Comparison of Hypothermic Versus Normothermic Ex-vivo Preservation.

Not Applicable

• Conditions: End Stage Liver DIsease
• Interventions: Device: Normothermic Machine Perfusion; Device: Hypothermic Machine Perfusion

• Registration Number: NCT04744389
• Lead Sponsor: Azienda Ospedaliero, Universitaria Pisana

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.

Study Timeline

• Study Start: 2020-12-15
• Study First Submitted: 2021-01-18
• Study First Submitted QC: 2021-02-03
• Study First Posted: 2021-02-09
• Status Verified: 2022-07
• Last Update Submitted: 2022-07-24
• Last Update Posted: 2022-07-26
• Primary Completion: 2022-09-30
• Study Completion: 2023-03-31

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 60

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Normothermic Machine Perfusion	Normothermic Machine Perfusion	uDCD and cDCD after Normothermic Regional Perfusion matching the inclusion criteria, ECD matching the inclusion criteria, uDCD and cDCD exceeding the inclusion criteria.
Hypothermic Machine Perfusion	Hypothermic Machine Perfusion	uDCD and cDCD after Normothermic Regional Perfusion matching the inclusion criteria, ECD matching the inclusion criteria, uDCD and cDCD exceeding the inclusion criteria.

Primary Outcome Measures

Name	Time	Method
Rate of Ischemic Type Biliary Lesions (ITBL)	at 6 months postoperatively	ITBL as assessed by MRI / MRCP. Composite Outcome
Rate of graft loss	at 6 months postoperatively	Death of patient, relisting or Retransplantation. Composite Outcome

Secondary Outcome Measures

Name	Time	Method
1-year graft survival	1-year postoperatively
level of HMGB1in the perfusate	after 2 hours of perfusion	HMGB1 Acts as danger associated molecular pattern (DAMP) molecule that amplifies immune responses during tissue injury and correlates with graft loss
1-year patients survival	1-year postoperatively
level of BCL-2/BAX at the liver histology	after 2 hours of perfusion	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	after 2 hours of perfusion	Soluble Keratin 18 is a marker of necrosis and apoptosis and correlates with graft loss

Trial Locations

Locations (1)

UO Chirurgia Epatica e del Trapianto di Fegato; 🇮🇹 Pisa, Italy