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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Endobiliary Radiofrequency Ablation + Plastic Stent + Durvalumab/Gemcitabine/Cisplatin | Experimental | Participants undergo endobiliary radiofrequency ablation (EB-RFA) followed by placement of a plastic biliary stent during the index endoscopy. A scheduled second endoscopy at Month 3 (window 2-4 months) includes repeat EB-RFA and stent exchange. Additional EB-RFA sessions (≥2-month intervals) may be performed if imaging suggests a potentially ablatable residual biliary lesion. All participants receive systemic therapy with durvalumab, gemcitabine, and cisplatin according to institutional standards. |
|
| Plastic Stenting + Durvalumab/Gemcitabine/Cisplatin | Active Comparator | Participants receive standard endoscopic placement of a plastic biliary stent during the index endoscopy without EB-RFA. A scheduled elective stent exchange is performed at Month 3 (window 2-4 months). Additional elective stent exchanges every ≥2 months may be performed at the investigator's discretion. All participants receive systemic therapy with durvalumab, gemcitabine, and cisplatin according to institutional standards. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Endobiliary Radiofrequency Ablation (EB-RFA) | Device | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| Overall 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. | From randomization until death from any cause (up to 36 months after last enrollment) |
| Measure | Description | Time Frame |
|---|---|---|
| Time to Recurrent Biliary Obstruction (TRBO) | TRBO is defined as the time from stent placement to recurrent biliary obstruction (RBO). | From stent placement to RBO or censoring (up to 36 months) |
| Progression-Free Survival (PFS) |
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Inclusion Criteria:
Histologically or cytologically confirmed extrahepatic cholangiocarcinoma (eCCA).
Unresectable disease (unresectable due to tumor/patient factors, or patient refusal of surgery).
Biliary obstruction requiring drainage, demonstrated by abnormal cholestatic liver tests, elevated bilirubin, radiologic evidence, or existing biliary drainage.
Planned initiation of first-line systemic therapy with durvalumab + gemcitabine + cisplatin (GCD).
Age ≥18 years.
Able to provide written informed consent.
Exclusion Criteria:
Prior radiotherapy or systemic therapy for the current eCCA.
Presence of a self-expanding metal stent that cannot be endoscopically removed.
Surgically altered anatomy except for Billroth-I; prior biliary reconstruction.
History of chronic cholangitis (e.g., primary sclerosing cholangitis, IgG4-related cholangitis).
Expected survival <3 months.
Inability to insert an oral endoscope or reach the papilla.
Contraindication to endobiliary RFA.
Pregnancy or possible pregnancy.
Any condition judged unsuitable by the investigator.
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Tadahisa Inoue | Contact | +81561623311 | tinoue-tag@umin.ac.jp |
| Name | Affiliation | Role |
|---|---|---|
| Tadahisa Inoue, Associate Professor | Department of Gastroenterology, Aichi Medical University | Principal Investigator |
| Jae Hee Cho, Professor | Department of Internal Medicine, Institute of Gastroenterology, Gangnam Severance Hospital, Yonsei University College of Medicine |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Aichi Medical University | Recruiting | Aichi | Japan | |||
| Nagoya City University Hospital |
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| Plastic Biliary Stent | Device | 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. |
|
Progression-free survival is defined per RECIST v1.1 based on imaging performed every 2-4 months.
| From randomization to radiologic progression or death (up to 36 months) |
| Non-RBO Survival | Time alive without recurrent biliary obstruction. | 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). | 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). | Up to 36 months |
| Early Adverse Events (≤14 days) | Procedure-related adverse events within 14 days, graded by Tokyo Criteria 2024. | 14 days |
| Late Adverse Events (≥15 days) | Procedure-related adverse events occurring ≥15 days post-procedure. | 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 | 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. | Within 14 days after stent placement |
| Number of RBO Events | Count of recurrent biliary obstruction events per participant. | Up to 36 months |
| Number of Endoscopic Reinterventions | Total number of endoscopic procedures including therapeutic interventions required during follow-up. | Up to 36 months |
| Principal Investigator |
| Recruiting |
| Aichi |
| Japan |
| Nagoya City University Midori Municipal Hospital | Recruiting | Aichi | Japan |
| Gifu University Hospital | Recruiting | Gifu | Japan |
| Pusan National University Hospital | Recruiting | Busan | South Korea |
| Gangnam Severance Hospital, Yonsei University College of Medicine | Recruiting | Seoul | South Korea |
| Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine | Recruiting | Seoul | South Korea |
| Severance Hospital, Yonsei University College of Medicine | Recruiting | Seoul | South Korea |
| ID | Term |
|---|---|
| D018281 | Cholangiocarcinoma |
| D001661 | Biliary Tract Neoplasms |
| ID | Term |
|---|---|
| D000230 | Adenocarcinoma |
| D002277 | Carcinoma |
| D009375 | Neoplasms, Glandular and Epithelial |
| D009370 | Neoplasms by Histologic Type |
| D009369 | Neoplasms |
| D004067 | Digestive System Neoplasms |
| D009371 | Neoplasms by Site |
| D001660 | Biliary Tract Diseases |
| D004066 | Digestive System Diseases |
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