Clinical trial NCT04744389: Comparison of Hypothermic Versus Normothermic Ex-vivo Preservation.
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
Overall status: UNKNOWN
Phase: NA
Conditions: End Stage Liver DIsease
Keywords: ex-situ perfusion
organ preservation
normothermic perfusion
hypothermic perfusion
Lead sponsor: Azienda Ospedaliero, Universitaria Pisana
Sponsor class: OTHER
Collaborators: name: Fondazione C.N.R./Regione Toscana "G. Monasterio", Pisa, Italy
name: Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico
First posted: 2021-02-09
Enrollment: 60
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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:

1. 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.
2. 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:

1. 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)
2. 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.

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

Primary outcomes:
measure: Rate of graft loss
timeFrame: at 6 months postoperatively
measure: Rate of Ischemic Type Biliary Lesions (ITBL)
timeFrame: at 6 months postoperatively
Secondary outcomes:
measure: 1-year graft survival
timeFrame: 1-year postoperatively
measure: 1-year patients survival
timeFrame: 1-year postoperatively
measure: level of BCL-2/BAX at the liver histology
timeFrame: after 2 hours of perfusion
measure: level of Soluble Keratin 18 in the perfusate
timeFrame: after 2 hours of perfusion
measure: level of HMGB1in the perfusate
timeFrame: after 2 hours of perfusion
Other outcomes:
Locations:
city: Pisa
country: Italy
facility: UO Chirurgia Epatica e del Trapianto di Fegato
Study officials:
References:
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.
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.