TOP-Study (Tacrolimus Organ Perfusion): Treatment of Ischemia Reperfusion Injury in Marginal Organs With an ex Vivo Tacrolimus Perfusion

NCT01564095 | Terminated Phase 2 DMC FDA Drug

• 1 other identifier: TOP-Study
• Study Type: interventional
• Target: 25
• Locations: 1 country
• Sites: 7

Brief Summary

Utilisation of extended criteria donors due to critical organ shortage contributes to increased ischemia reperfusion injury as well as mortality following liver transplantation. Experimental data show protective effects on hepatic ischemia reperfusion injury (IRI) using the calcineurin inhibitor Tacrolimus applied intravenously or directly as a hepatic rinse. Moreover clinical data indicate a protective role of a Tacrolimus rinse in human liver transplantation when using normal, healthy grafts. The effects of Tacrolimus on hepatic injury in extended donor criteria (EDC) liver grafts remain unclear. Therefore, the aim of the present study is to examine the effects of a Tacrolimus ex vivo rinse (20 ng/ml) on cellular injury after transplantation of marginal liver grafts exhibiting 2 or more EDCs according to Eurotransplant's definition of EDC grafts.

Conditions

Terminal Liver Disease; Ischemia Reperfusion Injury; Graft Dysfunction; Graft Failure; Poor Graft Quality

Keywords

Liver transplantation; EDC; IRI; graft survival; graft function; graft preconditioning; Tacrolimus rinse; randomised multicenter trial

Outcome Measures

Primary Outcomes (1)

• Maximum serum ALT-level

  48 hrs following liver transplantation

Secondary Outcomes (5)

• ALT

  1,2,4,7 days after surgery

• Graft survival

  7 days

• AST

  1,2,4,7 days after surgery

• Bilirubin

  1,2,4,7 days after surgery

• Creatinin

  1,2,4,7 days after surgery

Study Arms (2)

Tacrolimus + HTK

EXPERIMENTAL

Ex vivo Tacrolimus Rinse (20 ng/ml solved in 1000 ml HTK) of marginal liver grafts prior to implantation

Drug: Tacrolimus

HTK

PLACEBO COMPARATOR

Ex vivo Rinse (1000 ml HTK) of marginal liver grafts prior to implantation

Drug: HTK/Placebo

Interventions

Tacrolimus DRUG

Marginal liver grafts are flushed with Tacrolimus (20ng/ml) solved in 1000 ml HTK preservation solution (duration: 15 min) ex vivo at the end of backtable preparation in the experimental group.

Also known as: Tacrolimus, Prograf; Astellas Germany, HTK, histidin-tryptophane-ketoglurate organ preservation solution, Custodiol, Dr. Franz Köhler Chemie, Germany

Tacrolimus + HTK

HTK/Placebo DRUG

Marginal liver grafts are flushed with 1000 ml HTK preservation solution(duration: 15 min) ex vivo at the end of backtable preparation in the placebo group.

Also known as: HTK, histidin-tryptophane-ketoglurate organ preservation solution, Custodiol, Dr. Franz Köhler Chemie, Germany

HTK

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Recipient:
• Chronical terminal liver failure, age \> 18 years, first organ transplantation
• Donor:
• donor age \> 65 Jahre
• macrovesicular steatosis \> 40% (macroscopy or biopsy)
• BMI \> 30
• sodium \>165 mmol/l
• ICU stay and ventilation \> 7 days
• cold ischemia time \> 13 hours
• AST \> 99 U/l
• ALT \> 105 U/l
• bilirubin \> 3 mg/dl (\> 51 µmol/l)
• application of epinephrine

You may not qualify if:

• Donor:
• Hepatitis B- or Hepatitis C-infection
• Recipient:
• Multi organ transplantation
• high urgency listing
• extrahepatic tumor disease
• pregnancy

Sponsors & Collaborators

• Ludwig-Maximilians - University of Munich: lead

Study Sites (7)

Department of General, Visceral and Transplantation Surgery, Charité Campus Virchow-Klinikum

Berlin, 13353, Germany

Location

Department of General and Visceral Surgery, Johann Wolfgang Goethe-University

Frankfurt am Main, 60596, Germany

Location

Department of General, Visceral and Transplantation Surgery, Ruprecht Karls University

Heidelberg, 69120, Germany

Location

Department of Transplantation Surgery, Johannes Gutenberg University

Mainz, 55131, Germany

Location

Ludwig-Maximilians University, Campus Grosshadern, Department of Surgery

Munich, 81377, Germany

Location

Department of Surgery, University of Regensburg

Regensburg, 93053, Germany

Location

Department of General, Visceral and Transplantation Surgery, Eberhard Karls University

Tübingen, 72076, Germany

Location

Related Publications (5)

• Pratschke S, Bilzer M, Grutzner U, Angele M, Tufman A, Jauch KW, Schauer RJ. Tacrolimus preconditioning of rat liver allografts impacts glutathione homeostasis and early reperfusion injury. J Surg Res. 2012 Jul;176(1):309-16. doi: 10.1016/j.jss.2011.07.045. Epub 2011 Aug 25.

  PMID: 21962731 BACKGROUND

• St Peter SD, Post DJ, Rodriguez-Davalos MI, Douglas DD, Moss AA, Mulligan DC. Tacrolimus as a liver flush solution to ameliorate the effects of ischemia/reperfusion injury following liver transplantation. Liver Transpl. 2003 Feb;9(2):144-9. doi: 10.1053/jlts.2003.50018.

  PMID: 12548508 BACKGROUND

• 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.

  PMID: 21672049 BACKGROUND

• Pratschke S, Arnold H, Zollner A, Heise M, Pascher A, Schemmer P, Scherer MN, Bauer A, Jauch KW, Werner J, Guba M, Angele MK. Results of the TOP Study: Prospectively Randomized Multicenter Trial of an Ex Vivo Tacrolimus Rinse Before Transplantation in EDC Livers. Transplant Direct. 2016 May 4;2(6):e76. doi: 10.1097/TXD.0000000000000588. eCollection 2016 Jun.

  PMID: 27500266 RESULT

• Pratschke S, Eder M, Heise M, Nadalin S, Pascher A, Schemmer P, Scherer MN, Ulrich F, Wolters H, Jauch KW, Wohling D, Angele MK. Protocol TOP-Study (tacrolimus organ perfusion): a prospective randomized multicenter trial to reduce ischemia reperfusion injury in transplantation of marginal liver grafts with an ex vivo tacrolimus perfusion. Transplant Res. 2013 Mar 4;2(1):3. doi: 10.1186/2047-1440-2-3.

  PMID: 23497558 DERIVED

MeSH Terms

Conditions

Reperfusion Injury

Interventions

Tacrolimus; Receptor, EphB4

Condition Hierarchy (Ancestors)

Vascular Diseases; Cardiovascular Diseases; Postoperative Complications; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Macrolides; Lactones; Organic Chemicals; Receptors, Eph Family; Receptor Protein-Tyrosine Kinases; Protein-Tyrosine Kinases; Protein Kinases; Phosphotransferases (Alcohol Group Acceptor); Phosphotransferases; Transferases; Enzymes; Enzymes and Coenzymes; Intracellular Signaling Peptides and Proteins; Proteins; Amino Acids, Peptides, and Proteins; Receptors, Cell Surface; Membrane Proteins

Study Officials

• Martin Angele, M.D.

  Ludwig-Maximilians-University, Department of Surgery, Munich, Germany

  PRINCIPAL INVESTIGATOR

• Sebastian Pratschke, M.D.

  Ludwig-Maximilians-University, Department of Surgery, Munich, Germany

  STUDY DIRECTOR

• Karl-Walter Jauch, M.D.

  Ludwig-Maximilians-University, Department of Surgery, Munich, Germany

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Prof. Dr. med. Martin Angele

Study Record Dates

• First Submitted: March 14, 2012
• First Posted: March 27, 2012
• Study Start: October 1, 2011
• Primary Completion: July 1, 2013
• Study Completion: July 1, 2013
• Last Updated: March 23, 2017

Record last verified: 2017-03

Data Sharing

• IPD Sharing: Will not share

Locations

DE (7)