Endoscopic Step-up Approach vs Aggressive Debridement of Large Pancreatic Walled-off Necrosis

Study Overview
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Brief Summary
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The goal of this clinical trial is to compare a conventional endoscopic step-up approach with an accelerated treatment algorithm using direct endoscopic necrosectomy in patients with acute necrotizing pancreatitis and walled of necroses exceeding a diameter of 15 cm. It will be investigated whether an aggressive treatment algorithm instead of a classical step-up approach will shorten the length of stay in the hospital and also reduce the mortality in patients treated for large walled off necroses.

Detailed Description
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INTRODUCTION While most patients with acute pancreatitis suffer a mild and uncomplicated course of disease, up to 20% develop a more severe course with development of pancreatic and/or peripancreatic necroses. With time, these necroses become encapsulated with a well-defined inflammatory wall, so called walled-off necroses (WONs). Up to 30% of WONs become infected, which prolongs the length of hospital stay (LOS), increases morbidity and mortality significantly, and generally requires some kind of invasive intervention. During the last two decades, a minimally invasive step-up approach consisting of percutaneous and/or endoscopic, transluminal drainage followed, if necessary, by percutaneous, video-assisted retroperitoneal debridement (VARD) or endoscopic necrosectomy (EN), have replaced open surgery as the standard treatment resulting in improved patient outcomes. Copenhagen University Hospital Hvidovre have for nearly two decades treated more than 400 WON patients with an actual annual number of 40-50 patients. This center serves as a tertiary referral center, the only in East-Denmark, with a background population of 2.6 million. In line with international guidelines, endoscopic step-up approach has been practiced as standard care for infected WONs. This approach follows international recommendations of delaying index procedures until at least four weeks after debut of pancreatitis (to ensure encapsulation) and then only applying the least invasive intervention needed. The decision to step-up is triggered by absence of biochemical and/or clinical improvement or clinical deterioration. Recently, lumen-apposing metal stents (LAMS) have been introduced for the transluminal treatment of pancreatic fluid collections. The stent is fully-covered and shaped with two bilateral anchor flanges with a saddle in between. A dedicated through-the-scope delivery system, where the tip serves as an electrocautery device enables extra-luminal access and deployment of the stent. Conventionally, transmural drainage with installation of two double pigtail plastic stents (DPS) has been the method of choice. Although drainage with plastic stents seems non-inferior to LAMS, the DPS method implies a need for repetitive dilatation of the drainage tract because of spontaneous closure of the tract and thereby probably a higher number of endoscopic procedures. By keeping the transmural tract patent, LAMS may improve drainage and facilitate endoscopic necrosectomy, which may even be performed during the index procedure (direct endoscopic necrosectomy (DEN)). The LOS is considerable for patients treated for infected WON, especially those with complex and large fluid collections. Copenhagen University Hvidovre Hospital has one of the largest prospective single center databases registering all patients treated with WON. The median LOS for patients with large WONs exceeding 15 cm in diameter treated with the step-up approach, is 58 days. During the hospital stay, patients undergo weekly endoscopic or surgical procedures, and many patients additionally need treatment in the intensive care unit. Together, the treatment of patients with WON carries a substantial economic burden for the health care system. Furthermore, even in a tertiary care setting, the mortality is still up to 15% in complex cases with large fluid collections. The mortality in patient needing treatment in intensive care unit (ICU) is much higher, nearly 40%. Unprotocolized cases with urgent needs for an augmented course of treatment (e.g. cases with malignancy demanding surgery or oncological therapy) have been successfully treated with an accelerated treatment algorithm. Likewise, an international multicenter study found that an aggressive treatment was safe with promising results. The invastegators hypothesize, that a general alteration in the treatment algorithm instigating an aggressive treatment algorithm instead of a classical step-up approach might not only shorten LOS, but also reduce the mortality in patients treated for large WONs. AIM To compare a conventional endoscopic step-up approach with an accelerated treatment algorithm using DEN. STUDY DESIGN A single-center open-label, randomized, controlled 2 armed superiority study. Patients with acute, necrotizing pancreatitis and WON exceeding a diameter of 15 cm will be randomized to either the endoscopic step-up approach or direct endoscopic necrosectomy. The primary endpoint is a composite of death, major complications occurring within 6 months following randomization, or length of stay exceeding 58 days. From results previously published by Copenhagen University Hospital Hvidovre, it is shown that the risk of death for eligible patients is estimated to 5%, the risk of major complications is 5%, while the risk of exceeding a LOS of above 58 days is 50%. The investigators assume that the risk of death and major complications will remain at 5% and 5%, respectively, while the rate of patients exceeding a LOS of 58 days will be reduced by 75% to 12.5%. Based on these estimates, 48 patients are required to have an 80% change (5% significant level) of detecting an increase in success rate in the primary outcome measure from 40% in the control group to 77.5% in the interventional group. The investigators will after inclusion of 25 patients conduct an interim analysis to assess whether one of the study groups are superior to an extent that will ethically call for an early termination of the study. Likewise, safety will continually be assessed in conjunction with the ethics committee.

Official Title
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Endoscopic Step-up Approach vs Aggressive Debridement of Large Pancreatic Walled-off Necrosis - A Single-center, Open-label, Randomized, Superiority Trial (ACCELERATE)

Conditions
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Pancreatic Necrosis, Pancreatitis, Acute Necrotizing

Intervention / Treatment
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* Procedure: Direct Endoscopic Necrosectomy
* Procedure: Step-up Approach


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: All criteria must be fulfilled Patients with acute, necrotizing pancreatitis and WON exceeding a diameter of 15 cm. Imaging test(s) must be done within 1 week before the index drainage procedure. Debut of pancreatitis must be within 3 months before the index drainage procedure. One or more indication(s) for endoscopic, transmural drainage must be established: Confirmed or suspected infection. Severe intraabdominal hypertension or abdominal compartment syndrome. Persisting abdominal pain, early satiety, or general discomfort. Obstruction of the GI or biliary tract. Leakage of pancreatic juice, e.g. pancreatic ascites or pleural effusion. Preoperatively, the WON must be considered eligible for endoscopic, transgastric drainage. Distance between the gastric wall and WON must not exceed one cm and there must be no major interposed vessels. Exclusion Criteria: Patients under the age of 18. Pregnancy. Known or suspected malignant disease. Pancreatitis secondary to trauma or surgical intervention. Chronic pancreatitis. Previous surgical or endoscopic drainage or necrosectomy.

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: Patients shall be randomly assigned in a 1:1 ratio to either the step-up or the accelerated approach. Block randomization shall be performed with a concealed, fixed block size using a web-based randomization program. Random block sizes of 4 or 6 shall be used for preparation of the randomization sequence. The computer-generated block randomization assignments shall be placed in opaque sealed envelopes. Randomization shall be performed by a study coordinator when patients meet the inclusion criteria.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Step-up Approach<br>Standard procedure where necrosectomy is only performed in the absence of clinical improvement 72 hours after placements of lumen-apposing metal stent. | Procedure: Step-up Approach<br>* Endosonography-guided, transmural drainage of the WONs shall be performed using a lumen-apposing metal stent (LAMS). After placement of the LAMS, a 7-Fr/4cm double pigtail stent and a 7-Fr nasocystic catheter shall be placed through the LAMS. The effect of the index drainage procedure shall be evaluated every 72 hours and next treatment step will depend on whether the patient's condition improves. If clinical improvement is observed, the drainage regime continues, and no further therapeutic action shall be taken. In absence of clinical improvement after 72 hours and if supplementary drainage is impossible, the patient shall proceed to endoscopic necrosectomy (EN) or video-assisted retroperitoneal debridement (VARD). Absence of clinical improvement due to causes not related to the WON treatment, e.g., urinary tract or pulmonary infection or iv catheter sepsis, shall not influence the treatment algorithm of the WON.<br>|
| Experimental: Direct Endoscopic Necrosectomy<br>Necrosectomy will be performed in the same procedure as the placement of the lumen-apposing metal stent. | Procedure: Direct Endoscopic Necrosectomy<br>* Endosonography-guided, transmural drainage of the WONs shall be performed using a lumen-apposing metal stent (LAMS).After placement of the LAMS, EN shall be performed during the same procedure (Direct EN). After DEN, a 7-Fr/4cm double pigtail and a 7-Fr nasocystic irrigation catheter shall be placed through the LAMS. Endoscopic necrosectomy and VARD shall be repeated as often as clinically indicated and logistically possible with a minimum of one day between procedures<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| A composite of major complications, death, or length of stay exceeding 58 days | If patients either die, encounter a major complication, or stay in hospital for longer than 58 days, it will be registered as an event. Major complications are defined as new onset (i.e. not present 24 hours before randomization) organ failure (cardiovascular, pulmonary or renal), bleeding requiring intervention, perforation of a visceral organ requiring intervention, enterocutaneous fistula requiring intervention and incisional hernia (including burst abdomen). | From date of randomization until discharge, assessed up to 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Length of hospital stay from the index drainage procedure |  | From date of randomization until discharge, assessed up to 12 months | 
| Total number of debridement procedures | Number of endoscopic necrosectomies and video-assisted retroperitoneal debridements needed throughout the disease course. | From date of randomization until discharge, assessed up to 12 months | 
| Total number of endoscopic procedures |  | From date of randomization until discharge, assessed up to 12 months | 
| Total number of drainage and debridement procedures (radiological, endoscopic, and surgical) |  | From date of randomization until discharge, assessed up to 12 months | 
| Number of days from index drainage procedure until removal of naso-cystic catheter |  | From date of randomization until discharge, assessed up to 12 months | 
| Duration of drainage and debridement procedures (index and cumulated) measured in minutes |  | From date of randomization until discharge, assessed up to 12 months | 
| Days at the hospital during a 6-month follow up |  | Assessed up to 12 months following randomization | 
| Length of ICU stay | Days in the ICU during hospitalization | From date of randomization until discharge, assessed up to 12 months | 
| Number of days until resolution of pre-interventional systemic inflammatory response syndrome (SIRS) | Number of days from randomization to restoration of normal blood pressure, temperature, heart rate, inspiratory rate, and white blood cell count | From date of randomization until discharge, assessed up to 12 months | 
| New onset episodes of culture verified bacteremia |  | From date of randomization until discharge, assessed up to 12 months | 
| Occurrence of splanchnic vein thrombosis (portal-, splenic-, or superior mesenteric vein) | Portal-, splenic-, or superior mesenteric vein thrombosis | From date of randomization until discharge, assessed up to 12 months | 
| Need for tube feeding (naso-gastric or naso-jejunal) or parenteral nutrition |  | From date of randomization until discharge, assessed up to 12 months | 
| CRP-area under curve | AUC from the index drainage procedure until discharge from hospital | From date of randomization until discharge, assessed up to 12 months | 
| Number of adverse events | according to the ASGE lexicon and Clavien-Dindo | From date of randomization until discharge, assessed up to 12 months | 
| Mortality | The rate mortality compared between the two study groups | From date of randomization until discharge, assessed up to 12 months | 
| Unset of exocrine and endocrine insufficiency | The unset of diabetes and/or steatorrhea | From date of randomization until discharge, assessed up to 12 months | 
| Total treatment costs. | In euros and dollars | From date of randomization until discharge, assessed up to 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Walled-off necrosis, Walled-off pancreatic necrosis, Endoscopic necrosectomy, Video-assisted retroperitoneal debridement