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出境医 / 临床实验 / Efficacy of Ex-situ Normothermic Perfusion Versus Cold Storage in the Transplant With Steatotic Liver Graft. (ORGANOXLAFE)

Efficacy of Ex-situ Normothermic Perfusion Versus Cold Storage in the Transplant With Steatotic Liver Graft. (ORGANOXLAFE)

Study Description
Brief Summary:
Prospective, randomized, controlled clinical trial to determine the overall efficacy of normothermic machine perfusion (NMP) for steatotic liver preservation versus traditional static cold storage (SCS), in 50 liver transplant recipients with 1-year follow-up.

Condition or disease Intervention/treatment Phase
Liver Transplant Procedure: Static cold storage (SCS) Device: Normothermic machine perfusion (NMP) Not Applicable

Detailed Description:

This is a prospective, randomized, controlled clinical trial comparing static cold storage (SCS) versus normothermic machine perfusion (NMP) for organ preservation before liver transplantation with steatotic livers (between 30 % and 60% of histologic macrovesicular steatosis), in order to:

Main Objective:

To compare the effect of NMP versus SCS in preventing preservation injury and graft dysfunction, as measured by highest transaminase levels during the first week after liver transplantation.

Secondary Objectives:

  • To compare graft and patient survival between the NMP and SCS steatotic livers.
  • To compare the liver biochemical function between the NMP and SCS steatotic livers.
  • To compare the physiological response to the reperfusion between the NMP and SCS steatotic livers.
  • To compare the evidence of reperfusion injury between the NMP and SCS steatotic livers.
  • To compare the evidence of ischemic cholangiopathy between the NMP and SCS steatotic livers.
Study Design
Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 50 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
Official Title: Clinical Trial to Compare the Efficacy of Ex-situ Normothermic Perfusion With Cold Storage in the Transplant With Steatotic Liver Graft.
Actual Study Start Date : April 26, 2019
Estimated Primary Completion Date : March 2023
Estimated Study Completion Date : March 2023
Arms and Interventions
Arm Intervention/treatment
Experimental: Static cold storage (SCS)
Traditional method of organ preservation which involves flushing of cold preservation solution following complete dissection and interruption of blood supply to the donor organ. Although cold preservation slows metabolism by 10- to 12-fold, substantial anaerobic activity continues even at ice temperature. This lead to the generation of reactive oxygen species that are the basis of ischaemia-reperfusion injury, when the organ is re-exposed to oxygenated blood at the time of transplantation. This damage, exacerbated by any prior injury, limits the maximum safe preservation time of the donor organ.
 Procedure: Static cold storage (SCS)
The liver is flushed and cooled with specialist preservation fluid, then stored in an icebox.
Experimental: Normothermic machine perfusion (NMP)
The main goal of NMP is to optimize graft preservation by mimicking physiological conditions. The perfused organ is supplied with nutrients and oxygen to maintain metabolic hemostasis. Under these conditions, ATP and glycogen reserves can be maintained or actively restored. At the same time, toxic products from the cellular milieu are continuously eliminated, so the cell-mediated injury phase of reperfusion injury can be minimized. Thus, ischemic injury is avoided and the activation of cell death cascades is prevented. This allows both hepatocellular and biliary protection.
 Device: Normothermic machine perfusion (NMP)
During NMP, the liver is perfused with oxygenated blood, medications and nutrients at normal body temperature to maintain a physiological milieu.
Outcome Measures
Primary Outcome Measures :
  1. Peak of transaminases (AST and ALT) [ Time Frame: Day 1 post-transplant. ]
  2. Peak of transaminases (AST and ALT) [ Time Frame: Day 3 post-transplant. ]
  3. Peak of transaminases (AST and ALT) [ Time Frame: Day 5 post-transplant. ]
  4. Peak of transaminases (AST and ALT) l [ Time Frame: Day 7 post-transplant. ]

Secondary Outcome Measures :
  1. Primary graft failure [ Time Frame: Day 10 post-transplant. ]
    Primary graft failure: irreversible graft dysfunction that requires emergency hepatic replacement during the first 10 days after liver transplantation, in the absence of technical or immunological causes.

  2. Graft survival [ Time Frame: Day 30 post-transplant, month 6 post-transplant, month 12 post-transplant. ]
  3. Patient survival [ Time Frame: Day 30 post-transplant, month 6 post-transplant, month 12 post-transplant. ]
  4. Post-reperfusion syndrome, measured by mean arterial pressure (MAP) levels [ Time Frame: During the first 5 minutes after reperfusion ]
    Post-reperfusion syndrome is defined as a decrease in mean arterial pressure (MAP) of more than 30% of the baseline value for more than one minute during the first five minutes after reperfusion. This will be evaluated in the context of the use of vasopressors.

  5. Biochemical function of the liver measured by Bilirubin post-transplant levels [ Time Frame: Day 1, day 3, day 5, day 7, day 30, month 6, month 12 post- transplant ]
  6. Biochemical function of the liver measured by GGT post-transplant levels [ Time Frame: Day 1, day 3, day 5, day 7, day 30, month 6, month 12 post- transplant ]
  7. Biochemical function of the liver measured by AST post-transplant levels [ Time Frame: Day 1, day 3, day 5, day 7, day 30, month 6, month 12 post- transplant ]
  8. Biochemical function of the liver measured by ALT post-transplant levels [ Time Frame: Day 1, day 3, day 5, day 7, day 30, month 6, month 12 post- transplant ]
  9. Biochemical function of the liver measured by INR post-transplant levels [ Time Frame: Day 1, day 3, day 5, day 7, day 30, month 6, month 12 post- transplant ]
  10. Early graft dysfunction [ Time Frame: 7 days post-transplant ]

    Defined by:

    1. Bilirubin > 10 mg / dl daily 7 after transplant
    2. INR > 1.6 on day 7 after transplantation.
    3. Peak AST and ALT > 2000 IU / L in the first 7 days after transplantation

  11. Intensive care stay duration [ Time Frame: Day 30 ]
  12. Hospital stay duration [ Time Frame: Day 30 ]
  13. Renal replacement therapy need [ Time Frame: Day 30, month 6, month 12 post- transplant ]
  14. Intraoperative thromboelastogram result [ Time Frame: In transplant surgery ]
  15. Histological evidence of reperfusion injury [ Time Frame: In transplant surgery ]
    Post-reperfusion biopsies will be compared with baseline pre-reperfusion biopsies and classified according to standard histological criteria (blind comparison to third parties).

  16. Evidence of biliary stenosis in magnetic resonance cholangiography (MRS). [ Time Frame: 6 months after transplantation. ]

Eligibility Criteria
Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

LIVER DONOR:

  • Donors older than 16 years
  • Liver donation grafts due to brain death
  • Steatosis confirmed by histological study (between 30% and 60% of macrovesicular steatosis)

LIVER RECIPIENT:

  • Adult patients (18 years or older)
  • Active liver transplant waiting list candidate
  • Able to give informed consent

Exclusion Criteria:

LIVER DONOR:

  • Living donors
  • Liver destined to the transplant "split"
  • Donor age <16 years
  • Donation after death due to asystole.
  • When the biopsy establishes a steatosis ≥ 50%, patients who fulfill at least 3 of the following 5 risk factors will be excluded: Transaminases (AST and ALT) ≥ 200 U / L; Age ≥ 55 years; Hypernatremia ≥ 155 mEq / L; Cardiovascular risk factors, at least 2 of the following 5: DM, HTA, IMC ≥ 35, Active smoking, ischemic stroke; Days of stay in ICU ≥ 4 days with vasoactive drugs (noradrenaline or dobutamine at any dose)

LIVER RECIPIENT:

  • Age under 18
  • Acute/fulminant hepatic failure
  • Transplant of more than one organ (for example, liver and kidney)
  • Rejection of informed consent
  • Unable to give informed consent
Contacts and Locations

Contacts
Layout table for location contacts
Contact: Maria Cortell 0034961246711 investigacion_clinica@iislafe.es

Locations
Layout table for location information
Spain
Hospital Universitario y Politécnico La Fe Recruiting
Valencia, Spain
Contact: Maria Cortell         
Sponsors and Collaborators
Instituto de Investigacion Sanitaria La Fe
Tracking Information
First Submitted Date  ICMJE April 23, 2019
First Posted Date  ICMJE April 29, 2019
Last Update Posted Date August 6, 2019
Actual Study Start Date  ICMJE April 26, 2019
Estimated Primary Completion Date March 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 25, 2019)
  • Peak of transaminases (AST and ALT) [ Time Frame: Day 1 post-transplant. ]
  • Peak of transaminases (AST and ALT) [ Time Frame: Day 3 post-transplant. ]
  • Peak of transaminases (AST and ALT) [ Time Frame: Day 5 post-transplant. ]
  • Peak of transaminases (AST and ALT) l [ Time Frame: Day 7 post-transplant. ]
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: April 25, 2019)
  • Primary graft failure [ Time Frame: Day 10 post-transplant. ]
    Primary graft failure: irreversible graft dysfunction that requires emergency hepatic replacement during the first 10 days after liver transplantation, in the absence of technical or immunological causes.
  • Graft survival [ Time Frame: Day 30 post-transplant, month 6 post-transplant, month 12 post-transplant. ]
  • Patient survival [ Time Frame: Day 30 post-transplant, month 6 post-transplant, month 12 post-transplant. ]
  • Post-reperfusion syndrome, measured by mean arterial pressure (MAP) levels [ Time Frame: During the first 5 minutes after reperfusion ]
    Post-reperfusion syndrome is defined as a decrease in mean arterial pressure (MAP) of more than 30% of the baseline value for more than one minute during the first five minutes after reperfusion. This will be evaluated in the context of the use of vasopressors.
  • Biochemical function of the liver measured by Bilirubin post-transplant levels [ Time Frame: Day 1, day 3, day 5, day 7, day 30, month 6, month 12 post- transplant ]
  • Biochemical function of the liver measured by GGT post-transplant levels [ Time Frame: Day 1, day 3, day 5, day 7, day 30, month 6, month 12 post- transplant ]
  • Biochemical function of the liver measured by AST post-transplant levels [ Time Frame: Day 1, day 3, day 5, day 7, day 30, month 6, month 12 post- transplant ]
  • Biochemical function of the liver measured by ALT post-transplant levels [ Time Frame: Day 1, day 3, day 5, day 7, day 30, month 6, month 12 post- transplant ]
  • Biochemical function of the liver measured by INR post-transplant levels [ Time Frame: Day 1, day 3, day 5, day 7, day 30, month 6, month 12 post- transplant ]
  • Early graft dysfunction [ Time Frame: 7 days post-transplant ]
    Defined by:
    1. Bilirubin > 10 mg / dl daily 7 after transplant
    2. INR > 1.6 on day 7 after transplantation.
    3. Peak AST and ALT > 2000 IU / L in the first 7 days after transplantation
  • Intensive care stay duration [ Time Frame: Day 30 ]
  • Hospital stay duration [ Time Frame: Day 30 ]
  • Renal replacement therapy need [ Time Frame: Day 30, month 6, month 12 post- transplant ]
  • Intraoperative thromboelastogram result [ Time Frame: In transplant surgery ]
  • Histological evidence of reperfusion injury [ Time Frame: In transplant surgery ]
    Post-reperfusion biopsies will be compared with baseline pre-reperfusion biopsies and classified according to standard histological criteria (blind comparison to third parties).
  • Evidence of biliary stenosis in magnetic resonance cholangiography (MRS). [ Time Frame: 6 months after transplantation. ]
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Efficacy of Ex-situ Normothermic Perfusion Versus Cold Storage in the Transplant With Steatotic Liver Graft.
Official Title  ICMJE Clinical Trial to Compare the Efficacy of Ex-situ Normothermic Perfusion With Cold Storage in the Transplant With Steatotic Liver Graft.
Brief Summary Prospective, randomized, controlled clinical trial to determine the overall efficacy of normothermic machine perfusion (NMP) for steatotic liver preservation versus traditional static cold storage (SCS), in 50 liver transplant recipients with 1-year follow-up.
Detailed Description

This is a prospective, randomized, controlled clinical trial comparing static cold storage (SCS) versus normothermic machine perfusion (NMP) for organ preservation before liver transplantation with steatotic livers (between 30 % and 60% of histologic macrovesicular steatosis), in order to:

Main Objective:

To compare the effect of NMP versus SCS in preventing preservation injury and graft dysfunction, as measured by highest transaminase levels during the first week after liver transplantation.

Secondary Objectives:

  • To compare graft and patient survival between the NMP and SCS steatotic livers.
  • To compare the liver biochemical function between the NMP and SCS steatotic livers.
  • To compare the physiological response to the reperfusion between the NMP and SCS steatotic livers.
  • To compare the evidence of reperfusion injury between the NMP and SCS steatotic livers.
  • To compare the evidence of ischemic cholangiopathy between the NMP and SCS steatotic livers.
Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
Condition  ICMJE Liver Transplant
Intervention  ICMJE
  • Procedure: Static cold storage (SCS)
    The liver is flushed and cooled with specialist preservation fluid, then stored in an icebox.
  • Device: Normothermic machine perfusion (NMP)
    During NMP, the liver is perfused with oxygenated blood, medications and nutrients at normal body temperature to maintain a physiological milieu.
Study Arms  ICMJE
  • Experimental: Static cold storage (SCS)
    Traditional method of organ preservation which involves flushing of cold preservation solution following complete dissection and interruption of blood supply to the donor organ. Although cold preservation slows metabolism by 10- to 12-fold, substantial anaerobic activity continues even at ice temperature. This lead to the generation of reactive oxygen species that are the basis of ischaemia-reperfusion injury, when the organ is re-exposed to oxygenated blood at the time of transplantation. This damage, exacerbated by any prior injury, limits the maximum safe preservation time of the donor organ.
    Intervention: Procedure: Static cold storage (SCS)
  • Experimental: Normothermic machine perfusion (NMP)
    The main goal of NMP is to optimize graft preservation by mimicking physiological conditions. The perfused organ is supplied with nutrients and oxygen to maintain metabolic hemostasis. Under these conditions, ATP and glycogen reserves can be maintained or actively restored. At the same time, toxic products from the cellular milieu are continuously eliminated, so the cell-mediated injury phase of reperfusion injury can be minimized. Thus, ischemic injury is avoided and the activation of cell death cascades is prevented. This allows both hepatocellular and biliary protection.
    Intervention: Device: Normothermic machine perfusion (NMP)
Publications *
  • García-Valdecasas JC, Tabet J, Valero R, Taurá P, Rull R, García F, Montserrat E, González FX, Ordi J, Beltran J, López-Boado MA, Deulofeu R, Angás J, Cifuentes A, Visa J. Liver conditioning after cardiac arrest: the use of normothermic recirculation in an experimental animal model. Transpl Int. 1998;11(6):424-32.
  • St Peter SD, Imber CJ, Lopez I, Hughes D, Friend PJ. Extended preservation of non-heart-beating donor livers with normothermic machine perfusion. Br J Surg. 2002 May;89(5):609-16.
  • Imber CJ, St Peter SD, Lopez de Cenarruzabeitia I, Pigott D, James T, Taylor R, McGuire J, Hughes D, Butler A, Rees M, Friend PJ. Advantages of normothermic perfusion over cold storage in liver preservation. Transplantation. 2002 Mar 15;73(5):701-9.
  • Gaffey MJ, Boyd JC, Traweek ST, Ali MA, Rezeig M, Caldwell SH, Iezzoni JC, McCullough C, Stevenson WC, Khuroo S, Nezamuddin N, Ishitani MB, Pruett TL. Predictive value of intraoperative biopsies and liver function tests for preservation injury in orthotopic liver transplantation. Hepatology. 1997 Jan;25(1):184-9.
  • Karayalçin K, Mirza DF, Harrison RF, Da Silva RF, Hubscher SG, Mayer AD, Buckels JA, McMaster P. The role of dynamic and morphological studies in the assessment of potential liver donors. Transplantation. 1994 May 15;57(9):1323-7.
  • Abraham S, Furth EE. Quantitative evaluation of histological features in "time-zero" liver allograft biopsies as predictors of rejection or graft failure: receiver-operating characteristic analysis application. Hum Pathol. 1996 Oct;27(10):1077-84.
  • Dindo D, Demartines N, Clavien PA. Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg. 2004 Aug;240(2):205-13.
  • Olthoff KM, Kulik L, Samstein B, Kaminski M, Abecassis M, Emond J, Shaked A, Christie JD. Validation of a current definition of early allograft dysfunction in liver transplant recipients and analysis of risk factors. Liver Transpl. 2010 Aug;16(8):943-9. doi: 10.1002/lt.22091.
  • Chung IS, Kim HY, Shin YH, Ko JS, Gwak MS, Sim WS, Kim GS, Lee SK. Incidence and predictors of post-reperfusion syndrome in living donor liver transplantation. Clin Transplant. 2012 Jul-Aug;26(4):539-43. doi: 10.1111/j.1399-0012.2011.01568.x. Epub 2011 Dec 14.
  • Hilmi I, Horton CN, Planinsic RM, Sakai T, Nicolau-Raducu R, Damian D, Gligor S, Marcos A. The impact of postreperfusion syndrome on short-term patient and liver allograft outcome in patients undergoing orthotopic liver transplantation. Liver Transpl. 2008 Apr;14(4):504-8. doi: 10.1002/lt.21381.
  • Glanemann M, Langrehr JM, Stange BJ, Neumann U, Settmacher U, Steinmüller T, Neuhaus P. Clinical implications of hepatic preservation injury after adult liver transplantation. Am J Transplant. 2003 Aug;3(8):1003-9.
  • Eisenbach C, Encke J, Merle U, Gotthardt D, Weiss KH, Schneider L, Latanowicz S, Spiegel M, Engelmann G, Stremmel W, Büchler MW, Schmidt J, Weigand MA, Sauer P. An early increase in gamma glutamyltranspeptidase and low aspartate aminotransferase peak values are associated with superior outcomes after orthotopic liver transplantation. Transplant Proc. 2009 Jun;41(5):1727-30. doi: 10.1016/j.transproceed.2009.01.084.
  • Nasralla D, Coussios CC, Mergental H, Akhtar MZ, Butler AJ, Ceresa CDL, Chiocchia V, Dutton SJ, García-Valdecasas JC, Heaton N, Imber C, Jassem W, Jochmans I, Karani J, Knight SR, Kocabayoglu P, Malagò M, Mirza D, Morris PJ, Pallan A, Paul A, Pavel M, Perera MTPR, Pirenne J, Ravikumar R, Russell L, Upponi S, Watson CJE, Weissenbacher A, Ploeg RJ, Friend PJ; Consortium for Organ Preservation in Europe. A randomized trial of normothermic preservation in liver transplantation. Nature. 2018 May;557(7703):50-56. doi: 10.1038/s41586-018-0047-9. Epub 2018 Apr 18.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: April 25, 2019) 		50
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE March 2023
Estimated Primary Completion Date March 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

LIVER DONOR:

  • Donors older than 16 years
  • Liver donation grafts due to brain death
  • Steatosis confirmed by histological study (between 30% and 60% of macrovesicular steatosis)

LIVER RECIPIENT:

  • Adult patients (18 years or older)
  • Active liver transplant waiting list candidate
  • Able to give informed consent

Exclusion Criteria:

LIVER DONOR:

  • Living donors
  • Liver destined to the transplant "split"
  • Donor age <16 years
  • Donation after death due to asystole.
  • When the biopsy establishes a steatosis ≥ 50%, patients who fulfill at least 3 of the following 5 risk factors will be excluded: Transaminases (AST and ALT) ≥ 200 U / L; Age ≥ 55 years; Hypernatremia ≥ 155 mEq / L; Cardiovascular risk factors, at least 2 of the following 5: DM, HTA, IMC ≥ 35, Active smoking, ischemic stroke; Days of stay in ICU ≥ 4 days with vasoactive drugs (noradrenaline or dobutamine at any dose)

LIVER RECIPIENT:

  • Age under 18
  • Acute/fulminant hepatic failure
  • Transplant of more than one organ (for example, liver and kidney)
  • Rejection of informed consent
  • Unable to give informed consent
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Maria Cortell 0034961246711 investigacion_clinica@iislafe.es
Listed Location Countries  ICMJE Spain
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03930459
Other Study ID Numbers  ICMJE ORGANOXLAFE
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Instituto de Investigacion Sanitaria La Fe
Study Sponsor  ICMJE Instituto de Investigacion Sanitaria La Fe
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account Instituto de Investigacion Sanitaria La Fe
Verification Date August 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP

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