RESTORE Declined Livers Study

A Prospective, Single-Center, Non-Randomized, Clinical Trial of Transplantation of Discarded Livers Using Normothermic Machine Perfusion (NMP)

This is a prospective, non-randomized, clinical trial of discarded liver transplants that have received normothermic machine perfusion (NMP), compared with standard cold preservation liver transplants. The discarded livers rejected by all other centers and meeting pre-NMP eligibility criteria will receive NMP using the OrganOx® metra device. The NMP-treated liver that meets the viability criteria will be transplanted to patients who are eligible and consented to the study. Liver transplant outcomes will be ascertained during 12 months post-transplantation. The results of the trial will be compared with those of contemporary comparison groups of patients who received the standard criteria donor liver transplantation.

Study Overview

• Status: Recruiting
• Conditions: Liver Diseases; Surgery; Transplant; Failure, Liver
• Intervention / Treatment: Device: Declined liver in Normothermic Machine Perfusion (NMP); Procedure: Standard cold preservation of liver

Detailed Description

This is a single center, prospective, non-randomized, clinical trial to assess the feasibility of successful transplantation of NMP-treated livers to patients. First, up to 71 marginal livers declined for transplantation will be treated with NMP using the OrganOx® metra device and tested for viability using previously defined criteria. NMP-treated viable livers will be subsequently transplanted to patients (n=5 in the 1st stage; additional 10 transplantation in the 2nd stage; additional 10 transplantation in the 3rd stage: total N=25). Patients will be closely followed for clinical outcomes of the transplantation during 6 months post-transplantation. The follow-up will also be extended up to 1 year post-transplantation. The trial will compare the results to those of three comparison groups - 1) matched patients who received liver transplantation at Washington University/Barnes Jewish Hospital; 2) matched patients who received DBD liver transplantation in the OPTN/UNOS database; and 3) matched patients who received DCD liver transplantation in the OPTN/UNOS database. Given that patient safety is the priority, the trial uses a multi-stage design in which the study stops earlier when NMP-treated liver transplantation is observed to be ineffective (see trial schema in Section 3.1).

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

Contacts and Locations

• Study Contact: Name: Jessica Schnable, RN, BSN; Phone Number: (314) 362-5705; Email: j.carter@wustl.edu
• Study Contact Backup: Name: Kathleen McDonnell, RN, BSN; Phone Number: (314) 362-3791; Email: kathleenm@wustl.edu

Study Locations

• United States
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Recruiting
      • Washington University School of Medicine
      • Contact: Jessica Schnable, RN, BSN; Phone Number: (314) 362-5705; Email: j.carter@wustl.edu
      • Contact: Melissa Lichtenberger, RN, BNS; Phone Number: 314-362-3791; Email: lichtenberger@wustl.edu
      • Principal Investigator: Will Chapman, M.D.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

PRE-NMP DECLINED LIVER ELIGIBILITY:

Inclusion Criteria:

• DCD donor aged 6 years or greater and liver weight between 1 kg and 3.4 kg, with functional warm ischemic time (defined as the period between the systolic blood pressure less than 60 mmHg to the time of commencing donor aortic perfusion) in DCD donors less than 40 minutes
• DCD asystolic warm ischemia time (from heartbeat stopping to initiation of cold flush) less than 15 minutes
• DBD donor aged 6 years or greater and liver weight between 1 kg and 3.4 kg, with less than 8 hours cold ischemia time and DCD livers with less than 7 hours cold ischemia time (defined as the interim from initiation of donor in vivo cold organ preservation to removal of the liver graft from cold storage)
• 'Rapid Recovery' donors for liver procurement, meeting the above criteria
• Suboptimal in situ flush

Exclusion Criteria:

• DBD or DCD donor less than 6 years old
• DCD grafts with donor functional warm ischemic time (defined as the period between the systolic blood pressure less than 60 mmHg to the time of commencing donor aortic perfusion) greater than or equal to 40 minutes
• DCD asystolic warm ischemia time (from heartbeat stopping to initiation of cold flush) greater than or equal to 15 minutes
• DBD livers with cold ischemia time greater than or equal to 8 hours and DCD livers with greater than or equal to 7 hours cold ischemia time
• Donor serum bilirubin greater than or equal to 5 mg/dL
• Liver weight less than 1 kg or greater than or equal to 3.5 kg
• Grafts from patients with HIV infection
• Cirrhotic livers
• Livers with bridging fibrosis

LIVER TRANSPLANTATION - HUMAN

Inclusion criteria:

• Subject must be greater than or equal to 18 years of age.
• Subject with end-stage liver disease who is actively listed for primary liver transplantation on the UNOS waiting list
• Subject, or a legally authorized representative, has given informed consent to participate in the study

• Subject has a frailty classification of "Mild frailty/No frailty (Robust)", based on the Liver Frailty Index (LFI), which has been assessed within 6 months prior to liver transplant OR Subject is able to perform >350 m on a 6 minute walk test (6MWT) within 6 months prior to liver transplant.

  • In all cases, the "most recent" (and within 6 months prior to transplant) measurement of LFI or 6MWT will be used to determine eligibility.

Exclusion criteria:

• Subject is currently listed as a UNOS status 1A.
• Subject is requiring oxygen therapy via ventilator/respiratory support.
• Subject is planned to undergo simultaneous solid organ transplant.
• Subject is pregnant at the time of transplant.
• Subject MELD score 29 or higher
• Subject receives re-transplantation of liver.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Declined liver in Normothermic Machine Perfusion (NMP); The discarded livers rejected by all other centers and meeting pre-NMP eligibility criteria will receive NMP using the OrganOx® metra device. The NMP-treated liver that meets the viability criteria will be transplanted to patients who are eligible and consented to the study. NMP of the donated declined liver utilizing the OrganOx® metra device. NMP involves (warm) machine perfusion with oxygenated blood at normal body temperature. During NMP, the device also allows for ongoing assessment of donor liver function and further viability assessment to help determine suitability of the organ for transplant.	Device: Declined liver in Normothermic Machine Perfusion (NMP); The discarded livers rejected by all other centers and meeting pre-NMP eligibility criteria will receive NMP using the OrganOx® metra device. The NMP-treated liver that meets the viability criteria will be transplanted to patients who are eligible and consented to the study.; Other Names: NMP-treated livers
Active Comparator: Standard cold preservation of liver; This group will receive liver transplant using the standard method of preservation. There will be 3 comparison groups: one local comparison group and two comparison groups from the national UNOS data.	Procedure: Standard cold preservation of liver; The study will have three comparison groups - one local comparison group and two comparison groups from the national UNOS data. Comparison group 1 will be patients who received a standard liver transplantation and follow-up care at the Washington University/ Barnes Jewish Hospital (n=50). Patients will be matched by a 5-year age category, sex, MELD score, donor liver graft type (e.g., DCD, DBD), donor age (5-year category), and donor sex. Washington University/ Barnes Jewish Hospital maintains a liver transplantation database that prospectively collects pre- and post-transplantation patient data. Comparison group 2 will be patients who received DBD liver transplantation in the OPTN/UNOS database (n=100). Patients will be matched by age, sex, MELD score, donor age, and donor sex. Comparison group 3 will be patients who received DCD liver transplantation in the OPTN/UNOS database (n=100). Patients will be matched by age, sex, MELD score, donor age, and donor sex.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of patients with no graft failure at 6 months	6-month graft and patient survival as an indicator of liver function after NMP- treated liver transplantation. 6-month patient survival rate will be estimated as the number of patients who survive by 6 months post-transplantation with NMP-treated livers This is a nationally accepted outcome routinely assessed in organ transplantation programs. 6-month graft survival rate = (Number of patients with no graft failure at 6-month post transplantation)/(Total number patients who received transplantation with NMP-treated liver) 6-month graft and patient survival rates will be compared to those in each comparison group using Fisher's Exact test. Kaplan-Meier survival curve will be examined as well.	Up to 6 months
Total number of patients who received NMP-treated liver transplantation	6-month patient survival rate will be estimated as the number of patients who survive by 6 months post-transplantation with NMP-treated livers divided by the total number of patients who received NMP-treated liver transplantation. 6-month patient survival rate = (Number of patients who survive by 6-month post transplantation)/(Total number patients who received transplantation with NMP-treated liver) 6-month graft and patient survival rates will be compared to those in each comparison group using Fisher's Exact test. Kaplan-Meier survival curve will be examined as well.	Up to 6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Assess liver graft function and survival after transplantation	Liver graft function assessment: early allograft dysfunction (EAD) and primary non-function (PNF). Long-term survivals of patient and graft will provide additional evidence on the safety of using NMP-treated liver for transplantation.	3 months to 1 year
Assess survival after transplantation	90-day graft and patient survival 1-year graft and patient survival Long-term survivals of patient and graft will provide additional evidence on the safety of using NMP-treated liver for transplantation.	3 months to 1 year
To assess morbidity associated with receipt of NMP-treated liver	Incidence of intrahepatic biliary strictures; Incidence of vascular complications; Event rate of requirement of renal replacement therapy; Incidence of biopsy-proven acute rejection; Event rate of transplant related reoperation rate; Length of ICU and hospital stay; Event rate of readmissions and other transplant related serious adverse events Incidence rates of adverse outcomes will provide additional evidence on the safety of using previously declined, NMP-treated liver for transplantation	3 months to 1 year
Quality of Life Score Questionnaire	Quality of life score using EQ-5D-5L questionnaire. To evaluate the effect of liver transplantation on patient's quality of life. Quality of life questionnaire will be completed at 3 timepoints: Baseline (prior to transplantation), 90 days and month 6	6 months
Estimate proportion of declined livers that can be used for transplantation following NMP	To estimate the proportion of declined livers that can be used for transplantation following NMP. Rescue-rate that is the number of viable NMP- treated livers divided by the total number of NMP-treated livers. The organ recovery rate provides additional evidence on the feasibility of using NMP-treated liver for transplantation.	12 months to 18 months

Collaborators and Investigators

• Sponsor: Washington University School of Medicine
• Collaborators: OrganOx Ltd.; Mid-America Transplant
• Investigators: Principal Investigator: Will Chapman, MD, Washington University School of Medicine

Study record dates

Study Major Dates

• Study Start (Actual): December 3, 2020
• Primary Completion (Estimated): September 1, 2024
• Study Completion (Estimated): September 1, 2026

Study Registration Dates

• First Submitted: July 14, 2020
• First Submitted That Met QC Criteria: July 22, 2020
• First Posted (Actual): July 23, 2020

Study Record Updates

• Last Update Posted (Actual): April 16, 2024
• Last Update Submitted That Met QC Criteria: April 15, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Diseases; Hematinics; Liver Extracts
• Other Study ID Numbers: 202007093

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