Immediate Necrosectomy vs. Step-up Approach for Walled-off Necrosis (WONDER-01)

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

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.

Study Overview

• Status: Recruiting
• Conditions: Pancreatic Pseudocyst; Pancreatitis, Acute Necrotizing; Walled-off Necrosis; Pancreatic Fluid Collection
• Intervention / Treatment: Procedure: Immediate necrosectomy; Procedure: Step-up approach

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Anticipated): 70
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Yousuke Nakai; Phone Number: +81-3-3815-5411; Email: ynakai-tky@umin.ac.jp
• Study Contact Backup: Name: Tomotaka Saito; Phone Number: +81-3-3815-5411; Email: tomsaito-gi@umin.ac.jp

Study Locations

• Japan
  • Aichi, Japan
    • Recruiting
    • Department of Gastroenterology, Aichi Medical University
    • Contact: Tadahisa Inoue
  • Chiba, Japan
    • Recruiting
    • Department of Gastroenterology, Graduate School of Medicine, Chiba University
    • Contact: Hiroshi Ohyama
    • Contact: Koji Takahashi
  • Gifu, Japan
    • Recruiting
    • Department of Gastroenterology, Gifu Municipal Hospital
    • Contact: Keisuke Iwata
    • Contact: Mitsuru Okuno
  • Gifu, Japan
    • Recruiting
    • Department of Gastroenterology, Gifu Prefectural General Medical Center
    • Contact: Akinori Maruta
    • Contact: Kensaku Yoshida
  • Gifu, Japan
    • Not yet recruiting
    • First Department of Internal Medicine, Gifu University Hospital
    • Contact: Takuji Iwashita
    • Contact: Shinya Uemura
  • Hyōgo, Japan
    • Recruiting
    • Division of Gastroenterology and Hepatobiliary and Pancreatic Diseases, Department of Internal Medicine, Hyogo Medical University
    • Contact: Hideyuki Shiomi
    • Contact: Shogo Ota
    • Sub-Investigator: Ryota Nakano
  • Kagawa, Japan
    • Recruiting
    • Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University
    • Contact: Hideki Kamada
    • Contact: Daisuke Namima
  • Kagoshima, Japan
    • Recruiting
    • Digestive and Lifestyle Diseases, Kagoshima University Graduate School of Medical and Dental Sciences
    • Contact: Shinichi Hashimoto
    • Contact: Makoto Hinokuchi
  • Kamogawa, Japan
    • Recruiting
    • Department of Gastroenterology, Kameda Medical Center
    • Contact: Toshiyasu Shiratori
    • Contact: So Nakaji
  • Kanazawa, Japan
    • Not yet recruiting
    • Department of Gastroenterological Endoscopy, Kanazawa Medical University
    • Contact: Tsuyoshi Mukai
  • Kawagoe, Japan
    • Not yet recruiting
    • Department of Gastroenterology and Hepatology, Saitama Medical Center, Saitama Medical University
    • Contact: Saburo Matsubara
    • Contact: Keito Nakagawa
  • Kawasaki, Japan
    • Not yet recruiting
    • Department of Gastroenterology, Teikyo University Mizonokuchi Hospital
    • Contact: Shinpei Doi
    • Contact: Nobuhiro Katsukura
  • Kobe, Japan
    • Recruiting
    • Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine
    • Contact: Atsuhiro Masuda
    • Contact: Masahiro Tsujimae
  • Okinawa, Japan
    • Recruiting
    • Department of Gastroenterology, Yuuai Medical Center
    • Contact: Kenji Chinen
  • Osaka, Japan
    • Not yet recruiting
    • 2nd Department of Internal Medicine, Osaka Medical College
    • Contact: Takeshi Ogura
    • Contact: Atsushi Okuda
  • Sapporo, Japan
    • Recruiting
    • Department of Gastroenterology and Hepatology, Hokkaido University Hospital
    • Contact: Masaki Kuwatani
  • Tokyo, Japan
    • Not yet recruiting
    • Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine
    • Contact: Hirofumi Kogure
    • Contact: Kei Saito
  • Toyama, Japan
    • Recruiting
    • Third Department of Internal Medicine, University of Toyama
    • Contact: Ichiro Yasuda
    • Contact: Nobuhiko Hayashi
  • Ōsaka-sayama, Japan
    • Not yet recruiting
    • Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine
    • Contact: Mamoru Takenaka
    • Contact: Shunsuke Omoto
  • Tokyo
    • Bunkyō-Ku, Tokyo, Japan, 113-8655
      • Not yet recruiting
      • Department of Gastroenterology, The University of Tokyo Hospital
      • Contact: Tomotaka Saito; Phone Number: +81-3-3815-5411; Email: tomsaito-gi@umin.ac.jp
      • Contact: Yousuke Nakai
    • Bunkyō-Ku, Tokyo, Japan
      • Recruiting
      • Department of Gastroenterology, Graduate School of Medicine, Juntendo University
      • Contact: Hiroyuki Isayama
      • Contact: Toshio Fujisawa
      • Sub-Investigator: Sho Takahashi

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Immediate necrosectomy; 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; 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.
Active Comparator: Step-up approach; 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; 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).

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Tokyo University
• Investigators: Principal Investigator: Yousuke Nakai, Department of Endoscopy and Endoscopic Surgery, Graduate School of Medicine, The University of Tokyo

Publications and helpful links

General Publications

• Banks PA, Bollen TL, Dervenis C, Gooszen HG, Johnson CD, Sarr MG, Tsiotos GG, Vege SS; Acute Pancreatitis Classification Working Group. Classification of acute pancreatitis--2012: revision of the Atlanta classification and definitions by international consensus. Gut. 2013 Jan;62(1):102-11. doi: 10.1136/gutjnl-2012-302779. Epub 2012 Oct 25.

Study record dates

Study Major Dates

• Study Start (Actual): July 29, 2022
• Primary Completion (Anticipated): April 1, 2025
• Study Completion (Anticipated): April 11, 2031

Study Registration Dates

• First Submitted: July 3, 2022
• First Submitted That Met QC Criteria: July 6, 2022
• First Posted (Actual): July 11, 2022

Study Record Updates

• Last Update Posted (Actual): October 27, 2022
• Last Update Submitted That Met QC Criteria: October 26, 2022
• Last Verified: October 1, 2022

More Information

Terms related to this study

• Keywords: Stents; Drainage; Endosonography; Endoscopic necrosectomy; Step-up approach
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Neoplasms; Cysts; Pancreatic Diseases; Pancreatic Cyst; Necrosis; Pancreatitis; Pancreatic Pseudocyst; Pancreatitis, Acute Necrotizing
• Other Study ID Numbers: 2021005P; jRCT1032220055 (Registry Identifier: Japan Registry of Clinical Trials)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No