379335
Research type
Research Study
Full title
Hypothermic oxygenated perfusion (HOPE) of human liver grafts before transplantation - A multicenter, randomized controlled trial
IRAS ID
225689
Contact name
Andrea Schlegel
Contact email
Sponsor organisation
University Hospital Zurich
Eudract number
2016-002540-16
Clinicaltrials.gov Identifier
Clinicaltrials.gov Identifier
2011-0079/4, Swiss National Ethic Number (KEK); 2013-MD-0029, Swissmedic Notification; 33IC30_16690971, IICT Grant Number (Switzerland); CIV-1 3-1 0-011641, EUDAMED; BK2O1 3-nTxOO48, BAG (Bundesamt für Gesundheit, Switzerland)
Duration of Study in the UK
2 years, 0 months, 31 days
Research summary
Summary of Research
The purpose of this study is, in a phase III randomized trial, to test a newly developed machine perfusion technique of human liver allografts before transplantation.
Liver grafts from brain death donors (DBD) will be randomly divided in two groups,
receiving either conventional cold storage (n=85) or cold storage plus subsequent 1-2
hypothermic oxygenated perfusion (HOPE) before implementation (n=85). Inclusion
criteria are all adult liver transplant candidates, who receive a full DBD graft.
Exclusion criteria are partial liver grafts and grafts donated after cardiac death (DCD)
The primary endpoint is postoperative complication (> III), as quantified by the
comprehensive complication index (CCI) according to the Clavien classification.
Secondary endpoints include ALT/AST release, liver graft function, hospital/ICU stay,
biliary complications, and survival. Follow up of each included patient will be 12
months.
Ten well known European Transplant Centers from six countries with a total caseload
of 750 liver transplants per year confirmed their participation. Based on this, we
expect completion of patient recruiting within 24 months, and completion of the trial
within 3 years.Significance of planned research: Late biliary injury and graft loss remain a major
problem in the era of sick liver transplant recipients and marginal donors. Machine
liver perfusion techniques have been recognized as potentially protective, but are still not in use in human liver transplantation, because of low practicability and lack of prospective human studies. The suggested study will demonstrate, for the first time worldwide, the effect of an easy and applicable perfusion technique in human liver grafts. We postulate, therefore, a high acceptance rate among transplant surgeons. In case of convincing success, it can be applied at low cost and low resources in any center worldwide.Summary of Results
Conclusion of Results: The main finding of the clinical evaluation was that patients receiving a liver graft from a brain death donor had a lower risk for severe complications (Clavien grade ≥ IIIb) within one year after liver transplantation when hypothermic oxygenated perfusion (HOPE) was applied to the liver graft additionally to cold storage (HOPE group), compared to preservation of the graft in cold storage solution alone (Control group). Consequently, graft loss due to liver injury decreased by HOPE.
Purpose of the investigation: The purpose of the clinical investigation was to test a newly developed machine perfusion technique of human liver allografts before transplantation.
Results: Between April 2015 and August 2019, 170 livers were performed within the trial, with 85 patients in the Control group and 85 patients in the HOPE group. Additional randomizations have been carried out, but those patients have not been eligible for the Full Analysis Set (FAS), as either patients did not fulfil inclusion/exclusion criteria anymore or the donor liver did not fulfil quality criteria for transplantation. No patients were lost to follow-up.
Baseline characteristics of donors, recipients and preservation factors were similar in the two treatment arms, with well-balanced key parameters including donor age, donor height and weights, total preservation time, recipient laboratory MELD score (Model for End stage Liver Disease), recipient age, primary or secondary transplants, and the underlying diseases.
Machine perfusion parameters were within the protocol margins with mean liver weight 1517g, median perfusion time 95.5 min, median perfusion flow 150-200 ml/min, median perfusion pressure 3 mmHg, median perfusate temperature 10-11°C, and median oxygenation 80-100 kPa.
Primary endpoint: Number of patients with major postoperative complications (Clavien grade ≥ III) During the first year after liver transplantation, a total of 1190 Adverse Events (AEs) were documented. The proportion of patients with at least one major postoperative complication of Clavien grade ≥ III was similar in the two treatment arms with 46 out of 85 patients (54.1%) in the Control arm and 44 out of 85 patients (51.8%) in the HOPE arm.
Secondary endpoint: Comprehensive complication index (CCI) In the Control arm, 574 complications were recorded, and in the HOPE arm, 616 complications were recorded. The overall CCI of all complications increased significantly during the follow-up period of one year after liver transplantation and was similar in both study groups.
The majority of complications was minor and graded as Clavien grade I and II in both arms: 433/574 (75.4%) in the Control arm and 494/616 (80.2%) in the HOPE arm.
The number of complications of Clavien grade IIIa (complications treated under local anaesthesia) was also similar in both arms with 72/574 (12.5%) in the Control arm and 81/616 (13.1%) in the HOPE arm. The means a comparable number of minor biliary complications in both arms.
In contrast, severe complications of Clavien grade ≥IIIb (complications treated under general anaesthesia, operative re-exposures, single and multi-organ failure, or death) occurred more frequently in the Control arm (69/574 [12.0%] complications in 28 patients) compared to the HOPE arm (41/616 [6.7%] complications in 26 patients).
The number of liver-related complications of Clavien grade ≥IIIb per patient was almost four-fold higher in the Control arm compared to the HOPE arm: In the Control arm, 42 complications were reported in 17 patients, and in the HOPE arm, 11 complications were observed in 7 patients. Correspondingly, the CCI for patients with liver-related complications (n=83) was higher in the Control group (median 43.2) than in the HOPE group (median 30.6).
Liver-related graft failure did not occur in the HOPE group whereas 6 liver grafts were lost in the Control group due to liver-related complications.
Secondary endpoint: laboratory values
Serum peak transaminases and area under the curve for AST (Aspartate aminotransferase) and ALT (Alanine aminotransferase) after liver transplantation showed low values in both groups. Additional laboratory measurements (International Normalized Ratio, Factor V, Bilirubin, Gamma glutamyl transferase, Alkaline Phosphatase) were also similar in both groups.
Secondary endpoints: length of hospital/Intensive Care Unit stay, overall graft survival The median Intensive Care Unit (ICU) and length of hospital stay after liver transplantation was similar between both groups: In the Control group, the median ICU stay was 3 days and the median hospital stay was 15 days. In the HOPE group, the median ICU stay was 3 days and the median hospital stay was 17 days.
One-year graft survival was 95.3% (81/85) in the HOPE group, and 91.8% (78/85) in the Control group.
Safety, serious adverse events (SAEs) and deaths The number of SAEs was similar in the two study arms. There was no relevant clinical difference between the two arms with regards to the severity of the events.
Four device deficiencies occurred in 88 machine liver perfusions (4.5%), which resulted in two cases with insufficient perfusion flow through the portal vein. Those livers were transplanted according to standard of care (preservation of the graft in cold storage solution) without major complications within the one-year follow-up period.
There was one case where the perfusion flow was too high despite low pressure; this patient was included in the trial and followed according to protocol. No major complication occurred during the one-year follow-up.
Within the first year after liver transplantation, 4 patients in the HOPE arm (4.7%) and 4 patients in the control arm (4.7%) died.REC name
Yorkshire & The Humber - Sheffield Research Ethics Committee
REC reference
17/YH/0308
Date of REC Opinion
23 Nov 2017
REC opinion
Further Information Favourable Opinion