Survival impact of repeated endobiliary radiofrequency ablation in patients undergoing durvalumab plus gemcitabine and cisplatin for extrahepatic cholangiocarcinoma (BRAVE trial): study protocol for an international multicenter randomized controlled

Extrahepatic cholangiocarcinoma (eCCA) often presents with unresectable disease and obstructive jaundice. Systemic therapy with gemcitabine–cisplatin plus durvalumab (GCD) is an international standard; however, the median overall survival (OS) remains about 1 year. Endobiliary radiofrequency ablation (EB-RFA) performed during biliary stenting may improve local tumor control and potentially prolong survival. Meta-analyses and our multicenter preliminary data suggest that repeated EB-RFA, particularly when combined with systemic therapy, is associated with longer OS in unresectable eCCA; however, high-quality randomized evidence using a standardized protocol is lacking. We aimed to compare OS between patients receiving EB-RFA plus standardized endoscopic plastic stenting plus GCD and those receiving standardized plastic stenting plus GCD alone. The BRAVE trial is an interventional, international, multicenter, parallel-group, open-label randomized controlled trial. Eligible adults with unresectable eCCA requiring biliary drainage and planned first-line GCD are randomized 1:1 to (1) EB-RFA plus standardized plastic biliary stenting plus GCD (RFA arm) or (2) stenting alone plus GCD (Non-RFA arm). All patients undergo index endoscopy with stent placement; the RFA arm additionally receives EB-RFA. A protocol-defined second endoscopic session at approximately 3 months (window 2–4 months) includes repeat EB-RFA and stent exchange in the RFA arm and elective stent exchange in the Non-RFA arm. Third or subsequent EB-RFA sessions or elective exchanges at ≥ 2-month intervals are allowed according to the predefined criteria. The primary endpoint is OS. Key secondary endpoints include time to recurrent biliary obstruction (TRBO), progression-free survival, non-RBO survival, procedure-related adverse events, technical and clinical success, and re-intervention metrics. A total of 120 patients (60 per arm) will be enrolled. This pragmatic investigator-initiated trial will determine whether adding repeated EB-RFA to standard GCD and endoscopic biliary stenting improves survival in unresectable eCCA. By standardizing biliary drainage procedures and systemic therapy across high-volume centers in Japan and Korea, BRAVE aims to generate generalizable evidence to guide the use of EB-RFA as part of first-line management and optimize long-term outcomes and safety. ClinicalTrials.gov NCT07235007. Registered on November 19, 2025. ( https://clinicaltrials.gov/study/NCT07235007?term=NCT07235007&rank=1 ).