Statins for improving organ outcome in transplantation
| ISRCTN | ISRCTN11440354 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN11440354 |
| IRAS number | 288722 |
| Secondary identifying numbers | CPMS 49404, IRAS 288722 |
- Submission date
- 09/07/2021
- Registration date
- 03/08/2021
- Last edited
- 20/09/2024
- Recruitment status
- Recruiting
- Overall study status
- Ongoing
- Condition category
- Surgery
Plain English Summary
Background and study aims
All organs removed from donors have already suffered a degree of damage. As the brain dies (and all of these donors are brain-stem dead) chemicals are released which cause an “inflammation” of the whole body. Measurements of this “inflammation” link to how well the organs function in the recipient after transplant.
Statins are cholesterol-lowering drugs that have benefits across a range of health problems. In particular, statins damp down inflammation in the body and in individual organs. Statins protect the lungs and kidneys in a range of illnesses.
Recently, transplant doctors in Finland linked all this information in an innovative clinical study. Organ donors who were about to donate their heart were randomly allocated to receive a dose of a statin. After the transplant, the recipients who received a heart from a donor who had statins had less heart damage. The numbers were modest, and no survival advantage could be demonstrated. There was a small benefit for lung and liver recipients, but importantly there was no disadvantage in receiving any organ from a donor who had received the drug.
A significant number of hearts and other organs offered for transplant by the donor family are not used; for the heart, this figure is about 75%. The reason for being so selective is that poor function of the donor heart in the recipient is by far the most common cause of death after a transplant. Any step in the donor which might improve the transplanted heart could have a major benefit to the recipient. The same principle applies to all the other organs transplanted.
The aim of this study is to investigate whether giving deceased organ donors a single dose of the drug simvastatin, a very commonly used and safe drug, is beneficial for transplant recipients.
Who can participate?
Adult brain dead organ donors across the UK per year over 4 years
What does the study involve?
Half the donors will receive the drug (in addition to their standard donor care), compared to the other half of donors who will receive standard care only. The drug is given through a tube running into the stomach, already present in 80% of donors, but required to be placed in the other 20%. The drug will be given as soon as the donor family have consented to both organ donation and involvement of their loved one in research.
Half of all the transplant recipients will receive an organ from a donor given the drug. The researchers will follow the results of transplant, focussing on the heart recipients, but for all those receiving these organs, comparing what happens in those who received the drug-treated organs, and those who did not. This is done with data already collected in the national transplant database. No extra data or blood samples will be needed from recipients.
What are the possible benefits and risks of participating?
Unfortunately, there will be no benefit to the donors but there may be a benefit to the person receiving their organs if they are transplanted. People receiving an organ that has been treated with simvastatin may have better outcomes, and it is hoped that this will mean more organs can be transplanted successfully, but it is not known whether this will be the case. Simvastatin is a licensed drug and one of the most prescribed drugs in the UK. There are some risks associated with taking statins for a long time, but this will be a single dose so these risks are not considered a problem at all for this study. With any drug there is a risk of an allergic reaction. This is expected to be very rare as there has only been one case of this reported.
Where is the study run from?
NHS Blood and Transplant Clinical Trials Unit (UK)
When is the study starting and how long is it expected to run for?
October 2020 to June 2026
Who is funding the study?
National Institute of Health Research (NIHR) (UK)
Who is the main contact?
Miss Amy Evans
SIGNET@nhsbt.nhs.uk
Contact information
Scientific
NHS Blood and Transplant Clinical Trials Unit
Long Road
Cambridge
CB2 0PT
United Kingdom
| Phone | +44 (0)1223 588 016 |
|---|---|
| SIGNET@nhsbt.nhs.uk |
Study information
| Study design | Randomized; Interventional; Design type: Process of Care, Drug, Other |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised controlled trial |
| Study setting(s) | Hospital |
| Study type | Treatment |
| Participant information sheet | ISRCTN11440354_PIS_donor relative_v11_11Jun2021.pdf |
| Scientific title | Statins in organ donor management: an evaluation of the benefits of a single dose of simvastatin given to potential organ donors declared dead by neurological criteria on outcomes in organ recipients |
| Study acronym | SIGNET |
| Study hypothesis | Does treatment of potential organ donors with simvastatin during protocolised care after diagnosis of death using neurological criteria improve outcomes in patients undergoing transplantation? |
| Ethics approval(s) | Approved 28/06/2021, London - Queen Square Research Ethics Committee (HRA NRES Centre Bristol, 3rd Floor, Block B, Whitefriars, Lewins Mead, Bristol, BS1 2NT, UK; +44 (0)207 104 8061; queensquare.rec@hra.nhs.uk), REC ref: 21/LO/0412 |
| Condition | Organ transplantation |
| Intervention | This is a multi-centre, single-blind prospective, group sequential, randomised controlled trial. Randomisation will be in a 1:1 ratio and will be stratified according to whether the donor was receiving statin therapy at ICU admission. Setting ICUs within Level 1 or 2 donating hospitals: defined as a mean number of donors per year > 6 by NHS Blood and Transplant. Screening Adult organ donors will be identified by the Specialist Nurses in Organ Donation (SNODs). After they have been through the organ donation consent process with the donor family, they will go through the study-specific consent. The SNODs will complete an eligibility checklist which will be countersigned by the prescribing ICU doctor if the patient is randomised to receive the intervention. No screening logs will be completed. Randomisation Following study-specific consent, participants will be randomised using an online randomisation service, called SealedEnvelope, and given a unique Randomisation Number. The treatment allocation will also be provided. Treatment The study treatment is 80 mg simvastatin in addition to protocolised standard care. This will be compared to protocolised standard care alone. If randomised to receive the intervention, this will be prescribed by an ICU doctor and issued from hospital stock. The tablet will be crushed, mixed with 20 ml sterile water (hospital stock) and administered via nasogastric tube. Nasogastric tubes are already in place for 80% of organ donors but if this is not already in place, this will be required. Follow up Although there will be some intervention and donor data collected by the research team onto an eCRF, most of the data from the donors, and all recipient data, is already collected as part of standard care on the UK Transplant Registry. No additional information or samples will be needed from recipients. Safety reporting Serious adverse events will be reported to the REC within 15 days of the clinical team becoming aware. Due to the low-risk intervention and complex patient population, serious adverse events that need reporting will be those assessed by the PI as being related to the study and unexpected. The researchers will also record events that progress to the loss of capacity to donate as a result of the study procedure. |
| Intervention type | Drug |
| Pharmaceutical study type(s) | |
| Phase | Not Applicable |
| Drug / device / biological / vaccine name(s) | Simvastatin |
| Primary outcome measure | Updated primary outcome measure as of 01/05/2024: The primary outcome measure is a composite outcome of death, cardiac mechanical circulatory support or renal replacement therapy within the first 30 days post heart transplant Previous primary outcome measure: Composite of death, cardiac mechanical circulatory support or renal replacement therapy, determined by the recipient status on the UK Transplant Registry (UKTR) at 30 days |
| Secondary outcome measures | 1. Organ utilisation rate, measured by the proportion of organs offered that were transplanted for each organ separately and based on the records held by the UK Transplant Registry (UKTR) during the 60-month trial duration, records completed at 30-days or at initial discharge post-transplant whichever is sooner 2. Graft survival for all transplanted organs, based on the records held by the UKTR, at 30 days, 3 months and 12 months 3. Patient survival, determined by status on the UKTR, at 30 days, 3 months and 12 months 4. Length of ITU stay, measured by the number of days the patient was on ITU, based on the records held by the UKTR from the point of transplant to discharge from ITU at discharge from transplant admission 5. Length of hospital stay, measured by the number of days the patient was in hospital, based on the records held by the UKTR excluding kidney recipients at from the point of transplant to discharge from hospital at discharge from transplant admission 6. Proportion of heart recipients requiring mechanical circulatory support up to 30 days, based on the records held by the UKTR 7. Proportion of cardiac recipients requiring renal replacement therapy up to 30 days, based on the records held by the UKTR 8. Patient survival for heart recipients, measured by their status on the UKTR, at 30 days 9. Number of treated rejection episodes for each organ, based on records held by the UKTR, at 3 and 12 months 10. Estimated glomerular filtration rate for kidney recipients, calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation (2009) from data held by the UKTR at 12 months 11. Proportion of kidney recipients with delayed graft function, defined as the need for dialysis in the first 7 days, based on records held by the UKTR 12. Number of days liver recipients spent ventilated, based on records held by the UKTR at 30 days or at initial discharge post-transplant whichever is sooner 13. Proportion of liver recipients with individual post-operative complications, measured by indicators recording the presence or absence of hepatic artery thrombosis, portal vein thrombosis, inferior vena cava (IVC)/hepatic vein occlusion, haemorrhage requiring reoperation, biliary tract leaks, biliary tract stricture requiring intervention as recorded by the UKTR at 30-days or at initial discharge post-transplant whichever is sooner 14. For liver recipients, the levels of serum creatinine (μmol/), bilirubin (μmol/) and alkaline phosphatase (IU/L) at 12 months, based on the UKTR records 15. FEV1 in lung recipients based on records held in the UKTR and measured in both absolute terms in litres, from the two best recent measurements as well as % predicted1 as measured at 12 months 16. Proportion of pancreas recipients (including simultaneous pancreas-kidney recipients) with initial pancreas graft function, based on records held on the UKTR at 30-days or at initial discharge post-transplant whichever is sooner 17. Number of treated pancreas rejection episodes in pancreas and simultaneous pancreas-kidney recipients at 3 and 12 months based on the UKTR 18. Categorised causes of graft loss in pancreas and simultaneous pancreas-kidney recipients as recorded on the UKTR at 12 months (causes recorded for pancreas graft failure include: vascular thrombosis, infection, bleeding, anastomotic leak, pancreatitis, primary non-function, hyperacute, acute and chronic rejection, preservation/procurement problem, death with functioning graft, patient declined medication) 19. Proportion of pancreas and simultaneous pancreas-kidney recipients with pancreatitis as recorded in the UKTR up to 3 months 20. C-peptide in pancreas islet recipients, measured by meal tolerance test in units of pmol/l, at 3-month follow-up in the UKTR |
| Overall study start date | 01/10/2020 |
| Overall study end date | 30/06/2026 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Adult |
| Lower age limit | 18 Years |
| Sex | Both |
| Target number of participants | Planned Sample Size: 2600; UK Sample Size: 2600 |
| Participant inclusion criteria | 1. Within a recruiting Intensive Care Unit 2. Patients diagnosed dead using neurological criteria 3. Consent for organ donation in place, as defined by the Human Tissue Act and accompanying legislation and Codes of Practice 4. Study-specific consent from the donor family |
| Participant exclusion criteria | 1. Aged <18 years 2. Planned donation after cessation of circulation (DCD) 3. Known donor allergic hypersensitivity to simvastatin |
| Recruitment start date | 14/09/2021 |
| Recruitment end date | 13/09/2025 |
Locations
Countries of recruitment
- England
- Northern Ireland
- Scotland
- United Kingdom
- Wales
Study participating centres
Foresterhill Rd
Aberdeen
AB25 2ZN
United Kingdom
Newport
NP20 2UB
United Kingdom
Airdrie
ML6 0JS
United Kingdom
East Kilbride
Glasgow
G75 8RG
United Kingdom
Wishaw
ML2 0DP
United Kingdom
Willesborough
Ashford
TN24 0LZ
United Kingdom
Canterbury
CT1 3NG
United Kingdom
Margate
CT9 4AN
United Kingdom
Ayr
KA6 6DX
United Kingdom
Crosshouse
Kilmarnock
KA2 0BE
United Kingdom
Headington
Oxford
OX3 9DU
United Kingdom
Bangor
LL57 2PW
United Kingdom
Bodelwyddan
Rhyl
LL18 5UJ
United Kingdom
Wrexham
LL13 7TD
United Kingdom
Barnet
EN5 3DJ
United Kingdom
London
NW3 2QG
United Kingdom
Bath
BA1 3NG
United Kingdom
Belfast
BT9 7AB
United Kingdom
Belfast
BT14 6AB
United Kingdom
Belfast
BT12 6BA
United Kingdom
Birmingham
B15 2TH
United Kingdom
Birmingham
B18 7QH
United Kingdom
West Bromwich
B71 4HJ
United Kingdom
Blackburn
BB2 3HH
United Kingdom
Blackpool
FY3 8NR
United Kingdom
Farnworth
Bolton
BL4 0JR
United Kingdom
Boston
PE21 9QS
United Kingdom
Lincoln
LN2 5QY
United Kingdom
Bournemouth
BH7 7DW
United Kingdom
Bridgend
CF31 1RQ
United Kingdom
Merthyr Tydfil
CF47 9DT
United Kingdom
Pontyclun
CF72 8XR
United Kingdom
Eastern Rd
Brighton
BN2 5BE
United Kingdom
Haywards Heath
RH16 4EX
United Kingdom
Bristol
BS2 8HW
United Kingdom
Bristol
BS10 5NB
United Kingdom
Derby
DE22 3NE
United Kingdom
Bury
BL9 7TD
United Kingdom
Oldham
OL1 2JH
United Kingdom
Frimley
Camberley
GU16 7UJ
United Kingdom
Slough
SL2 4HL
United Kingdom
Cambridge
CB2 0QQ
United Kingdom
Cardiff
CF14 4XW
United Kingdom
Lyne
Chertsey
KT16 0PZ
United Kingdom
Chester
CH2 1UL
United Kingdom
Chichester
PO19 6SE
United Kingdom
Worthing
BN11 2DH
United Kingdom
Fulwood
Preston
PR2 9HT
United Kingdom
Colchester
CO4 5JL
United Kingdom
Ipswich
IP4 5PD
United Kingdom
Hull
HU3 2JZ
United Kingdom
Coventry
CV2 2DX
United Kingdom
Darlington
DL3 6HX
United Kingdom
Durham
DH1 5TW
United Kingdom
Dundee
DD2 1SG
United Kingdom
Eastbourne
BN21 2UD
United Kingdom
Saint Leonards-on-Sea
TN37 7RD
United Kingdom
Old Dalkeith Rd
Edinburgh
EH16 4SA
United Kingdom
Edinburgh
EH4 2XU
United Kingdom
Howden W Rd
Howden
Livingston
EH54 6PP
United Kingdom
Enniskillen
BT74 6DN
United Kingdom
Londonderry
BT47 6SB
United Kingdom
Gillingham
ME7 5NY
United Kingdom
Glasgow
G4 0SF
United Kingdom
Glasgow
G51 4TF
United Kingdom
Paisley
PA2 9PJ
United Kingdom
Grimsby
DN33 2BA
United Kingdom
Scunthorpe
DN15 7BH
United Kingdom
HX3 0PW
United Kingdom
Lindley
Huddersfield
HD3 3EA
United Kingdom
Harefield
Uxbridge
UB9 6JH
United Kingdom
London
SW3 6NP
United Kingdom
Harrow
HA1 3UJ
United Kingdom
Southall
UB1 3HW
United Kingdom
Ilford
IG3 8YB
United Kingdom
Romford
RM7 0AG
United Kingdom
Ipswich
IP4 5PD
United Kingdom
Leeds
LS1 3EX
United Kingdom
Harehills
Leeds
LS9 7TF
United Kingdom
Leicester
LE3 9QP
United Kingdom
Leicester
LE1 5WW
United Kingdom
Liverpool
L7 8XP
United Kingdom
Liverpool
L9 7AL
United Kingdom
Liverpool
L9 7LJ
United Kingdom
London
W6 8RF
United Kingdom
London
W12 0HS
United Kingdom
London
W2 1NY
United Kingdom
London
SE5 9RS
United Kingdom
Orpington
BR6 8ND
United Kingdom
London
WC1N 3BG
United Kingdom
London
NW1 2BU
United Kingdom
London
E13 8SL
United Kingdom
London
EC1A 7BE
United Kingdom
London
E1 1FR
United Kingdom
London
E11 1NR
United Kingdom
London
SW17 0QT
United Kingdom
London
SE1 7EH
United Kingdom
London
SE18 4QH
United Kingdom
London
SE13 6LH
United Kingdom
Luton
LU4 0DZ
United Kingdom
Manchester
M13 9WL
United Kingdom
Wythenshawe
Manchester
M23 9LT
United Kingdom
Middlesbrough
TS4 3BW
United Kingdom
High Heaton
Newcastle upon Tyne
NE7 7DN
United Kingdom
Newcastle upon Tyne
NE1 4LP
United Kingdom
Cramlington
NE23 6NZ
United Kingdom
Colney
Norwich
NR4 7UY
United Kingdom
Nottingham
NG5 1PB
United Kingdom
Lenton
Nottingham
NG7 2UH
United Kingdom
Plymouth
PL6 8DH
United Kingdom
Portsmouth
PO6 3LY
United Kingdom
Rainhill
Prescot
L35 5DR
United Kingdom
Redditch
B98 7UB
United Kingdom
Worcester
WR5 1DD
United Kingdom
Salford
M6 8HD
United Kingdom
Scarborough
YO12 6QL
United Kingdom
York
YO31 8HE
United Kingdom
Sheffield
S5 7AU
United Kingdom
Broomhall
Sheffield
S10 2JF
United Kingdom
Southampton
SO16 6YD
United Kingdom
Stevenage
SG1 4AB
United Kingdom
Stoke-on-Trent
ST4 6QG
United Kingdom
Swindon
SN3 6BB
United Kingdom
Watford
WD18 0HB
United Kingdom
Heath Town
Wolverhampton
WV10 0QP
United Kingdom
Cwmrhydyceirw
Swansea
SA6 6NL
United Kingdom
Harton Lane
South Shields
NE34 0PL
United Kingdom
Sunderland
SR4 7TP
United Kingdom
Nethermayne
Basildon
SS16 5NL
United Kingdom
Gloucester
GL1 3NN
United Kingdom
Cheltenham
GL53 7AN
United Kingdom
Craigavon
BT63 5QQ
United Kingdom
Aylesbury
HP21 8AL
United Kingdom
High Wycombe
HP11 2TT
United Kingdom
Treliske
Truro
TR1 3LJ
United Kingdom
Pinderfields General Hospital
Aberford Road
Wakefield
WF1 4EE
United Kingdom
Holdforth Road
Hartlepool
TS24 9AH
United Kingdom
London Road
Reading
RG1 5AN
United Kingdom
Calow
Chesterfield
S44 5BL
United Kingdom
Thorne Road
Doncaster
DN2 5LT
United Kingdom
Thorne Road
Doncaster
DN2 5LT
United Kingdom
Haverfordwest
SA61 2PZ
United Kingdom
Carmarthen
SA31 2AF
United Kingdom
Caradoc Road
Aberystwyth
SY23 1ER
United Kingdom
Carlisle
CA2 7HY
United Kingdom
Hensingham
Whitehaven
CA28 8JG
United Kingdom
Taunton
TA1 5DA
United Kingdom
Larbert
FK5 4WR
United Kingdom
Hermitage Lane
Maidstone
ME16 9QQ
United Kingdom
Tonbridge Road
Pembury
Tunbridge Wells
TN2 4QJ
United Kingdom
Inverness
IV2 3UJ
United Kingdom
Shrewsbury
SY3 8XQ
United Kingdom
Sponsor information
Hospital/treatment centre
c/o Rebecca Johnson
Regulatory Compliance Team
Newcastle Joint Research Office
Level 1, Regent Point
Regent Farm
Newcastle-Upon-Tyne
NE3 3HD
England
United Kingdom
| Phone | +44 (0)191 282 4454 |
|---|---|
| tnu-tr.sponsormanagement@nhs.net | |
| Website | http://www.newcastle-hospitals.org.uk/ |
"ROR" |
https://ror.org/05p40t847 |
Funders
Funder type
Government
No information available
Results and Publications
| Intention to publish date | 30/06/2027 |
|---|---|
| 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 | Access to the final dataset for additional analyses will be permitted with the agreement of the Trial Steering Committee. Participant-level data will be held by NHS Blood and Transplant. |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Participant information sheet | For organ donor's relative version 11 |
11/06/2021 | 04/05/2023 | No | Yes |
| Participant information sheet | For organ recipient version 10 |
12/04/2021 | 04/05/2023 | No | Yes |
| Protocol (other) | v20 | 07/12/2022 | 04/05/2023 | No | No |
| Protocol file | version 20 | 07/12/2022 | 04/05/2023 | No | No |
| HRA research summary | 28/06/2023 | No | No | ||
| Protocol article | 18/09/2024 | 20/09/2024 | Yes | No |
Additional files
- ISRCTN11440354_PIS_donor relative_v11_11Jun2021.pdf
- For organ donor's relative
- ISRCTN11440354_PIS_recipient_v10_12Apr2021.pdf
- For organ recipient
- ISRCTN11440354_Protocol_v20_07Dec2022.pdf
Editorial Notes
20/09/2024: Publication reference added.
01/05/2024: The following changes were made to the study record:
1. Primary outcome measure updated.
2. The study participating centres were updated to remove Nevill Hall Hospital, Horton General Hospital, Birmingham Heartlands Hospital, Good Hope Hospital, Queens Hospital, North Manchester General Hospital, Chorley and South Ribble Hospital, Castle Hill Hospital, Perth Royal Infirmary, Inverclyde Royal Hospital, Hinchingbrooke Hospital, Peterborough City Hospital, Northampton General Hospital, Royal Papworth Hospital and add Morriston Hospital, South Tyneside NHS Foundation Trust, Sunderland Royal Hospital, Basildon Hospital, Gloucestershire Royal Hospital, Cheltenham General Hospital, Craigavon Area Hospital, Stoke Mandeville Hospital, Wycombe General Hospital, Royal Cornwall Hospitals NHS Trust, Pinderfields and Pontefract Hospitals NHS Trust, North Tees and Hartlepool NHS Foundation Trust, Royal Berkshire Hospital, Chesterfield Royal Hospital NHS Foundation Trust, Doncaster & Bassetlaw Hospitals, Doncaster & Bassetlaw Hospitals, Withybush General Hospital, West Wales General Hospital, Bronglais General Hospital, Cumberland Infirmary, West Cumberland Hospital, Musgrove Park Hospital (taunton), Forth Valley Royal Hospital, Maidstone Hospital, Tunbridge Wells Hospital, Raigmore Hospital, Royal Shrewsbury Hospital.
04/05/2023: The following changes have been made:
1. The protocol has been linked and uploaded.
2. Two participant information sheets have been uploaded.
09/07/2021: Trial's existence confirmed by the NIHR.
