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 trial

Abstract

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 ).