan
RECRUITINGNagoya City University Hospital
Aichi, Japan
RECRUITINGNagoya City University Midori Municipal Hospital
Aichi, Japan
RECRUITINGGifu University Hospital
Gifu, Japan
RECRUITINGPusan National University Hospital
Busan, South Korea
RECRUITINGGangnam Severance Hospital, Yonsei University College of Medicine
Seoul, South Korea
RECRUITINGKangbuk Samsung Hospital, Sungkyunkwan University School of Medicine
Seoul, South Korea
RECRUITINGSeverance Hospital, Yonsei University College of Medicine
Seoul, South Korea
RECRUITINGOverall Survival (OS)
Overall survival is defined as the time from randomization to death from any cause. Participants still alive at the last confirmed contact will be censored at that date.
Time frame: From randomization until death from any cause (up to 36 months after last enrollment)
Time to Recurrent Biliary Obstruction (TRBO)
TRBO is defined as the time from stent placement to recurrent biliary obstruction (RBO).
Time frame: From stent placement to RBO or censoring (up to 36 months)
Progression-Free Survival (PFS)
Progression-free survival is defined per RECIST v1.1 based on imaging performed every 2-4 months.
Time frame: From randomization to radiologic progression or death (up to 36 months)
Non-RBO Survival
Time alive without recurrent biliary obstruction.
Time frame: Up to 36 months
Survival Free From Late Biliary-Procedure-Related Adverse Events
Late adverse events are defined as events occurring ≥15 days after the procedure (Tokyo Criteria 2024).
Time frame: Up to 36 months
Incidence and Etiology of Recurrent Biliary Obstruction (RBO)
Number and types of RBO events and their causes (sludge, tumor ingrowth/overgrowth, migration, dysfunction).
Time frame: Up to 36 months
Early Adverse Events (≤14 days)
Procedure-related adverse events within 14 days, graded by Tokyo Criteria 2024.
Time frame: 14 days
Late Adverse Events (≥15 days)
Procedure-related adverse events occurring ≥15 days post-procedure.
Time frame: Up to 36 months
Technical Success
Successful completion of the intended procedure: EB-RFA + plastic stent placement in the experimental arm Plastic stent placement in the comparator arm
Time frame: At index procedure
Clinical Success
Defined as: Hyperbilirubinemia: total bilirubin reduction ≥50% or ≤1.5 mg/dL within 14 days Others: normalization of ≥2 abnormal cholestatic/hepatocellular enzymes If baseline values are normal after prior drainage, absence of re-worsening beyond abnormal thresholds.
Time frame: Within 14 days after stent placement
Number of RBO Events
Count of recurrent biliary obstruction events per participant.
Time frame: Up to 36 months
Number of Endoscopic Reinterventions
Total number of endoscopic procedures including therapeutic interventions required during follow-up.
Time frame: Up to 36 months
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