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

Not Applicable

Completed

• Conditions: Pancreatic Necrosis; Pancreatitis, Acute Necrotizing
• Interventions: Procedure: Direct Endoscopic Necrosectomy; Procedure: Step-up Approach

• Registration Number: NCT05601687
• Lead Sponsor: Copenhagen University Hospital, Hvidovre

Brief Summary

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

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.

Study Timeline

• Study First Submitted: 2022-10-21
• Study First Submitted QC: 2022-10-26
• Study Start: 2022-11-01
• Study First Posted: 2022-11-01
• Primary Completion: 2024-09-15
• Study Completion: 2025-01-01
• Status Verified: 2025-02
• Last Update Submitted: 2025-02-11
• Last Update Posted: 2025-02-13

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 25

Inclusion Criteria

All criteria must be fulfilled

1. 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.

2. One or more indication(s) for endoscopic, transmural drainage must be established:

   1. Confirmed or suspected infection.
   2. Severe intraabdominal hypertension or abdominal compartment syndrome.
   3. Persisting abdominal pain, early satiety, or general discomfort.
   4. Obstruction of the GI or biliary tract.
   5. Leakage of pancreatic juice, e.g. pancreatic ascites or pleural effusion.

3. 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

1. Patients under the age of 18.
2. Pregnancy.
3. Known or suspected malignant disease.
4. Pancreatitis secondary to trauma or surgical intervention.
5. Chronic pancreatitis.
6. Previous surgical or endoscopic drainage or necrosectomy.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Direct Endoscopic Necrosectomy	Direct Endoscopic Necrosectomy	Necrosectomy will be performed in the same procedure as the placement of the lumen-apposing metal stent.
Step-up Approach	Step-up Approach	Standard procedure where necrosectomy is only performed in the absence of clinical improvement 72 hours after placements of lumen-apposing metal stent.

Primary Outcome Measures

Name	Time	Method
A composite of major complications, death, or length of stay exceeding 58 days	From date of randomization until discharge, assessed up to 12 months	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).

Secondary Outcome Measures

Name	Time	Method
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	From date of randomization until discharge, assessed up to 12 months	Number of endoscopic necrosectomies and video-assisted retroperitoneal debridements needed throughout the disease course.
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	From date of randomization until discharge, assessed up to 12 months	Days in the ICU during hospitalization
Number of days until resolution of pre-interventional systemic inflammatory response syndrome (SIRS)	From date of randomization until discharge, assessed up to 12 months	Number of days from randomization to restoration of normal blood pressure, temperature, heart rate, inspiratory rate, and white blood cell count
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)	From date of randomization until discharge, assessed up to 12 months	Portal-, splenic-, or superior mesenteric vein thrombosis
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	From date of randomization until discharge, assessed up to 12 months	AUC from the index drainage procedure until discharge from hospital
Number of adverse events	From date of randomization until discharge, assessed up to 12 months	according to the ASGE lexicon and Clavien-Dindo
Mortality	From date of randomization until discharge, assessed up to 12 months	The rate mortality compared between the two study groups
Unset of exocrine and endocrine insufficiency	From date of randomization until discharge, assessed up to 12 months	The unset of diabetes and/or steatorrhea
Total treatment costs.	From date of randomization until discharge, assessed up to 12 months	In euros and dollars

Trial Locations

Locations (1)

Copenhagen University Hospital, Hvidovre; 🇩🇰 Hvidovre, Denmark