Clinical trial NCT05601687: Endoscopic Step-up Approach Vs Aggressive Debridement of Large Pancreatic Walled-off Necrosis
Official title: Endoscopic Step-up Approach Vs Aggressive Debridement of Large Pancreatic Walled-off Necrosis - a Single-center, Open-label, Randomized, Superiority Trial (ACCELERATE)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Pancreatic Necrosis
Pancreatitis, Acute Necrotizing
Keywords: Walled-off necrosis
Walled-off pancreatic necrosis
Endoscopic necrosectomy
Video-assisted retroperitoneal debridement
Lead sponsor: Copenhagen University Hospital, Hvidovre
Sponsor class: OTHER
First posted: 2022-11-01
Enrollment: 25
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention 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.
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: A composite of major complications, death, or length of stay exceeding 58 days
timeFrame: From date of randomization until discharge, assessed up to 12 months
Secondary outcomes:
measure: Length of hospital stay from the index drainage procedure
timeFrame: From date of randomization until discharge, assessed up to 12 months
measure: Total number of debridement procedures
timeFrame: From date of randomization until discharge, assessed up to 12 months
measure: Total number of endoscopic procedures
timeFrame: From date of randomization until discharge, assessed up to 12 months
measure: Total number of drainage and debridement procedures (radiological, endoscopic, and surgical)
timeFrame: From date of randomization until discharge, assessed up to 12 months
measure: Number of days from index drainage procedure until removal of naso-cystic catheter
timeFrame: From date of randomization until discharge, assessed up to 12 months
measure: Duration of drainage and debridement procedures (index and cumulated) measured in minutes
timeFrame: From date of randomization until discharge, assessed up to 12 months
measure: Days at the hospital during a 6-month follow up
timeFrame: Assessed up to 12 months following randomization
measure: Length of ICU stay
timeFrame: From date of randomization until discharge, assessed up to 12 months
measure: Number of days until resolution of pre-interventional systemic inflammatory response syndrome (SIRS)
timeFrame: From date of randomization until discharge, assessed up to 12 months
measure: New onset episodes of culture verified bacteremia
timeFrame: From date of randomization until discharge, assessed up to 12 months
measure: Occurrence of splanchnic vein thrombosis (portal-, splenic-, or superior mesenteric vein)
timeFrame: From date of randomization until discharge, assessed up to 12 months
measure: Need for tube feeding (naso-gastric or naso-jejunal) or parenteral nutrition
timeFrame: From date of randomization until discharge, assessed up to 12 months
measure: CRP-area under curve
timeFrame: From date of randomization until discharge, assessed up to 12 months
measure: Number of adverse events
timeFrame: From date of randomization until discharge, assessed up to 12 months
measure: Mortality
timeFrame: From date of randomization until discharge, assessed up to 12 months
measure: Unset of exocrine and endocrine insufficiency
timeFrame: From date of randomization until discharge, assessed up to 12 months
measure: Total treatment costs.
timeFrame: From date of randomization until discharge, assessed up to 12 months
Other outcomes:
Locations:
city: Hvidovre
country: Denmark
facility: Copenhagen University Hospital, Hvidovre
Study officials:
affiliation: Pancreatitis Centre East (PACE), Gastro Unit, Copenhagen University Hospital Hvidovre, Denmark
name: John G Karstensen, MD Ph.d.
role: STUDY_DIRECTOR
References:
citation: Ebrahim M, Werge MP, Hadi A, Lahchich M, Nagras ZG, Lauritsen ML, Schmidt PN, Hansen EF, Novovic S, Karstensen JG. Clinical outcomes following endoscopic or video-assisted retroperitoneal management of acute pancreatitis with large (>15 cm) walled-off pancreatic necrosis: Retrospective, single tertiary center cohort study. Dig Endosc. 2022 Sep;34(6):1245-1252. doi: 10.1111/den.14295. Epub 2022 Mar 29.
citation: Banks PA, Freeman ML; Practice Parameters Committee of the American College of Gastroenterology. Practice guidelines in acute pancreatitis. Am J Gastroenterol. 2006 Oct;101(10):2379-400. doi: 10.1111/j.1572-0241.2006.00856.x. No abstract available.
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citation: Seewald S, Groth S, Omar S, Imazu H, Seitz U, de Weerth A, Soetikno R, Zhong Y, Sriram PV, Ponnudurai R, Sikka S, Thonke F, Soehendra N. Aggressive endoscopic therapy for pancreatic necrosis and pancreatic abscess: a new safe and effective treatment algorithm (videos). Gastrointest Endosc. 2005 Jul;62(1):92-100. doi: 10.1016/s0016-5107(05)00541-9.