EarLy Elimination of Fatty Acids iN hypertriglyceridemia-induced acuTe pancreatitis (ELEFANT trial): Protocol of an open-label, multicenter, adaptive randomized clinical trial

Noémi Zádori, Noémi Gede, Judit Antal, Andrea Szentesi, Hussain Alizadeh, Áron Vincze, Ferenc Izbéki, Mária Papp, László Czakó, Márta Varga, Enrique de-Madaria, Ole H. Petersen, Vijay P. Singh, Julia Mayerle, Nándor Faluhelyi, Attila Miseta, István Reiber, Péter Hegyi

Research output: Contribution to journalArticle

Abstract

Introduction: Acute pancreatitis (AP) is a life-threatening inflammatory disease, with no specific pharmacological treatment. However, concerning some etiologies, early specific intervention (such as ERCP in biliary AP) has proven to be remarkably beneficial. Hypertriglyceridemia (HTG) induces severe pancreatic damage by several direct (cellular damage) and indirect (deterioration of microcirculation) mechanisms. Published data suggest that early removal of triglycerides (TGs) and toxic free fatty acids (FFAs) may be advantageous; however, high-quality evidence is still missing in the literature. Methods: Design: ELEFANT is a randomized controlled, multicenter, international trial testing the concept that early elimination of TGs and FFAs from the blood is beneficial in HTG-AP. The study will be performed with the adaptive “drop-the-loser” design, which supports the possibility of dropping the inferior treatment arm, based on the results of the interim analysis. Patients with HTG-AP defined by TG level over 11.3 mmol/l (1000 mg/dL) are randomized into three groups: (A) patients who undergo plasmapheresis and receive aggressive fluid resuscitation; (B) patients who receive insulin and heparin treatment with aggressive fluid resuscitation; and (C) patients with aggressive fluid resuscitation. Please note that all intervention must be started within 48 h from the onset of abdominal pain. Exclusion criteria are designed logically to decrease the possibility of any distorting effects of other diseases. The composite primary endpoint will include both severity and mortality. Results: Our null hypothesis is that early elimination of HTG and FFAs reduces the risk of mortality and severity of AP. Sample size calculation suggests that 495 patients will need to be enrolled in order to confirm or reject the hypothesis with a 10% dropout, 80% power and 95% significance level. The general safety and quality checks required for high-quality evidence will be adhered to. The study will be organized between February 2020 and December 2025. Conclusion: Our study would provide the first direct evidence for or against early intervention in HTG-induced AP.

Original languageEnglish
JournalPancreatology
DOIs
Publication statusAccepted/In press - Jan 1 2020

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Hypertriglyceridemia
Clinical Protocols
Pancreatitis
Fatty Acids
Randomized Controlled Trials
Nonesterified Fatty Acids
Resuscitation
Triglycerides
Plasmapheresis
Mortality
Endoscopic Retrograde Cholangiopancreatography
Poisons
Microcirculation
Sample Size
Abdominal Pain
Multicenter Studies
Heparin
Therapeutics
Pharmacology
Insulin

Keywords

  • Acute pancreatitis
  • Free fatty acids
  • Heparin
  • Hypertriglyceridemia
  • Insulin
  • Plasmapheresis
  • Randomized clinical trial

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Hepatology
  • Gastroenterology

Cite this

EarLy Elimination of Fatty Acids iN hypertriglyceridemia-induced acuTe pancreatitis (ELEFANT trial) : Protocol of an open-label, multicenter, adaptive randomized clinical trial. / Zádori, Noémi; Gede, Noémi; Antal, Judit; Szentesi, Andrea; Alizadeh, Hussain; Vincze, Áron; Izbéki, Ferenc; Papp, Mária; Czakó, László; Varga, Márta; de-Madaria, Enrique; Petersen, Ole H.; Singh, Vijay P.; Mayerle, Julia; Faluhelyi, Nándor; Miseta, Attila; Reiber, István; Hegyi, Péter.

In: Pancreatology, 01.01.2020.

Research output: Contribution to journalArticle

Zádori, N, Gede, N, Antal, J, Szentesi, A, Alizadeh, H, Vincze, Á, Izbéki, F, Papp, M, Czakó, L, Varga, M, de-Madaria, E, Petersen, OH, Singh, VP, Mayerle, J, Faluhelyi, N, Miseta, A, Reiber, I & Hegyi, P 2020, 'EarLy Elimination of Fatty Acids iN hypertriglyceridemia-induced acuTe pancreatitis (ELEFANT trial): Protocol of an open-label, multicenter, adaptive randomized clinical trial', Pancreatology. https://doi.org/10.1016/j.pan.2019.12.018
Zádori, Noémi ; Gede, Noémi ; Antal, Judit ; Szentesi, Andrea ; Alizadeh, Hussain ; Vincze, Áron ; Izbéki, Ferenc ; Papp, Mária ; Czakó, László ; Varga, Márta ; de-Madaria, Enrique ; Petersen, Ole H. ; Singh, Vijay P. ; Mayerle, Julia ; Faluhelyi, Nándor ; Miseta, Attila ; Reiber, István ; Hegyi, Péter. / EarLy Elimination of Fatty Acids iN hypertriglyceridemia-induced acuTe pancreatitis (ELEFANT trial) : Protocol of an open-label, multicenter, adaptive randomized clinical trial. In: Pancreatology. 2020.
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abstract = "Introduction: Acute pancreatitis (AP) is a life-threatening inflammatory disease, with no specific pharmacological treatment. However, concerning some etiologies, early specific intervention (such as ERCP in biliary AP) has proven to be remarkably beneficial. Hypertriglyceridemia (HTG) induces severe pancreatic damage by several direct (cellular damage) and indirect (deterioration of microcirculation) mechanisms. Published data suggest that early removal of triglycerides (TGs) and toxic free fatty acids (FFAs) may be advantageous; however, high-quality evidence is still missing in the literature. Methods: Design: ELEFANT is a randomized controlled, multicenter, international trial testing the concept that early elimination of TGs and FFAs from the blood is beneficial in HTG-AP. The study will be performed with the adaptive “drop-the-loser” design, which supports the possibility of dropping the inferior treatment arm, based on the results of the interim analysis. Patients with HTG-AP defined by TG level over 11.3 mmol/l (1000 mg/dL) are randomized into three groups: (A) patients who undergo plasmapheresis and receive aggressive fluid resuscitation; (B) patients who receive insulin and heparin treatment with aggressive fluid resuscitation; and (C) patients with aggressive fluid resuscitation. Please note that all intervention must be started within 48 h from the onset of abdominal pain. Exclusion criteria are designed logically to decrease the possibility of any distorting effects of other diseases. The composite primary endpoint will include both severity and mortality. Results: Our null hypothesis is that early elimination of HTG and FFAs reduces the risk of mortality and severity of AP. Sample size calculation suggests that 495 patients will need to be enrolled in order to confirm or reject the hypothesis with a 10{\%} dropout, 80{\%} power and 95{\%} significance level. The general safety and quality checks required for high-quality evidence will be adhered to. The study will be organized between February 2020 and December 2025. Conclusion: Our study would provide the first direct evidence for or against early intervention in HTG-induced AP.",
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AU - Zádori, Noémi

AU - Gede, Noémi

AU - Antal, Judit

AU - Szentesi, Andrea

AU - Alizadeh, Hussain

AU - Vincze, Áron

AU - Izbéki, Ferenc

AU - Papp, Mária

AU - Czakó, László

AU - Varga, Márta

AU - de-Madaria, Enrique

AU - Petersen, Ole H.

AU - Singh, Vijay P.

AU - Mayerle, Julia

AU - Faluhelyi, Nándor

AU - Miseta, Attila

AU - Reiber, István

AU - Hegyi, Péter

PY - 2020/1/1

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N2 - Introduction: Acute pancreatitis (AP) is a life-threatening inflammatory disease, with no specific pharmacological treatment. However, concerning some etiologies, early specific intervention (such as ERCP in biliary AP) has proven to be remarkably beneficial. Hypertriglyceridemia (HTG) induces severe pancreatic damage by several direct (cellular damage) and indirect (deterioration of microcirculation) mechanisms. Published data suggest that early removal of triglycerides (TGs) and toxic free fatty acids (FFAs) may be advantageous; however, high-quality evidence is still missing in the literature. Methods: Design: ELEFANT is a randomized controlled, multicenter, international trial testing the concept that early elimination of TGs and FFAs from the blood is beneficial in HTG-AP. The study will be performed with the adaptive “drop-the-loser” design, which supports the possibility of dropping the inferior treatment arm, based on the results of the interim analysis. Patients with HTG-AP defined by TG level over 11.3 mmol/l (1000 mg/dL) are randomized into three groups: (A) patients who undergo plasmapheresis and receive aggressive fluid resuscitation; (B) patients who receive insulin and heparin treatment with aggressive fluid resuscitation; and (C) patients with aggressive fluid resuscitation. Please note that all intervention must be started within 48 h from the onset of abdominal pain. Exclusion criteria are designed logically to decrease the possibility of any distorting effects of other diseases. The composite primary endpoint will include both severity and mortality. Results: Our null hypothesis is that early elimination of HTG and FFAs reduces the risk of mortality and severity of AP. Sample size calculation suggests that 495 patients will need to be enrolled in order to confirm or reject the hypothesis with a 10% dropout, 80% power and 95% significance level. The general safety and quality checks required for high-quality evidence will be adhered to. The study will be organized between February 2020 and December 2025. Conclusion: Our study would provide the first direct evidence for or against early intervention in HTG-induced AP.

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KW - Free fatty acids

KW - Heparin

KW - Hypertriglyceridemia

KW - Insulin

KW - Plasmapheresis

KW - Randomized clinical trial

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