Does normothermic machine preservation increase the availability of livers for transplantation without compromising outcome?
| ISRCTN | ISRCTN11552402 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN11552402 |
| IRAS number | 283200 |
| Secondary identifying numbers | CPMS 50567, NIHR201003, IRAS 283200, PID 15694 |
- Submission date
- 01/10/2021
- Registration date
- 16/11/2021
- Last edited
- 22/11/2024
- Recruitment status
- No longer recruiting
- Overall study status
- Ongoing
- Condition category
- Other
Plain English summary of protocol
Background and study aims
Liver transplantation is a highly effective treatment, but the supply of suitable donor organs is greatly exceeded by the number of patients who would benefit. More than 10% of patients on the waiting list die before receiving a transplant and many others are never placed on the list because access is restricted to patients with the best chance of success.
Less than 2/3 of deceased donors in the UK result in a liver transplant, because the livers from many donors are less suitable, due to older age, medical conditions or circumstances of death, and are much more likely to cause complications. To use these higher-risk livers safely, we need to find better ways to preserve, repair and test livers so that more of the available donor organs can be transplanted without compromising the survival rate.
Normothermic machine perfusion (NMP) is a novel method of organ preservation which replaces the conventional icebox, using a machine which restores the flow of blood at body temperature allowing the liver to function during storage. This results in (i) better preservation of the liver (less injury), (ii) repair of the donor organ (reconditioning), and (iii) assessment of the organ’s functional state (viability assessment).
Previous studies, from the UK and elsewhere, showed a substantial reduction in injury. They also suggested that transplant surgeons could accept higher risk organs with confidence, mainly due to the ability to assess function prior to transplant. However, these studies were not primarily designed to test the effects of NMP on organ use, and there remains a crucial need for high-quality evidence as to whether this more complex and expensive technology should become the standard of care.
The UK-designed and manufactured NMP device proposed in this study has already been used in small numbers of transplants in all of the UK’s seven liver transplant units. This has mostly relied upon charitable funding, because this technology has not yet been funded by NHS commissioners.
In this study, we will identify offers of those donor livers less likely to be used and make the NMP machine available for storage and assessment. We will compare the proportion resulting in successful transplants with a group of offers where NMP was not used to see if a pre-defined threshold for increased use is met. We will also collect information about the overall cost of the new technology compared to the old, so that the NHS can decide whether NMP is good value for money.
Who can participate?
Liver transplant recipients 18 years of age or above
What does the study involve for participants?
Eligible livers will be preserved using the NMP machine. The transplant surgeon will use information about the donor and the appearance of the liver, as well as information from the NMP machine, to make a decision as to whether the liver is safe to transplant.
We will ask for consent to collect information and outcomes from recipients during the transplant operation, during hospital stay and at routine hospital appointments 3 and 12 months after the transplant. We will also ask permission to continue to use the information routinely collected in the UK Transplant Registry to check the health status and care of recipients for up to 5 years after enrolment in the study.
All scans and blood tests will be the same as normal care after a transplant, however, participants will be asked to consent to optional additional samples of blood from the NMP machine during perfusion and a small biopsy sample after the liver has been transplanted at the end of the operation.
When assessing whether a new treatment is cost-effective, it is important that we understand quality of life. Will we ask participants to complete a short quality-of-life questionnaire (EQ5D-5L) before their transplant and at 3 and 12 months afterwards. This questionnaire includes questions about mobility, self-care, activity levels, pain levels and symptoms of anxiety and depression.
What are the possible benefits and risks of participating?
The allocated liver will only be transplanted if the transplant surgeon feels that it is safe to do so, given all of the information available. We will not be using any livers that would not normally have been offered. It is possible that the additional information from the NMP device may improve the confidence of surgeons in deciding whether to transplant the liver, and/or improve the condition of the liver. However, the reason that we are undertaking this study is that this effect 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?
June 2020 to September 2026
Who is funding the study?
National Institute for Health Research (NIHR) (UK).
Who is the main contact?
Simon Knight, plus@nhsbt.nhs.uk
Contact information
Public
NHS Blood & Transplant
John Radcliffe Hospital
Headington
Oxford
OX3 9DU
United Kingdom
| Phone | +44 (0)7385 384882 |
|---|---|
| plus@nhsbt.nhs.uk |
Scientific
Nuffield Department of Surgical Sciences
University of Oxford
Oxford
OX3 9DU
United Kingdom
 ORCID ID |
0000-0003-4837-9446 |
|---|---|
| Phone | +44(0)1865 227131 |
| simon.knight@nds.ox.ac.uk |
Study information
| Study design | Threshold-crossing design with a prospectively-defined efficacy threshold |
|---|---|
| Primary study design | Observational |
| Secondary study design | Threshold crossing design |
| Study setting(s) | Hospital |
| Study type | Other |
| Participant information sheet | https://www.nhsbt.nhs.uk/clinical-trials-unit/current-trials-and-studies/plus |
| Scientific title | Utilisation of normothermic machine preservation in extended criteria livers - a national threshold-crossing study |
| Study acronym | PLUS |
| Study objectives | Does normothermic machine perfusion increase the availability of livers for transplantation without compromising outcome? |
| Ethics approval(s) | Approved 10/11/2021, South Central - Oxford C Research Ethics Committee (The Old Chapel, Royal Standard Place, Nottingham, NG1 6FS, UK; +44 (0)207 104 8041; oxfordc.rec@hra.nhs.uk), ref: 21/SC/0297 |
| Health condition(s) or problem(s) studied | Preservation of donor liver before transplant |
| Intervention | Study cohort (normothermic machine perfusion; NMP): Prospectively identified, consecutive liver offers with a donor utilisation index (DUI) > 0.27, in which NMP is made available NMP with oxygenated blood, using the OrganOx metra, prior to implantation, for a minimum of 4 hours and maximum of 24 hours. Device-to-donor or back-to-base at the discretion of the accepting centre. Control cohort (static cold storage; SCS): A priori defined real-world control cohort meeting study inclusion criteria, identified from the NHSBT registry, in which NMP was not used. |
| Intervention type | Other |
| Primary outcome measure | Functional utilisation defined as the defined as the number of livers transplanted where the patient is alive, without the need for a re-transplant, 12 months postoperatively. This is a binary outcome extracted from records held by the UK Transplant Registry (UKTR). |
| Secondary outcome measures | 1. Graft survival defined as a functioning transplant in the absence of death and re-transplantation (death censored). These are measured at 7 days, 3 and 12 months and 5 years following re-transplantation. These are time to event outcomes and are also based on records held by the UK Transplant Registry (UKTR). 2. Graft loss including death or re-transplantation. These are measured at 7 days, 3 and 12 months and 5 years following transplantation. These are time to event outcomes and are also based on records held by the UK Transplant Registry (UKTR). 3. Patient survival at 7 days, 3 and 12 months and 5 years following transplantation. These are time to event outcomes and are also based on records held by the UK Transplant Registry (UKTR). 4. Primary non-function, defined as irreversible graft dysfunction requiring emergency liver replacement during the first 10 days after liver transplantation, in the absence of technical or immunological causes. This is a binary outcome extracted from records held by the UK Transplant Registry (UKTR). 5. NHS resource use based on published data and hospital episode statistics on the number of inpatient and outpatients’ episodes and treatments at 7 days, 3 and 12 months from Hospital Episode Statistics (HES) data. These will be valued using standard NHS unit costs. 6. Health-related quality of life for patients on the waiting list and post-transplant at 3 and 12 months, assessed by completion of the EQ-5D-5L questionnaire. 7. Post-operative resource use and quality of life (comparative and collected for both the study and historical cohort from data extracted from records held by the UK Transplant Registry) 7.1. Length of stay in high level (HDU/ITU) care post-transplant (days). 7.2. Length of initial hospital stay post-transplant (days). 7.3. Need for renal replacement therapy (haemodialysis, haemofiltration, haemodiafiltration) measured during transplant admission. The data indicate transient filtration, short or long-term dialysis. 7.4. Presence of transplant related renal dysfunction at 12 months 7.5. Number of re-admissions during the 12 months post-transplant and reason for re-admission 7.6. Lifestyle activity score post-transplant and at 12 months. This is a 5-scale categorical outcome, reflecting the recipient’s ability to carry out daily activity at different levels. 8. Safety measured by 8.1. Organ discard. Binary outcome data extracted from records held by the UK Transplant Registry (UKTR), for both cohorts. These are also tracked in study CRFs for the study cohort. 8.2. Recipient infection : Data on presence of CVM infection, fungal infection and sepsis including site of sepsis (sputum, blood, urine) are extracted from records held by the UK Transplant Registry (UKTR). These are available post-operatively, for both cohorts. 8.3. Biopsy proven rejections. Categorical variable denoting the presence and acute or chronic rejection during the first year of follow-up. Data at the 12-month routine visit are extracted from records held by the UK Transplant Registry (UKTR) and available for both cohorts. 8.4. Presence of biliary complications, their type (biliary strictures and bile duct leaks), and whether these required intervention along with type of intervention are collected post-transplant, at 3 months and 12 months through study CRFs for the study cohort. These are only available post-transplant for the historical cohort. 8.5. Presence of vascular complications requiring intervention, their type (bleeding, hepatic artery stenosis, hepatic artery thrombosis, portal vein thrombosis, portal vein stenosis), and whether these required intervention, along with type of intervention are collected post-transplant, at 3 months and 12 months through study CRFs for the study cohort. These are only available post-transplant for the historical cohort. 9. Safety (Study cohort only) 9.1. Presence of any adverse event rates, expectancy and relatedness to study intervention and severity, graded according to the Clavien-Dindo classification system. These are collected by study CRFs, for the prospective cohort at any time they may present. 9.2. Presence of any technical complications/device failures, binary indicatory collected through study CRFs for the study cohort at organ retrieval and when NRP is used. 10. Concomitant care: Details of induction and maintenance immunosuppression in total dosage in mg will be collected at day 7, 3 months and 12 months for the study cohort. This is available only post-transplant and at 12 months for the historical cohort. 11. Biochemical liver function (Study cohort only) 11.1. Biochemical liver function (ALT (IU/L), GGT (IU/L), INR, Bilirubin(umol/L)) (Days 1-7 post-transplant) 11.2. Daily serum lactate (mmol/L) (whilst on ITU/HDU) 11.3. Model for Early Allograft Function predictive score (MEAF). This is a composite score based upon the maximum values of ALT, INR and bilirubin during the first 3 days postoperatively. (Areja E, Cortes M, Hervás D et al. A score model for the continuous grading of early allograft dysfunction severity. Liver Transplantation: Official Publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society 2015; 21 (1): 38.) 12. Value of perfusion parameters to predict clinical outcomes and support clinical decision making (Study cohort only) 12.2. Perfusion parameters (logged automatically by the device): Arterial and caval pressures (in mmHg) Arterial, portal and caval flow rates (in mmHg) pO2, pCO2 and pH Blood temperature (oC), Glucose (mmol/L) and bile production (ml/h) 12.3. Perfusate lactate (mmol/lL) at 5 minutes, 1, 2 and 4 hours and end of NMP 12.4. Perfusate ALT (IU/L) at 2 and 4 hours and end of NMP 12.5. Perfusate glucose (mmol/L) at 2 and 4 hours and end of NMP 12.6. Bile pH at 2 and 4 hours and end of NMP 12.7. Bile glucose (mmol/L) at 2 and 4 hours and end of NMP 12.8. Total bile volume (ml) for the duration of perfusion. 12.9. Graft histology, including degree of macrosteatosis (semi-quantitative score for macrosteatosis as mild, moderate and severe), following organ reperfusion. |
| Overall study start date | 01/06/2020 |
| Completion date | 30/09/2026 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Adult |
| Lower age limit | 18 Years |
| Sex | Both |
| Target number of participants | 2465 retrospective and 1035 prospective livers |
| Total final enrolment | 3500 |
| Key inclusion criteria | The enrolled entity in this study is a liver offer, rather than a transplant recipient. Inclusion criteria for liver offers: 1. Deceased donors aged 16 years or over 2. Offered through the national offering scheme 3. Donor Utilisation Index (DUI) greater than 0.27 Inclusion criteria for liver transplant recipients: 1. Recipients 18 years of age or above 2. Elective and super-urgent 3. Participant is willing and able to give informed consent for participation in the study |
| Key exclusion criteria | Current exclusion criteria as of 06/06/2023: Exclusion criteria for liver offers: 1. Donors falling outside national offering scheme 2. Donors from outside of the UK 3. Donor is HIV or hepatitis C positive 4. Donor Utilisation Index ≤0.27 5. Donor not donation after brain death (DBD) or donation after circulatory death (DCD) 6. Donors aged <16 years 7. Livers undergoing any other form of ex-situ machine preservation 8. Participating centre cannot offer NMP due to logistical reasons (e.g., lack of appropriate personnel or device availability) Liver transplant recipients: 1. Have not agreed to use of NMP according to local consent policy 2. Receipt of a split liver or reduced liver transplant 3. Receipt of a multi-organ transplant 4. Transplanted outside of the 7 participating centres Previous exclusion criteria: Exclusion criteria for liver offers: 1. Donors falling outside national offering scheme 2. Donors where information about participation was not sent with the organ offer 3. Donors from outside of the UK 4. Donor is HIV or hepatitis C positive 5. Livers undergoing any other form of ex-vivo 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 been recruited to the study 2. Have not agreed to use of NMP according to local consent policy 3. Receipt of a split liver transplant 4. Receipt of a multi-organ transplant 5. Transplanted outside of the 7 participating centres |
| Date of first enrolment | 11/04/2022 |
| Date of final enrolment | 04/04/2023 |
Locations
Countries of recruitment
- England
- Scotland
- United Kingdom
Study participating centres
Hills Road
Cambridge
CB2 0QQ
United Kingdom
Mindelsohn Way
Birmingham
B15 2TH
United Kingdom
51 Little France Crescent
Old Dalkeith Road
Edinburgh
EH16 4SA
United Kingdom
London
SE5 9RS
United Kingdom
Beckett Street
Leeds
LS9 7TF
United Kingdom
Freeman Road
High Heaton
Newcastle
NE7 7DN
United Kingdom
London
NW3 2QG
United Kingdom
Sponsor information
University/education
Clinical Trials & Research Governance
Boundary Brook House, Churchill Drive
Headington
Oxford
OX3 7GB
England
United Kingdom
| Phone | +44 (0)1865 289885 |
|---|---|
| ctrg@admin.ox.ac.uk | |
| Website | http://www.ox.ac.uk/ |
"ROR" |
https://ror.org/052gg0110 |
Funders
Funder type
Government
No information available
Government organisation / National government
- Alternative name(s)
- National Institute for Health Research, NIHR Research, NIHRresearch, NIHR - National Institute for Health Research, NIHR (The National Institute for Health and Care Research), NIHR
- Location
- United Kingdom
Results and Publications
| Intention to publish date | 30/09/2027 |
|---|---|
| Individual participant data (IPD) Intention to share | No |
| IPD sharing plan summary | Data sharing statement to be made available at a later date |
| Publication and dissemination plan | Planned publication in a high-impact peer-reviewed journal. |
| IPD sharing plan | The current data sharing plans for this study are unknown and will be available at a later date |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| HRA research summary | 28/06/2023 | No | No | ||
| Protocol file | version 3.1 | 24/07/2023 | 22/11/2024 | No | No |
Additional files
Editorial Notes
22/11/2024: Uploaded protocol (not peer-reviewed) as an additional file.
06/06/2023: The following changes were made to the study record:
1. The exclusion criteria were updated.
2. The target number of participants was changed from Planned Sample Size: 3264; UK Sample Size: 260 to 2465 retrospective and 1035 prospective livers.
3. Total final enrolment added.
4. The recruitment start date was changed from 01/11/2021 to 11/04/2022.
5. The recruitment end date was changed from 01/05/2023 to 04/04/2023.
02/06/2023: The study design was changed from interventional non-randomised study to observational threshold crossing design.
31/12/2021: Addenbrooke’s Hospital has been added to the trial participating centres and John Radcliffe Hospital removed.
01/10/2021: Trial's existence confirmed by the National Institute for Health Research (NIHR) (UK).
