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Research

Analysis of Pediatric Pancreatitis (APPLE trial): Pre-study protocol of a multinational prospective clinical trial.

Project endorsed by IAP Council
Coordinated by: Péter Hegyi, MD, PhD, DSc

Abstract

Background: Single-centered studies show increased incidence of acute pancreatitis (AP) in children. Here, the Pediatric Section of the Hungarian Pancreatic Study Group introduce an international observational clinical trial (APPLE) to collect a critical mass of clinical data and biomedical research samples in a uniform prospective manner.

Summary: The APPLE-R is for patients with history of pancreatitis under 18 years old. The study primarily provides information on possible genetic variants behind the disease and their impact on the prognosis. The APPLE-P is for patients under 18 years old with a diagnosis of acute pancreatitis. Children with AP diagnosed based on the fulfillment of “2 out of 3” of the Atlanta criteria will be selected. This subtrial requests detailed information from the medical history, etiology, complains and symptoms, physical examinations, laboratory parameters, imaging, immediate therapy at admission and complications of the disease. The APPLE trial has been registered at the ISRCTN registry and received the relevant ethical approval. The study is open for all pediatric centers throughout the world.

Key message: this is the first worldwide study tracking earlier (APPLE-R) and ongoing episodes (APPLE-P) of pancreatitis.

Hypothesis

This multicenter prospective trial helps to understand the genetic background of pediatric pancreatitis. We will be able to identify early risk factors and a scoring system to stratify patients according to severity.

Objectives

The APPLE trials are designed to develop a simple and accurate clinical scoring system that can stratify children with AP during the first 6-12 hours of hospitalization according to their risk for severe disease course and specify the genetic background and recognize better the course of the pediatric pancreatitis.

Population

The APPLE-R is for patients with history of pancreatitis under 18 years old. Approximately 800 patients are planned to be collected within 3 years.

The APPLE-P is for patients under 18 years old with freshly diagnosed ongoing acute pancreatitis. Approximately 300 patients are planned to be enrolled within 3 years. Patients with AP diagnosed based on the fulfillment of “2 out of 3” of the criteria (presence of abdominal pain, signs of pancreatitis on imaging, 3x elevated pancreas enzyme level) will be selected.

Inclusion Period

Sun 1 February 2015 - Thu 1 February 2018

Clinical End Points

The multinational observational clinical trial (APPLE) is designed to collect a critical mass of clinical data from children suffering in AP in a uniform prospective manner to help fill the knowledge gap and provide simple, pediatric-specific, clinical scoring system that can stratify patients with AP on presentation.

Inclusion and Exclusion Criteria

APPLE-R inclusion criteria:

  • history of pancreatitis before the age of 18 years

APPLE-P inclusion criteria:
  • under 18 years old

  • newly diagnosed ongoing acute pancreatitis

APPLE-P Exclusion criteria:
  • above 18 years old

Authorship Rules

In order to give appropriate credit to each investigator/center we will use standardized authorship policy. At least 5 patients are required for a co-authorship. All other investigators/contributors who do not meet the criteria for authorship will be listed in an ‘acknowledgements’ section. For example those who provide purely technical help or a department chair who provided only general support.

Other Information

All information and documents (ethical approval, protocol, letter of intent to join, patient informed consent form, questionnaires) are available in different languages on the www.pancreas.hu website.

Case Report Form Templates

Download the template using the links below and submit via email to

Or submit your Case Report Form online at:

http://

References

  1. Lopez MJ, The changing incidence of acute pancreatitis in children: a single-institution perspective. J Pediatr. 2002;140:622-4.

  2. Morinville VD, Barmada MM, Lowe ME, Increasing incidence of acute pancreatitis at an American pediatric tertiary care center: is greater awareness among physicians responsible? Pancreas. 2010;39:5-8.

  3. Nydegger A, Heine RG, Ranuh R, Gegati-Levy R, Crameri J, Oliver MR, Changing incidence of acute pancreatitis: 10-year experience at the Royal Children's Hospital, Melbourne. J Gastroenterol Hepatol. 2007;22:1313-6.

  4. Park A, Latif SU, Shah AU, Tian J, Werlin S, Hsiao A, Pashankar D, Bhandari V, Nagar A, Husain SZ, Changing referral trends of acute pancreatitis in children: A 12-year single-center analysis. J Pediatr Gastroenterol Nutr. 2009;49:316-22.

  5. Sanchez-Ramirez CA, Larrosa-Haro A, Flores-Martinez S, Sanchez-Corona J, Villa-Gomez A, Macias-Rosales R, Acute and recurrent pancreatitis in children: etiological factors. Acta Paediatr. 2007;96:534-7.

  6. Werlin SL, Kugathasan S, Frautschy BC, Pancreatitis in children. J Pediatr Gastroenterol Nutr. 2003;37:591-5.

  7. Pant C, Deshpande A, Olyaee M, Anderson MP, Bitar A, Steele MI, Bass PF, 3rd, Sferra TJ, Epidemiology of acute pancreatitis in hospitalized children in the United States from 2000-2009. PLoS One. 2014;9:e95552.

  8. Meyer A, Coffey MJ, Oliver MR, Ooi CY, Contrasts and comparisons between childhood and adult onset acute pancreatitis. Pancreatology. 2013; 13:429-35.

  9. Parniczky A, Czako L, Dubravcsik Z, Farkas G, Hegyi P, Hritz I, Kelemen D, Morvay Z, Olah A, Pap A, Sahin-Toth M, Szabo F, Szentkereszti Z, Szmola R, Takacs T, Tiszlavicz L, Veres G, Szucs A, Lasztity N, Magyar Hasnyalmirigy M, [Pediatric pancreatitis. Evidence based management guidelines of the Hungarian Pancreatic Study Group]. Orv Hetil. 2015; 156:308-25.

  10. Morinville VD, Husain SZ, Bai H, Barth B, Alhosh R, Durie PR, Freedman SD, Himes R, Lowe ME, Pohl J, Werlin S, Wilschanski M, Uc A, Group I, Definitions of pediatric pancreatitis and survey of present clinical practices. J Pediatr Gastroenterol Nutr. 2012; 55:261-5.

  11. Hritz I, Czako L, Dubravcsik Z, Farkas G, Kelemen D, Lasztity N, Morvay Z, Olah A, Pap A, Parniczky A, Sahin-Toth M, Szentkereszti Z, Szmola R, Szucs A, Takacs T, Tiszlavicz L, Hegyi P, Magyar Hasnyalmirigy M, [Acute pancreatitis. Evidence based management guidelines of the Hungarian Pancreatic Study Group]. Orv Hetil. 2015; 156 (7):244-61.

  12. Dubravcsik Z, Farkas G, Hegyi P, Hritz I, Kelemen D, Lasztity N, Morvay Z, Olah A, Pap A, Parniczky A, Sahin-Toth M, Szentkereszti Z, Szmola R, Takacs T, Tiszlavicz L, Szucs A, Czako L, Magyar Hasnyalmirigy M, [Autoimmune pancreatitis. Evidence based management guidelines of the Hungarian Pancreatic Study Group]. Orv Hetil. 2015; 156:292-307.

  13. Szmola R, Farkas G, Hegyi P, Czako L, Dubravcsik Z, Hritz I, Kelemen D, Lasztity N, Morvay Z, Olah A, Parniczky A, Rubovszky G, Sahin-Toth M, Szentkereszti Z, Szucs A, Takacs T, Tiszlavicz L, Pap A, Magyar Hasnyalmirigy M, [Pancreatic cancer. Evidence based management guidelines of the Hungarian Pancreatic Study Group]. Orv Hetil. 2015; 156:326-39.

  14. Hritz I, Hegyi P: Early Achievable Severity (EASY) index for simple and accurate expedite risk stratification in acute pancreatitis. J Gastrointestin Liver Dis. 2015 Jun;24(2):177-82.

  15. Dubravcsik Z, Madácsy L, Gyökeres T, Vincze Á, Szepes Z, Hegyi P, Hritz I, Szepes A, Hungarian Pancreatic Study Group: Preventive pancreatic stents in the management of acute biliary pancreatitis (PREPAST trial): pre-study protocol for a multicenter, prospective, randomized, interventional, controlled trial. Pancreatology. 2015 Mar-Apr;15(2):115-23.

  16. Nemeth BC, Sahin-Toth M, Human cationic trypsinogen (PRSS1) variants and chronic pancreatitis. Am J Physiol Gastrointest Liver Physiol. 2014;306:G466-73. 17. Derikx MH, Kovacs P, Scholz M, Masson E, Chen JM, Ruffert C, Lichtner P, Te Morsche RH, Cavestro GM, Algul H, Berg T, Bodeker H, Bluher M, Bruno MJ, Buch S, Bugert P, Cichoz-Lach H, Dabrowski A, Farre A, Frank J, Gasiorowska A, Geisz A, Goni E, Grothaus J, Grutzmann R, Haas S, Hampe J, Hellerbrand C, Hegyi P, Huster D, Ioana M, Iordache S, Jurkowska G, Keim V, Landt O, Di Leo M, Lerch MM, Levy P, Lohr MJ, Macek M, Malats N, Malecka-Panas E, Mariani A, Martorana D, Mayerle J, Mora J, Mossner J, Muller S, Ockenga J, Paderova J, Pedrazzoli S, Pereira SP, Pfutzer R, Real FX, Rebours V, Ridinger M, Rietschel M, Rohde K, Sack S, Saftoiu A, Schneider A, Schulz HU, Soyka M, Simon P, Skipworth J, Stickel F, Stumvoll M, Testoni PA, Tonjes A, Treiber M, Weiss FU, Werner J, Wodarz N, Ferec C, Drenth JP, Witt H, Rosendahl J, Polymorphisms at PRSS1-PRSS2 and CLDN2-MORC4 loci associate with alcoholic and non-alcoholic chronic pancreatitis in a European replication study. Gut. 2014; DOI: 10.1136/gutjnl-2014-307453.

  17. Schnur A, Beer S, Witt H, Hegyi P, Sahin-Toth M, Functional effects of 13 rare PRSS1 variants presumed to cause chronic pancreatitis. Gut. 2014; 63:337-43.

  18. Joergensen MT, Geisz A, Brusgaard K, Schaffalitzky de Muckadell OB, Hegyi P, Gerdes AM, Sahin-Toth M, Intragenic duplication: a novel mutational mechanism in hereditary pancreatitis. Pancreas. 2011;40:540-6.

  19. Rosendahl J, Witt H, Szmola R, Bhatia E, Ozsvari B, Landt O, Schulz HU, Gress TM, Pfutzer R, Lohr M, Kovacs P, Bluher M, Stumvoll M, Choudhuri G, Hegyi P, te Morsche RH, Drenth JP, Truninger K, Macek M, Jr., Puhl G, Witt U, Schmidt H, Buning C, Ockenga J, Kage A, Groneberg DA, Nickel R, Berg T, Wiedenmann B, Bodeker H, Keim V, Mossner J, Teich N, Sahin-Toth M, Chymotrypsin C (CTRC) variants that diminish activity or secretion are associated with chronic pancreatitis. Nat Genet. 2008;40:78-82.

  20. Geisz A, Hegyi P, Sahin-Toth M, Robust autoactivation, chymotrypsin C independence and diminished secretion define a subset of hereditary pancreatitis-associated cationic trypsinogen mutants. FEBS J. 2013;280:2888-99.

  21. Sharer N, Schwarz M, Malone G, Howarth A, Painter J, Super M, Braganza J, Mutations of the cystic fibrosis gene in patients with chronic pancreatitis. N Engl J Med. 1998;339:645-52.

  22. Masson E, Chen JM, Audrezet MP, Cooper DN, Ferec C, A conservative assessment of the major genetic causes of idiopathic chronic pancreatitis: data from a comprehensive analysis of PRSS1, SPINK1, CTRC and CFTR genes in 253 young French patients. PLoS One. 2013;8:e73522.

  23. Witt H, Luck W, Hennies HC, Classen M, Kage A, Lass U, Landt O, Becker M, Mutations in the gene encoding the serine protease inhibitor, Kazal type 1 are associated with chronic pancreatitis. Nat Genet. 2000;25:213-6.

  24. Witt H, Beer S, Rosendahl J, Chen JM, Chandak GR, Masamune A, Bence M, Szmola R, Oracz G, Macek M, Jr., Bhatia E, Steigenberger S, Lasher D, Buhler F, Delaporte C, Tebbing J, Ludwig M, Pilsak C, Saum K, Bugert P, Masson E, Paliwal S, Bhaskar S, Sobczynska-Tomaszewska A, Bak D, Balascak I, Choudhuri G, Nageshwar Reddy D, Rao GV, Thomas V, Kume K, Nakano E, Kakuta Y, Shimosegawa T, Durko L, Szabo A, Schnur A, Hegyi P, Rakonczay Z, Jr., Pfutzer R, Schneider A, Groneberg DA, Braun M, Schmidt H, Witt U, Friess H, Algul H, Landt O, Schuelke M, Kruger R, Wiedenmann B, Schmidt F, Zimmer KP, Kovacs P, Stumvoll M, Bluher M, Muller T, Janecke A, Teich N, Grutzmann R, Schulz HU, Mossner J, Keim V, Lohr M, Ferec C, Sahin-Toth M, Variants in CPA1 are strongly associated with early onset chronic pancreatitis. Nat Genet. 2013;45:1216-20.

  25. Ragvin A, Fjeld K, Weiss FU, Torsvik J, Aghdassi A, Mayerle J, Simon P, Njolstad PR, Lerch MM, Johansson S, Molven A, The number of tandem repeats in the carboxyl-ester lipase (CEL) gene as a risk factor in alcoholic and idiopathic chronic pancreatitis. Pancreatology. 2013;13:29-32.

  26. Banks PA, Bollen TL, Dervenis C, Gooszen HG, Johnson CD, Sarr MG, Tsiotos GG, Vege SS, Acute Pancreatitis Classification Working G, Classification of acute pancreatitis--2012: revision of the Atlanta classification and definitions by international consensus. Gut. 2013;62:102-11.

  27. Abu-El-Haija M, Lin TK, Palermo J, Update to the management of pediatric acute pancreatitis: highlighting areas in need of research. J Pediatr Gastroenterol Nutr. 2014; 58:689-93.

  28. Bai HX, Lowe ME, Husain SZ, What have we learned about acute pancreatitis in children? J Pediatr Gastroenterol Nutr. 2011;52:262-70.

  29. Joergensen M, Brusgaard K, Cruger DG, Gerdes AM, Schaffalitzky de Muckadell OB, Incidence, etiology and prognosis of first-time acute pancreatitis in young patients: a population-based cohort study. Pancreatology. 2010;10:453-61.

  30. Lucidi V, Alghisi F, Dall'Oglio L, D'Apice MR, Monti L, De Angelis P, Gambardella S, Angioni A, Novelli G, The etiology of acute recurrent pancreatitis in children: a challenge for pediatricians. Pancreas. 2011;40:517-21.

  31. Park AJ, Latif SU, Ahmad MU, Bultron G, Orabi AI, Bhandari V, Husain SZ, A comparison of presentation and management trends in acute pancreatitis between infants/toddlers and older children. J Pediatr Gastroenterol Nutr. 2010;51:167-70.

  32. Ranson JH, Rifkind KM, Roses DF, Fink SD, Eng K, Localio SA, Objective early identification of severe acute pancreatitis. Am J Gastroenterol. 1974;61:443-51.

  33. Ranson JH, Etiological and prognostic factors in human acute pancreatitis: a review. Am J Gastroenterol. 1982;77:633-8.

  34. Blamey SL, Imrie CW, O'Neill J, Gilmour WH, Carter DC, Prognostic factors in acute pancreatitis. Gut. 1984;25:1340-6.

  35. Knaus WA, Draper EA, Wagner DP, Zimmerman JE, APACHE II: a severity of disease classification system. Crit Care Med. 1985;13:818-29.

  36. Suzuki M, Fujii T, Takahiro K, Ohtsuka Y, Nagata S, Shimizu T, Scoring system for the severity of acute pancreatitis in children. Pancreas. 2008;37:222-3.

  37. Lautz TB, Chin AC, Radhakrishnan J, Acute pancreatitis in children: spectrum of disease and predictors of severity. J Pediatr Surg. 2011;46:1144-9.

  38. Fabre A, Petit P, Gaudart J, Mas E, Vial J, Olives JP, Sarles J, Severity scores in children with acute pancreatitis. J Pediatr Gastroenterol Nutr. 2012;55:266-7.

  39. DeBanto JR, Goday PS, Pedroso MR, Iftikhar R, Fazel A, Nayyar S, Conwell DL, Demeo MT, Burton FR, Whitcomb DC, Ulrich CD, 2nd, Gates LK, Jr., Midwest Multicenter Pancreatic Study G, Acute pancreatitis in children. Am J Gastroenterol. 2002;97:1726-31.

  40. Uc A, Predicting the severity of pediatric acute pancreatitis: are we there yet? J Pediatr Gastroenterol Nutr. 2013;56:584-5.

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