Digestive System Diseases

All Conditions

Neoplasms

Symptoms and General Pathology

Pancreatitis

Pancreatic Pseudocyst

Pancreatic Diseases

Gastrointestinal Diseases

Cysts

Pancreatic Cyst

In the plastic stent group, two (at least one) 7-Fr double pigtail stents will be placed. Following EUS-guided puncture of a pseudocyst, a guidewire will be coiled within the lesion, and another guidewire will be inserted alongside the prepositioned guidewire. The puncture tract will be dilated if needed.

In the LAMS group, a LAMS with electrocautery enhanced delivery will be placed (Hot AXIOS; Boston Scientific Japan, Tokyo, Japan). A guidewire or dilator will be used if needed.

EUS-guided drainage will be conducted under endosonographic and fluoroscopic guidance within 72 hours of the randomisation. A linear echoendoscope will be advanced to the stomach or duodenum with moderate sedation, and the targeted pseudocyst will be visualised and punctured under endosonographic guidance. In cases with an insufficient improvement in inflammatory indicators (i.e., body temperature, white blood cell count, and C-reactive protein), the investigators will perform additional interventions including the addition of or replacement with a plastic stent or LAMS and/or percutaneous drainage if needed.

In the plastic stent group, two (at least one) 7-Fr double pigtail stents will be placed. Following EUS-guided puncture of a pseudocyst, a guidewire will be coiled within the lesion, and another guidewire will be inserted alongside the prepositioned guidewire. The puncture tract will be dilated if needed.

Plastic stent

EUS-guided drainage will be conducted under endosonographic and fluoroscopic guidance within 72 hours of the randomisation. A linear echoendoscope will be advanced to the stomach or duodenum with moderate sedation, and the targeted pseudocyst will be visualised and punctured under endosonographic guidance. In cases with an insufficient improvement in inflammatory indicators (i.e., body temperature, white blood cell count, and C-reactive protein), the investigators will perform additional interventions including the addition of or replacement with a plastic stent or LAMS and/or percutaneous drainage if needed.

In the LAMS group, a LAMS with electrocautery enhanced delivery will be placed (Hot AXIOS; Boston Scientific Japan, Tokyo, Japan). A guidewire or dilator will be used if needed.

LAMS

Yousuke Nakai

Tomotaka Saito

Tadahisa Inoue

Hiroyuki Isayama

Toshio Fujisawa

Sho Takahashi

Hiroshi Ohyama

Koji Takahashi

Nao Fujimori

Kazuhide Matsumoto

Keisuke Iwata

Mitsuru Okuno

Akinori Maruta

Kensaku Yoshida

Takuji Iwashita

Shinya Uemura

Hideyuki Shiomi

Ryota Nakano

Hideki Kamada

Ryota Nakabayashi

Shinichi Hashimoto

Makoto Hinokuchi

Toshiyasu Shiratori

So Nakaji

Kazunari Nakahara

Yusuke Satta

Tsuyoshi Mukai

Saburo Matsubara

Kentaro Suda

Shinpei Doi

Nobuhiro Katsukura

Atsuhiro Masuda

Arata Sakai

Masahiro Tsujimae

Reiko Yamada

Kenji Nose

Hironari Kato

Kazuyuki Matsumoto

Ryosuke Sato

Takeshi Ogura

Saori Ueno

Masaki Kuwatani

Ryou Sugiura

Hirofumi Kogure

Kei Saito

Ichiro Yasuda

Nobuhiko Hayashi

Masayuki Kitano

Takashi Tamura

Sumio Hirose

Mamoru Takenaka

Shunsuke Omoto

Endoscopic ultrasound (EUS)-guided transluminal drainage has become a first-line treatment modality for symptomatic pancreatic pseudocysts. Despite the increasing popularity of lumen-apposing metal stents (LAMSs), the use of a LAMS is limited by its high costs and specific adverse events compared to plastic stent placement. To date, there has been a paucity of data on the appropriate stent type in this setting. This trial aims to assess the non-inferiority of plastic stents to a LAMS for the initial EUS-guided drainage of pseudocysts.

Pancreatic fluid collections (PFCs) develop as local complications of acute pancreatitis after four weeks of the disease onset. Pancreatic pseudocysts are a type of PFC, which is characterised by encapsulated non-necrotic contents. Pseudocysts occasionally become symptomatic (e.g., infection, GI symptoms), and given the high morbidity and mortality, it is mandatory to manage symptomatic pseudocysts appropriately to improve clinical outcomes of patients with acute pancreatitis overall. EUS-guided transluminal drainage has become a first-choice treatment option for symptomatic PFCs. In the setting of EUS-guided treatment of walled-off necrosis (WON, the other type of PFC), the potential benefits of LAMSs have been reported. Compared to plastic stents, LAMSs can serve as a transluminal port and thereby, facilitate the treatment of WON that often requires a long treatment duration with repeated interventions including direct endoscopic necrosectomy. With the increasing popularity and availability of LAMSs in interventional EUS overall, several retrospective studies have reported the feasibility of LAMS use for EUS-guided drainage of pancreatic pseudocysts.

While a LAMS may enhance the drainage efficiency of pseudocysts due to its large calibre, the benefits of this stent may be mitigated in pseudocysts that, by definition, contain non-necrotic liquid contents and can be managed without necrosectomy. Indeed, several retrospective comparative studies failed to demonstrate the superiority of plastic stents to a LAMS. In addition, the use of a LAMS has been limited by higher costs compared to plastic stents and potential specific adverse events (e.g., bleeding, buried stent). Studies suggest that a prolonged duration of LAMS placement (approximately ≥ 4 weeks) may predispose the patients to an elevated risk of adverse events associated with LAMSs. Therefore, patients requiring long-term drainage (e.g., cases with disconnected pancreatic duct syndrome) should be subjected to a reintervention in which a LAMS is replaced by a plastic stent. However, the technical success rate of the replacement has not been high. Given these lines of evidence, the investigators hypothesised that plastic stents might be non-inferior to a LAMS in terms of the potential of resolving a pseudocyst and associated symptoms.

To test the hypothesis, the investigators have planned a multicentre randomised controlled trial (RCT) to examine the non-inferiority of plastic stents to a LAMS as the initial stent for EUS-guided drainage of pancreatic pseudocysts in terms of the achievement of clinical treatment success (the resolution of a pseudocyst). Given the lower costs of plastic stents compared to a LAMS, the results would help not only establish a new treatment paradigm for pancreatic pseudocysts but also improve the cost-effectiveness of the resource-intensive treatment.

WONDER-02 Trial: Plastic Stent vs. Lumen-apposing Metal Stent for Pancreatic Pseudocysts

WONDER-02: Plastic Stent vs. Lumen-apposing Metal Stent for Endoscopic Ultrasound-guided Drainage of Pancreatic Pseudocysts-a Multicentre Randomised Non-inferiority Trial

Clinical success is defined as 1) a decrease in the size of a targeted pancreatic pseudocyst to 2 cm or less and 2) an improvement of at least two out of the following inflammatory indicators: body temperature, white blood cell count, and C-reactive protein.

The adverse events are defined and graded by the ASGE lexicon guideline.

Technical success is defined as the successful placement of any stent in the targeted pseudocyst during the initial EUS-guided drainage.

Time from randomization to clinical success

Gastrointestinal obstruction due to a pseudocyst

Time requiring endoscopic drainage for a pseudocyst

Time requiring percutaneous drainage for a pseudocyst

Total number of interventions needed for the treatment of a pseudocyst

Total procedure time needed for the treatment of a pseudocyst

Total ICU stay of the index hospitalisation

Incidence of pseudocyst recurrence after clinical success

Time from clinical success to recurrence of pancreatic pseudocyst

Total treatment days for recurrent pancreatic pseudocyst

Incidence of new-onset pancreatic pseudocyst

Total treatment days for new-onset pancreatic pseudocyst

The start of medications for pancreatic exocrine insufficiency and the date

The presence of sarcopenia and the date of diagnosis

Change in volume of pancreas. Volume is evaluated by contrast-enhanced Computed Tomography (CT) using SYNAPSE VINCENT (FUJIFILM).

Success rate of surgeries associated with pancreatic pseudocyst

New-onset clinical symptoms associated with pancreatic exocrine insufficiency, such as steatorrhea , constipation, diarrhea, maldigestion, flatulence, and tenesmus

Tokyo University

Associate professor, Department of Endoscopy and Endoscopic Surgery, The University of Tokyo Hospital

Rare Diseases

Necrosis

Pancreatitis, Acute Necrotizing

Acute Graft Versus Host Disease

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.

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.

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.

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 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).

Step-up approach

Shogo Ota

Daisuke Namima

Keito Nakagawa

Kenji Chinen

Atsushi Okuda

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.

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.

Immediate Necrosectomy vs. Step-up Approach for Walled-off Necrosis

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

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.

All procedure-related adverse events including bleeding, perforation, peritonitis, etc.

Successful placement of EUS-guided drainage including a lumen-apposing metal stent and plastic stents

Inflammatory-induced obstruction of bile duct and gastrointestinal tract

Total number of interventions and total procedure time

Indwelling period of stents and drainage tube

Success rate of surgeries associated with WON and total operation time

Total hospitalization days and total ICU stay

Total cost of interventions and total cost of hospitalization

Time from clinical success to recurrence of WON

Total treatment period for new-onset pancreatic pseudocyst

New-onset diabetes mellitus, pancreatic cancer, and clinical symptoms associated with pancreatic exocrine insufficiency, such as steatorrhea , constipation, diarrhea, maldigestion, flatulence, and tenesmus

Change in the morphology and the volume of pancreas

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
WONDER-02 Trial: Plastic Stent vs. Lumen-apposing Metal Stent for Pancreatic Pseudocysts	NCT06133023	Pancreatic Flui... Pancreatitis Pancreatic Pseu...	Plastic stent LAMS	18 Years -	Tokyo University
Immediate Necrosectomy vs. Step-up Approach for Walled-off Necrosis	NCT05451901	Pancreatic Flui... Walled-off Necr... Pancreatitis, A... Pancreatic Pseu...	Immediate necro... Step-up approac...	18 Years -	Tokyo University
Immediate Necrosectomy vs. Step-up Approach for Walled-off Necrosis	NCT05451901	Pancreatic Flui... Walled-off Necr... Pancreatitis, A... Pancreatic Pseu...	Immediate necro... Step-up approac...	18 Years -	Tokyo University

Spots Global Cancer Trial Database for pancreatic fluid collection