title: Evaluating the efficacy, safety and evolution of renal function with early initiation of everolimus-facilitated tacrolimus reduction in de novo liver transplant recipients: Study protocol for a randomized controlled trial.
abstract: BACKGROUND
  Introduction of calcineurin inhibitors had led to improved survival rates in liver transplant recipients. However, long-term use of calcineurin inhibitors is associated with a higher risk of chronic renal failure, neurotoxicity, de novo malignancies, recurrence of hepatitis C viral (HCV) infection and hepatocellular carcinoma. Several studies have shown that everolimus has the potential to provide protection against viral replication, malignancy, and progression of fibrosis, as well as preventing nephrotoxicity by facilitating calcineurin inhibitor reduction without compromising efficacy. The Hephaistos study evaluates the beneficial effects of early initiation of everolimus in de novo liver transplant recipients.
  
  
  METHODS
  Hephaistos is an ongoing 12-month, multi-center, open-label, controlled study aiming to enroll 330 de novo liver transplant recipients from 15 centers across Germany. Patients are randomized in a 1:1 ratio (7-21 days post-transplantation) to receive everolimus (trough levels 3-8 ng/mL) with reduced tacrolimus (trough levels <5 ng/mL), or standard tacrolimus (trough levels 6-10 ng/mL) after entering a run-in period (3-5 days post-transplantation). In the run-in period, patients are treated with induction therapy, mycophenolate mofetil, tacrolimus, and corticosteroids according to local practice. Randomization is stratified by HCV status and model of end-stage liver disease scores at transplantation. The primary objective of the study is to exhibit superior renal function (estimated glomerular filtration rate assessed by the Modification of Diet in Renal Disease (MDRD)-4 formula) with everolimus plus reduced tacrolimus compared to standard tacrolimus at Month 12. Other objectives are: to assess the incidence of treated biopsy-proven acute rejection, graft loss, or death; the incidences of components of the composite efficacy endpoint; renal function via estimated glomerular filtration rate using various formulae (MDRD-4, Nankivell, Cockcroft-Gault, chronic kidney disease epidemiology collaboration and Hoek formulae); the incidence of proteinuria; the incidence of adverse events and serious adverse events; the incidence and severity of cytomegalovirus and HCV infections and HCV-related fibrosis.
  
  
  CONCLUSIONS
  This study aims to demonstrate superior renal function, comparable efficacy, and safety in de novo liver transplant recipients receiving everolimus with reduced tacrolimus compared with standard tacrolimus. This study also evaluates the antiviral benefit by early initiation of everolimus.
  
  
  BACKGROUND
  NCT01551212 .
authors: Department of Hepatobiliary Surgery and Visceral Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. nashan@uke.de.
authors: Bjorn
authors: B
authors: Nashan
authors: Department of General, Visceral and Transplant Surgery, University Hospital Heidelberg, Heidelberg, Germany. peter.schemmer@med.uni-heidelberg.de.
authors: Peter
authors: P
authors: Schemmer
authors: Department of General Surgery and Thoracic Surgery, University Hospital Schleswig, Kiel, Holstein, Germany. felix.braun@uksh-kiel.de.
authors: Felix
authors: F
authors: Braun
authors: Novartis Pharma GmbH, Nürnberg, Germany. markus.dworak@novartis.com.
authors: Markus
authors: M
authors: Dworak
authors: Novartis Pharma GmbH, Nürnberg, Germany. peter-1.wimmer@novartis.com.
authors: Peter
authors: P
authors: Wimmer
authors: Department of Surgery, University Hospital Regensburg, Regensburg, Germany. Hans.Schlitt@ukr.de.
authors: Hans
authors: H
authors: Schlitt
mesh_terms: D000328:Adult; D065095:Calcineurin Inhibitors / Q000008:administration & dosage / Q000009:adverse effects; D002985:Clinical Protocols; D004359:Drug Therapy, Combination; D000068338:Everolimus; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006084:Graft Rejection; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000009:adverse effects; D007668:Kidney / Q000187:drug effects*; D007676:Kidney Failure, Chronic / Q000601:surgery; D016031:Liver Transplantation; D008875:Middle Aged; D012107:Research Design; D020123:Sirolimus / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D016559:Tacrolimus / Q000008:administration & dosage* / Q000009:adverse effects
chemical_list: D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D000068338:Everolimus; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus; D016559:Tacrolimus