RESTORE Declined Livers Study

Washington University School of Medicine24 enrolled

Overview

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.

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

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

Interventions

Declined liver in Normothermic Machine Perfusion (NMP)DEVICE

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.

Standard cold preservation of liverPROCEDURE

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.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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.

Outcomes

Primary Outcomes

Number of Patients With no Graft Failure at 6 Months

6-month graft survival as an indicator of liver function after NMP- treated liver transplantation. 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)

Time frame: Up to 6 months

6-month Patient Survival

6-month patient survival rate = (Number of patients who survive by 6-month post transplantation)/(Total number patients in the cohort who received transplantation)

Time frame: Up to 6 months

Secondary Outcomes

Liver Graft Function Assessment: Early Allograft Dysfunction

The presence of one or more of the following will be defined as early allograft dysfunction (EAD): bilirubin greater than or equal to 10 mg/dL on day 7\*, international normalized ratio greater than or equal to 1.6 on day 7\*, and alanine or aspartate aminotransferases greater than 2000 IU/L within the first 7 days\*. (\* day 7 or discharge, whichever occurs first). EAD = (Number of patients who experienced EAD)/(Total number patients who received transplantation with NMP-treated liver)

Time frame: First 7 days

Liver Graft Function Assessment: Primary Non-Function (PNF)

If one of the following criteria is met, and in the absence of a technical reason for graft failure, e.g. hepatic arterial thrombosis, and the subject requires re-listing for re-transplantation, it will be defined as primary non-function of a transplanted liver within 7 days of implantation if: 1) AST greater than or equal to 3000 and one or both of a) INR greater than or equal to 2.5 and b) acidosis (arterial pH less than or equal to 7.30 or venous pH less than or equal to 7.25 and/or lactate greater than or equal to 4 mmol/L); 2) anhepatic candidate. PNF= (number of participants that experienced PNF/ total number of patients who received transplantation with NMP-treated liver)

Time frame: First 7 days

No Graft Failure at 90 Days

90-day graft survival= (number of patients with no graft failure at 90 days/total number of patients who received transplantation with NMP-treated liver)

Time frame: 3 months

90-day Patient Survival

90 day patient survival= (Number of patients who survived by 90 days/ number of patients who received transplantation with NMP-treated liver)

Time frame: 3 months

Number of Patients With no Graft Failure at 12 Months

12 Month Graft Survival: (Number of patients with no graft failure at 12 months / number of patients who received transplantation with NMP-treated liver)

Time frame: 12 months

12-Month Patient Survival

12-month patient survival rate = (Number of patients who survive by 12-month post transplantation)/(Total number patients in the cohort who received transplantation)

Time frame: 12 months

Incidence of Intrahepatic Biliary Strictures

Number of patients who experienced intrahepatic biliary strictures / Number of patients who received transplantation with NMP-treated liver

Time frame: 12 Months

Incidence of Vascular Complications

Number of patients that experienced vascular complications / number of patients who received transplantation with NMP-treated liver

Time frame: 0-12 months

Event Rate of Requirement of Renal Replacement Therapy

Number of patients that required renal replacement therapy / number of patients who received transplantation with NMP-treated liver

Time frame: 0-12 Months

Incidence of Biopsy-Proven Acute Rejection

Number of patients that experienced acute rejection / number of patients who received transplantation with NMP-treated liver

Time frame: 0-12 months

Event Rate of Transplant Related Reoperation Rate

Number of patients that experienced transplant related reoperation / number of patients who received transplantation with NMP-treated liver For graft related complications that more specifically target the transplanted liver allograft and associated structures (e.g. bile duct, hepatic artery, portal vein, hepatic duct, hepatic vein, inferior vena cava)

Time frame: 0-12 Months

Length of ICU Stay

The number of days the patient was in the ICU post-transplant

Time frame: 0-3 Months

Length of Hospital Stay

Number of days the patient was hospitalized after transplantation.

Time frame: 0-2 Months

Event Rate of Readmissions

Number of patients that experienced a hospital readmission / number of patients who received transplantation with NMP-treated liver

Time frame: 0-12 Months

Quality of Life Score

EQ-5D-5L administered, which assessed the following domains: Mobility- minimum vale (I have no problems walking) and maximum value (I am unable to walk) Self-Care- minimum vale (I have no problems washing or dressing myself) and maximum value (I am unable to wash or dress myself) Usual Activities- minimum vale (I have no problems doing my usual activities) and maximum value (I am unable to do my usual activities) Pain/Discomfort- minimum vale (I have no pain or discomfort) and maximum value (I have extreme pain or discomfort) Anxiety/Depression- minimum vale (I am not anxious or depressed) and maximum value (I am extremely anxious or depressed) \*for above, minimum values considered a better outcome How good or bad your health is today- minimum value 0 (worst health you can imagine) and maximum value 100 (best health you can imagine) \*for above, maximum value considered a better outcome

Time frame: 0-6 Months

NMP-treated Liver Rescue Rate

Rescue Rate = (number of viable NMP- treated livers / total number of NMP-treated livers)

Time frame: course of study

RESTORE Declined Livers Study

Overview

Conditions

Interventions

Eligibility

Locations (1)

Outcomes

Primary Outcomes

Secondary Outcomes