Timing of Necrosectomy After Endoscopic Drainage of Walled-off Pancreatic Necrosis (WON)

Study Overview
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Brief Summary
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Walled-off pancreatic necrosis (WON) is associated with a mortality of 20-30%. The current evidence supports a minimally invasive drainage approach to infected WON. The current suggested approach in international guidelines is the endoscopic step-up approach. However, recent evidence from large national cohorts support the use of direct endoscopic necrosectomy (DEN) at the time of stent placement, resulting in earlier resolution of WON and less number of necrosectomies. This study aims to investigate the clinical outcomes of the DEN versus the step-up approach for necrosectomy after endoscopic drainage of WON.

Detailed Description
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INTRODUCTION Acute pancreatitis is one of the most common gastrointestinal diseases requiring emergency admissions to the hospital. 10-20% of these patients develop pancreatic necrosis and subsequent walled-off pancreatic necrosis (WON) and is associated with a mortality of 20-30%. Grade 1A evidence exists to support an initial minimally invasive drainage approach to infected WON. However, the optimal approach and timing of necrosectomy remains unaddressed. The current suggested approach in international guidelines is the endoscopic step-up approach. However, recent evidence from large national cohorts support the use of direct endoscopic necrosectomy (DEN) at the time of stent placement, resulting in earlier resolution of WON and less number of necrosectomies. OBJECTIVE This study aims to investigate the clinical outcomes of the DEN versus the step-up approach for necrosectomy after endoscopic drainage of WON. HYPOTHESIS The hypothesis is that DEN at the time of LAMS placement improves clinical outcomes after endoscopic drainage of WON as compared to the endoscopic step-up approach. DESIGN AND SUBJECTS This is a multicentre international randomized controlled trial. Patients with suspected or confirmed infected or symptomatic WON on computed tomography (CT) and who are deemed feasible for endoscopic drainage will be included in the study. Endoscopic drainage with lumen-apposing metal stents (LAMS) will be performed. Patients will be randomised to either the endoscopic step-up approach or direct endoscopic necrosectomy (DEN) approach. The primary endpoint is a composite of major complications or death within 6 months after randomisation. Secondary endpoints include time to resolution of WON, pancreatic functions, biliary strictures, need for necrosectomy, total number of interventions, length of hospital and ICU stay, recurrence of WON and unplanned readmissions related to WON. A reduction in cumulative primary endpoint with the DEN approach by 22.4% (32.2% to 9.8%) in comparison to endoscopic step-up approach was assumed. With a 2-sided significance level of 5% and power of 80%, taking into account a 5% drop-out rate, a total of 108 patients was required to demonstrate this effect. Study collaboration has been established with four other international centres. A estimation of 3 years is required to complete study recruitment.

Official Title
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Direct Endoscopic Necrosectomy Versus Endoscopic Step-up Approach After Endoscopic Drainage of Walled-off Pancreatic Necrosis (WON)

Conditions
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Pancreatic Necrosis

Intervention / Treatment
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* Procedure: Endoscopic necrosectomy with step up approach
* Procedure: Endoscopic necrosectomy with direct approach


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult (≥18 years of age) patients Diagnosis of walled-off pancreatic necrosis (WON) based on imaging criteria based on the revised Atlanta classification5 Documented history of acute pancreatitis Suspected or confirmed infected WON and/or symptomatic WON causing (i) persistent pancreatic-type pain, and/or ii) gastric outlet or biliary obstruction, and/or (iii) ongoing systemic illness, anorexia, and weight loss, and/or (iv) rapidly enlarging WONs, and/or (v) infected WON* WON identified at contrast-enhanced computed tomography (CECT) and deemed amenable for EUS-guided drainage WON with a solid component >30% and/ or percentage of necrosis >= 30% Exclusion Criteria: Previous invasive interventions for necrotising pancreatitis An acute flare up of chronic pancreatitis Recurrent acute pancreatitis Indicated for emergency laparotomy (i.e. abdominal compartment syndrome, perforation of a visceral organ, bleeding and bowel ischaemia) Contraindications to endoscopic drainage: previous total gastrectomy, gastric bypass surgery, prior surgery for pancreas-related diseases WON not adherent to the GI wall or not accessible for endoscopic drainage Coagulopathy (INR >1.5), and/or thrombocytopenia (platelets <50,000/mm3) Pregnancy

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
Interventional Model Description: randomised controlled 2 arm trial
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Endoscopic step-up approach<br>After endoscopic drainage of WON, patients will be reassessed 72 hours after the procedure. If there is no clinical improvement 72 hours after drain placement, a CECT is performed to check the adequacy of the drainage. Irrigation of the WON via a nasocystic drain or endoscopic irrigation (step 1) is performed in case of inadequate drainage. If a nasocystic drain is inserted, 500ml of normal saline, twice a day will be used to irrigate the WON. If endoscopic irrigation is performed, only irrigation with normal saline without necrosectomy is allowed. Patients are again evaluated 72 hours after step 1. In case of improvement, treatment is conservative; otherwise step 2 will be initiated, which is endoscopic necrosectomy. Further endoscopic necrosectomy will be performed until there is clinical improvement. | Procedure: Endoscopic necrosectomy with step up approach<br>* Endoscopic necrosectomy will be performed with a forward-viewing gastroscope into the WON cavity. Debridement of necrotic tissue will be performed with irrigation and/or mechanical removal with endoscopic instruments. For this arm, step up approach will be adopted.<br>|
| Active Comparator: Direct endoscopic necrosectomy approach<br>Patients in the DEN group will undergo an immediate endoscopic necrosectomy after LAMS placement and balloon dilatation. A 10Fr 5cm double pigtail plastic stent will be inserted within the LAMS after necrosectomy. Patients will be assessed in 72 hours after the procedure. If there is no clinical improvement, a CECT is performed to check the adequacy of the drainage. DEN will be repeated in case of inadequate drainage. Patients will be reassessed every 72 hours and DEN repeated until there is clinical improvement. Subsequently, necrosectomy is performed weekly until a reassessment CECT at 3 weeks. | Procedure: Endoscopic necrosectomy with direct approach<br>* Endoscopic necrosectomy will be performed with a forward-viewing gastroscope into the WON cavity. Debridement of necrotic tissue will be performed with irrigation and/or mechanical removal with endoscopic instruments. For this arm, the direct approach will be adopted.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| A composite of major complications or death within 6 months after randomisation | Major complications include new onset multi-organ failure, multiple organ failure, persistent organ failure, bleeding requiring intervention, perforation of visceral organ requiring intervention, gas embolism | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The individual components of the primary endpoint | The individual components include new onset multi-organ failure, multiple organ failure, persistent organ failure, bleeding requiring intervention, perforation of visceral organ requiring intervention, gas embolism | 6 months | 
| Time to resolution of WOPN | LAMS insertion to LAMS removal | 6 months | 
| Exocrine pancreatic insufficiency | Exocrine pancreatic insufficiency defined as Oral pancreatic-enzyme supplementation required to treat clinical symptoms of steatorrhea 6 months after randomization; this requirement was not present before onset of acute pancreatitis | 6 months | 
| Biliary strictures | Presence of biliary strictures on cholangiogram/ CT/ MRI | 6 months | 
| Total no. of interventions | The total number of interventions including necrosectomy or other surgical/ radiological interventions | 6 months | 
| Length of hospital | The total length of hospital stay | 6 months | 
| Recurrence of WOPN | The recurrence of WOPN detected on imaging (CT/ USG/ MRI/ EUS) | 6 months | 
| Unplanned readmissions related to WOPN | The no. of unplanned readmissions related to WOPN | 6 months | 
| Endocrine pancreatic insufficiency | Insulin or oral antidiabetic drugs required 6 months after randomization; this requirement was not present before onset of acute pancreatitis | 6 months | 
| The no. of necrosectomies | The number of necrosectomies required | 6 months | 
| Total ICU stay | No. of days for ICU stay | 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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walled off pancreatic necrosis, endoscopic drainage, direct endoscopic necrosectomy, endoscopic step up approach