Normothermic (normal body temperature) machine perfusion to remove fat from donor livers prior to transplantation
| ISRCTN | ISRCTN14957538 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN14957538 |
| IRAS number | 300545 |
| Secondary identifying numbers | CPMS 52503, NIHR131163, IRAS 300545 |
- Submission date
- 22/09/2022
- Registration date
- 07/10/2022
- Last edited
- 25/06/2024
- Recruitment status
- No longer recruiting
- Overall study status
- Ongoing
- Condition category
- Surgery
Plain English Summary
Background and study aims
Liver disease is the third leading cause of premature death in the UK. Liver transplantation is the only successful treatment for end-stage liver disease but is limited by a shortage of suitable donor organs.
A third of donated livers are declined for transplants due to the presence of fat within the liver cells (known as non-alcoholic fatty liver disease, NAFLD). Transplanting a fatty liver carries a greater risk to the patient compared to a normal liver as these livers do not tolerate conventional ice-box storage before transplantation.
Our preliminary experiments point to an innovative defatting strategy for treatment of fatty human livers that were declined for transplantation. These livers were preserved on a machine in very similar conditions to those in the body (termed normothermic machine perfusion; NMP). We added a combination of currently available drugs to release fat from liver cells, and we then removed the fat from the perfusion machine using a filter. This reduced the amount of fat in the liver and improved its function.
None of the livers treated in this experimental study were actually transplanted: if used for patients, we believe that this might increase the number of livers that could be transplanted safely.
Who can participate?
Liver donors and liver transplant recipients aged 18 years and older.
What does the study involve?
In the proposed trial, we will randomly assign 60 livers from donors with a high risk of fatty liver disease to either NMP alone or NMP with fat removal treatment. We will assess how many of these livers are safe to transplant and, in those that are transplanted, follow the outcomes after the operation. The main objective is to show whether this treatment is safe; it will also help us to design a future, larger study which will test the extent to which fat removal actually leads to additional transplants.
What are the possible benefits and risks of participating?
The aim of the study is to demonstrate whether the fat removal process during normothermic machine perfusion is safe. Your new liver will be randomly allocated to receive either normothermic perfusion alone or normothermic perfusion with the additional process of fat removal treatment (defatting) in order to test whether liver function improves prior to transplantation. There are no anticipated side effects or risks related to the preservation and defatting process itself on the machine – all defatting agents are flushed from the liver before transplant.
As your liver will undergo normothermic machine perfusion alone or with fat removal treatment, it is possible that the additional information from the device may improve the confidence of your surgeons in deciding whether to transplant the liver, and/or improve the condition of the liver. Taking part in this study does not increase your chances of an organ offer – your place on the waiting list will not change.
However, the reason that we are undertaking this study is that the effect of defatting on post-transplant outcomes is uncertain, so no benefit can be promised. The study may help us understand how we can increase the availability of donor organs and may benefit other people in the future.
Where is the study run from?
University of Oxford (UK)
When is the study starting and how long is it expected to run for?
April 2021 to November 2025
Who is funding the study?
National Institute for Health and Care Research (NIHR) (UK).
Who is the main contact?
Hussain Abbas, Hussain.Abbas@nds.ox.ac.uk
Contact information
Scientific
Nuffield Department of Surgical Sciences
University of Oxford
Oxford Transplant Centre
Churchill Hospital
Oxford
OX3 7LJ
United Kingdom
 ORCID ID |
0000-0002-9434-2970 |
|---|---|
| Phone | +44 7858167196 |
| Hussain.Abbas@nds.ox.ac.uk |
Principal Investigator
Nuffield Department of Surgical Sciences
University of Oxford
Oxford Transplant Centre
Churchill Hospital
Oxford
OX3 7LJ
United Kingdom
| ORCID ID |
0000-0003-0841-9685 |
|---|---|
| Peter.Friend@nds.ox.ac.uk |
Principal Investigator
Nuffield Department of Surgical Sciences
University of Oxford
Oxford Transplant Centre
Churchill Hospital
Oxford
OX3 7LJ
United Kingdom
| ORCID ID |
0000-0003-4837-9446 |
|---|---|
| Simon.Knight@nds.ox.ac.uk |
Study information
| Study design | Interventional randomized controlled trial |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised controlled trial |
| Study setting(s) | Hospital |
| Study type | Other |
| Participant information sheet | https://www.nhsbt.nhs.uk/clinical-trials-unit/current-trials-and-studies/defat/ |
| Scientific title | Defatting of donor transplant livers during normothermic perfusion - a randomised clinical trial |
| Study acronym | DeFat |
| Study hypothesis | The combination of normothermic machine perfusion (NMP) with defatting strategies may be effective in reducing the fat content of donor livers with evidence of moderate-severe steatosis and improving perfusion parameters to meet functional criteria for transplantation. In this first clinical study, we intend to test the safety and feasibility of the intervention, and to obtain initial data regarding efficacy and effect size. |
| Ethics approval(s) | Approved 26/05/2022, London – Brighton & Sussex Research Ethics Committee (Health Research Authority, 2 Redman Place, Stratford, London, E20 1JQ, UK; +44 207 104 8241; brightonandsussex.rec@hra.nhs.uk), ref: 22/LO/0257 |
| Condition | Defatting of donor transplant livers |
| Intervention | In the proposed multi-centre pilot clinical trial, we will randomly assign 60 livers from donors with a high-risk of hepatic steatosis to either NMP alone or NMP with defatting interventions. We aim to test the safety and feasibility of the defatting intervention, and will explore efficacy by comparing ex-situ and post-reperfusion liver function between the groups. The primary endpoint will be the proportion of livers that achieve predefined functional criteria during perfusion which indicate potential suitability for transplantation. These criteria reflect hepatic metabolism and injury and include: lactate clearance; perfusate pH; glucose metabolism; bile composition; vascular flows; transaminase levels. Clinical secondary endpoints will include: proportion of livers transplanted in the 2 arms, graft function; cell-free DNA (cfDNA) at follow-up visits (cfDNA has been correlated with allograft injury, rejection and formation of de novo donor specific antibodies); patient and graft survival; hospital and ITU stay; evidence of ischemia-reperfusion injury (IRI); ischaemic cholangiopathy; recurrence of steatosis (determined on MRI at 6 months). Mechanistic secondary endpoints will include histological quantification of steatosis sequentially during perfusion and following reperfusion (in recipients). We will measure markers of hepatic lipid metabolism, allograft injury (cfDNA) and cytokines implicated in ischaemia-reperfusion injury (IRI) during ex-situ perfusion and peri-operatively (prior to and following reperfusion in the recipient). RNA sequencing, proteomic and glycomic analysis will investigate the effect of defatting on the expression of genes and proteins associated with post-transplant outcome, testing proposed viability markers for use in future studies and/or clinical practice. |
| Intervention type | Other |
| Primary outcome measure | The primary endpoint is the proportion of livers that achieve all of the following functional criteria at 6 hours of perfusion, as defined by: 1. Clearance of lactate to a level <2.5mmol/L 2. Perfusate pH ≥7.20 3. Evidence of glucose metabolism (spontaneous fall in perfusate glucose) 4. Minimum bile pH ≥7.5 (if bile produced) 5. Bile glucose concentration ≤3 mmol/L or ≥10 mmol less than perfusate glucose 6. Hepatic arterial flow ≥100ml/min; portal venous flow ≥500ml/min 7. Perfusate alanine aminotransferase (ALT) <6000U/L at 6 hours These objective criteria, reflecting hepatic metabolism and injury, have been derived by a process of consensus amongst current NMP users and are increasingly recognised as a way to discriminate livers with favourable post-transplant outcomes. These parameters are not intended as an instruction to the implanting surgeon, but rather as a consistent endpoint for the trial. The decision as to whether a liver is actually transplanted will remain with the implanting surgeon, who will base this on a number of criteria, including some that are recipient-related rather than donor organ-related (e.g. the urgency with which the patient needs a transplant may determine the decision). |
| Secondary outcome measures | Clinical secondary endpoints: 1. Proportion of livers transplanted in the 2 arms, graft function; 2. Cell-free DNA (cfDNA) at follow-up visits (cfDNA has been correlated with allograft injury, rejection and formation of de novo donor specific antibodies); 3. Patient and graft survival; 4. Hospital and ITU stay; 5. Evidence of ischemia-reperfusion injury (IRI); 6. Ischaemic cholangiopathy; 7. Recurrence of steatosis (determined on MRI at 6 months). Mechanistic secondary endpoints (analysed subsequent to the main clinical outcomes): Histological quantification of steatosis sequentially during perfusion and following reperfusion (in recipients). We will measure markers of hepatic lipid metabolism, allograft injury (cfDNA) and cytokines implicated in ischaemia-reperfusion injury (IRI) during ex-situ perfusion and peri-operatively (prior to and following reperfusion in the recipient). RNA sequencing, proteomic and glycomic analysis will investigate the effect of defatting on the expression of genes and proteins associated with post-transplant outcome, testing proposed viability markers for use in future studies and/or clinical practice. |
| Overall study start date | 01/04/2021 |
| Overall study end date | 30/11/2025 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Adult |
| Lower age limit | 18 Years |
| Sex | Both |
| Target number of participants | Planned Sample Size: 60; UK Sample Size: 60 |
| Participant inclusion criteria | Donor Livers: 1. Donors aged 18 years or over 2. Offered through the national offering scheme and accepted by participating liver transplant centre 3. Moderate-severe steatosis: macroscopic characteristics based on colour, texture, rounded edges, size and weight at point of inspection at the transplant hospital to confirm suitability for randomisation. Where available, the results of clinical biopsies demonstrating moderate-severe steatosis (> 30%) will also be taken into account to assess suitability for randomisation. Liver transplant recipients: 1. Recipients 18 years of age or above 2. Elective waiting list at a participating centre 3. Willing to consent for inclusion into the study and collection and use of their data |
| Participant exclusion criteria | Current exclusion criteria as of 17/10/2023: Donor Livers: 1. Donors from outside of the UK 2. Donor is HIV, hepatitis B or C positive 3. Cold ischaemia time (CIT) expected to exceed > 10 hours 4. Macroscopic evidence of fibrosis 5. Livers undergoing any other form of ex-situ machine preservation 6. Participating centre cannot offer NMP due to device, logistical or staffing reasons Liver transplant recipients: 1. Receipt of a liver that has not undergone randomisation 2. Receipt of super urgent transplant for acute liver failure 3. Receipt of a split liver transplant 4. Receipt of a multi-organ transplant 5. Transplanted outside of the participating centres 6. Contra-indication to MRI e.g. pacemaker _____ Previous exclusion criteria: Donor Livers: 1. Donors from outside of the UK 2. Donor is HIV, hepatitis B or C positive 3. Cold ischaemia time (CIT) expected to exceed > 10 hours 4. Macroscopic evidence of fibrosis 5. Livers undergoing normothermic regional perfusion (NRP) 6. Livers undergoing any other form of ex-situ machine preservation 7. Participating centre cannot offer NMP due to device, logistical or staffing reasons Liver transplant recipients: 8. Receipt of a liver that has not undergone randomisation 9. Receipt of super urgent transplant for acute liver failure 10. Receipt of a split liver transplant 11. Receipt of a multi-organ transplant 12. Transplanted outside of the participating centres 13. Contra-indication to MRI e.g. pacemaker |
| Recruitment start date | 23/02/2023 |
| Recruitment end date | 31/07/2024 |
Locations
Countries of recruitment
- England
- United Kingdom
Study participating centres
Hills Road
Cambridge
CB2 0QQ
United Kingdom
Pond Street
London
NW3 2QG
United Kingdom
Mindelsohn Way
Edgbaston
Birmingham
B15 2GW
United Kingdom
Denmark Hill
London
SE5 9RS
United Kingdom
Beckett Street
Leeds
LS9 7TF
United Kingdom
Sponsor information
University/education
University Offices
Oxford
OX1 2JD
England
United Kingdom
| ctrg@admin.ox.ac.uk | |
| Website | http://www.ox.ac.uk/ |
"ROR" |
https://ror.org/052gg0110 |
Funders
Funder type
Government
No information available
Results and Publications
| Intention to publish date | 01/10/2025 |
|---|---|
| Individual participant data (IPD) Intention to share | Yes |
| IPD sharing plan summary | Available on request |
| Publication and dissemination plan | Planned publication in a high-impact peer-reviewed journal |
| IPD sharing plan | The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request from DeFat@nhsbt.nhs.uk |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| HRA research summary | 26/07/2023 | No | No | ||
| Protocol article | 17/06/2024 | 25/06/2024 | Yes | No |
Editorial Notes
25/06/2024: Publication reference added.
10/04/2024: The overall end date was changed from 31/07/2025 to 30/11/2025.
17/10/2023: The following changes were made to the trial record:
1. The recruitment end date was changed from 01/10/2023 to 31/07/2024.
2. The overall end date was changed from 01/04/2024 to 31/07/2025.
3. The intention to publish date was changed from 01/04/2025 to 01/10/2025.
4. The plain English summary was updated to reflect these changes.
5. The exclusion criteria were changed.
27/02/2023: The recruitment start date was changed from 01/02/2023 to 23/02/2023.
04/01/2023: The recruitment start date was changed from 01/11/2022 to 01/02/2023.
19/10/2022: Internal review.
22/09/2022: Trial's existence confirmed by the National Institute for Health and Care Research (NIHR) (UK).
