Gornals et al. Trials (2019) 20:791 https://doi.org/10.1186/s13063-019-3988-x STUDY PROTOCOL Open Access Multicenter study of plastic vs. self- expanding metal stents in endoscopic ultrasound-guided drainage of walled-off pancreatic necrosis – PROMETHEUS: a randomized controlled trial protocol Joan B. Gornals1,2* , Manuel Perez-Miranda3, Enrique Vazquez-Sequeiros4, Juan Vila5, José M. Esteban6, Ferran Gonzalez-Huix7, Carlos Guarner-Argente8, Andres Sanchez-Yague9, Alvaro Teran10, Francesc Bas-Cutrina1, Carlos De La Serna3, Ana Garcia De Paredes4, Raquel Ballester7, Julio Velasquez-Rodriguez1, Silvia Salord11, Cristian Tebe12, Pilar Hereu13, Sebas Videla13 and On behalf of the Spanish Working Group on Pancreatic Collection Therapy Abstract Background: It seems that lumen-apposing metal stents (LAMS) are displacing plastic stents in the therapy of pancreatic-fluid collection in walled-off necrosis (WON). To date, there is no quality of evidence to recommend LAMS as the standard treatment in the management of WON. The theoretical benefit of LAMS over plastic stents needs to be proven. Methods/design: This is a randomized controlled, multicenter, prospective clinical trial with two parallel groups, without masking. One-hundred and fourteen patients with WON will undergo endoscopic ultrasound (EUS)-guided transmural draining in nine tertiary hospitals in Spain and will be randomized to the LAMS or plastic-stent group. The primary endpoint is the short-term (4 weeks) clinical success determined by the reduction of the collection (to < 50% or < 5 cm in size), along with clinical improvement. Secondary endpoints: long-term (4 months) clinical success (total resolution or 5 cm), procedure duration, level of difficulty, safety, and recurrences. Discussion: The PROMETHEUS trial has been designed to determine whether LAMS are superior to plastic stents in EUS-guided transmural drainage of WON. Trial registration: ClinicalTrials.gov, ID: NCT03100578. Registered on 4 April 2017. https://clinicaltrials.gov/ct2/home Keywords: Endoscopic ultrasound, Lumen-apposing metal stent, Metal self-expanding stent, Plastic stent, Trial, Walled-off necrosis, self-expanding metal stent, Randomized clinical trial * Correspondence: jgornals@bellvitgehospital.cat 1 Endoscopy Unit, Department of Digestive Diseases, Hospital Universitari de Bellvitge, Bellvitge Biomedical Research Institute (IDIBELL), University of Barcelona, Feixa Llarga s/n, 08907 L’Hospitalet de Llobregat, Barcelona, Catalonia, Spain 2 Health Sciences, Universitat Oberta de Catalunya, Barcelona, Spain Full list of author information is available at the end of the article © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Gornals et al. Trials (2019) 20:791 Page 2 of 10 Background reduced using the specific stent design of LAMS. However, The Atlanta classification of pancreatic-fluid collection es- LAMS are more expensive, and their safety is controver- tablishes that walled-off necrosis (WON) consists of a sial, with a significantly higher rate of AEs, such as bleed- variable amount of necrotic tissue within a reactive-tissue ing, compared with plastic stents [11–14] (Table 1). wall. This derives from the encapsulation of acute necrotic Although some international systematic endoscopic re- collections. Imaging tests reveal a well-defined wall sur- views and meta-analyses have recommended LAMS as the rounding the collection, the formation of which typically care standard for WON drainage, the quality of evidence occurs at about 4 week from the origin of the acute or is not high (retrospective, registry-based, or non- chronic pancreatitis. The presence of more necrosis comparative) that LAMS are superior to PLASTIC stents worsens the prognosis; mortality in patients with necrotiz- in the management of WON by EUS-guided transmural ing pancreatitis is as high as 15%, and it can reach 30% in drainage, and few studies have compared LAMS and plas- patients with infected necrosis [1, 2]. In case of symptom- tic stents [15–20]. For all these reasons, a multicenter, atic WON, drainage is considered, and in the last two de- prospective, parallel-group, randomized controlled clinical cades minimally invasive approaches (surgical or trial was designed to assess whether LAMS are superior to endoscopic) have enjoyed increased acceptance in the plastic stents in the endoscopic treatment of WON. management of necrotic collections over open surgical necrosectomy, with fewer adverse events (AEs) and less long-term morbidity. Recent trials have shown that endo- Methods/design scopic approaches offer better clinical outcomes, with im- The PROMETHEUS trial is a randomized controlled, mul- provement in quality of life and lower costs [3–6]. ticenter, prospective clinical trial with two parallel groups, In the last few decade, endoscopic techniques, such as without masking and with a 1:1 allocation ratio. One hun- the use of endoscopic ultrasound-guided transmural dred and fourteen patients with WON will be scheduled drainage, have been increasingly used as a first-line option for endoscopic ultrasound (EUS)-guided transmural drain- for the treatment of symptomatic WON [5, 7]. To date, age in nine tertiary Spanish hospitals and will be random- plastic stents (such as double plastic stents) have been be- ized to the LAMS and plastic-stent groups. All the centers come the mainstay of endoscopic therapy for WON, until are members of the Spanish Society of Digestive Endoscopy the introduction of lumen-apposing metal stents (LAMS) (SEED), which acts as the promoter of this trial. [8–10]. There is the hypothesis that the large diameter of Central ethical approval of the study protocol has been LAMS improves the drainage of WON with respect to confirmed from the Comité Ético de Investigación Clín- plastic stents (7–10 Fr) and carries less time-consuming ica (CEIC) del Hospital Universitari de Bellvitge- interventions, with a smaller number of endoscopic proce- IDIBELL (ref approval no. 140/15) and we will not begin dures to achieve final success. Regarding safety, the risk of recruiting at other centers in the trial until local ethical leakage, perforation, or migration would theoretically be approval has been obtained. A Standard Protocol Items: Table 1 Comparative table of the two kinds of stents used in transmural drainage of pancreatic collections Lumen-apposing metal stent Plastic Advantages Disadvantages Advantages Disadvantages Easy release Expensive Economical Smaller diameter Wide diameter Less scientific evidence Easy extraction Shorter patency Better drainage of solid waste and necrosis Temporary placement May be left permanently in place High occlusion rate Direct necrosectomy via stent Traumatism caused by the ends Greater experience (studies) A single stent is not enough for WON Longer patency Not known whether permanent High success rate (> 80–90%, Multiple > demanding placement is possible all types of collections) technique (MTGT for WOPN) Correct visibility Worse visibility (fluoroscopy) Short therapeutic time Hemostatic effect Prevents migration Leakage of liquid (in ostomy) Anchoring effect Prevents liquid leakage Migration Easy extraction MTGT Multiple transluminal gateway technique, WOPN Walled-off pancreatic necrosis Gornals et al. Trials (2019) 20:791 Page 3 of 10 Recommendations for Interventional Trials (SPIRIT) Randomization and masking Checklist is attached as Additional file 1. Patients will be enrolled in this trial by gastroenterolo- gists, surgeons, and endoscopists who will evaluate the cases in the inpatient wards or in the outpatient consult- Study population ation areas. The participants will be randomized with a This clinical trial will be performed at the endoscopy unit random-number table generated by an online platform. of the digestive diseases departments of nine tertiary and A code list will be generated by randomization with a 1:1 university centers in Spain. In order to participate in this randomization ratio, by blocks, stratified by centers and by study, the patient must be a candidate for guided trans- American Society of Anesthesiologists’ classification (ASA) mural drainage with EUS of WON-type pancreatic collec- score. Each individual will be assigned a randomization code tion as a local complication in acute pancreatitis. The along with the treatment that corresponds. Once the patient investigator at each center will be contacted to evaluate meets the eligibility criteria and has provided informed con- the inclusion of the patient in the study. The patient will sent, we will proceed to the allocation of each participant cen- be correctly informed by personnel knowledgeable about trally, ensuring allocation concealment, and based on the the specifics of the study, who will help to resolve any randomization list. To prevent different subject recruitment questions that may arise. The informed consent form will rates at the various hospitals from interfering with the devel- be signed in the presence of participating personnel opment of the study, the entire population will be randomized knowledgeable about the study. The patient has the right in blocks of four between the two treatment possibilities. to opt out of the study at any time. The inclusion and exclusion criteria are listed in Table 2. Procedural technique Qualification of centers The participation of a minimum of nine hospitals with an Recruitment inclusion of about 13–15 patients per year per hospital is Principal investigators from each center will have the required. The investigators at the participating centers will task of presenting strategies to promote enrollment and all have experience in endoscopic intervention and thera- to ensure the target sample size. peutics, previous experience in EUS-guided transmural drainage with metal and plastic stents (> 25 overall), and a minimum of 10 procedures per year, in addition to appro- Table 2 Selection criteria for WON walled-off necrosis. priate material at their disposal for carrying out trans- a Diagnosis of WON based on imaging procedures mural drainage with both types of stent. Inclusion criteria: Patients eligible for the trial must comply with all of the following at General description of the technique randomization • Age 18 years or older Each selected case will ensure a conclusive diagnostic revi- • Patient with indication (ASGE, Jacobson BC, GIE2005) of drainage of sion with WON. In case of doubt, EUS-guided, fine- only one typea related to the symptomatology, as a local needle aspiration will be considered prior to drainage to complication of previous acute pancreatitis • Patient capable of understanding and signing informed consent rule out cystic tumor. Prophylactic antibiotic therapy will form be administered in accordance with the protocol of each • Patient understanding the type of study and complying with the center. In case of INR > 1.5, this will be corrected in ac- follow-up of complementary tests during the study’s duration cordance with the protocol of each center until INR < 1.5. Exclusion criteria Procedures will be performed under deep sedation in ac- • Pregnancy or breast-feeding cordance with the directives of each center. In case of col- • Severe coagulation disorder: INR > 1.5 not correctible with administration of plasma and/or platelets < 50,000/mm3 lection > 10 cm (> 700 mL), tracheal intubation by • Asymptomatic patients, without clinical indication of drainage, anesthesiologist is recommended. Carbon dioxide insuffla- except for those with vascular compression involvement tion is recommended, especially for endoscopic necrosect- • Non-identification of solid content during EUS procedure • Failure to sign informed consent form omy. The WON will be localized by using a linear • Patients with intellectual handicap who are unable to understand echoendoscope, selecting the appropriate optimal region the nature and possible consequences of the study, unless there is a for carrying out the EUS-guided puncture. The collection competent legal representative • Patients unable to adhere to subsequent follow-up requirements will be punctured with a 19-G needle (plastic or LAMS • Conditions that preclude upper digestive endoscopy, such as group) or directly with an electrocauterizing device (free- stenosis hand technique, only in the LAMS group). The guidewire Note: If there are several pancreatic collections, this does not exclude the will be advanced and coiled into the WON cavity. Then, patient from the trial. The patient is only excluded if there is more than one symptomatic collection to be drained the transmural ostomy will be carried out in accordance EUS endoscopic ultrasound, INR international normalized ratio with the normal procedure of the experienced Gornals et al. Trials (2019) 20:791 Page 4 of 10 endoscopist. The use of a fluoroscope will be decided Additional interventions upon on the basis of technical considerations and the Necrosectomy will be considered in WON with predom- opinion of the endoscopic interventionist. The use (or inantly solid debris, using the technique at the discretion not) of a fluoroscope will be noted in the case report form of the endoscopist. In cases that require sessions of endo- (CRF). The scale of the ostomy will be determined by the scopic necrosectomy, the different technical variants de- size of the collection (see Table 3). scribed in the literature will be used (irrigation technique After the interventional procedure, all inpatients cases with normal saline; mechanical technique using the com- will be returned to the hospital ward and will discharged mon devices as snares, Dormia baskets or retrieval nets after clinical improvement. Outpatients will spend a for extraction of necrotic debris; or combined with naso- minimal of 24 h under observation and will be dis- cystic catheters). The periodicity will be every 2–5 days charged the next day unless there is no improvement of depending on the decision of the expert endoscopist and symptoms or the appearance of AEs. the clinical evolution of the patient. Additional comments Plastic-stent group In the event of technical failure in the placement of the Double-pigtail plastic stents (5–10 cm in length, diameter stent (plastic or LAMS) for any reason, alternative treat- 7–8.5 10 French gauge (Fr), Advanix, Boston Scientific, ment will be decided upon in accordance with the direc- Spencer, USA) will be used. A minimum of one 10Fr pigtail tives of the endoscopic interventionist, with the aim of plastic stent will be placed. After initial EUS-guided access, offering the patient the best possible solution. the ostomy will be dilated first, using a cystotome, and sec- The first controls will be on the first day following and at 4 ondly with a balloon dilation. The plastic stent will be weeks (see Table 4). If there is no short-term clinical success, inserted and delivered following the routine technique of the most beneficial therapeutic approach for the patient will each interventional endoscopist. The number of the plastic be adopted in accordance with the criteria of the patient’s stent and size of the balloon used to dilate the ostomy will medical team (for example: the use of technical variants at depend on the WON size and content (see Table 3). The initial drainage such as placement of coaxial plastic pigtail time to plastic stent withdrawal will be considered until within the LAMS, replacement or change the stent type, use total resolution by imaging. If there is pancreatic-duct in- of nasocystic drainage or other known variants). volvement, non-withdrawal of stent will be considered. Every intervention, diagnostic procedure, and additional therapeutic contribution will be noted in the CRF. Metal group In the case of collections of significant size (i.e., 14 cm) with The metal stents used in this study will be LAMS (10, clinical-radiological success but without the disappearance of 15, or 20 mm in diameter, and 10 mm in length, the collection (i.e., CTMD reduction from 14 to 6 cm), pre- HotAXIOS stent with an electrocautery-enhanced deliv- cluding the removal of the stent, a new CTMD will be per- ery system, Boston Scientific, Madrid, Spain). This is a formed at 4 weeks (8 weeks) to assess removal of the stent. self-expanding metal stent totally covered with luminal Therefore, the removal of a stent is contemplated apposition. After the EUS-guided access into the WON when there is disappearance of the collection or a de- using first a 19-G or directly with the electrocautery tip, crease < 5 cm. the delivery system will be advanced into the cavity and Patients will remain in the hospital for a minimum of the distal flange will be deployed under EUS guidance. 24 h for clinical observation, under medical supervision. Otherwise, the proximal flange will be released under EUS or endoscopic guidance. The time to stent with- Clinical evaluation and follow-up drawal will depend on total resolution by imaging. How- Data collection ever, there will be the intention to remove a LAMS no The collecting of clinical information on the patients will later than 4–6 weeks. begin at the outset (baseline) and will continue with follow-up as established and defined in the study. AEs Table 3 Number of stents along with technical variations will be noted from the beginning of the test until the depending on size of WON, observed with EUS during conclusion of follow-up by means of scheduled controls. procedure Type LAMS (n, ø) Plastic (n, ø) Calendar WON < 10 cm 1, 10–15–20 mm ≥ 1, minimum 1 of 10Fr The following time-points and data items will consti- (+ ostomy 8–10 mm) tute the data collection from the beginning through WON > 10 cm ≥ 1, > 15 mm ≥ 2, minimum 1 of 10Fr successive controls: The collecting of data for pur- (+ ostomy 10–15 mm) poses of documentation will be carried out using a LAMS lumen-apposing metal stent; WON walled-off necrosis, FR French CRF, which will serve as an easily accessed source of Gornals et al. Trials (2019) 20:791 Page 5 of 10 Table 4 Data management, calendar Timepoint/stages Study Period Baseline Intervention 24 7 4 8 weeks ± 5 16 weeks (4 6 months ± 10 8 12 months ± 10 h days weeks ± days months) ± 10 days months ± days (Telephone) ± 3 days (Telephone) days (Telephone) 10 days Enrollment Informed X consent Clinical history X and exploration Eligibility screen X Allocation X Intervention Implantation X Removal X INR X Assessments: Blood test X X X X X a Imaging test X X X X X X X X X X X X X X X Symptomatology Visit X X X X Telephone X X X X contact Adverse effects X X X X X X X X X X Primary X outcome Secondary X outcomes Medication X X X X X X X X X X a Only in case of radiological clinical success but with persistence of the collection > 5 cm information. After collection, the data will be intro- Complications will be handled and treated in accordance duced into an electronic database by the participating with the directives of the patient’s medical team. All add- investigator of each center. itional tests and interventions will be duly documented. Follow-up Definitions Patients will be assessed (visit, telephone call) on days 1 and The term WON is in accordance with the literature (lat- 7, at 4, 8, and 16 weeks, and at 6, 8, and 12 months by est revision of Atlanta, Banks PA et al. Gut 2013) [1]. At personnel participating in the study, with the aim of obtaining least two imaging tests will be required (CTMD, MRI, information regarding signs and symptoms pointing to pos- EUS) prior to the transmural drainage, the results of sible stent obstruction or migration, recurrence, or other AEs. which must be in agreement on the classification of the Any instances of death during the follow-up will be in- collection as WON. vestigated to rule out any possible relation to the endo- Technical success is defined as the correct release of the scopic procedure. Such occurrences will also be stent at both ends, with observed drainage of the liquid. recorded in the CRF. Clinical success is defined as the significant reduction If there is clinical suspicion of obstruction or migra- of the collection along with clinical resolution. tion of the stent, an upper endoscopy will be carried out. Recurrence is defined as a symptomatic pancreatic col- Based on the findings of this procedure, the problem will lection diagnosed with imaging test during the follow-up be resolved in accordance with the directives of the of prior procedure with initial clinical success. intervening endoscopist. Any additional procedure or AEs are defined as undesirable situations suffered by endoscopic intervention will be duly documented. patients during the study, whether related or not to the Gornals et al. Trials (2019) 20:791 Page 6 of 10 EUS-guided transmural drainage with a stent (plastic or chi-square test or Fisher’s exact test will be used de- metal). All AEs referred by patients or observed by the pending on of the application criteria. For the calcula- medical team will be duly documented. All serious AEs tion, a planned interim analysis will be made for half of will be detailed, and the study promoter/principal inves- the recruitment using O’Brien-Fleming’s type-I error ex- tigator will be notified within 7 days. In the event of a pense function and a global loss rate of 5%. http://www. death, notification will be made within 24 h. AEs will be stat.ubc.ca/~rollin/stats/ssize/b2.html recorded in both the clinical history of the patient and the CRF, with appropriate medical terminology. When- Statistical analysis ever possible, the diagnosis rather than the symptoms All study variables will be presented for stent groups and in will be recorded. These guidelines are to be followed total, using descriptive statistics consistent with the nature from the time of the signing of informed consent until of the variable. The continuous variables will be described 30 days after the final visit in the study calendar. AEs will indicating the number of non-missing observations, the be classified as mild, moderate, serious, or fatal, in accord- mean, the standard deviation, the minimum, the first quar- ance with the nomenclature for AEs in endoscopy (ASGE tile, the median, the third quartile, and the maximum. Cat- Workshops 2010, Cotton GIE 2010; 71:446–54). The de- egorical variables will be described indicating the number termination as to whether an AE is related to the EUS- of non-missing observations and the percentages of the dif- guided transmural drainage with stent (plastic or metal) ferent categories by column. will be made by the patient’s medical team, the local inves- Main analysis: main outcome is the percentage of pa- tigator, and the principal investigator of the study. tients’ radiological (morphological) success between In Additional file 2 is included information about AE transmural drainage of the collection, measured at 4 definitions and MEDDEV guidelines. “Research product weeks from intervention. The null hypothesis suggests security surveillance” section, according to the definitions that there are no differences between the proportions of set out in the MEDDEV 2.7/3 guidelines (rev 3, May the intervention group and the control group. 2015) “Guidelines on medical devices: Clinical investiga- The level of statistical significance has been set at 5%. tions: Serious adverse event reporting under Directives To test the hypothesis, use the chi-square test or Fisher’s 90/385/EECC and 93/42/EEC” (Additional file 2). exact test depending on the application criteria will be used. To quantify the magnitude of the difference, the Outcomes relative risk of success will be estimated, in the metal- The primary outcome is the short-term (4 weeks) clinical stent group with respect to the plastic-stent group and success (metal vs. plastic) determined by the reduction its confidence interval will be calculated at 95%. of the collection (to < 50% or < 5 cm in size), along with clinical improvement. Secondary variable analyses The secondary outcomes are long-term (4 months) To determine which factors are associated with clinical- clinical success (metal vs. plastic) determined by total radiological success in the short term, a multivariate logis- resolution or 5 cm, along with clinical improvement. tic regression will be carried out. The variables of age and Technical: to assess the duration of the procedure and sex, and factors predicting the location of the disease, the level of difficulty. Safety: to assess AE (early and treatments received, size, and characteristics of the collec- late). Hospital length of stay. Recurrences. Financial: tion, previous ASA, etc. will be taken. In addition, the ap- evaluate the relative costs of the two strategies. pearance of clinical recurrence will be considered by means of an analysis of Kaplan-Meier survival. The factors associated with clinical recurrence will be explored Sample-size calculation through a multivariate Cox proportional risk model and The sample-size calculation is based on the primary hy- adjustment variables will also be taken. pothesis of detecting statistically significant differences in the percentage of clinical success in the LAMS and Subgroup analysis plastic-stents groups at 4 weeks after the intervention. The main analysis will also be carried out in the follow- Published data suggest that the clinical success rate at 4 ing subgroups: weeks in the LAMS group is expected to be 0.75 and in ASA patients I–II vs. II–IV. the plastic-stent group it is expected to be 0.5. Fifty- seven patients will be recruited in each group to reject the null hypothesis that the proportion of clinical suc- Data management cess in the LAMS group is equal to that of the plastic Throughout the study the promoters will monitor the group with an 80% power. The type-I error associated quality of the trial with special attention to protocol de- with this test will be 5%. To evaluate the hypothesis, the viations and the quality of the data entered in the Gornals et al. Trials (2019) 20:791 Page 7 of 10 database. At the end of the trial, a meeting will be held Withdrawal to consider the data management report. This report will Any AE or other clinical condition of the patient which, describe the different deviations from the protocol iden- at the clinician’s discretion, warrants withdrawal of the tified in each of the patients. These deviations will be patient from the study; pregnancy; or expressed wishes classified as major or minor, and those patients with of the patient. Withdrawal from treatment will not mean major deviations will be excluded from the protocol ana- suspension of the study, given that follow-up will be lysis. After the meeting, the suitability of the database maintained until the end of the study in accordance with for analysis will be considered, and the database will the protocol. then be closed. The need for surgical intervention for: in these cases, patient follow-up will be ended. Statistical analysis plan Ethical aspects and confidentiality The statistical analysis plan will be finalized before the The protocol will be approved by the CEIC of each par- close of the database. This plan will include all the ana- ticipating hospital as well as that of the coordinating lysis described and others, mainly on the sensitivity of center (HUB). The study researchers will carry out their the results and the management of the missing data. In tasks in compliance with ethical principles of clinical re- the event that in the plan of statistical analysis there is search established in the Declaration of Helsinki, and some deviation in the analysis of the main variable, an with the norms of Good Clinical Practices. It is planned addendum to the protocol will be made. No changes will to hire a policy to cover the concepts and compensations be made to the original analysis plan once the database according to current legislation (RD 1591/2009) that is closed. regulates clinical investigation with healthcare products. Before starting the clinical trial, it is planned to request authorization of the Spanish Agency for Medicines and Cost analysis Health Products (AEMPS) and the CEICs. Before inclu- The procedure for determining the cost of the diagnostic sion of the patient in the trial, a written informed con- test is made up of several steps: calculation of the unit sent will be requested. In relation to the study data we cost, and accounting for all the costs associated with the will follow the provisions of Organic Law 15/1999 of 13 test, both direct and indirect. December on “Protection of Personal Data.” Calculation process: observation of the performance and accounting for all the factors involved in the proced- Publication of results ure (units, time, number of professionals involved). There is a commitment to publish the results of this Criteria to be considered: human resources, disposable study in high-impact international journals, should the material, generic fungible supplies, pharmacy, laundry, results be of sufficient scientific interest. However, no equipment, repairs/maintenance of equipment and facil- patient names will appear in any article, and no one, ities, energy, cleaning, waste handling, rental, telephone with the exception of the researchers in this study and (calls to contact subjects in follow-up), structural costs, the members of the Hospital Ethical Committees, will and hospital admissions. have access to the data, in accordance with the Law on the Protection of Data of a Personal Nature. Other considerations Discussion Rescue Although open surgical necrosectomy has been the trad- Depending on the initial endoscopic treatment carried itional treatment of choice in patients with infected or out, a cross-over rescue treatment may be considered symptomatic pancreatic necrosis, other minimally invasive when the initial protocol treatment fails. For the plastic techniques have been developed in recent years (endo- treatment group ➔ metal stent (LAMS); for the metal scopic necrosectomy, guided radiological percutaneous treatment group ➔ plastic stent. Another accepted res- drainage, and retroperitoneal treatment) for treating col- cue technique (only in cases of initial treatment failure) lections, so as to improve on the high morbidity and mor- in the branch of metal stent: insertion of coaxial plastic tality rates of traditional surgical treatment [3, 21–23]. pigtail within a LAMS. At present, endoscopic transmural drainage plus endo- In all these cases, the follow-up of the patients will be scopic necrosectomy represents a viable technique that maintained until the end of the study according to is reasonably safe and effective when carried out in cen- protocol. Alternatively, if a cross-over treatment or tech- ters that have experience in doing so. Although each of nical variant is not possible, percutaneous surgical or these is a minimally invasive endoscopic technique, they radiological treatment will be offered. are not entirely free of complications, the most common Gornals et al. Trials (2019) 20:791 Page 8 of 10 of which are bleeding, perforation, post-procedural in- Recruitment: Start date 27 June 2017 and recruitment fection, and stent migration [7, 24]. Additionally, with will be completed by June 2020 the continuous technological advances being made and Revision chronology: the appearance of new materials for endoscopic use, doubts have arisen as to which devices are best to use. a- PROMETHEUS, June 2017, original: version 1, first One clear example of this uncertainty is the choice of draft of the study protocol. stent. To date, most published studies on guided trans- b- PROMETHEUS, September 2017, amendment n° 1: mural drainage with endoscopy have involved double version 2. pigtail plastic stents, with the number and diameter  Main amendments: (1) to clarify the second varying depending on the collection type [23, 24]. In the inclusion criterion – in case of more than one past years, some reports have been published on the use collection, the EUS-guided drainage will be of self-expanding covered metal stents offering greater limited to only one pancreatic collection (WON), diameter, and therefore greater volume in the drainage related to the symptomatology (Table 2); (2) of the collection [25–27]. However, both types of stent addition of the “Research product security are intended for bile drainage and are not expressly de- surveillance” section, according to the definitions signed for transmural drainage of abdominal collections, set out in the MEDDEV 2.7/3 guidelines (rev 3, so more dedicated stents were investigated [8]. May 2015) “Guidelines on medical devices: Recently, LAMS designed for the drainage of pancreatic Clinical investigations: Serious Adverse event collections have appeared with demonstrated efficacy in a reporting under Directives 90/385/EECC and 93/ number of studies but they are also more costly [16–20]. 42/EEC” (Additional file 2); (3) extension to nine These stents are totally covered and offer a maximum cali- centers with respect to the initial protocol (four ber of 15–20 mm, thereby allowing for endoscopic necro- centers); (4) procedural technique, rescue sectomy in repeated sessions without the need for section: in case of failure, adding of the replacement. In our experience, they permit transmural possibility of a “Technical variant” in LAMS drainage of pancreatic collections and endoscopic necro- group – an insertion of coaxial plastic pigtail sectomy if it is needed, they are safe and effective, and they within the metal stent reduce the duration of the procedure [10, 28].  Additional changes: (1) addition of new and However, with the increasing use of these stents, sig- relevant references; change of the grading of the nificant LAMS-related AEs (i.e., severe delayed bleeding, AE classification (immediate, early, and late); (2) buried stent syndrome, obstruction, migration) have commercial name of each stent; (3) start delayed, been reported in several papers. from the beginning of 2016 to June 2017; (4) To date there is only one comparative prospective procedural technique section: additional study of self-expanding LAMS type metal stents, versus comments regarding when and how some plastic stents in the endoscopic treatment of WON-type technical variants can be made; and technical pancreatic collections, and it concluded that there were notes about necrosectomy technique; (5) data no significant differences in treatment outcomes be- management paragraph in the statistical section; tween the two. In order to minimize LAMS-related AEs, and (6) telephone call at 7 days, and additional they recommend follow-up imaging and LAMS removal new legend explaining the possibility of a second at 3 weeks if collection is resolved [29]. imaging procedure at 8 weeks, only in case of The PROMETHEUS trial is supported by the Spanish radiological clinical success but with persistence Society of Digestive Endoscopy and includes nine tertiary of the collection > 5 cm (Table 4, Timeline) centers, as well as experts in the management of WON. c- PROMETHEUS, June 2018, amendment n°2: version Hospital Universitari de Bellvitge has the leadership and 2.1 – definitive main role in centralizing the decisions in case of doubts  Minor changes: addition of a new size of LAMS and controversies, and in limiting heterogeneity. (20 mm in diameter). In conclusion, this randomized multicenter trial is ne- AEMPS and CEIC have been notified after every cessary and essential in the effort to clarify the safety amendment, with acceptance by each institution and theoretical superiority of LAMS in the management of WON, compared with plastic stents. Supplementary information Supplementary information accompanies this paper at https://doi.org/10. 1186/s13063-019-3988-x. Trial status Protocol of submitted version, number and date: number Additional file 1. Standard Protocol Items: Recommendations for Interventional Trial (SPIRIT) Checklist. 2.1; date June 2018 Gornals et al. Trials (2019) 20:791 Page 9 of 10 Additional file 2. Safety definitions adverse events (AEs). Competing interests M Pérez-Miranda is consultant and speaker for Medtronic, Olympus, Taewoong, and MI-Tech E Vazquez-Sequeiros is a consultant for Boston Scientific Abbreviations F Gonzalez-Huix is a consultant for Boston Scientific AE: Adverse event; AEMPS: Spanish Agency for Medicines and Health JB Gornals is a consultant for Boston Scientific and has received a research Products; ASA: American Society of Anesthesiologists’ classification; grant from Boston Scientific CEIC: Clinical Research Ethics Committee; CRF: Case report form; The other authors declare that they have no competing interests. CTMD: Computed tomography multidetector; EUS: Endoscopic ultrasound; LAMS: Lumen-apposing metal stent; MRI: Magnetic resonance imaging; Author details SEED: Spanish Society of Digestive Endoscopy; WON: Walled-off necrosis 1 Endoscopy Unit, Department of Digestive Diseases, Hospital Universitari de Bellvitge, Bellvitge Biomedical Research Institute (IDIBELL), University of Acknowledgements Barcelona, Feixa Llarga s/n, 08907 L’Hospitalet de Llobregat, Barcelona, To the Spanish Working Group on Pancreatic Collection of the Spanish Catalonia, Spain. 2Health Sciences, Universitat Oberta de Catalunya, Society of Digestive Endoscopy. This work has had the support of the Barcelona, Spain. 3Endoscopy Unit, Hospital Universitario Rio Hortega, Spanish Platform of Clinical Research and Clinical Trials, SCReN (Spanish Valladolid, Spain. 4Endoscopy Unit, Gastroenterology and Hepatology Service, Clinical Research Network), financed by the ISCIII-General Sub directorate for Hospital Ramon y Cajal, IRYCIS, Madrid, Spain. 5Endoscopy Unit, Complejo the Evaluation and Promotion of Research, through project PT13/0002/00585 Hospitalario de Navarra, Pamplona, Spain. 6Endoscopy Unit, Department of integrated in the State Plan of R + D + I 2013–2016 and co-financed by and Digestive Diseases, Hospital Clínico San Carlos, Madrid, Spain. 7Endoscopy the European Regional Development Fund (FEDER). Unit, Hospital Arnau de Vilanova, Lleida, Spain. 8Endoscopy Unit, Hospital To Mireia Sanllorente from Clinical Research and Clinical Trial Unit (UICEC Sant Pau i Santa Creu, Barcelona, Spain. 9Endoscopy Unit, Hospital Costa del IDIBELL), SCReN platform, for her help in applying the different amendments Sol, Marbella, Spain. 10Department of Digestive Diseases, Hospital to each version of the trial protocol. Universitario Marqués de Valdecilla, Santander, Spain. 11 To Nuria Pelaez, Claudia F Consiglieri, and Albert Garcia-Sumalla of Hospital Hepato-Bilio-Pancreatic Unit, Department of Digestive Diseases, Hospital Universitari de Bellvitge, who will assist in the enrollment of patients. Universitari de Bellvitge, Bellvitge Biomedical Research Institute (IDIBELL), Steering Committee University of Barcelona, Barcelona, Spain. 12Biostatistics Unit, Institute of Carlos de La Serna: Hospital Universitario Rio Ortega, Valladolid, Spain Biomedical Research of Bellvitge, L’Hospitalet de Llobregat, Barcelona, Spain. 13 Manuel Perez-Miranda: Hospital Universitario Rio Ortega, Valladolid, Spain Clinical Research and Clinical Trial Unit (UICEC IDIBELL), Plataforma SCRen, Enrique Vázquez Sequeiros: Hospital Universitario Ramon y Cajal, Madrid, Clinical Pharmacology Department, Hospital Universitari de Bellvitge, Spain Bellvitge Biomedical Research Institute (IDIBELL), University of Barcelona, Juan Vila: Complejo Hospitalario de Navarra, Pamplona, Spain Barcelona, Catalonia, Spain. Joan B Gornals: Hospital Universitari Bellvitge-IDIBELL, Barcelona, Spain Received: 30 September 2019 Accepted: 11 December 2019 Authors’ contributions JBG, CT, and PH drafted the manuscript. RB, FBC, CDL, JME, AGP, FGH, CGA, ASY, AT, MPM, EVS, JVR, SS, JV, and JBG provided a critical review, and, as investigators at each institution, will promote the enrollment of patients. JBG References and JBC registered the study. JBG and CT contributed to the statistical 1. Banks PA, Bollen TL, Dervenis C, Gooszen HG, Johnson CD, Sarr MG, Tsiotos analysis and interpretation. JBG, MPM, EVS, JV, PH, CT, and SV participated in GG, Vege SS, Acute Pancreatitis Classification Working Group. Classification the design of the study. JBG, PH, and CT conceived the project, designed the of acute pancreatitis--2012: revision of the Atlanta classification and study, revised the manuscript, and approved the final submission. All authors definitions by international consensus. Gut. 2013;62:102–11. read and approved the final manuscript. 2. Boadas J, Balsells J, Busquets J, Codina-B A, Darnell A, Garcia-Borobia F, Ginés A, Gornals J, Gruartmoner G, Ilzarbe L, Merino X, Oms L, Puig I, Puig- Diví V, Vaquero E, Vida F, Molero X. Assessment and treatment of acute Funding pancreatitis. Position document of the Catalan Society of Gastroenterology, Instituto Carlos III (PI15/00585), Convocatoria 2015 Proyectos de Salud-ISCIII. Catalan Society of Surgery and Catalan Society of the Pancreas. This study was supported by a grant (PI15/00585) from the Instituto de Salud Gastroenterol Hepatol. 2015;38:82–96. Carlos III (ISCIII), Ministry of Economy and Competitiveness (Spain), and co- 3. van Santvoort HC, Besselink MG, Bakker OJ, et al. A step-up approach or open financed by the European Development Regional Fund “A way to achieve necrosectomy for necrotizing pancreatitis. N Engl J Med. 2010;362:1491–502. Europe” (ERDF). 4. van Brunschot S, van Grinsven J, van Santvoort HC, Bakker OJ, Besselink MG, This study received a grant (Fundacion SEED) from Sociedad Española de Boermeester MA, et al. Endoscopic or surgical step-up approach for infected Endoscopia Digestiva in 2015, and a grant (beca d’intensificació) from necrotising pancreatitis: a multicentre randomised trial. Lancet. 2018;391:51–8. Societat Catalana de Digestologia in 2016. 5. Varadarajulu S, Bang JY, Sutton BS, Trevino JM, Christein JD, Wilcox CM. Equal The funding bodies have no role in the trial design or interpretation of the efficacy of endoscopic and surgical cystogastrostomy for pancreatic pseudocyst data. drainage in a randomized trial. Gastroenterology. 2013;145:583–90.e1. 6. Bang JY, Arnoletti JP, Holt BA, Sutton B, Hassan MH, Navaneethan U, et al. Availability of data and materials AN endoscopic transluminal approach compared with minimally invasive Minimal dataset necessary to interpret the findings available from the surgery reduces complications and costs for patients with necrotizing corresponding author on reasonable request. pancreatitis. Gastroenterology. 2019;156:1027–40. 7. Trikudanathan G, Arain M, Attam R, Freeman ML. Interventions for necrotizing pancreatitis: an overview of current approaches. Expert Rev Ethics approval and consent to participate Gastroenterol Hepatol. 2013;7:463–75. Ethical approval has been obtained from the Comité Ético de Investigación 8. Weilert F, Binmoeller KF, Shah JN, et al. Endoscopic ultrasound-guided Clínica del Hospital Universitari de Bellvitge-IDIBELL (Barcelona; ref. approval drainage of pancreatic fluid collections with indeterminate adherence using no. 140/15), on 17 May 2015, reference number 140/15. Written informed temporary covered metal stents. Endoscopy. 2012;44:780–3. consent will be obtained from each patient before randomization. Any sub- 9. Itoi T, Binmoeller KF, Shah J, et al. Clinical evaluation of a novel lumen- sequent amendments of the protocol need to be approved by the relevant apposing metal stent for endosonography-guided pancreatic pseudocyst ethical bodies before implementation. and gallbladder drainage (with videos). Gastrointest Endosc. 2012;75:870–6. 10. Gornals JB, De la Serna-Higuera C, Sanchez-Yague A, et al. Endosonography- Consent for publication guided drainage of pancreatic fluid collections with a novel lumen- Not applicable apposing stent. Surg Endosc. 2013;27:1428–34. Gornals et al. Trials (2019) 20:791 Page 10 of 10 11. Lang GD, Fritz C, Bhat T, Das KK, Murad FM, Early DS, et al. EUS-guided 29. Bang JY, Navaneethan U, Hassan M, Sutton B, Hawes R, Varadarajulu S. Non- drainage of peripancreatic fluid collections with lumen-apposing metal superiority of lumen-apposing metal stents over plastic stents for drainage stents and plastic double-pigtail stents: comparison of efficacy and adverse of walled-off necrosis in a randomised trial. Gut. 2019;68:1200–9. event rates. Gastrointest Endosc. 2018;87:150–7. 12. Brimhall B, Han S, Tatman PD, Clark TJ, Wani S, Brauer B, et al. Increased incidence of pseudoaneurysm bleeding with lumen-apposing metal stents Publisher’s Note compared to double pigtail plastic stents in patients with peripancreatic Springer Nature remains neutral with regard to jurisdictional claims in fluid collections. Clin Gastroenterol Hepatol. 2018;16:1521–8. published maps and institutional affiliations. 13. Bang JY, Hasan M, Navaneethan U, Hawes R, Varadarajulu S. Lumen- apposing metal stents (LAMS) for pancreatic fluid collection (PFC) drainage: may not be business as usual. Gut. 2017;66:2054–6. 14. Stecher SS, Simon P, Friesecke S, et al. Delayed severe bleeding complications after treatment of pancreatic fluid collections with lumen-apposing metal stents. Gut. 2017;0:1–2. https://doi.org/10.1136/gutjnl-2016-313562. 15. Guo J, Saftoiu A, Vilmann P, Fusaroli P, Giovannini M, Mishra, et al. A multiinstitutional consensus on how to perform endoscopic ultrasound- guided peri-pancreatic fluid collection drainage and endoscopic necrosectomy. Endosc Ultrasound. 2017;6:285–91. 16. Saunders R, Ramesh J, Cicconi S, Evans J, Yip VS, Raraty M, Ghaneh P, Sutton R, Neoptolemos JP, Halloran C. A systematic review and meta-analysis of metal versus plastic stents for drainage of pancreatic fluid collections: metal stents are advantageous. Surg Endosc. 2019;33:1412–25. 17. Chen YI, Chen YI, Barkun AN, Adam V, Bai G, Singh VK, Bukhari M, Gutierrez OB, Elmunzer BJ, Moran R, Fayad L, El Zein M, Kumbhari V, Repici A, Khashab MA. Cost-effectiveness analysis comparing lumen-apposing metal stents with plastic stents in the management of pancreatic walled-off necrosis. Gastrointest Endosc. 2018;88:267–76. 18. Yoon SB, Lee IS, Choi MG. Metal versus plastic stents for drainage of pancreatic fluid collection: a meta-analysis. United European Gastroenterol J. 2018;6:729–38. 19. Bazerbachi F, Sawas T, Vargas EJ, Prokop LJ, Chari ST, Gleeson FC, Levy MJ, Martin J, Petersen BT, Pearson RK, Topazian MD, Vege SS, Abu Dayyeh BK. Metal stents versus plastic stents for the management of pancreatic walled- off necrosis: a systematic review and meta-analysis. Gastrointest Endosc. 2018;87:30–42. 20. Hammad T, Khan MA, Alastal Y, Lee W, Nawras A, Ismail MK, Kahaleh M. Efficacy and safety of lumen-apposing metal stents in management of pancreatic fluid collections: are they better than plastic stents? A systematic review and meta-analysis. Dig Dis Sci. 2018;63:289–301. 21. Yasuda I, Nakashima M, Iwai T, Isayama H, Itoi T, Hisai H, Inoue H, Kato H, Kanno A, Kubota K, Irisawa A, Igarashi H, Okabe Y, Kitano M, Kawakami H, Hayashi T, Mukai T, Sata N, Kida M, Shimosegawa T. Japanese multicenter experience of endoscopic necrosectomy for infected walled-off pancreatic necrosis: the JENIPaN study. Endoscopy. 2013;45:627–34. 22. Gardner TB, Coelho-Prabhu N, Gordon SR, Gelrud A, Maple JT, Papachristou GI, Freeman ML, Topazian MD, Attam R, Mackenzie TA, Baron TH. Direct endoscopic necrosectomy for the treatment of walled-off pancreatic necrosis: results from a multicenter U.S. series. Gastrointest Endosc. 2011;73:718–26. 23. Seifert H, Biermer M, Schmitt W, Jürgensen C, Will U, Gerlach R, Kreitmair C, Meining A, Wehrmann T, Rösch T. Transluminal endoscopic necrosectomy after acute pancreatitis: a multicentre study with long-term follow-up (the GEPARD study). Gut. 2009;58:1260–6. 24. Seewald S, Ang TL, Richter H, et al. Long-term results after endoscopic drainage and necrosectomy of symptomatic pancreatic fluid collections. Dig Endosc. 2012;24:36–41. 25. Fabbri C, Luigiano C, Cennamo V, et al. Endoscopic ultrasound-guided transmural drainage of infected pancreatic fluid collections with placement of covered self-expanding metal stents: a case series. Endoscopy. 2012;44:429–33. 26. Vazquez-Sequeiros E, Baron TH, Pérez-Miranda M, Sánchez-Yagüe A, Gornals J, Gonzalez-Huix F, Spanish Group for FCSEMS in Pancreas Collections, et al. Evaluation of the short- and long-term effectiveness and safety of fully covered self-expandable metal stents for drainage of pancreatic fluid collections: results of a Spanish nationwide registry. Gastrointest Endosc. 2016;84:450–7. 27. Penn DE, Draganov PV, Wagh MS, et al. Prospective evaluation of the use of fully covered selfexpanding metal stents for EUS-guided transmural drainage of pancreatic pseudocysts. Gastrointest Endosc. 2012;76:679–84. 28. Gornals JB, Consiglieri CF, Busquets J, Salord S, de-la-Hera M, Secanella L, Redondo S, Pelaez N, Fabregat J. Endoscopic necrosectomy of walled-off pancreatic necrosis using a lumen-apposing metal stent and irrigation technique. Surg Endosc. 2016;30:2592–602.