Early Allograft DysfunctionPATACNCT01887171

Evaluation of Preimplantation Portal Vein and Hepatic Artery Flushing With Tacrolimus

A study testing Tacrolimus in people with Early Allograft Dysfunction and Ischemic Reperfusion Injury, run by Republican Scientific and Practical Center for Organ and Tissue Transplantation at 1 site in Belarus.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

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Trial summary

The purpose of this study is to determine whether the Tacrolimus added to histidine-tryptophan-ketoglutarate (HTK) solution given through intraportal and intraarterial infusion during back-table procedure is capable of reducing the degree of early allograft liver dysfunction, as assessed by postoperative levels of… Read more about this study

Who is it for?: Ages 18 to 69 years
Conditions the study is for: Early Allograft Dysfunction, Ischemic Reperfusion Injury, Liver Transplantation
What is being tested?: Tacrolimus
Type of treatment: Injection or infusion
Could I receive a placebo?: No, everyone receives an active treatment
How many people: 86 participants
Where: 1 siteBelarus
Study dates: Jul 2013to Jul 2014
Phase: Interventional
Are there results?: Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 18 to 69 years
All sexes
No healthy volunteers
Adult, Older adult

Who may be able to join

Donor:
age 15-65 years macrovesicular steatosis < 40% (macroscopy or biopsy) sodium <165 mmol/l ICU stay and ventilation < 11 days cold ischemia time < 13 hours AST < 200 U/l ALT < 200 U/l bilirubin < 50 μmol/l application of norepinephrine is allowed
Recipient age: 18-69

Who cannot join

Recipient:
live donor liver transplant
reduced and split grafts
multi organ failure

Trial locations and contacts

1 site in 1 country.

Belarus1 site

RSPC for organ and tissue transplantation, Minsk 9th clinic
Minsk, 220116

Other trials in Belarus

About this study

Official title: A Randomized Study of Effect of Preimplantation Portal Vein and Hepatic Artery Liver Flushing With Tacrolimus on Ischemia-reperfusion Injury, Allograft Dysfunction and Liver Histology

Read the detailed description

Early allograft liver dysfunction remains a significant complication of cadaveric liver transplantation with resource consuming and costly treatment, increased risk of multiorgan failure and 6-months mortality.

Ischemic reperfusion injury (IRI) is a main reason for early allograft liver dysfunction. Inflammatory response to brain death in donor can precipitate the extent of dysfunction after reperfusion in recipient (1). Clear inflammatory pathways in response to IRI have been reported to be associated with early allograft liver dysfunction (2,3). It was shown that ex vivo intraportal tacrolimus perfusion suppressed inflammation and immune response in the transplanted liver on a genome-wide basis (4).

We hypothesize that Tacrolimus added to HTK solution given through intraportal and intraarterial back-table infusion is capable of reducing the degree of early allograft liver dysfunction, as assessed by incidence of postreperfusion hyperfibrinolysis, postoperative levels of AST,ALT, during 1-7 postoperative days as well as serum and histochemical markers of liver injury and inflammation compared to no intraportal and intraarterial back-table infusion.

Conditions: Early Allograft Dysfunction, Ischemic Reperfusion Injury, Liver Transplantation, Hyperfibrinolysis
Being tested: Tacrolimus
Keywords: Liver transplantation, Early allograft dysfunction, Ischemic reperfusion injury, Portal and arterial ex vivo HTK flush

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

TacrolimusDrug
Also called Tacrolimus, Astellas Pharma Europe, Custodiol, Dr. Franz Köhler Chemie GmBH
1000 ml of HTK solution (Custodiol, Dr. Franz Köhler Chemie GmBH) cooled to 2-4˚C containing 20 ng/ml Tacrolimus would be given through intraportal (under gravity pressure of 40 cm H2O) and intraarterial infusion (under pressure of 40-50 mm Hg) followed by intraportal infusion of 200 ml 5% solution of Albumin containing 20 ng/ml Tacrolimus under gravity pressure of 40 cm H2O.

Study groups in NCT01887171
Study group	Role	What they receive
Tacrolimus + HTK	Experimental	During back-table operation 1000 ml of HTK solution cooled to 2-4˚C containing 20 ng/ml Tacrolimus would be given through intraportal (under gravity pressure of 40 cm H2O) and intraarterial infusion (under pressure of 40-50 mm Hg) followed by intraportal infusion of 200 ml 5% solution of Albumin containing 20 ng/ml Tacrolimus under gravity pressure of 40 cm H2O. Receives: Drug: Tacrolimus
HTK	No intervention	During back-table operation 1000 ml of HTK solution cooled to 2-4˚C would be given through intraportal (under gravity pressure of 40 cm H2O) and intraarterial infusion (under pressure of 40-50 mm Hg) followed by intraportal infusion of 200 ml 5% solution of Albumin under gravity pressure of 40 cm H2O.

What is being measured

The primary outcome is the main question the study is designed to answer.

Early Allograft Dysfunction
Protocol is restricted to liver transplants performed with classic technique with sequential portal-arterial reperfusion.
Early allograft dysfunction will be assessed on the basis of highest levels of AST and ALT during 1-7 postoperative days.
Measured: 1-7 postoperative days after liver transplant procedure

Secondary outcomes (3)

Ischemic Reperfusion Injury of the Liver Allograft
Protocol is restricted to liver transplants performed with classic technique with sequential portal-arterial reperfusion.
A wedge resection of small (5x5mm) part of liver segment-III will be sampled at 2 hours after venous reperfusion. Rate of necrosis, inflammation, vascular thrombosis, cluster of differentiation (CD) 68 and High mobility group box 1 protein (HMGB1) staining will be assessed thereafter.
Measured: liver biopsy taken at 2 hours after portal reperfusion
Inflammatory Response to Reperfusion
Protocol is restricted to liver transplants performed with classic technique with sequential portal-arterial reperfusion.
After unclamping portal vein but before unclamping the inferior vena cava and after venting of first 100 ml of blood a 5 ml sample of blood (code is "HV") from a tube inserted into caval suture line will be taken. Another 5 ml sample of blood (code is "C") will be taken by puncture of one of hepatic veins 20 min later. Samples (5 ml each) of peripheral blood will be taken on 1st and 3d postoperative day (POD). P-selectin, interleukin-6, interleukin-8, tumor necrosis factor alfa (TNF-a) and macrophage inflammatory protein 1 alpha (MIP-1a) will be determined in samples "HV" and "C". Interleukin-8, elastase, TNF-a and vascular endothelial growth factor (VEGF) will be determined in samples of 1st and 3d POD.
Measured: 0 and 20 min after portal reperfusion, 1 and 3 postoperative day
Postreperfusion Hyperfibrinolysis
Protocol is restricted to liver transplants performed with classic technique with sequential portal-arterial reperfusion.
Peripheral blood samples will be taken 15 min and 2 hours after portal reperfusion.
Hyperfibrinolysis will be diagnosed by Thromboelastometry (ROTEM) if one or more following criteria are met:
LI30<85% or ML>15% or LI60<85% or A10 in Extem is by 15% is less then A10 in Aptem.
Measured: 15 min and 2 hours after portal reperfusion

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

Jul 2013Jul 2014

First posted26 Jun 2013 (estimated)
Study startJul 2013
Primary completionJul 2014
Study completionJul 2014

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
Publications (7)Papers the sponsor has linked to this study.
Other trials for Early Allograft DysfunctionStudies of the same condition, open and under way.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase N/A
Primary purpose: Prevention
Allocation: Randomised
Intervention model: Parallel groups
Masking: Double blind
Who is masked: Care provider, Outcomes assessor
Enrolment: 86 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT01887171
Sponsor's protocol ID: 1633
Acronym: PATAC
Status last verified: Nov 2014
First submitted: 6 Apr 2013
Last updated: 23 Feb 2017
Results posted: Yes, on ClinicalTrials.gov
Data monitoring committee: Yes

Publications

Friedman BH, Wolf JH, Wang L, Putt ME, Shaked A, Christie JD, Hancock WW, Olthoff KM. Serum cytokine profiles associated with early allograft dysfunction in patients undergoing liver transplantation. Liver Transpl. 2012 Feb;18(2):166-76. doi: 10.1002/lt.22451.
PubMed 22006860
Busuttil RW, Tanaka K. The utility of marginal donors in liver transplantation. Liver Transpl. 2003 Jul;9(7):651-63. doi: 10.1053/jlts.2003.50105.
PubMed 12827549
Ilmakunnas M, Tukiainen EM, Rouhiainen A, Rauvala H, Arola J, Nordin A, Makisalo H, Hockerstedt K, Isoniemi H. High mobility group box 1 protein as a marker of hepatocellular injury in human liver transplantation. Liver Transpl. 2008 Oct;14(10):1517-25. doi: 10.1002/lt.21573.
PubMed 18825712
Kristo I, Wilflingseder J, Kainz A, Marschalek J, Wekerle T, Muhlbacher F, Oberbauer R, Bodingbauer M. Effect of intraportal infusion of tacrolimus on ischaemic reperfusion injury in orthotopic liver transplantation: a randomized controlled trial. Transpl Int. 2011 Sep;24(9):912-9. doi: 10.1111/j.1432-2277.2011.01284.x. Epub 2011 Jun 14.
PubMed 21672049
Olthoff KM, Kulik L, Samstein B, Kaminski M, Abecassis M, Emond J, Shaked A, Christie JD. Validation of a current definition of early allograft dysfunction in liver transplant recipients and analysis of risk factors. Liver Transpl. 2010 Aug;16(8):943-9. doi: 10.1002/lt.22091.
PubMed 20677285
Shcherba A.E., Minou A.F., Efimov D.J., Korotkov S.V., LebedzO.A., Dzyadzko A.M., Karitka A., Santotski E.O., Rummo O.O.//Influence of Back Table Portal And Arterial Flushing with HTK and Tacrolimus on the Incidence of Liver Graft Dysfunction. Materials of "Avantguardia in the HPB - surgery and Liver transplantation: When East meets West". Volume 61, June 2014, Supplement 1.- P. S13-14.
Abstracts of the ILTS 20(th) Annual International Congress, June 3-7, 2014, London, United Kingdom. Liver Transpl. 2014 Jun;20 Suppl 1:S1-399. doi: 10.1002/lt.23901. No abstract available.
PubMed 25044812

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

See locations

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All Early Allograft Dysfunction trials

Study at a glance

From the registry record, last updated by the sponsor on 23 Feb 2017. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: A Randomized Study of Effect of Preimplantation Portal Vein and Hepatic Artery Liver Flushing With Tacrolimus on Ischemia-reperfusion Injury, Allograft Dysfunction and Liver Histology
ClinicalTrials.gov ID: NCT01887171
Acronym / sponsor ID: PATAC / 1633
Conditions: Early Allograft Dysfunction, Ischemic Reperfusion Injury, Liver Transplantation, Hyperfibrinolysis
Keywords: Liver transplantation, Early allograft dysfunction, Ischemic reperfusion injury, Portal and arterial ex vivo HTK flush
Study type: Interventional
Recruitment status: Completed
Enrolment: 86 participants (actual)
Lead sponsor: Republican Scientific and Practical Center for Organ and Tissue TransplantationUniversity, hospital or other
Study start: Jul 2013
Primary completion: Jul 2014 (actual)
Study completion: Jul 2014 (actual)
First posted: 26 Jun 2013 (estimated)
Results: Posted 23 Feb 2017

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

Detailed description

Study design

Primary purpose: Prevention
Allocation: Randomised
Intervention model: Parallel groups
Masking: Double blind (care provider, outcomes assessor)
Number of arms: 2

Arm	Type	Receives
Tacrolimus + HTK	Experimental	Drug: TacrolimusDuring back-table operation 1000 ml of HTK solution cooled to 2-4˚C containing 20 ng/ml Tacrolimus would be given through intraportal (under gravity pressure of 40 cm H2O) and intraarterial infusion (under pressure of 40-50 mm Hg) followed by intraportal infusion of 200 ml 5% solution of Albumin containing 20 ng/ml Tacrolimus under gravity pressure of 40 cm H2O.
HTK	No intervention	–During back-table operation 1000 ml of HTK solution cooled to 2-4˚C would be given through intraportal (under gravity pressure of 40 cm H2O) and intraarterial infusion (under pressure of 40-50 mm Hg) followed by intraportal infusion of 200 ml 5% solution of Albumin under gravity pressure of 40 cm H2O.

Who may qualify

Ages: 18 to 69 years
Sex: All
Healthy volunteers: Not accepted
Age groups: Adult, Older adult

Key inclusion criteria (3 listed)

Donor:
age 15-65 years macrovesicular steatosis < 40% (macroscopy or biopsy) sodium <165 mmol/l ICU stay and ventilation < 11 days cold ischemia time < 13 hours AST < 200 U/l ALT < 200 U/l bilirubin < 50 μmol/l application of norepinephrine is allowed
Recipient age: 18-69

Key exclusion criteria (4 listed)

live donor liver transplant
reduced and split grafts
multi organ failure

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
TacrolimusAlso: Tacrolimus, Astellas Pharma Europe, Custodiol, Dr. Franz Köhler Chemie GmBH1000 ml of HTK solution (Custodiol, Dr. Franz Köhler Chemie GmBH) cooled to 2-4˚C containing 20 ng/ml Tacrolimus would be given through intraportal (under gravity pressure of 40 cm H2O) and intraarterial infusion (under pressure of 40-50 mm Hg) followed by intraportal infusion of 200 ml 5% solution of Albumin containing 20 ng/ml Tacrolimus under gravity pressure of 40 cm H2O.	Drug	Tacrolimus + HTK

Primary outcome

Early Allograft Dysfunction
Time frame: 1-7 postoperative days after liver transplant procedure
Protocol is restricted to liver transplants performed with classic technique with sequential portal-arterial reperfusion. Early allograft dysfunction will be assessed on the basis of highest levels of AST and ALT during 1-7 postoperative days.

3 secondary outcomes

Ischemic Reperfusion Injury of the Liver Allograft
Time frame: liver biopsy taken at 2 hours after portal reperfusion
Inflammatory Response to Reperfusion
Time frame: 0 and 20 min after portal reperfusion, 1 and 3 postoperative day
Postreperfusion Hyperfibrinolysis
Time frame: 15 min and 2 hours after portal reperfusion

Results and safety

Results posted to the registry on 23 Feb 2017, as reported by the sponsor. Figures are copied from the record, not re-analysed. Full results on ClinicalTrials.gov.

Participant flow

Group	Started	Completed
Tacrolimus + HTK	43	43
HTK Solution Only	43	43

Primary outcome: Early Allograft Dysfunction

Time frame: 1-7 postoperative days after liver transplant procedure. Count of participants. Unit: Participants

Measure	Tacrolimus + HTK n = 43	HTK Solution Only n = 43
Value	6	18

3 secondary outcomes are reported in the full results.

Adverse events

Other adverse events reported at 5% frequency or more

Group	Serious adverse events	Other adverse events	Deaths
Tacrolimus + HTK	8 of 12 (66.7%)	0 of 0	Not reported
HTK Solution	20 of 22 (90.9%)	0 of 0	Not reported

Loading the posted results from ClinicalTrials.gov…

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 23 Feb 2017.
Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
Background: PubMed 22006860Friedman BH, Wolf JH, Wang L, Putt ME, Shaked A, Christie JD, Hancock WW, Olthoff KM. Serum cytokine profiles associated with early allograft dysfunction in patients undergoing liver transplantation. Liver Transpl. 2012 Feb;18(2):166-76. doi: 10.1002/lt.22451.
Background: PubMed 12827549Busuttil RW, Tanaka K. The utility of marginal donors in liver transplantation. Liver Transpl. 2003 Jul;9(7):651-63. doi: 10.1053/jlts.2003.50105.
Background: PubMed 18825712Ilmakunnas M, Tukiainen EM, Rouhiainen A, Rauvala H, Arola J, Nordin A, Makisalo H, Hockerstedt K, Isoniemi H. High mobility group box 1 protein as a marker of hepatocellular injury in human liver transplantation. Liver Transpl. 2008 Oct;14(10):1517-25. doi: 10.1002/lt.21573.
Background: PubMed 21672049Kristo I, Wilflingseder J, Kainz A, Marschalek J, Wekerle T, Muhlbacher F, Oberbauer R, Bodingbauer M. Effect of intraportal infusion of tacrolimus on ischaemic reperfusion injury in orthotopic liver transplantation: a randomized controlled trial. Transpl Int. 2011 Sep;24(9):912-9. doi: 10.1111/j.1432-2277.2011.01284.x. Epub 2011 Jun 14.
Background: PubMed 20677285Olthoff KM, Kulik L, Samstein B, Kaminski M, Abecassis M, Emond J, Shaked A, Christie JD. Validation of a current definition of early allograft dysfunction in liver transplant recipients and analysis of risk factors. Liver Transpl. 2010 Aug;16(8):943-9. doi: 10.1002/lt.22091.
Results publicationShcherba A.E., Minou A.F., Efimov D.J., Korotkov S.V., LebedzO.A., Dzyadzko A.M., Karitka A., Santotski E.O., Rummo O.O.//Influence of Back Table Portal And Arterial Flushing with HTK and Tacrolimus on the Incidence of Liver Graft Dysfunction. Materials of "Avantguardia in the HPB - surgery and Liver transplantation: When East meets West". Volume 61, June 2014, Supplement 1.- P. S13-14.
Results publication: PubMed 25044812Abstracts of the ILTS 20(th) Annual International Congress, June 3-7, 2014, London, United Kingdom. Liver Transpl. 2014 Jun;20 Suppl 1:S1-399. doi: 10.1002/lt.23901. No abstract available.
Related InfoLink provided by the sponsor.
Related InfoLink provided by the sponsor.

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Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

Aliaksei E Shcherba, PhD principal investigator

RSPC for tissue and organ transplantation

Oleg O Rumo, MD PhD study chair

RSPC for organ and tissue transplantation, Minsk 9th clinic

1 site in 1 country: see every site and its status.

Questions about this trial

What is this clinical trial studying?

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 3 inclusion and 4 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 23 Feb 2017. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in Belarus. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

Are results available for this study?

Yes. Results are posted in the registry (first posted 23 Feb 2017). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Early Allograft Dysfunction (time frame: 1-7 postoperative days after liver transplant procedure). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01887171, which also lists 7 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 23 Feb 2017.