A trial of a clot-busting treatment in livers before transplantation

ISRCTN	ISRCTN15211703
DOI	https://doi.org/10.1186/ISRCTN15211703
ClinicalTrials.gov (NCT)	Nil known
Clinical Trials Information System (CTIS)	Nil known
Integrated Research Application System (IRAS)	297403
Protocol serial number	IRAS 297403
Sponsor	Cambridge University Hospitals NHS Foundation Trust
Funder	Investigator initiated and funded

Submission date: 05/06/2021
Registration date: 03/08/2021
Last edited: 15/01/2025

Recruitment status: No longer recruiting
Overall study status: Completed
Condition category: Surgery

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Record updated in last year

Plain English summary of protocol

Background and study aims
Transplanted livers are susceptible to develop scarring in the bile ducts due to blockage of the blood supply to the wall of the bile duct around the time of transplant. These blocks are thought to be caused by blood clots developing as the liver recovers from a period of storage outside the body. The walls of bile ducts that have had their blood supply blocked heal by scarring, causing narrowed areas in the duct (strictures). Livers from donors donating after circulatory death, as opposed to brain dead donors, are particularly prone to develop this problem.
This study will place a liver on a perfusion machine outside the body and use a clot busting treatment that has been shown to work in non-transplanted livers to break down any clots that form before the liver is transplanted. This clot busting treatment cannot be given after a transplant because of the risk of bleeding in the recipient, something that is not a problem on a perfusion machine.
This study will look at the incidence of bile duct scarring, but the main aim is verify the safety of this approach looking at the incidence of bleeding post-transplant intraoperatively

Who can participate?
Patients having a liver transplant in the participating centres

What does the study involve?
The liver is treated with a clot-busting treatment while it is being perfused on a machine before transplantation

What are the possible benefits and risks of participating?
Benefits: There may be a reduced chance of developing bile duct strictures
Risks: Bleeding post-transplant

Where is the study being run from?
Cambridge University (UK)

When is the study starting and how long is it expected to run for?
June 2021 to December 2024

Who is funding the study?
Investigator initiated and funded

Who is the main contact?
Professor Watson, cjew2@cam.ac.uk

Contact information

Prof Christopher Watson
Scientific

Dept of Surgery, Box 210
Addenbrookes Hospital
Cambridge
CB2 2QQ
United Kingdom

ORCID ID	0000-0002-0590-4901
Phone	+44 (0)12232216108
Email	cjew2@cam.ac.uk

Study information

Primary study design	Interventional
Study design	Interventional open label safety and feasibility study
Secondary study design	Non randomised study
Study type	Participant information sheet
Scientific title	A pilot study of thrombolysis during machine perfusion of circulatory death donor livers to prevent biliary strictures
Study objectives	Thrombolytic treatment to livers undergoing machine perfusion reduces cholangiopathy
Ethics approval(s)	Approved 16/12/2021, East of England - Cambridge East Research Ethics Committee (Currently being held remotely via Teleconference/ZOOM, The Fulbourn Centre, Home End, Fulbourn, Cambridgeshire, CB21 5BS; +44 (0)207 104 8102, +44 (0)207 104 8102, +44 (0)207 104 8134; cambridgeeast.rec@hra.nhs.uk), ref: 21/EE/0237
Health condition(s) or problem(s) studied	Liver transplantation
Intervention	Livers from donors dying following circulatory arrest (DCD donors) undergoing normothermic perfusion will receive a bolus of 10 mg alteplase and 50 ml fresh frozen plasma at the start of perfusion, followed by an infusion of 40 ml alteplase and 200 ml fresh frozen plasma over the next 80 min. A minimum of 100 min perfusion will follow before the liver can be considered for transplantation.
Intervention type	Drug
Phase	Phase II
Drug / device / biological / vaccine name(s)	Alteplase
Primary outcome measure(s)	Post reperfusion intra-operative blood loss. These data will be obtained from the anaesthetic records and are recored realtime on the electronic patient record
Key secondary outcome measure(s)	1. Total and post reperfusion intra-operative blood transfusion and blood loss measured using recorded values on electronic anaesthetic record 2. Proportion of liver perfusions resulting in a transplant measured using aptient records at the end of the study 3. Incidence of symptomatic anastomotic and non-anastomotic strictures at 6 months post-transplant determined at cholangiography; symptomatic meaning associated with raised bilirubin or ALP or cholangitis. 4. Incidence of any anastomotic or non-anastomotic stricture excluding those related to hepatic artery thrombosis determined at cholangiography 5. Incidence of “clinically relevant” non-anastomotic strictures, using the van Rijn definition (associated with raised bilirubin or ALP or cholangitis.) at 6 months 6. Incidence of post reperfusion syndrome: 30% fall in systolic BP lasting at least a minute in the first 5 minutes post reperfusion in the recipient or the need for adrenaline or doubling of noradenaline to support the circulation 7. Early allograft function (Olthoff criteria and model for early allograft function score) at 7 days 8. Incidence of hepatic artery thrombosis in the first 6 months post transplant: determined by CT or angiography 9. Incidence of acute kidney injury (RIFLE criteria) (increase in recipient serum creatinine on days 1 to 7 post transplant compared to the baseline creatinine
Completion date	29/04/2024

Eligibility

Participant type(s)	Patient
Age group	Adult
Lower age limit	18 Years
Sex	All
Target sample size at registration	60
Total final enrolment	80
Key inclusion criteria	1. Aged ≥18 years 2. Patient requiring a liver transplant under the care of the participating hospitals
Key exclusion criteria	1. Inability to give consent 2. Recipient of a brain dead donor liver
Date of first enrolment	01/08/2021
Date of final enrolment	01/12/2024

Locations

Countries of recruitment

United Kingdom
England

Study participating centres

Addenbrooke's Hospital

Cambridge University Hospitals NHS Foundation Trust
Hills Road
Cambridge
CB2 0QQ
United Kingdom

Royal Free Hospital

Pond Street
London
NW3 2QG
United Kingdom

Results and Publications

Individual participant data (IPD) Intention to share	Yes
IPD sharing plan summary	Other
IPD sharing plan	All data generated or analysed during this study will be included in the subsequent results publication

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
HRA research summary			28/06/2023	No	No
Participant information sheet	Participant information sheet	11/11/2025	11/11/2025	No	Yes
Protocol file	version 1.0	03/08/2021	09/09/2021	No	No
Protocol file	version 3.2	07/05/2022	15/06/2022	No	No
Protocol file	version 5.1	07/02/2023	31/07/2023	No	No

Additional files

ISRCTN15211703_Protocol_v1.0_03Aug21.pdf: Protocol file
ISRCTN15211703_Protocol_v3.2_07May2022.pdf: Protocol file
ISRCTN15211703_Protocol_v5.1_07Feb2023.pdf: Protocol file

Editorial Notes

15/01/2025: The following changes were made:
1. The overall study end date was changed from 01/06/2023 to 01/12/2024.
2. The total final enrolment was added.
3. The recruitment end date was changed from 01/12/2024 to 29/04/2024.
4. The intention to publish date was changed from 01/01/2024 to 01/03/2025.
31/07/2023: The following changes have been made:
1. Protocol file uploaded.
2. The trial phase has been added.
3. The recruitment end date has been changed from 01/06/2022 to 01/12/2024.
15/06/2022: The following changes have been made:
1. The ethics approval has been updated.
2. The secondary study design has been changed from 'Non-randomised study' to 'Randomised controlled trial'.
3. The overall trial end date has been changed from 06/06/2022 to 01/06/2023 and the plain English summary updated accordingly.
4. The total target enrolment has been changed from 20 to 60.
5. The intention to publish date has been changed from 01/01/2023 to 01/01/2024.
6. An updated protocol has been uploaded.
09/09/2021: The following changes have been made:
1. The protocol (not peer reviewed) has been uploaded as an additional file.
2. The ethics approval has been added.
07/09/2021: Internal review.
03/08/2021: Trial's existence confirmed by Cambridge South REC.