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HOPE With Cytokine Filtration in Liver Transplantation (Cyto-HOPE) (Cyto-HOPE)

Primary Purpose

Liver Transplantation, Post-Reperfusion Syndrome, Ischaemia-Reperfusion Injury

Status
Recruiting
Phase
Not Applicable
Locations
Italy
Study Type
Interventional
Intervention
HOPE with cytokine filtration by CytoSorb
Sponsored by
Papa Giovanni XXIII Hospital
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Liver Transplantation focused on measuring Hypothermic oxygenated perfusion (HOPE), Cytokine filtration, Liver transplantation

Eligibility Criteria

18 Years - 70 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

RECIPIENTS

  • Inclusion criteria: age ≥18 years, signed informed consent form
  • Exclusion criteria: age <18 years, combined liver-other organ transplantation, pre-transplant treatment with plasmapheresis, refusal to consent to the study

GRAFTS ELIGIBILITY CRITERIA TO HOPE:

  • grafts from extended criteria donors with any combination of the following characteristics: age ≥70 years; macrosteatosis ≥35%; diabetes mellitus; severe vasculopathy; anti-HCV or HBsAg positivity (upon biopsy)
  • grafts from donors with hemodynamic instability
  • graft from DCD (occasionally)
  • grafts with an anticipated long cold ischemia time
  • PARTIAL GRAFTS ARE EXCLUDED FROM THE STUDY

Sites / Locations

  • Papa Giovanni XXIII HospitalRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

No Intervention

Arm Label

HOPE-CytoSorb

HOPE-standard

Arm Description

Patients transplanted with livers preserved by HOPE with cytokine filtration by CytoSorb, a CE approved medical device for extracorporeal cytokine removal

Patients transplanted with livers preserved by HOPE without cytokine filtration

Outcomes

Primary Outcome Measures

Incidence of post-reperfusion syndrome
Aggarwal definition: a decrease in mean arterial pressure >30% below the baseline value, for at least 1 minute, occurring during the first 5 minutes after reperfusion of the liver graft

Secondary Outcome Measures

Entity of ischemia-reperfusion injury
Assessment of liver biopsy according to Suzuki histological grading system modified by UCLA group [Sosa RA et al. JCI Insight 2016; 1(20): e89679]
Incidence of early allograft dysfunction
Olthoff definition: presence of almost one of the following variables: bilirubin ≥10 mg/dl on postoperative day 7, INR ≥1.6 on postoperative day 7, ALT or AST >2000 UI/ml within the first 7 postoperative days

Full Information

First Posted
December 16, 2019
Last Updated
May 20, 2023
Sponsor
Papa Giovanni XXIII Hospital
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1. Study Identification

Unique Protocol Identification Number
NCT04203004
Brief Title
HOPE With Cytokine Filtration in Liver Transplantation (Cyto-HOPE)
Acronym
Cyto-HOPE
Official Title
Hypothermic Oxygenated Perfusion With Cytokine Filtration in Clinical Liver Transplantation: a Randomised Controlled Trial
Study Type
Interventional

2. Study Status

Record Verification Date
May 2023
Overall Recruitment Status
Recruiting
Study Start Date
September 23, 2021 (Actual)
Primary Completion Date
December 31, 2023 (Anticipated)
Study Completion Date
December 31, 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Papa Giovanni XXIII Hospital

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Ischemia-reperfusion injury (IRI) is unavoidably typical of solid organ transplantation. Post-reperfusion syndrome (PRS), characterized by hemodynamic instability at reperfusion of the implanted graft, is a possible complication of liver transplantation. For sure, IRI plays a fundamental role in the multifactorial pathogenesis of PRS. IRI and PRS are associated with a higher risk of early allograft dysfunction (EAD) and, consequently, graft failure. Liver grafts from both extended criteria donors (ECD) and donation after circulatory death (DCD) are particularly susceptible to IRI and, accordingly, are at higher risk of PRS, EAD and graft failure. Anyway, in the present scenario of organ shortage, such donors greatly contribute to enlarge the organ pool. So, various strategies have been developed for the purpose of a safer use of this kind of grafts. Among them, ex vivo hypothermic oxygenated perfusion (HOPE) reduces IRI and is beneficial for high-risk liver grafts. The pathogenesis of IRI is an extremely complex downstream inflammation process, involving many different cytokines, chemokines and growth factors. In particular, tumor necrosis factor-alfa (TNF-alfa), interleukin-6 (IL-6), IL-8 and endothelin-1 (ET-1) are crucial in the development of IRI in liver transplantation. In experimental models, cytokine filtration during ex vivo lung perfusion (EVLP) was proved to be safe and effective in reducing inflammatory response and, thus, pulmonary edema development. Since in liver transplantation, IRI and PRS are associated with a higher risk of EAD and graft failure liver grafts from ECD and DCD are particularly susceptible to IRI and are at higher risk of PRS, EAD and graft failure HOPE of high-risk liver grafts reduces IRI in solid organ transplantation, various cytokines, chemokines and growth factors are involved in the pathogenesis of IRI in experimental models of EVLP, cytokine filtration was proved to reduce inflammatory response and subsequent organ damage, our hypothesis is that cytokine filtration during HOPE of high-risk liver grafts may potentiate the beneficial effects of HOPE, further reducing IRI and, consequently, further decreasing the incidence of PRS and EAD. So, the aim of this study is to verify the feasibility and safety of cytokine filtration during end-ischemic HOPE of liver grafts.
Detailed Description
This is a monocentric, pilot, randomized controlled study. Each eligible transplant candidate will be enrolled once an eligible graft has been allocated to him/her. Each enrolled patient will be randomized to either the experimental arm (HOPE-CytoSorb) or the control arm (HOPE-standard). End-ischemic HOPE will be performed at our center after standard procurement of the graft at the donor hospital, static cold storage preservation during transport and back-table preparation. Dual HOPE, by portal continuous flow and arterial pulsatile flow, will be pressure controlled: portal pressure will be ≤5 mmHg and mean arterial pressure will be ≤30 mmHg. HOPE will be performed in an open system, so the graft will swim in the perfusate flowing out of the vena cava. The recirculating perfusion solution will have the same composition of University of Wisconsin Machine Perfusion Solution. HOPE will be maintained for 4 hours. CytoSorb will be included in the circuit only in the experimental arm. Scheduled samples of both the perfusate and patient's blood will be analyzed for the levels of TNF-alfa, IL-6, IL-8 and ET-1. A biopsy of the implanted graft will be taken 2 hours after its reperfusion. The patient will be followed for 1 year after transplantation. Once 10 patients have been enrolled, an interim analysis will be performed by an independent Clinical Endpoint Committee.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Liver Transplantation, Post-Reperfusion Syndrome, Ischaemia-Reperfusion Injury, Early Allograft Dysfunction
Keywords
Hypothermic oxygenated perfusion (HOPE), Cytokine filtration, Liver transplantation

7. Study Design

Primary Purpose
Treatment
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
20 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
HOPE-CytoSorb
Arm Type
Experimental
Arm Description
Patients transplanted with livers preserved by HOPE with cytokine filtration by CytoSorb, a CE approved medical device for extracorporeal cytokine removal
Arm Title
HOPE-standard
Arm Type
No Intervention
Arm Description
Patients transplanted with livers preserved by HOPE without cytokine filtration
Intervention Type
Procedure
Intervention Name(s)
HOPE with cytokine filtration by CytoSorb
Intervention Description
Cytokine filtration during HOPE
Primary Outcome Measure Information:
Title
Incidence of post-reperfusion syndrome
Description
Aggarwal definition: a decrease in mean arterial pressure >30% below the baseline value, for at least 1 minute, occurring during the first 5 minutes after reperfusion of the liver graft
Time Frame
Intraoperatively, during the first 5 minutes after reperfusion of the liver graft
Secondary Outcome Measure Information:
Title
Entity of ischemia-reperfusion injury
Description
Assessment of liver biopsy according to Suzuki histological grading system modified by UCLA group [Sosa RA et al. JCI Insight 2016; 1(20): e89679]
Time Frame
2 hours after reperfusion of the liver graft
Title
Incidence of early allograft dysfunction
Description
Olthoff definition: presence of almost one of the following variables: bilirubin ≥10 mg/dl on postoperative day 7, INR ≥1.6 on postoperative day 7, ALT or AST >2000 UI/ml within the first 7 postoperative days
Time Frame
Postoperative day 7

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
RECIPIENTS Inclusion criteria: age ≥18 years, signed informed consent form Exclusion criteria: age <18 years, combined liver-other organ transplantation, pre-transplant treatment with plasmapheresis, refusal to consent to the study GRAFTS ELIGIBILITY CRITERIA TO HOPE: grafts from extended criteria donors with any combination of the following characteristics: age ≥70 years; macrosteatosis ≥35%; diabetes mellitus; severe vasculopathy; anti-HCV or HBsAg positivity (upon biopsy) grafts from donors with hemodynamic instability graft from DCD (occasionally) grafts with an anticipated long cold ischemia time PARTIAL GRAFTS ARE EXCLUDED FROM THE STUDY
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Stefania Camagni, MD
Phone
0352674771
Ext
0039
Email
scamagni@asst-pg23.it
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Michele Colledan, MD, FEBS
Organizational Affiliation
Papa Giovanni XXIII Hospital
Official's Role
Study Director
Facility Information:
Facility Name
Papa Giovanni XXIII Hospital
City
Bergamo
ZIP/Postal Code
24127
Country
Italy
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Stefania Camagni, MD
Email
scamagni@asst-pg23.it

12. IPD Sharing Statement

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HOPE With Cytokine Filtration in Liver Transplantation (Cyto-HOPE)

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