Immediate Necrosectomy vs. Step-up Approach for Walled-off Necrosis

Study Overview
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Brief Summary
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Walled-off necrosis (WON) is a pancreatic fluid collection, which contains necrotic tissue after four weeks of the onset of acute pancreatitis. Interventions are required to manage patients with infected WON, for which endoscopic ultrasonography (EUS)-guided drainage has become a first-line treatment modality. For patients who are refractory to EUS-guided drainage, the step-up treatment including endoscopic necrosectomy (EN) and/or additional drainage is considered to subside the infection. Recent evidence suggests that EN immediately after EUS-guided drainage may shorten treatment duration without increasing adverse events. In this randomized trial, the investigators will compare treatment duration between EN immediately after EUS-guided drainage versus the step-up approach in patients with symptomatic WON.

Detailed Description
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Pancreatic fluid collection is a late complication of severe acute pancreatitis. According to the revised Atlanta classification, walled-off necrosis (WON) is defined as an encapsulated collection of necrotic tissue that is observed after four weeks of the onset of acute pancreatitis. Infected WON is associated with high morbidity and mortality; therefore, an appropriate treatment, including antibiotics and drainage, is mandatory. With the development of endoscopic equipment, endoscopic ultrasonography (EUS)-guided drainage has become a first-line treatment modality for infected WON. For patients who are refractory to EUS-guided drainage, endoscopic necrosectomy (EN) is a treatment option to facilitate direct removal of infected necrotic tissue within the WON. However, due to potentially lethal adverse events of EN, such as bleeding, perforation, and peritonitis, EN is usually withheld for several days after EUS-guided drainage. This strategy is known as the step-up approach. Recently, with the accumulated evidence supporting the safety of EN, especially with the use of a dedicated lumen-apposing metal stent, it has been reported that EN immediately after EUS-guided drainage can shorten the treatment duration without increasing adverse events. Given these lines of evidence, the investigators hypothesized that immediate EN following EUS-guided drainage of WON might shorten time to clinical success compared to the step-up approach. To examine this hypothesis, the investigators planned to conduct a multicenter randomized controlled trial comparing treatment duration between EN immediately after EUS-guided drainage versus the step-up approach in patients with symptomatic WON.

Official Title
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Immediate Necrosectomy vs. Step-up Approach After EUS-guided Drainage of Walled-off Necrosis: a Multicenter Randomized Controlled Trial (WONDER-01)

Conditions
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Pancreatic Pseudocyst, Pancreatic Fluid Collection, Walled-off Necrosis, Pancreatitis, Acute Necrotizing

Intervention / Treatment
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* Procedure: Immediate necrosectomy
* Procedure: Step-up approach


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with WON defined according to the revised Atlanta classification The longest diameter of WON is 4 cm or larger Patients with at least one out of the following conditions; signs of infection, gastrointestinal symptoms, abdominal symptoms, obstructive jaundice Patients who need drainage for WON Age of 18 years or older Patients or their representatives provide informed consent Patients who visit or are hospitalized at the participating institutions Exclusion Criteria: WON inaccessible by EUS-guided approach AXIOS stent has already been placed into the WON prior to the enrollment Severe coagulopathy; Platelet count < 50,000/mm3 or prothrombin time international normalized ratio (PT-INR) >1.5 Patients on antithrombotic agents which cannot be managed according to the guideline for gastroenterological endoscopy in patients undergoing antithrombotic treatment (Dig Endosc. 2014 Jan;26(1):1-14.) Patients who cannot tolerate endoscopic procedures Pregnant women Patients considered inappropriate for inclusion by investigators

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Immediate necrosectomy<br>Endoscopic necrosectomy will be conducted in the same session of EUS-guided drainage (or at least within 72 hours of randomization) and be repeated until clinical success. | Procedure: Immediate necrosectomy<br>* Endoscopic ultrasonography (EUS)-guided drainage will be conducted within 72 hours from randomization. A convex-type echoendoscope is advanced to the stomach or duodenum, and the walled-off necrosis (WON) is visualized and punctured under EUS guidance. A lumen-apposing metal stent (LAMS), such as Hot AXIOS system (Boston Scientific Japan, Tokyo, Japan), is recommended for the initial EUS-guided drainage. For the immediate necrosectomy group, endoscopic necrosectomy (EN) will be performed in the same session of EUS-guided drainage using a gastroscope. The endoscope is inserted into the WON cavity through the LAMS, and necrotic tissue is removed using biopsy forceps, snare, or basket catheter. The EN procedures will be repeated until clinical improvement.<br>|
| Active Comparator: Step-up approach<br>Step-up treatment will be conducted if a patient's condition does not improve after EUS-guided drainage. The step-up approach includes increasing the number of stents, adding another EUS-guided drainage, and performing percutaneous drainage after 72-96 hours of the initial drainage. Endoscopic necrosectomy is considered when clinical improvement is not observed even after two times of step-up treatment. | Procedure: Step-up approach<br>* Endoscopic ultrasonography (EUS)-guided drainage will be conducted within 72 hours from randomization. A convex-type echoendoscope is advanced to the stomach or duodenum, and the walled-off necrosis (WON) is visualized and punctured under EUS guidance. A lumen-apposing metal stent (LAMS), such as Hot AXIOS system (Boston Scientific Japan, Tokyo, Japan), is recommended for the initial EUS-guided drainage. For the step-up approach group, an additional interventional procedure will be withheld for 72-96 hours after initial EUS-guided drainage. In cases without clinical improvement after 72-96 hours, additional drainage will be permitted, which includes increasing the number of stents, additional EUS-guided drainage, and performing percutaneous drainage (step-up treatment). Insufficient improvement even after two times of step-up treatment allows subsequent endoscopic necrosectomy (EN).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to clinical success from randomization | Clinical success is defined as 1) a decrease in the WON size to 3 cm or less and 2) an improvement of more than two out of the three following inflammatory markers; body temperature, white blood cell count, and C-reactive protein. | Six months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse events | All procedure-related adverse events including bleeding, perforation, peritonitis, etc. | Five years | 
| Mortality | Mortality from any cause | Five years | 
| Technical success rate of initial EUS-PCD (Endoscopic ultrasonography-guided pseudocyst drainage) | Successful placement of EUS-guided drainage including a lumen-apposing metal stent and plastic stents | One day | 
| Incidence of biliary and gastrointestinal stricture | Inflammatory-induced obstruction of bile duct and gastrointestinal tract | Five years | 
| Number and time of interventions | Total number of interventions and total procedure time | Six months | 
| Indwelling time of endoscopic and percutaneous drainage | Indwelling period of stents and drainage tube | Six months | 
| Success rate and operation time of surgical procedures | Success rate of surgeries associated with WON and total operation time | Six months | 
| Hospital stay and ICU stay | Total hospitalization days and total ICU stay | Six months | 
| Duration of antibiotics administration | Total administration days of antibiotics | Six months | 
| Cost of interventions and hospital stay | Total cost of interventions and total cost of hospitalization | Six months | 
| Recurrence of WON | Incidence of recurrence of WON | Five years | 
| Time to recurrence of WON | Time from clinical success to recurrence of WON | Five years | 
| Treatment duration of recurrent WON | Total treatment period for recurrent WON | Five years | 
| New onset of pseudocyst | Incidence of new-onset pancreatic pseudocyst | Five years | 
| Treatment duration of new onset pseudocyst | Total treatment period for new-onset pancreatic pseudocyst | Five years | 
| Incidence of new onset diabetes, clinical symptoms of pancreatic exocrine insufficiency, and pancreatic cancer | New-onset diabetes mellitus, pancreatic cancer, and clinical symptoms associated with pancreatic exocrine insufficiency, such as steatorrhea , constipation, diarrhea, maldigestion, flatulence, and tenesmus | Five years | 
| The presence and timing of medications for pancreatic exocrine insufficiency | The start of medications for pancreatic exocrine insufficiency and the date | Five years | 
| The presence and timing of sarcopenia | The presence of sarcopenia and the date of diagnosis | Five years | 
| Morphological change of pancreas | Change in the morphology and the volume of pancreas | Five years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Drainage, Endoscopic necrosectomy, Step-up approach, Endosonography, Stents