Pilot Study to Assess Safety and Feasibility of Normothermic Machine Preservation In Human Liver Transplantation

A Phase I Pilot Study to Assess Safety and Feasibility of Normothermic Machine Preservation In Human Liver Transplantation

Normothermic machine perfusion (NMP) preservation is a promising method to decrease the complication of marginal donor livers compared to cold storage (CS). The aim of this project is to assess safety and feasibility of NMP in human liver transplantation. This will be a single center prospective cohort pilot study. Thirty-two livers with acceptable quality for transplantation will be preserved with NMP in 2-18 hours and transplanted. The follow-up period will be 6 months post-transplantation. The outcome will be compared to 100 historical patients transplanted in our program in the past 5 years (liver preserved using CS) with matched characteristics on age, Model for End-Stage Liver Disease (MELD) score, preservation time, etc.

Study Overview

• Status: Completed
• Conditions: Liver Transplantation
• Intervention / Treatment: Device: Normothermic Liver perfusion Device

Detailed Description

The shortage of donor organs leads to the use of marginal donors including donors after cardiac death. Normothermic machine perfusion (NMP) preservation is a promising method to decrease their high risk of complication compared to the standard cold storage (CS). The aim of this project is to assess safety and feasibility of NMP in human liver transplantation.

This will be a single center prospective cohort pilot study. Thirty-two livers that have acceptable quality for transplantation will be preserved with NMP in 2-18 hours after cross clamp and cold flush. The liver grafts at NMP will be at physiological temperature and have oxygen and nutrient supply with continuous perfusion. The transplantation and post-transplant care will follow the standard of care. The follow-up period is 12 months after transplantation. The primary end point will be the rate of post-transplant Early Allograft Dysfunction (EAD), while the secondary end points will be: primary non function (PNF) rate, 1 and 6 months patient and graft survival, peak liver function tests in the first 7 days after transplantation, intraoperative hepatic arterial and portal flow measurement, rate and magnitude of post-reperfusion syndrome, surgical outcomes (operative time, transfusion requirement etc.), rate of post-transplant kidney failure, assessment of histological ischemia reperfusion (liver and bile duct), rate of vascular complications, rate of biliary complications, hospital and ICU length of stay, rejection rate, infection rate, the ability to predict function based on "on-pump" viability markers, and the incidence of adverse effect (AE).

The outcome will be compared to a control group of 100 historical patients (matched with a 1:4 ratio) transplanted in our program in the past 10 years (liver preserved using CS). Control subjects will be matched using donor and recipient age, Model for End-Stage Liver Disease (MELD) score, cold ischemia time, donor risk index and presence of steatosis.

• Study Type: Interventional
• Enrollment (Actual): 25
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients undergoing primary liver transplantation
• Age 18-75 years at the time of transplantation
• Willingness and ability to comply with the study procedures
• Signed Informed Consent Form
• For patients with hepatocellular carcinoma as indication for Orthoptic Liver Transplantation (OLT), tumor must be within Milan Criteria or down-staged to Milan Criteria.

Exclusion Criteria:

Recipient Exclusion Criteria:

• History of prior solid organ transplantation
• Patient on a respiratory and/or cardiocirculatory support at the time of transplant
• MELD score >35
• HIV positive patient
• Patient with current severe systemic infection
• Multiorgan transplant

Donor Exclusion Criteria:

• Donor age <14 or >70 years
• Liver steatosis (on visual estimate or on liver biopsy) > 30%
• Donors with Grade 2-3 traumatic liver laceration
• Partial grafts (living donors and split liver donors)
• Liver in which the investigator is unwilling or unable (for logistical reasons) to perform normothermic machine perfusion (NMP) preservation
• Inability to NMP perfuse the liver within 4 hours after cross clamp

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Normothermic Liver perfusion; This group has the liver grafts preserved using the Normothermic Liver perfusion Device.	Device: Normothermic Liver perfusion Device; The liver grafts will be preserved at physiological temperature and have continuous perfusion with oxygen and nutrient supply in the ex vivo organ preservation phase.
Other: Normothermic Machine Perfusion (single pump); This group has the liver grafts preserved using a single-pump variant of the Normothermic Liver perfusion Device.	Device: Normothermic Liver perfusion Device; The liver grafts will be preserved at physiological temperature and have continuous perfusion with oxygen and nutrient supply in the ex vivo organ preservation phase.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
the rate of Early Allograft Dysfunction post-transplantation in Normothermically Machine Perfused (NMP) livers	The presence of at least one of the following at post-transplant 7 days: serum bilirubin >= 10 mg/dL, international normalized ratio (INF) >= 1.6; and/or aspartate aminotransferase (AST) > 2000 U/L at any time in the first 7 post-transplant days (POD)	7 days post-transplantation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
primary non-function rate		in the first 10 days post-transplantation
graft survival	The allograft will be considered lost if a patient has a liver re-transplant or in the event of patient death.	6 months post-transplantation
peak liver function tests in the first 7 days post-transplantation		in the first 7 days post-transplantation
intraoperative flow measurement	Flows will be measured with a transit time flowmeter (VeriQ system, MediStim A/S, Oslo, Norway) after graft reperfusion. The following parameters will be recorded as per our standard practice during liver transplantation: portal venous flow, hepatic artery flow, and hepatic artery flow after temporary portal vein occlusion.	intraoperative
post reperfusion syndrome (composite)	rate and magnitude	in the first 7 days post-transplantation
surgical outcomes (composite)	operative time, transfusion requirement	intraoperative
rate of post-transplant kidney failure		in the 1, 3, 6 ,9 months post-transplantation
histology of liver parenchyma		On the day of transplantation
vascular complications rate		in the first day post-transplantation
biliary complications rate		6 months post-transplantation
hospital and ICU length of stay (composite)		6 months post-transplantation
rejection rate		6 months post-transplantation
opportunistic viral infection rate		6 months post-transplantation
patient survival		6 months post-transplantation
histology of bile duct		On the day of transplantation

Collaborators and Investigators

• Sponsor: Cristiano Quintini

Study record dates

Study Major Dates

• Study Start (Actual): May 16, 2016
• Primary Completion (Actual): June 9, 2020
• Study Completion (Actual): June 9, 2020

Study Registration Dates

• First Submitted: July 30, 2015
• First Submitted That Met QC Criteria: August 4, 2015
• First Posted (Estimate): August 5, 2015

Study Record Updates

• Last Update Posted (Actual): October 19, 2020
• Last Update Submitted That Met QC Criteria: October 15, 2020
• Last Verified: October 1, 2020

More Information

Terms related to this study

• Other Study ID Numbers: 15-549

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: Yes