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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.

Nashan B, Schemmer P, Braun F, Dworak M, Wimmer P, Schlitt H - Trials (2015)

Bottom Line: 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.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.NCT01551212 .

View Article: PubMed Central - PubMed

Affiliation: Department of Hepatobiliary Surgery and Visceral Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. nashan@uke.de.

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/design: 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.

Discussion: 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.

Trial registration: NCT01551212 .

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Related in: MedlinePlus

Study design. *As per center practice. C0, trough levels; CS, corticosteroids; EVR, everolimus; HCV, hepatitis C virus; LTx, liver transplantation; M, month; MELD, model of end-stage liver disease; MMF, mycophenolate mofetil; RND, randomization; TAC, tacrolimus.
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Fig1: Study design. *As per center practice. C0, trough levels; CS, corticosteroids; EVR, everolimus; HCV, hepatitis C virus; LTx, liver transplantation; M, month; MELD, model of end-stage liver disease; MMF, mycophenolate mofetil; RND, randomization; TAC, tacrolimus.

Mentions: Hephaistos (protocol version 3, 14 June 2013) is an ongoing, 12-month, multicenter, open-label, randomized, controlled study aimed to evaluate efficacy, safety, and evolution of renal function of everolimus with reduced tacrolimus in de novo liver transplant recipients. Patients undergoing a successful liver transplantation enter a run-in period between 3 and 5 days post-transplantation. During the run-in period, induction therapy, mycophenolate mofetil, tacrolimus and corticosteroids are initiated at the investigator’s discretion. Between 7 and 21 days post-transplantation, patients are randomized in a 1:1 ratio to receive either: (i) everolimus (trough level (C0) 3–8 ng/mL) with reduced tacrolimus (C0 <5 ng/mL), or (ii) standard tacrolimus (C0 6–10 ng/mL; Figure 1). Everolimus is initiated on the day of randomization and will be monitored throughout the study period (post 5 ± 2 days of everolimus/tacrolimus dose changes).Figure 1


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.

Nashan B, Schemmer P, Braun F, Dworak M, Wimmer P, Schlitt H - Trials (2015)

Study design. *As per center practice. C0, trough levels; CS, corticosteroids; EVR, everolimus; HCV, hepatitis C virus; LTx, liver transplantation; M, month; MELD, model of end-stage liver disease; MMF, mycophenolate mofetil; RND, randomization; TAC, tacrolimus.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4384314&req=5

Fig1: Study design. *As per center practice. C0, trough levels; CS, corticosteroids; EVR, everolimus; HCV, hepatitis C virus; LTx, liver transplantation; M, month; MELD, model of end-stage liver disease; MMF, mycophenolate mofetil; RND, randomization; TAC, tacrolimus.
Mentions: Hephaistos (protocol version 3, 14 June 2013) is an ongoing, 12-month, multicenter, open-label, randomized, controlled study aimed to evaluate efficacy, safety, and evolution of renal function of everolimus with reduced tacrolimus in de novo liver transplant recipients. Patients undergoing a successful liver transplantation enter a run-in period between 3 and 5 days post-transplantation. During the run-in period, induction therapy, mycophenolate mofetil, tacrolimus and corticosteroids are initiated at the investigator’s discretion. Between 7 and 21 days post-transplantation, patients are randomized in a 1:1 ratio to receive either: (i) everolimus (trough level (C0) 3–8 ng/mL) with reduced tacrolimus (C0 <5 ng/mL), or (ii) standard tacrolimus (C0 6–10 ng/mL; Figure 1). Everolimus is initiated on the day of randomization and will be monitored throughout the study period (post 5 ± 2 days of everolimus/tacrolimus dose changes).Figure 1

Bottom Line: 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.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.NCT01551212 .

View Article: PubMed Central - PubMed

Affiliation: Department of Hepatobiliary Surgery and Visceral Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. nashan@uke.de.

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/design: 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.

Discussion: 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.

Trial registration: NCT01551212 .

Show MeSH
Related in: MedlinePlus