PROTon Pump Inhibitors and Stent OCclusion Rate Of Lumen Apposing Metal Stents (PROTOCOL)

PROTon Pump Inhibitors and Stent OCclusion Rate Of Lumen Apposing Metal Stents (PROTOCOL)

The goal of this observational retrospective cohort study in combination with an expert study is to assess the clinical relevance and management of Lumen apposing metal stent (LAMS)-occlusion and LAMS-occlusion-related complications as well as the influence of proton pump inhibitors (PPI) on LAMS-occlusion.

The main questions this study aims to answer are:

• the individual management of LAMS-occlusion and LAMS-occlusion-related complications in the respective centers participating in the study.
• if there is an association between PPI-intake and LAMS-occlusion. Participants for the retrospective cohort study will be enrolled retrospectively among European centers with expertise in pancreatology. The expert survey will be distributed European-wide to centers with special expertise in pancreatology.

Study Overview

• Status: Recruiting
• Conditions: Acute Pancreatitis
• Intervention / Treatment: Drug: Proton pump inhibitor; Device: LAMS-implantation

Detailed Description

A common complication of acute pancreatitis is the formation of necrosis in 5-10% of all patients, which leads to an increased overall mortality of 28% for infected necroses. Currently, lumen apposing metal stents (LAMS) are widely used to address necrotic masses. LAMS-occlusion is postulated to be a considerable complication. However, the prevalence, clinical impact and management of LAMS-occlusion-related complications remains uncertain. Moreover, the German guidelines for management of acute pancreatitis do not specify whether a concomitant proton pump inhibitor (PPI)-therapy should be discontinued or not. A recent study suggested a lower rate of LAMS-occlusions, but a higher number of required endoscopic necrosectomies upon concomitant PPI-therapy. Thus, current data are conflicting.

The investigators therefore aim to perform an expert survey and a retrospective cohort study to elucidate the clinical importance of LAMS-occlusion-related complications and the effect of PPI-intake on occlusion. First, a survey will be sent to European centers with special expertise in pancreatology. Here, the investigators aim to assess the number of LAMS applied annually, whether the experts consider occlusion a clinically relevant complication, and whether there are standard operating procedures for LAMS-occlusion and PPI-discontinuation. Second, the investigators will perform a retrospective multicenter cohort study to assess patient data for PPI intake, frequency of LAMS-occlusion and other complications using a RedCap database.

Quality assurance and data checks of the data entered will be performed by the study coordinator after the initial data entry of the participating centers. For missing data, for which the RedCap form cannot be filled out, the online forms comprise extra fields for "missing data". The data entered in the RedCap online survey will stem from paper or electronic case report forms depending which of these are used at the respective centers. Source data verification will be performed by the participating centers themselves upon data entry into the online questionnaires.

A standard operating procedure will be handed out to the participating centers which will feature any information about how data should be entered. Here, the minimum number of patients which needs to be entered into the study in order to participate will be addressed. The maximum of patients who can be entered is dependent on the respective centers; in principle all patients who received a LAMS for drainage of a WON in the respective centers can be included. As the investigators perform a retrospective study, there will be no need to account for reporting of adverse events.

Based on a power calculation of a preliminary in-house dataset from the University Hospital Goettingen the investigators aim to include a total number of 639 patients.

For missing, unavailable, non-reported or uninterpretable data, the RedCap survey will comprise extra fields as described above. In these, the participating researcher can state that data is missing. If this information is essential for the primary or secondary endpoints of our study, the data entry can be excluded from further analyses by the data monitoring committee.

For the statistical analyses of the data gathered from the expert survey the investigators will apply a Fisher/Chi2-test to assess the clinical relevance as well as the clinical management of LAMS-occlusion and LAMS-occlusion-related complications. For the retrospective cohort study, a Chi2-test will be used to address correlations between PPI-intake and LAMS-occlusion. To assess the frequency of occlusion-related-complications, risk factors for LAMS-occlusion beyond PPI-intake and differences in clinical management of LAMS-occlusion in the respective centers, logistic regression/LASSO will be applied.

• Study Type: Observational
• Enrollment (Estimated): 639

Contacts and Locations

• Study Contact: Name: Jacob Hamm; Phone Number: +49 551 39 65659; Email: jacob.hamm@med.uni-goettingen.de
• Study Contact Backup: Name: Christoph Ammer-Herrmenau, MD; Phone Number: +495513962301; Email: christoph.herrmenau@med.uni-goettingen.de

Study Locations

• Austria
  • Niederösterreich
    • St. Pölten, Niederösterreich, Austria, 3100
      • Not yet recruiting
      • University Hospital St. Pölten
      • Contact: Emanuel Steiner, MD; Phone Number: +43 2742/9004-0; Email: Emanuel.Steiner@stpoelten.lknoe.at
• Germany
  • Baden-Württemberg
    • Heidelberg, Baden-Württemberg, Germany, 69120
      • Not yet recruiting
      • University Hospital Heidelberg
      • Contact: Ana Dugic, MD; Email: dugica@gmail.com
  • Bavaria
    • Munich, Bavaria, Germany, 80336
      • Recruiting
      • Ludwig Maximilians University
      • Contact: Simon Sirtl, MD; Phone Number: +49 89 4400 72391; Email: Simon.Sirtl@med.uni-muenchen.de
    • Munich, Bavaria, Germany, 80939
      • Recruiting
      • Technical University Munich
      • Contact: Veit Philip, MD; Phone Number: +49 89/4140-9350; Email: veit.phillip@mri.tum.de
    • Regensburg, Bavaria, Germany, 93053
      • Not yet recruiting
      • University Hospital Regensburg
      • Contact: Sophie Schlosser-Hupf, MD; Email: Sophie.Schlosser-Hupf@klinik.uni-regensburg.de
  • Hessen
    • Hanau, Hessen, Germany, 63450
      • Not yet recruiting
      • Klinikum Hanau
      • Contact: Lukas Welsch, MD; Email: lukas-welsch@web.de
  • Lower Saxony
    • Goettigen, Lower Saxony, Germany, 37075
      • Recruiting
      • University Medical Center Goettingen
      • Contact: Jacob Hamm; Phone Number: +49 551 3965659; Email: jacob.hamm@med.uni-goettingen.de
      • Contact: Christoph Ammer-Herrmenau, MD; Phone Number: +49 551 3962301; Email: christoph.herrmenau@med.uni-goettingen.de
  • Northrine Westfalia
    • Aachen, Northrine Westfalia, Germany, 52062
      • Not yet recruiting
      • University Hospital Aachen
      • Contact: Karim Hamesch, MD
  • Sachsen
    • Leipzig, Sachsen, Germany, 04103
      • Not yet recruiting
      • University Hospital Leipzig
      • Contact: Albrecht Hoffmeister, MD; Phone Number: +49 341 - 97 12240; Email: gastroenterologie@medizin.uni-leipzig.de
  • Sachsen-Anhalt
    • Halle, Sachsen-Anhalt, Germany, 06120
      • Not yet recruiting
      • University Hospital Halle
      • Contact: Julian Cardinal von Widdern, MD; Phone Number: +49 345 557 2661; Email: julian.cardinal-von-widdern@uk-halle.de
  • Schleswig-Holstein
    • Kiel, Schleswig-Holstein, Germany, 24105
      • Not yet recruiting
      • University Hospital Schleswig-Holstein
      • Contact: Mark Ellrichmann, MD; Email: Mark.Ellrichmann@uksh.de

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Probability Sample

Study Population

All patients included in the retrospective cohort study will be from private/public non-academic or academic teaching hospitals in Europe.

All patients above 18 years of age who received a lumen apposing metal stent (LAMS) for drainage of a walled off necrosis (WON) upon acute pancreatitis will be included.

Moreover, the expert survey will be distributed to European experts (gastroenterological interventionalists) from private/public non-academic or academic teaching hospitals with special expertise in pancreatology.

Description

Retrospective cohort study:

Inclusion Criteria:

- Patients in which a Lumen apposing metal stent (LAMS) was applied into a walled off necrosis (WON) as a complication of an acute pancreatitis (AP).

Exclusion Criteria:

• Patients in which a LAMS was applied into a pseudocyst instead of a WON.
• Patients in which a LAMS was used to address a postoperative pancreatic fistula (POPF).
• Patients in which concomitant PPI-treatment was not assessed/not documented.

Expert survey:

Inclusion Criteria:

- European experts (gastroenterological interventionalists) with expertise in pancreatology

Exclusion Criteria:

• Centers which apply less than 10 LAMS per year
• Centers with less than two years experience with LAMS

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
PPI-group; Patients who received a lumen apposing metal stent (LAMS) for drainage of a walled off necroses (WON) upon acute pancreatitis (AP) and were prescribed proton pump inhibitors (PPI) concomitantly	Drug: Proton pump inhibitor; Patients who received a lumen apposing metal stent (LAMS) for drainage of a walled off necrosis (WON) upon acute pancreatitis will be divided into a PPI/Non-PPI group depending on if they concomitantly were prescribed a PPI or not; Device: LAMS-implantation; Patients who received a lumen apposing metal stent (LAMS) for drainage of a walled off necrosis (WON) upon acute pancreatitis
Non-PPI-group; Patients who received a lumen apposing metal stent (LAMS) for drainage of a walled off necroses (WON) upon acute pancreatitis (AP) and were not prescribed proton pump inhibitors (PPI) concomitantly	Device: LAMS-implantation; Patients who received a lumen apposing metal stent (LAMS) for drainage of a walled off necrosis (WON) upon acute pancreatitis

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Retrospective Cohort Study Primary Outcome Measure: Association between frequency of LAMS-occlusion and concomitant PPI-intake	All patients who received a LAMS from the time-point since LAMS have been used at the respective centers will be included. In all patients who received LAMS, their medical records will be checked if a PPI was taken or not. Next, it will be assessed how many patients who took PPI (PPI-group) had a LAMS-occlusion in comparison with the patients who did not take a PPI (Non-PPI-group).	Until LAMS-removal, an average of 4 weeks after implantation
Expert Survey Primary Outcome Measure Number 1: Assessment of the clinical relevance of LAMS-occlusion and LAMS-occlusion-related complications	The expert will be asked if he had experiences with complications after total/partial LAMS-occlusion (yes/no). Moreover, the expert will be asked if he would consider these as frequent complications (yes/no). Next, the expert will be asked how frequent he would consider complications after total/partial LAMS-occlusion to occur (scale 0-20%). Finally, the expert will be asked which complications he had witnessed after total/partial LAMS-occlusion (progression of the pancreatic collection, infection of the WON, sepsis, other).	Until LAMS-removal, an average of 4 weeks after implantation
Expert Survey Primary Outcome Measure Number 2: Assessment of the clinical management of LAMS-occlusion in the respective participating centers	Two clinical cases will be presented. The first case will be suggestive for a total LAMS occlusion with infection/sepsis as a complication consecutive to the stent-occlusion. The second case will be suggestive for a partial LAMS occlusion with no apparent complication. For each case, the expert will be asked if he would consider this a complication (yes/no). Moreover, it will be asked if the expert would remove the LAMS (yes/no), if he would place pigtails over the ostium afterwards (yes/no) and if not what he would do otherwise (endoscopic necrosectomy, place pigtail through the LAMS, disrupted pancreatic duct evaluation via endoscopic retrograde cholangiopancreatography/magnet resonance cholangiopancreatography (ERCP/MRCP), endoscopic papillotomy, other).	Until LAMS-removal, an average of 4 weeks after implantation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Retrospective Cohort Study Secondary Outcome Number 1: Determination of the frequency of LAMS-occlusion-related complications	For every case it will be assess whether ther was a LAMS-occlusion and if this led to a complication (yes/no). Moreover, the type of complication will be assessed (progress of the pancreatic collection, infection of the WON, sepsis, other/unknown).	Until LAMS-removal, an average of 4 weeks after implantation
Retrospective Cohort Study Secondary Outcome Number 2: Assessment of other risk factor for LAMS-occlusion beyond PPI-intake	For every case, other potential risk factors for LAMS-occlusion will be assessed such as the gender (female, male, diverse), the body mass index (BMI), the type of pancreatitis (acute pancreatitis, recurrent acute pancreatitis, chronic pancreatitis) and the etiology of pancreatitis (biliary, alcohol-induced, idiopathic, iatrogenic, hypercalcemia, hypertriglyceridemia, drugs, traumatic, other/unknown). Moreover, the access way of LAMS-application (transgastric, transduodenal, other/unknown), the type of LAMS used (Hot Axios, Axios, Spaxus, Hot Spaxus, Nagi, Hanaro-Stent, GEN II, other/unknown) and the lumen diameter of the LAMS (e.g. Hot Axios/Axios: 6,8,10,15,20mm, not documented/not assessed) will be assessed.	Until LAMS-removal, an average of 4 weeks after implantation
Retrospective Cohort Study Secondary Outcome Number 3: Assessment of differences in the clinical management of LAMS-occlusion and LAMS-occlusion-related complications between the participating centers	For each case it will be assessed if a LAMS-occlusion occured after application (yes/no). Moreover, the type of LAMS-occlusion will be assessed (partial LAMS-occlusion, total LAMS-occlusion, unknown/not documented). Next, it will be asked how the occlusion was diagnosed (gastroscopy, endoscopic ultrasound, computer tomography, abdominal ultrasound, other). Moreover, the total number of necrosectomies will be assessed (free text). In addition it will be assessed if the LAMS was removed due to a complication (yes/no, unknown/not documented) and what was done in the following if the LAMS was removed (pigtails were placed over the ostium, another LAMS was applied, surgical procedure, percutaneous drainage, other/unknown). If the LAMS was not removed, it will be asked what else was done in the following (nothing, endoscopic necrosectomy, pigtails were placed through the LAMS, disrupted pancreatic duct evaluation via ERCP/MRCP, endoscopic papillotomy, other/unknown).	Until LAMS-removal, an average of 4 weeks after implantation
Expert Survey Secondary Outcome Number 1: To assess if a standard operating procedure (SOP) for follow-up-examinations regarding stent occlusion after LAMS-implantation exists in the respective centers.	The expert will basked if a SOP for apparative follow-up-examinations after LAMS application exists at their center (yes/no/unknown). Moreover, it will be asked how many follow up examinations are performed (1, 2, 3 or more), at which time-points (<3 days, within 1 week, 2,3,4,5-8 weeks) and how (CT, MRI, gastroscopy, endoscopic ultrasound, abdominal ultrasound) these are performed. Additionally, it will be asked when the LAMS would be removed normally (≤4weeks, 5-8 weeks, ≥9 weeks after implantation). Moreover, it will be asked which procedure is normally followed after LAMS removal (change LAMS to pigtails, just remove the LAMS, other).	Until LAMS-removal, an average of 4 weeks after implantation
Expert Survey Secondary Outcome Number 2: To assess whether the respective clinical center has a SOP regarding LAMS and concomitant PPI-intake.	The expert will be asked, if proton pump inhibitors are continued/discontinued upon LAMS-application at his/her center (should be discontinued, should be continued with the same dosage, should be continued with another dosage, currently no standard procedure). If the PPI should be continued in another dosage, it will be asked whether it should be continued in half the standard dose, standard dose, double standard dose or more than standard dose. Moreover, it will be asked if any specific PPI should be discontinued and if yes which of the following (Omeprazole, Esomeprazole, Pantoprazole, Lansoprazole, Rabeprazole).	Until LAMS-removal, an average of 4 weeks after implantation
Expert Survey Secondary Outcome Number 3: To assess the experts definition of the term "LAMS-occlusion" in general, as well as the term "partial LAMS occlusion".	The expert will be asked which of the following potential causes of LAMS occlusion he/she would include in a universal valid definition for reasons of LAMS-occlusion: tissue ingrowth, tissue overgrowth, food impaction, impaction with liquid necrotic debris, impaction with solid necrotic debris, blood clot formation, stent migration, stent kinking, stent compression, stent fracture, other. Moreover, the expert will be asked how he/she would define partial LAMS-occlusion: An occlusion which is still passable with the endoscope; An occlusion in which you can still see through the LAMS with the optics of the endoscope; An occlusion with liquid parts, other.	Until LAMS-removal, an average of 4 weeks after implantation

Collaborators and Investigators

• Sponsor: University Medical Center Goettingen
• Collaborators: Ludwig-Maximilians - University of Munich; University of Leipzig; University Hospital Heidelberg; Technical University of Munich; University Hospital Schleswig-Holstein; University Hospital Regensburg; University Hospital, Aachen; Landesklinikum Sankt Polten; St. Josef Hospital Bochum; Klinikum Stadt Hanau; University Hospital in Halle
• Investigators: Principal Investigator: Jacob Hamm, Department of Gastroenterology, University Hopsital Goettingen; Principal Investigator: Christoph Ammer-Herrmenau, MD, Department of Gastroenterology, University Hopsital Goettingen; Study Chair: Volker Ellenrieder, Professor, Department of Gastroenterology, University Hopsital Goettingen

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.
• Werge M, Novovic S, Schmidt PN, Gluud LL. Infection increases mortality in necrotizing pancreatitis: A systematic review and meta-analysis. Pancreatology. 2016 Sep-Oct;16(5):698-707. doi: 10.1016/j.pan.2016.07.004. Epub 2016 Jul 9.
• Yasuda I, Takahashi K. Endoscopic management of walled-off pancreatic necrosis. Dig Endosc. 2021 Mar;33(3):335-341. doi: 10.1111/den.13699. Epub 2020 Jun 7.
• Chandrasekhara V, Barthet M, Deviere J, Bazerbachi F, Lakhtakia S, Easler JJ, Peetermans JA, McMullen E, Gjata O, Gourlay ML, Abu Dayyeh BK. Safety and efficacy of lumen-apposing metal stents versus plastic stents to treat walled-off pancreatic necrosis: systematic review and meta-analysis. Endosc Int Open. 2020 Nov;8(11):E1639-E1653. doi: 10.1055/a-1243-0092. Epub 2020 Oct 22.
• Scarpignato C, Gatta L, Zullo A, Blandizzi C; SIF-AIGO-FIMMG Group; Italian Society of Pharmacology, the Italian Association of Hospital Gastroenterologists, and the Italian Federation of General Practitioners. Effective and safe proton pump inhibitor therapy in acid-related diseases - A position paper addressing benefits and potential harms of acid suppression. BMC Med. 2016 Nov 9;14(1):179. doi: 10.1186/s12916-016-0718-z.
• Lorenz P, Lynen Jansen P, Beyer G, Hoffmeister A, Lerch MM, Mayerle J. S3-Leitlinie Pankreatitis - Leitlinienreport der Deutschen Gesellschaft fur Gastroenterologie, Verdauungs- und Stoffwechselkrankheiten (DGVS) - September 2021 - AWMF Registernummer 021-003. Z Gastroenterol. 2022 Mar;60(3):e236-e247. doi: 10.1055/a-1713-4244. Epub 2022 Mar 9. No abstract available. German.
• Murata A, Ohtani M, Muramatsu K, Matsuda S. Effects of proton pump inhibitor on outcomes of patients with severe acute pancreatitis based on a national administrative database. Pancreatology. 2015 Sep-Oct;15(5):491-496. doi: 10.1016/j.pan.2015.07.006. Epub 2015 Aug 8.
• Yoo JH, Kwon CI, Yoo KH, Yoon H, Kim WH, Ko KH, Hong SP, Park PW. [Effect of proton pump inhibitor in patients with acute pancreatitis - pilot study]. Korean J Gastroenterol. 2012 Dec;60(6):362-7. doi: 10.4166/kjg.2012.60.6.362. Korean.
• Powers PC, Siddiqui A, Sharaiha RZ, Yang G, Dawod E, Novikov AA, Javia A, Edirisuriya C, Noor A, Mumtaz T, Iqbal U, Loren DE, Kowalski TE, Cosgrove N, Alicea Y, Tyberg A, Andalib I, Kahaleh M, Adler DG. Discontinuation of proton pump inhibitor use reduces the number of endoscopic procedures required for resolution of walled-off pancreatic necrosis. Endosc Ultrasound. 2019 May-Jun;8(3):194-198. doi: 10.4103/eus.eus_59_18.
• Martins de Oliveira R, Antunes E, Pedrazzoli J Jr, Gambero A. The inhibitory effects of H+ K+ ATPase inhibitors on human neutrophils in vitro: restoration by a K+ ionophore. Inflamm Res. 2007 Mar;56(3):105-11. doi: 10.1007/s00011-006-6127-6.
• Handa O, Yoshida N, Fujita N, Tanaka Y, Ueda M, Takagi T, Kokura S, Naito Y, Okanoue T, Yoshikawa T. Molecular mechanisms involved in anti-inflammatory effects of proton pump inhibitors. Inflamm Res. 2006 Nov;55(11):476-80. doi: 10.1007/s00011-006-6056-4.
• Hackert T, Tudor S, Felix K, Dovshanskiy D, Hartwig W, Simon WA, Werner J. Effects of pantoprazole in experimental acute pancreatitis. Life Sci. 2010 Oct 23;87(17-18):551-7. doi: 10.1016/j.lfs.2010.09.008. Epub 2010 Sep 17.

Study record dates

Study Major Dates

• Study Start (Actual): May 5, 2023
• Primary Completion (Estimated): December 1, 2023
• Study Completion (Estimated): December 1, 2023

Study Registration Dates

• First Submitted: March 30, 2023
• First Submitted That Met QC Criteria: April 16, 2023
• First Posted (Actual): April 18, 2023

Study Record Updates

• Last Update Posted (Actual): May 31, 2023
• Last Update Submitted That Met QC Criteria: May 26, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Keywords: acute pancreatitis; lumen apposing metal stents (LAMS); proton pump inhibitors (PPI)
• Additional Relevant MeSH Terms: Digestive System Diseases; Pancreatic Diseases; Pancreatitis; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Proton Pump Inhibitors
• Other Study ID Numbers: 2023-02441

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: Collaborators of this study that recruited patients in the PROTOCOL trial may claim access to the final dataset to perform post-hoc studies; these proposals will be reviewed and granted by the steering committee.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes