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Trial registered on ANZCTR


Registration number
ACTRN12616000278437
Ethics application status
Approved
Date submitted
23/02/2016
Date registered
2/03/2016
Date last updated
22/11/2019
Date data sharing statement initially provided
5/06/2019
Date results information initially provided
5/06/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Pathophysiology and Prevention of Early Bile Duct Injury in Liver Transplantation: The role of the additional In-Situ Bile Duct Flush
Scientific title
Pathophysiology and Prevention of Early Bile Duct Injury in Liver Transplantation: The role of the additional In-Situ Bile Duct Flush
Secondary ID [1] 288644 0
None
Universal Trial Number (UTN)
U1111-1179-9801
Trial acronym
IBF - Intraoperative Bile Duct Flush Study
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Bile Duct Injury in Liver Transplantation 297761 0
Biliary complications after liver transplantation 297823 0
Condition category
Condition code
Surgery 297944 297944 0 0
Surgical techniques
Oral and Gastrointestinal 297998 297998 0 0
Other diseases of the mouth, teeth, oesophagus, digestive system including liver and colon

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Intervention: Intraoperative Bile Duct Flush (Double Flush Group)
Standard Australian National Liver Transplant Unit (ANLTU) Protocol will be followed. The bile duct is partially transected and prolene stitch is placed on the distal end to mark the duct and facilitate manoeuvres. The intervention will then take place.

Before application of the aortic cross clamp, 8g silastic feeding tube will be inserted retrograde into the distal Bile Duct via the partial transection made during the Gallbladder flush. The 8g feeding tube is inserted at least 6cm into the bile duct and should reach the second order biliary branch. The 8g feeding tube is secured using the two threads of the tie used to secure the distal bile duct. The 8g feeding tube will then be connected to a 50mL syringe filled with 60mL of modified Ross/Marshall’s Solution (Soltran) (Maximum capacity of 50mL syringe).

The Bile Duct will be flushed with the syringe within 5 minutes of aortic cross clamp application and start of cold perfusion. The flush will be performed by the leading surgeon.

When the Bile Duct is flushed, the flush must be over a period of at least 1 minute with care taken not to induce high intraluminal
pressures. The bile duct should not be clamped, and excess fluid should be free to flow from the point of insertion of the feeding tube.

Following the flush, ANLTU standard protocol (Control/Single Flush Procedure) will take place and a second flush will occur at the backtable procedure of the donor surgery as follows;
After Liver Explantation and during the backtable procedure of the donor surgery, a 8g silastic feeding tube is inserted into the distal Bile Duct up to the second order biliary branch. Using a 25mL syringe, the Bile Duct is flushed slowly with 75mL of U.W. (Viaspan). The bile duct should not be clamped, and excess fluid should be free to flow from the point of insertion of the feeding tube. This is to prevent high pressures damaging the Bile Duct.

Before the procedure, a checklist and form will be supplied to the perfusionist to ensure protocol adherence and to obtain further information for analysis
Intervention code [1] 294013 0
Prevention
Intervention code [2] 294060 0
Treatment: Surgery
Comparator / control treatment
Control: Standard ANLTU Protocol/ Single Flush Group
The Single Flush (SF) group is subject to standard procedure according to ANLTU protocol. After Liver Explantation and during the backtable procedure of the donor surgery, a 8g silastic feeding tube is inserted into the distal Bile Duct up to the second order biliary branch. Using a 25mL syringe, the Bile Duct is flushed slowly with 75mL of U.W. (Viaspan). The bile duct should not be clamped, and excess fluid should be free to flow from the point of insertion of the feeding tube. This is to prevent high pressures damaging the Bile Duct
Control group
Active

Outcomes
Primary outcome [1] 297466 0
Incidence of biliary complications 12-months post-transplant Biliary complications defined as bile leaks, anastomotic strictures and non-anastomotic strictures
Timepoint [1] 297466 0
12 Months Post-Transplant
Primary outcome [2] 322049 0
Clinical development of biliary complications (bile leaks, biliary strictures) at 24 months.
Recipients' medical records were reviewed and outcomes were identified through post-transplant imaging reports on post-transplant admissions or routine follow up.
Timepoint [2] 322049 0
24 months
Secondary outcome [1] 321122 0
Histological Injury in Donor Bile Duct Specimens
Timepoint [1] 321122 0
At end of cold storage during the backtable procedure.
Secondary outcome [2] 321123 0
To determine whether there is a difference in severity of pretransplant bile duct injury, including peribiliary glands and vascular plexus between the intervention group and control livers
Timepoint [2] 321123 0
Histological samples are taken at the backtable procedure at the recipient transplant surgery and 10minutes after reperfusion of the liver, before bile duct anastomosis
Secondary outcome [3] 321133 0
To clarify the potential role of biliary stem cells in biliary complications after LT
Timepoint [3] 321133 0
Histological samples are taken at the backtable procedure at the recipient transplant surgery and 10minutes after reperfusion of the liver, before bile duct anastomosis
Secondary outcome [4] 372719 0
To determine impact of injury of peribiliary glands in development of post-transplant biliary strictures
Timepoint [4] 372719 0
12 months post-transplant

Eligibility
Key inclusion criteria
All liver donors retrieved with the intent to be transplanted at the ANLTU will be included in the study
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Organ donors who are not eligible for Liver donation

Study design
Purpose of the study
Prevention
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Allocation was unconcealed as Transplant Co-ordinators were required to inform the operating surgeon on the allocation group.

Allocation was randomised by random number generator. Donors were allocated pre-operatively by central randomisation by phone.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Random Number Generation 1-10. Even numbers (2, 4, 6, 8, 10) are allocated to intervention group (Double Flush). Odd numbers (1, 3, 5, 7, 9) are allocated to control group (single flush)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint(s)
Efficacy
Statistical methods / analysis
Chi-Squared for Primary Outcome
Survival Analysis for secondary outcome

n=60

Sample size powered to detect significant for a clinically relevant outcome in histological parameters (mild vs severe Mural necrosis)
Sample size considerations: Absence of pilot data, large sample sizes (n=150+) required to detect clinical impact. Histological injury was chosen for primary outcome

Recruitment
Recruitment status
Active, not recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 5329 0
Royal Prince Alfred Hospital - Camperdown

Funding & Sponsors
Funding source category [1] 292961 0
Hospital
Name [1] 292961 0
Royal Prince Alfred Transplant Institute
Address [1] 292961 0
Level 9 East, Royal Prince Alfred Hospital, Missenden Road, Camperdown NSW 2050
Country [1] 292961 0
Australia
Primary sponsor type
Hospital
Name
Royal Prince Alfred Transplant Institute
Address
Level 9 East, Royal Prince Alfred Hospital, Missenden Road, Camperdown NSW 2050
Country
Australia
Secondary sponsor category [1] 291731 0
None
Name [1] 291731 0
Address [1] 291731 0
Country [1] 291731 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 294463 0
Sydney Local Health District (Royal Prince Alfred Hospital)
Ethics committee address [1] 294463 0
Royal Prince Alfred Hospital
100 Carillon Ave
CAMPERDOWN NSW 2050
Ethics committee country [1] 294463 0
Australia
Date submitted for ethics approval [1] 294463 0
25/11/2015
Approval date [1] 294463 0
03/02/2016
Ethics approval number [1] 294463 0
X15-0444

Summary
Brief summary
Biliary complications are significant cause of graft failure and morbidity in Liver Transplantation. Cellular injury has been shown in the literature to contribute to the development of biliary complications. A growing body of evidence demonstrate that bile duct injury occurs early after organ retrieval.

Bile salt toxicity is a vector of injury to bile ducts which may be preventable. Experimental animal studies on pigs have indicated that flush the bile duct with hydrophobic bile salts and preservation solution can induce injury to the biliary epithelium during cold ischaemia. In addition, there have been studies demonstrating the importance of adequate biliary flush out before cold storage in liver transplantation, however this would typically occur at the backtable procedure in the donor surgery, which may be up to 20minutes from cross clamping.

Our hypothesis is that an intraoperative bile duct flush (IBF) before cross clamping, will decrease exposure of hydrophobic bile salts to bile duct and reduce bile salt toxicity. The reduced bile salt toxicity should decrease injury to the bile duct which has been associated with the development of biliary strictures and biliary complications and highlights the expected benefit of the intervention.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 63830 0
Dr Mark Ly
Address 63830 0
Level 9 East, Royal Prince Alfred Hospital, Missenden Road, Camperdown NSW 2050
Country 63830 0
Australia
Phone 63830 0
+61422921566
Fax 63830 0
Email 63830 0
Markmgly@gmail.com
Contact person for public queries
Name 63831 0
Dr Mark Ly
Address 63831 0
Level 9 East, Royal Prince Alfred Hospital, Missenden Road, Camperdown NSW 2050
Country 63831 0
Australia
Phone 63831 0
+61422921566
Fax 63831 0
Email 63831 0
Markmgly@gmail.com
Contact person for scientific queries
Name 63832 0
Dr Mark Ly
Address 63832 0
Level 9 East, Royal Prince Alfred Hospital, Missenden Road, Camperdown NSW 2050
Country 63832 0
Australia
Phone 63832 0
+61422921566
Fax 63832 0
Email 63832 0
Markmgly@gmail.com

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No/undecided IPD sharing reason/comment
What supporting documents are/will be available?
Summary results
Have study results been published in a peer-reviewed journal?
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary