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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04203004
Recruitment Status : Recruiting
First Posted : December 18, 2019
Last Update Posted : May 23, 2023
Sponsor:
Information provided by (Responsible Party):
Stefania Camagni, Papa Giovanni XXIII Hospital

Study Description
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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.


Condition or disease Intervention/treatment Phase
Liver Transplantation Post-Reperfusion Syndrome Ischaemia-Reperfusion Injury Early Allograft Dysfunction Procedure: HOPE with cytokine filtration by CytoSorb Not Applicable

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.

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 20 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Hypothermic Oxygenated Perfusion With Cytokine Filtration in Clinical Liver Transplantation: a Randomised Controlled Trial
Actual Study Start Date : September 23, 2021
Estimated Primary Completion Date : December 31, 2023
Estimated Study Completion Date : December 31, 2023

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: HOPE-CytoSorb
Patients transplanted with livers preserved by HOPE with cytokine filtration by CytoSorb, a CE approved medical device for extracorporeal cytokine removal
 Procedure: HOPE with cytokine filtration by CytoSorb
Cytokine filtration during HOPE
No Intervention: HOPE-standard
Patients transplanted with livers preserved by HOPE without cytokine filtration


Outcome Measures
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Primary Outcome Measures :
  1. Incidence of post-reperfusion syndrome [ Time Frame: Intraoperatively, during the first 5 minutes after reperfusion of the liver graft ]
    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 :
  1. Entity of ischemia-reperfusion injury [ Time Frame: 2 hours after reperfusion of the liver graft ]
    Assessment of liver biopsy according to Suzuki histological grading system modified by UCLA group [Sosa RA et al. JCI Insight 2016; 1(20): e89679]

  2. Incidence of early allograft dysfunction [ Time Frame: Postoperative day 7 ]
    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


Eligibility Criteria
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Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04203004


Contacts
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Contact: Stefania Camagni, MD 0352674771 ext 0039 scamagni@asst-pg23.it

Locations
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Italy
Papa Giovanni XXIII Hospital Recruiting
Bergamo, Italy, 24127
Contact: Stefania Camagni, MD       scamagni@asst-pg23.it   
Sponsors and Collaborators
Papa Giovanni XXIII Hospital
Investigators
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Study Director: Michele Colledan, MD, FEBS Papa Giovanni XXIII Hospital
More Information
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Responsible Party: Stefania Camagni, MD, Principal Investigator, Papa Giovanni XXIII Hospital
ClinicalTrials.gov Identifier: NCT04203004    
Other Study ID Numbers: HOPE-2
First Posted: December 18, 2019    Key Record Dates
Last Update Posted: May 23, 2023
Last Verified: May 2023

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Stefania Camagni, Papa Giovanni XXIII Hospital:
Hypothermic oxygenated perfusion (HOPE)
Cytokine filtration
Liver transplantation
Additional relevant MeSH terms:
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Reperfusion Injury
Ischemia
Pathologic Processes
 Vascular Diseases
Cardiovascular Diseases
Postoperative Complications