Acute Necrotic Collection, Necrotizing Pancreatitis, Pancreatitis, Pancreatitis, Acute Necrotizing, Walled Off Necrosis
Conditions
Keywords
Endosonography, Drainage, Walled Off Necrosis, necrotizing pancreatitis, pancreatitis
Brief summary
This multicenter, randomized controlled trial (WONDER-03 study) investigates the optimal timing for endoscopic ultrasound (EUS)-guided drainage in patients with necrotizing pancreatitis. Although current guidelines recommend delaying drainage until at least four weeks after the onset of acute pancreatitis to allow for encapsulation of necrosis, recent observational data suggest that the degree of encapsulation itself may more strongly influence treatment success and safety. In this trial, patients are randomly assigned to one of two groups: an encapsulation-oriented group, in which EUS-guided drainage is performed when imaging confirms ≥80% encapsulation of the necrotic collection with symptoms, and a timing-oriented group, in which drainage is performed at four to five weeks after disease onset, regardless of encapsulation status. The primary endpoint is clinical success within 180 days, defined as both radiologic resolution of necrosis and improvement in symptoms. Secondary endpoints include adverse event rates, recurrence of fluid collections, technical and clinical success rates, and healthcare resource use. This study aims to determine whether a strategy based on encapsulation leads to better clinical outcomes than the conventional time-based approach and may help establish a new evidence-based treatment algorithm for necrotizing pancreatitis.
Detailed description
Necrotizing pancreatitis is a severe and potentially life-threatening condition characterized by pancreatic and/or peripancreatic tissue necrosis. Endoscopic ultrasound (EUS)-guided transmural drainage has become widely adopted as a minimally invasive approach for the management of symptomatic necrotizing pancreatitis, particularly in cases of infected collections or organ compression. Traditionally, clinical guidelines have recommended delaying such drainage procedures until four weeks after the onset of acute pancreatitis, under the assumption that encapsulation of the necrotic tissue during this time enhances safety and technical success. However, this timing-based strategy lacks robust prospective validation and may not be optimal for all patients. Recent data from multicenter cohort studies conducted in Japan have indicated that the degree of encapsulation at the time of drainage may be a more critical factor than the elapsed time since disease onset. In these studies, patients with ≥80% encapsulation demonstrated significantly higher rates of clinical success and lower complication rates compared to those with partial or no encapsulation, regardless of the timing of intervention. This observation suggests that the current standard approach, which relies solely on time from onset, may not adequately capture individual patient readiness for intervention. The WONDER-03 study is designed as a multicenter, open-label, randomized controlled trial to compare two treatment strategies in patients with necrotizing pancreatitis. Participants are randomly assigned to either the encapsulation-oriented group or the timing-oriented group. In the encapsulation-oriented group, EUS-guided drainage is performed once imaging, preferably contrast-enhanced CT, confirms that the necrotic collection is at least 80% encapsulated and the patient presents with symptoms such as infection, abdominal pain, gastrointestinal obstruction, or biliary obstruction. In the timing-oriented group, drainage is scheduled for four to five weeks after the onset of acute pancreatitis if the patient is symptomatic, irrespective of the encapsulation status. Eligible patients must be 18 years or older, have a diagnosis of necrotizing pancreatitis based on imaging, and be enrolled within 28 days of disease onset. Exclusion criteria include unclear onset timing, prior drainage procedures, a diagnosis of chronic pancreatitis, contraindications to endoscopic treatment, or pregnancy. Randomization is stratified by participating institution and the presence of organ failure. The primary outcome of the study is clinical success within 180 days of randomization, defined as both a reduction in the maximum diameter of the necrotic collection to ≤2 cm on CT or MRI, and resolution of the symptoms that necessitated intervention. These may include normalization of inflammatory markers in infected cases, relief of abdominal pain or gastrointestinal obstruction, or resolution of biliary obstruction. Secondary outcomes include the incidence of procedure-related complications, technical success of EUS drainage, time to clinical success, recurrence of pancreatic fluid collections, mortality, total number and duration of interventions, need for surgery, length of hospitalization and ICU stay, duration of antibiotic therapy, and related medical costs. In addition, long-term outcomes such as the development of diabetes, exocrine pancreatic insufficiency, sarcopenia, and pancreatic cancer will be monitored over a follow-up period of five years. The trial also incorporates centralized oversight through an expert panel, which assists in evaluating imaging findings to confirm eligibility and encapsulation status. All procedures are performed by experienced endoscopists, and treatment protocols, including use of lumen-apposing metal stents (LAMS), necrosectomy, and step-up interventions, are standardized across sites. By directly comparing the two strategies in a prospective, randomized setting, this study aims to generate high-quality evidence to guide clinical decision-making in the management of necrotizing pancreatitis. If encapsulation-oriented timing proves superior, it could shift clinical practice toward a more individualized, pathology-driven approach, improving patient outcomes while reducing the risk of complications and unnecessary delays in treatment.
Interventions
PROCEDUREThe timing of endoscopic intervention for necrotizing pancreatitis is determined based on the degree of encapsulation
In the encapsulation-oriented group, participants undergo EUS-guided drainage of necrotizing pancreatitis when the degree of encapsulation reaches ≥80%, as confirmed by cross-sectional imaging (preferably contrast-enhanced CT). Imaging is repeated every 7-10 days after enrollment to assess encapsulation. Once sufficient encapsulation is observed and the patient presents with symptoms such as infection, abdominal pain, GOO or biliary obstruction, endoscopic drainage is performed. Drainage is typically performed using a lumen-apposing metal stent (LAMS) placed under EUS guidance, often accompanied by placement of an external drain. Step-up therapy, including endoscopic necrosectomy or additional drainage procedures, may be used if symptoms do not improve. If the patient improves with conservative therapy before encapsulation is achieved, drainage may be deferred. Endoscopic/percutaneous interventions should, in principle, be discussed with the expert panel beforehand.
PROCEDUREEUS-guided drainage based on the interval from the onset of acute pancreatitis
In the timing-oriented group, participants undergo EUS-guided drainage of necrotizing pancreatitis at 4 to 5 weeks after the onset of acute pancreatitis, regardless of the degree of encapsulation. Drainage is performed only in symptomatic patients who meet predefined clinical criteria, such as signs of infection, significant pain, GOO, or biliary obstruction. Imaging is performed before the procedure. The standard approach involves placing a LAMS under EUS guidance, optionally supplemented by external drains. If symptoms do not improve, step-up interventions such as endoscopic necrosectomy, percutaneous drainage may be considered. If inflammation and symptoms improve with conservative treatment (e.g., antibiotics), EUS-guided drainage may be omitted. Conversely, even before 4-5 weeks from onset, early drainage is allowed if conservative treatment is deemed insufficient by the attending physician. In principle, intervention decisions should be discussed with the expert panel.
Sponsors
Tokyo Women's Medical University
Tokyo University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients diagnosed with necrotizing pancreatitis according to the revised Atlanta classification, confirmed by contrast-enhanced CT (plain CT or MRI may be substituted if contrast-enhanced CT is not feasible). * Within 28 days of onset of acute pancreatitis. * Age ≥ 18 years at the time of consent, regardless of sex. * Provided written informed consent from the patient or a legally authorized representative after sufficient explanation. * Patients who are either hospitalized or being followed as outpatients at participating study institutions.
Exclusion criteria
* Unknown date of onset of acute pancreatitis. * Patients who have already undergone transluminal drainage with stent placement for necrotizing pancreatitis. * Diagnosis of chronic pancreatitis. * Patients for whom endoscopic treatment is deemed unsafe. * Pregnant women. * Patients deemed inappropriate for the study by the principal investigator or sub-investigator.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Clinical success rate within 180 days after randomization | Six months | Defined as reduction of necrotic collection to ≤2 cm on imaging and resolution of symptoms that required intervention (infection: at least two out of the following inflammatory indicators: body temperature, white blood cell count, and C-reactive protein, pain, GI obstruction, or jaundice). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| All-cause mortality | 5 years | Includes any death occurring during the study period. |
| Time to clinical success | 180 days | Defined as the number of days between randomization and the achievement of both imaging and symptom resolution criteria. |
| Technical success of initial EUS-guided drainage | At the time of first EUS-guided drainage procedure | Defined as successful drainage of necrotizing pancreatitis |
| Incidence of biliary or gastrointestinal stricture | 5 years | New diagnosis of bile duct or gastrointestinal tract stricture confirmed by imaging or endoscopy. |
| Number of total interventions related to necrotizing pancreatitis | 5 years | Includes all endoscopic, percutaneous, and surgical interventions performed. |
| Total duration of intervention procedures | 5 years | Sum of procedural times for all interventions. |
| Duration of stent placement for drainage | 5 years | Number of days a drainage stent remains in situ. |
| Need for surgical intervention related to necrotizing pancreatitis | 5 years | Whether surgical drainage or necrosectomy is required, including procedural details. |
| Total duration of hospitalization for necrotizing pancreatitis | 5 years | Cumulative inpatient days related to pancreatitis treatment. |
| Total ICU stay duration | 5 years | Total days spent in the intensive care unit. |
| Rate of procedure-related adverse events | 5 years | Adverse events will be classified according to the ASGE lexicon and AGREE classification. |
| Total cost of interventions and hospitalization | 5 years | Calculated from procedural costs and hospitalization records. |
| Recurrence rate of pancreatic fluid collections (PFCs) | 5 years | Defined as symptomatic recurrence of PFCs requiring treatment. |
| Time to recurrence of PFCs | 5 years | Days between clinical success and recurrence requiring intervention. |
| Duration of treatment for recurrent PFCs | 5 years | Number of days required for treatment of recurrent fluid collections. |
| New-onset diabetes mellitus | 5 years | Defined by clinical diagnosis and laboratory evidence (e.g., elevated HbA1c). |
| Development of exocrine pancreatic insufficiency | 5 years | Based on clinical symptoms such as steatorrhea or need for enzyme supplementation. |
| Initiation of pancreatic enzyme replacement therapy | 5 years | Whether enzyme therapy is started and when. |
| Development of pancreatic cancer | 5 years | Confirmed by imaging and pathology. |
| Development of sarcopenia | 5 years | Based on imaging analysis of muscle mass and clinical frailty indicators. |
| Changes in pancreatic morphology (volume) | 5 years | Evaluated using 3D CT analysis to measure pancreatic volume |
| Total number of days of antibiotic use | 5 years | Includes both oral and intravenous antibiotic administration. |
Countries
Japan
Contacts
Primary ContactYousuke Nakai
Backup ContactTomotaka Saito
Outcome results
None listed