Comparison of Hypothermic Versus Normothermic Ex-vivo Preservation. (DCDNet)
Primary Purpose
End Stage Liver DIsease
Status
Recruiting
Phase
Not Applicable
Locations
Italy
Study Type
Interventional
Intervention
Hypothermic Machine Perfusion
Normothermic Machine Perfusion
Sponsored by
About this trial
This is an interventional treatment trial for End Stage Liver DIsease focused on measuring ex-situ perfusion, organ preservation, normothermic perfusion, hypothermic perfusion
Eligibility Criteria
GRAFT:
Inclusion criteria:
DCD:
- no absolute contraindications as per Italian National Transplant center (CNT)
- donor age ≤70 years
- witnessed and documented cardiac arrest
- macro-vescicular steatosis <30% at liver biopsy
- necrosis <5% at liver biopsy
- fibrosis <2 as per Ishak's score at liver biopsy
- arteriolar thickening <60% at liver biopsy
- WIT ≤160 minutes
- ALT <1000 UI/L during NRP
- downward trend lactate during NRP
DBD:
- no absolute contraindications as per Italian National Transplant center (CNT)
- donor age > 70 years
- macro-steatosis between 30 and 50% at liver biopsy
Exclusion criteria:
DCD:
- absolute contraindications as per Italian National Transplant center (CNT)
- donor age >70 years
- macro-vescicular steatosis >30% at liver biopsy
- necrosis >5% at liver biopsy
- fibrosis >2 as per Ishak's score at liver biopsy
- severe macroangiopathy (arteriolar thickening >60% at liver biopsy)
- WIT >160 minutes
- ALT >1000 UI/L during NRP
- uptrend lactate during NRP
DBD:
- absolute contraindications as per Italian National Transplant center (CNT)
- donor age < 70 years
- macro-steatosis between > 50% at liver biopsy
RECIPIENTS
Inclusion criteria:
- Subject must be greater than or equal to 18 years of age.
- Subject with end-stage liver disease who is actively listed for primary liver transplantation
- Subject, or a legally authorized representative, has given informed consent to participate in the study
Exclusion criteria:
- Subject is currently listed as a UNOS status 1A.
- Subject is requiring oxygen therapy via ventilator/respiratory support.
- Subject is planned to undergo simultaneous solid organ transplant.
- Subject is pregnant at the time of transplant.
- Subject MELD score 25 or higher
- Subject receives re-transplantation of liver.
- Any medical conditions contro-indicating the use of DCD grafts at transplant surgeon/hepatologist evaluation
Sites / Locations
- UO Chirurgia Epatica e del Trapianto di FegatoRecruiting
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Experimental
Arm Label
Hypothermic Machine Perfusion
Normothermic Machine Perfusion
Arm Description
uDCD and cDCD after Normothermic Regional Perfusion matching the inclusion criteria, ECD matching the inclusion criteria, uDCD and cDCD exceeding the inclusion criteria.
uDCD and cDCD after Normothermic Regional Perfusion matching the inclusion criteria, ECD matching the inclusion criteria, uDCD and cDCD exceeding the inclusion criteria.
Outcomes
Primary Outcome Measures
Rate of graft loss
Death of patient, relisting or Retransplantation. Composite Outcome
Rate of Ischemic Type Biliary Lesions (ITBL)
ITBL as assessed by MRI / MRCP. Composite Outcome
Secondary Outcome Measures
1-year graft survival
1-year patients survival
level of BCL-2/BAX at the liver histology
BCL-2/BAX is members of the Bcl-2 family of regulator proteins that regulate cell death and correlates with graft loss
level of Soluble Keratin 18 in the perfusate
Soluble Keratin 18 is a marker of necrosis and apoptosis and correlates with graft loss
level of HMGB1in the perfusate
HMGB1 Acts as danger associated molecular pattern (DAMP) molecule that amplifies immune responses during tissue injury and correlates with graft loss
Full Information
NCT ID
NCT04744389
First Posted
January 18, 2021
Last Updated
July 24, 2022
Sponsor
Azienda Ospedaliero, Universitaria Pisana
Collaborators
Fondazione C.N.R./Regione Toscana "G. Monasterio", Pisa, Italy, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico
1. Study Identification
Unique Protocol Identification Number
NCT04744389
Brief Title
Comparison of Hypothermic Versus Normothermic Ex-vivo Preservation.
Acronym
DCDNet
Official Title
Optimization of an Evidence-based Organizational Model of Liver and Pancreas Transplant Using Cardiac Death Donors: a Pilot, Prospective, Randomized, Multicenter Study for the Comparison of Hypothermic Versus Normothermic Ex-vivo Preservation.
Study Type
Interventional
2. Study Status
Record Verification Date
July 2022
Overall Recruitment Status
Recruiting
Study Start Date
December 15, 2020 (Actual)
Primary Completion Date
September 30, 2022 (Anticipated)
Study Completion Date
March 31, 2023 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Azienda Ospedaliero, Universitaria Pisana
Collaborators
Fondazione C.N.R./Regione Toscana "G. Monasterio", Pisa, Italy, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No
5. Study Description
Brief Summary
Study groups:
The study is a multicenter (Pisa and Milan), prospective, randomized study comparing D-HOPE (HMP) vs NMP in DCD and ECD-DBD (extended criteria brain-dead donors). Once a DCD or a DBD with extended criteria (ECD-DBD) meets the inclusion criteria, they are randomized as follow:
20 liver grafts from DCD after normothermic regional perfusion (NRP) matching the inclusion criteria are randomized 1:1 to hypothermic machine perfusion (HMP) vs normothermic machine perfusion (NMP) and then transplanted.
40 liver grafts from ECD-DBD matching the inclusion criteria are randomized 1:1 to hypothermic machine perfusion (HMP) vs normothermic machine perfusion (NMP) and then transplanted
Detailed Description
The persistent mismatch between patients waiting for a liver transplant (LT) and grafts availability promoted the use of donation after circulatory death (DCD). Italian law requires 20 minutes of continous flatline electrocardiogram to declared individual's circulatory death and such a long period of warm ischemia time forced the development of protocols using abdominal normothermic regional perfusion (NRP) followed by ex-vivo graft reperfusion by means of machine perfusion technology (MP) for its potential to minimize ischemia/reperfusion damage and promote organ repair and reconditioning prior to transplantation. An extensive evaluation of all DCD donors might increase donation rate by 30%, but, while kidney transplant from DCD donors is well implemented, no definitive data exist on the optimal use of NRP and MP in liver and pancreas transplantation and an organizational model is far to be implemented. Moreover, a randomized trial comparing hypothermic vs normothermic ex-vivo perfusion has never been performed. The proposed project will perform a pilot, open, randomized, prospective trials to evaluate the sequential use of NRP followed by ex-vivo MP (hypothermic (HMP) vs normothermic (NMP)) by measuring several indicators of organ damage and recovery with the target to set up the optimal organizational model for DCD donation:
Twenty LT from DCD donors after NRP (considered transplantable for the acceptance criteria in use) will be randomized 1:1 to ex-vivo HMP or NMP (multicenter study together with the center in Milan)
40 liver grafts from ECD-DBD matching the inclusion criteria are randomized 1:1 to hypothermic machine perfusion (HMP) vs normothermic machine perfusion (NMP) and then transplanted To assess organ damage and repair capacity, the following investigations will be performed: -biomarkers of apoptosis, necrosis, innate-mediated inflammation and its resolution, angiogenesis and thrombosis during NRP -circulating biomarkers indicating damage, proliferation, angiogenetic and tissue remodelling factors; a targeted-metabolomic and lipidomic profiling during ex-vivo HMP or NMP in the perfusate and on blood samples in the peri and post-operative period; bile composition on graft subjected to NMP. Evaluation of necrosis, apoptosis and proliferation, immunohistochemical analysis, a targeted-metabolomic and lipidomic profiling, ATP measurement, and electronic microscopy investigations will be performed on liver tissue and bile duct biopsies after NRP, before and after ex-vivo reperfusion, and immediately after reperfusion in the recipient (only for transplantable grafts) Based on the collected data a new algorithm of organ evaluation, procurement, preservation and reconditioning will be formulated and disseminated.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
End Stage Liver DIsease
Keywords
ex-situ perfusion, organ preservation, normothermic perfusion, hypothermic perfusion
7. Study Design
Primary Purpose
Treatment
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Masking
Participant
Allocation
Randomized
Enrollment
60 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Hypothermic Machine Perfusion
Arm Type
Experimental
Arm Description
uDCD and cDCD after Normothermic Regional Perfusion matching the inclusion criteria, ECD matching the inclusion criteria, uDCD and cDCD exceeding the inclusion criteria.
Arm Title
Normothermic Machine Perfusion
Arm Type
Experimental
Arm Description
uDCD and cDCD after Normothermic Regional Perfusion matching the inclusion criteria, ECD matching the inclusion criteria, uDCD and cDCD exceeding the inclusion criteria.
Intervention Type
Device
Intervention Name(s)
Hypothermic Machine Perfusion
Other Intervention Name(s)
Hypothermic machine perfusion (HMP)
Intervention Description
The perfusion system was primed with 4 L of Belzer machine perfusion solution University of Wisconsin Machine Perfusion Solution (Bridge for Life, Ltd., Columbia, SC). The arterial and portal pressures were set at 25 mm Hg with a flow and at 3-4 mm Hg with a continuous flow, respectively. The oxygen flow was set at 0.25 L/minute. The target liver temperature was between 4°C and 10°C.
Intervention Type
Device
Intervention Name(s)
Normothermic Machine Perfusion
Other Intervention Name(s)
Normothermic machine perfusion (NMP)
Intervention Description
Grafts were perfused at 37°C in an OR next to the transplant OR and under medical supervision using a blood-based perfusate. Initial perfusate temperature was set at 20°C and raised by 1°C every 2 minutes. Oxygenation was provided by an anesthesia ventilator initially set at 4 L/minute with 30% fraction of inspired oxygen, and later adjusted based on perfusate pH, partial pressure of oxygen, and partial pressure of carbon dioxide. Blood gas analyses were drawn every 20 minutes during the first hour and every 30 minutes thereafter with the aim to maintain a physiological pH and ionogram result, and a partial pressure of oxygen between 200 and 250 mm Hg. Perfusate glucose, transaminases, and lactate were measured during NMP as were bile production and quality (pH, sodium, glycemia, lactate, and HCO3)
Primary Outcome Measure Information:
Title
Rate of graft loss
Description
Death of patient, relisting or Retransplantation. Composite Outcome
Time Frame
at 6 months postoperatively
Title
Rate of Ischemic Type Biliary Lesions (ITBL)
Description
ITBL as assessed by MRI / MRCP. Composite Outcome
Time Frame
at 6 months postoperatively
Secondary Outcome Measure Information:
Title
1-year graft survival
Time Frame
1-year postoperatively
Title
1-year patients survival
Time Frame
1-year postoperatively
Title
level of BCL-2/BAX at the liver histology
Description
BCL-2/BAX is members of the Bcl-2 family of regulator proteins that regulate cell death and correlates with graft loss
Time Frame
after 2 hours of perfusion
Title
level of Soluble Keratin 18 in the perfusate
Description
Soluble Keratin 18 is a marker of necrosis and apoptosis and correlates with graft loss
Time Frame
after 2 hours of perfusion
Title
level of HMGB1in the perfusate
Description
HMGB1 Acts as danger associated molecular pattern (DAMP) molecule that amplifies immune responses during tissue injury and correlates with graft loss
Time Frame
after 2 hours of perfusion
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
GRAFT:
Inclusion criteria:
DCD:
no absolute contraindications as per Italian National Transplant center (CNT)
donor age ≤70 years
witnessed and documented cardiac arrest
macro-vescicular steatosis <30% at liver biopsy
necrosis <5% at liver biopsy
fibrosis <2 as per Ishak's score at liver biopsy
arteriolar thickening <60% at liver biopsy
WIT ≤160 minutes
ALT <1000 UI/L during NRP
downward trend lactate during NRP
DBD:
no absolute contraindications as per Italian National Transplant center (CNT)
donor age > 70 years
macro-steatosis between 30 and 50% at liver biopsy
Exclusion criteria:
DCD:
absolute contraindications as per Italian National Transplant center (CNT)
donor age >70 years
macro-vescicular steatosis >30% at liver biopsy
necrosis >5% at liver biopsy
fibrosis >2 as per Ishak's score at liver biopsy
severe macroangiopathy (arteriolar thickening >60% at liver biopsy)
WIT >160 minutes
ALT >1000 UI/L during NRP
uptrend lactate during NRP
DBD:
absolute contraindications as per Italian National Transplant center (CNT)
donor age < 70 years
macro-steatosis between > 50% at liver biopsy
RECIPIENTS
Inclusion criteria:
Subject must be greater than or equal to 18 years of age.
Subject with end-stage liver disease who is actively listed for primary liver transplantation
Subject, or a legally authorized representative, has given informed consent to participate in the study
Exclusion criteria:
Subject is currently listed as a UNOS status 1A.
Subject is requiring oxygen therapy via ventilator/respiratory support.
Subject is planned to undergo simultaneous solid organ transplant.
Subject is pregnant at the time of transplant.
Subject MELD score 25 or higher
Subject receives re-transplantation of liver.
Any medical conditions contro-indicating the use of DCD grafts at transplant surgeon/hepatologist evaluation
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Davide Ghinolfi, MD, PhD
Phone
00393282185278
Email
d.ghinolfi@ao-pisa.toscana.it
Facility Information:
Facility Name
UO Chirurgia Epatica e del Trapianto di Fegato
City
Pisa
ZIP/Postal Code
56124
Country
Italy
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Davide Ghinolfi, MD
Phone
+39050995421
Email
d.ghinolfi@ao-pisa.toscana.it
First Name & Middle Initial & Last Name & Degree
Fabio Melandro, MD, PhD
12. IPD Sharing Statement
Plan to Share IPD
No
Citations:
PubMed Identifier
30362649
Citation
Ghinolfi D, Rreka E, De Tata V, Franzini M, Pezzati D, Fierabracci V, Masini M, Cacciatoinsilla A, Bindi ML, Marselli L, Mazzotti V, Morganti R, Marchetti P, Biancofiore G, Campani D, Paolicchi A, De Simone P. Pilot, Open, Randomized, Prospective Trial for Normothermic Machine Perfusion Evaluation in Liver Transplantation From Older Donors. Liver Transpl. 2019 Mar;25(3):436-449. doi: 10.1002/lt.25362.
Results Reference
background
PubMed Identifier
32949117
Citation
Ghinolfi D, Dondossola D, Rreka E, Lonati C, Pezzati D, Cacciatoinsilla A, Kersik A, Lazzeri C, Zanella A, Peris A, Maggioni M, Biancofiore G, Reggiani P, Morganti R, De Simone P, Rossi G. Sequential Use of Normothermic Regional and Ex Situ Machine Perfusion in Donation After Circulatory Death Liver Transplant. Liver Transpl. 2021 Feb;27(3):385-402. doi: 10.1002/lt.25899. Epub 2020 Nov 8.
Results Reference
background
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Comparison of Hypothermic Versus Normothermic Ex-vivo Preservation.
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