Bridge to HOPE: Hypothermic Oxygenated Perfusion Versus Cold Storage Prior to Liver Transplantation

Study Overview
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Brief Summary
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This is a prospective, multi-center, controlled, randomized, pivotal study to evaluate the safety and effectiveness of the VitaSmart Liver Machine Perfusion System by comparing clinical outcomes in patients undergoing liver transplantation with ex-vivo liver preservation using static cold storage (SCS) followed by hypothermic oxygenated machine perfusion (HOPE) versus SCS only.

Detailed Description
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Patients on the UNOS waiting list for liver transplantation who have been consented, meet study eligibility criteria and are matched to a liver allograft from donation after brain death (DBD) or donation after circulatory death (DCD) that meet the extended risk eligibility criteria will be randomized 1:1 to SCS followed by HOPE (HOPE arm) or to SCS only (SCS arm). The objective of the study is to demonstrate the safety and effectiveness of the VitaSmart Liver Machine by comparing endpoints between the HOPE and SCS arms. Following transplantation, patients will be monitored daily (labs, adverse events, medications/procedures) while inpatient, and then additionally on Days 14 and 30 and Months 3, 6 and 12. The primary efficacy endpoint of early allograft dysfunction (EAD) rate will be assessed between HOPE and control using a non-inferiority design. An interim analysis is planned after approximately 70% of patients have been completed primary endpoint data collection to assess for early study completion based on non-inferiority or superiority.

Official Title
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A Multicenter, Prospective, Open-label, Randomized Controlled Clinical Trial to Compare the Safety and Effectiveness of the VitaSmart Liver Machine Perfusion System With Static Cold Storage for Organ Preservation Prior to Liver Transplantation

Conditions
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End Stage Liver DIsease, Liver Failure

Intervention / Treatment
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* Device: VitaSmart Liver Machine Perfusion System
* Other: Static cold storage


Participation Criteria
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Eligibility Criteria
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Donation after Brain Death (DBD) Liver Inclusion Criteria (one or more): Donor age 50-85 years Anticipated cold ischemia time 10-15 hours (excluding HOPE duration) Macrosteatosis 10-40% Terminal ALT 250-1500 IU/ml Peak ALT within 3 days 1000-3000 IU/ml Terminal total bilirubin 2-4 mg/dl Donation after Brain Death (DBD) Liver Exclusion Criteria (one or more): Donor age <18 or >85 years Anticipated cold ischemia >15 hours Macrosteatosis >40% Terminal ALT >1500 IU/ml Peak ALT within 3 days >3000 IU/ml Terminal total bilirubin >4 mg/dl Presence of hemodynamic and/or anatomical donor abnormalities that, in the opinion of the Investigator, make the liver allograft unsuitable for transplant into the recipient subject Liver intended for split transplant Liver from living donor Donor terminal serum Na >160 mmol/L Donation after Cardio-circulatory Death (DCD) Liver Inclusion Criteria (all): Donor age 18-60 years Anticipated cold ischemia time <12 hours (excluding HOPE duration) Functional warm ischemia time ≤35 minutes, defined as interval from the time of onset of donor hypotension (MAP <50mmHg) until the time of donor cross clamp Macrosteatosis ≤20% Terminal ALT ≤500 IU/ml Peak ALT within 3 days ≤2000 IU/ml Terminal total bilirubin ≤3 mg/dl Donation after Cardio-circulatory Death (DCD) Liver Exclusion Criteria (one or more): Presence of hemodynamic and/or anatomical donor abnormalities that, in the opinion of the Investigator, make the liver allograft unsuitable for transplant into the recipient subject Liver intended for split transplant Liver from living donor Donor terminal serum Na >160 mmol/L Recipient Inclusion Criteria (one or more): Subject (or legally authorized representative) is able to provide informed consent and HIPAA authorization Subject is male or female and at least 18 years of age Subject is registered as an active liver recipient on the UNOS waiting list for liver transplantation Subject will undergo primary liver transplantation Subject is willing to comply with the study requirements and procedures Subject with hepatocellular carcinoma as indication for Orthotopic Liver Transplantation; the tumor must be within Milan Criteria or down-staged to Milan Criteria Recipient Exclusion Criteria (one or more): Subject will undergo multiple organ transplantations (liver-kidney, liver-lung, etc.) Subject is listed for liver transplantation due to fulminant liver failure (UNOS status 1A) Subject is pregnant Subject is on respiratory (ventilator dependent) and/or cardiocirculatory support (requires at least one intravenous inotrope to maintain hemodynamics) Subject is enrolled in an interventional clinical trial with an investigational drug or device

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: This is a randomized, controlled, open-label, sequential assignment, non-inferiority design comparing two treatment arms (HOPE, static cold storage)
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Hypothermic oxygenated perfusion (HOPE)<br>Ex-vivo donor liver preservation using static cold storage followed by HOPE using the VitaSmart Liver Machine | Device: VitaSmart Liver Machine Perfusion System<br>* Following donor liver retrieval, preservation using static cold storage, and back table preparation in the transplant center operating room, the organ will be flushed with Belzer UW Machine Perfusion Solution (MPS) and perfused through the cannulated portal vein using cold, actively oxygenated MPS that is circulated at low pressure for 90 minutes to 5 hours. After disconnection from the device, donor liver implantation and reperfusion will proceed in accordance with institutional care standards.<br>* Other names: Hypothermic oxygenated perfusion;Other: Static cold storage<br>* Donor liver retrieval and preservation using standard of care cold storage methods<br>|
| Other: Static cold storage<br>Ex-vivo donor liver preservation using static cold storage only | Other: Static cold storage<br>* Donor liver retrieval and preservation using standard of care cold storage methods<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients with early allograft dysfunction (EAD) |  | At Day 7 post-transplant | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Model for early allograft function (MEAF) score | Based on definition by Olthoff et al, 2010 (doi: 10.1002/lt.22091) | Within 3 days post-transplant | 
| Proportion of patients with primary non-function (PNF) | Based on definition by Pareja et al, 2015 (doi: 10.1002/lt.23990) | Within 7 days post-transplant | 
| Length of hospital stay | Duration from initial ICU admission to hospital discharge order (measured in days) | Up to study participation ends at 1-year follow-up | 
| Length of intensive care unit stay | Duration from initial ICU admission to ICU discharge order (measured in days) | Up to study participation ends at 1-year follow-up | 
| Duration on dialysis | Duration from establishment of graft reperfusion until discontinuation of dialysis (measured in days) | Up to study participation ends at 1-year follow-up | 
| Donor liver utilization rate |  | Up to study participation ends at 1-year follow-up | 
| Patient survival rate |  | 30 days, 6 months, 1 year post-transplant | 
| Graft survival rate |  | 30 days, 6 months, 1 year post-transplant | 
| Incidence of adverse events (AEs) |  | 1 year post-transplant | 
| Incidence of serious AEs (SAEs) |  | 1 year post-transplant | 
| Incidence of unanticipated adverse device effects (UADEs) |  | 1 year post-transplant | 
| Incidence of ischemic cholangiopathy |  | 6 months, 1 year post-transplant | 
| Incidence of biopsy-proven liver rejection |  | 6 months, 1 year post-transplant | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hypothermic oxygenated machine perfusion, Liver preservation, Liver transplantation