End Stage Liver DIsease, Liver Failure
Conditions
Keywords
Hypothermic oxygenated machine perfusion, Liver preservation, Liver transplantation
Brief summary
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
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.
Interventions
DEVICEVitaSmart™Liver Machine Perfusion System
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.
OTHERStatic cold storage
Donor liver retrieval and preservation using standard of care cold storage methods
Sponsors
Bridge to Life Ltd.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Masking description
A centralized radiologist who evaluates imaging (MRCP and ERCP) for one of the secondary endpoints (ischemic cholangiopathy) will be blinded to treatment assignment. The study is otherwise open label.
Intervention model description
This is a randomized, controlled, open-label, sequential assignment, non-inferiority design comparing two treatment arms (HOPE, static cold storage)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Early Allograft Dysfunction (EAD) | 7 days | Proportion of participants with EAD by 7 days post-transplant (or at hospital discharge if prior to 7 days). Defined by the presence of one or more of the following outcomes: * Serum bilirubin ≥10 mg/dL at day 7 post-transplant * INR ≥1.6 at day 7 post-transplant * ALT or AST \>2000 IU/L within the first 7 days post-transplant |
| Graft Survival at 6 Months | 6 months following transplantation | Graft survival is defined as absence of death or graft failure |
| Participant Survival at 6 Months | 6 months following transplantation | Participant survival is defined as absence of death. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Graft Survival at 12 Months/30 Days | Up to 12 months following transplantation | Graft survival is defined as absence of death or graft failure |
| Participant Survival at 12 Months/30 Days | Up to 12 months following transplantation | Participant survival is defined as absence of death. |
| Model for Early Allograft Function (MEAF) Score | Within 3 days post-transplant | Model for Early Allograft Score (MEAF) is a continuous scoring system based on the subject's maximum labs within the first three days post transplant, alanine aminotransferase (ALT) and international normalized ratio (INR) plus day-3 bilirubin. The score ranges from 0-10 with 0 being the worst to 10 being the best and provides a grade for liver dysfunction severity. |
| Primary Non-function (PNF) | Within 7 days post-transplant | Defined as early graft failure resulting in re-transplantation or death with no hepatic artery thrombosis or other detectible technical complications and with AST≥3000 IU/L and either INR≥2.5, arterial pH≤7.30, venous pH≤7.25 or serum lactate≥4mmol/L |
| Length of Hospital Stay | End of surgery to hospital discharge | Duration from initial ICU or floor admission to hospital discharge order (measured in days) |
| Length of Intensive Care Unit Stay | End of surgery to ICU discharge | Duration from initial intensive care unit (ICU) admission to ICU discharge order (measured in days), patients that did not go to ICU were assumed '0' days |
| Duration on Renal Replacement Therapy (RRT) | Post-transplantation until RRT discontinued for >2 weeks | Includes patient that required RRT within 2 weeks post-transplantation; duration from until discontinuation of dialysis for \>2 weeks |
| Donor Liver Utilization | Randomization to transplantation | Defined as the proportion of randomized donor/recipients to transplanted recipients |
| Biopsy-proven Liver Rejection | Up to 12 months following transplantation | Rejections confirmed on biopsy were tabulated between the 2 groups. |
| Central Radiologist Diagnosed Non-anastomotic Strictures (NAS) | Up to 12 months after transplantation | Non-anastomotic strictures (NAS) were diagnosed by the blinded, central radiologist on cholangiograms (ERCP, MRCP) |
| Unanticipated Adverse Device Effects (UADEs) | 12 months after transplantation | UADE is defined as an adverse event that is serious and device related. UADE reporting is only applicable to the HOPE arm. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORDavid Reich, MD
Drexel University
Participant flow
Pre-assignment details
228 recipient subjects and donors were randomized (ITT population), 113 in the HOPE arm and 115 in the SCS arm. Following randomization, a total of 9 subjects (4 HOPE, 5 SCS) did not complete transplant surgery because of clinical contraindications that were unrelated to the study. None of the 4 liver grafts in the HOPE arm underwent any treatment with the investigational device prior to being clinically declined. 219 subjects completed transplant surgery (safety and mITT populations).
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 59.0 years |
| Body mass index (BMI) | 30.0 kg/m^2 |
| Donor type Donor after brain death (DBD) | 81 Participants |
| Donor type Donor after circulatory death (DCD) | 55 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 33 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 96 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Model for End-Stage Liver Disease (MELD) score | 21.5 scores on a scale |
| Primary etiology of liver disease Alcoholic induced | 54 Participants |
| Primary etiology of liver disease Autoimmune | 7 Participants |
| Primary etiology of liver disease Cholestatic liver disease | 14 Participants |
| Primary etiology of liver disease Cryptogenic | 4 Participants |
| Primary etiology of liver disease Hepatocellular carcinoma | 3 Participants |
| Primary etiology of liver disease MASH | 59 Participants |
| Primary etiology of liver disease Other | 1 Participants |
| Primary etiology of liver disease Viral hepatitis | 9 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants |
| Race (NIH/OMB) Asian | 4 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants |
| Race (NIH/OMB) More than one race | 3 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) White | 199 Participants |
| Region of Enrollment United States | 109 participants |
| Sex: Female, Male Female | 41 Participants |
| Sex: Female, Male Male | 68 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 3 / 109 | 4 / 110 |
| other Total, other adverse events | 107 / 109 | 107 / 110 |
| serious Total, serious adverse events | 70 / 109 | 72 / 110 |
Outcome results
None listed