NCT03672110

Slow and Low Start of a Tacrolimus Once Daily Immunosuppressive Regimen

Slow and Low Start of a Tacrolimus Once Daily Immunosuppressive Regimen: A Multicentre Prospective Randomized Controlled Study

• Status: Unknown
• Phase: Phase 3
• Study type: Interventional
• Enrollment: 400 (estimated)
• Sponsor: Technische Universität Dresden · Academic / Other
• Sex: All
• Age: 18 Years
• Healthy volunteers: Not accepted

Summary

The purpose of this study is to demonstrate non-inferiority of an advagraf based immunosuppressive regimen with slower dose tapering and lower starting dose of Advagraf compared with a standard Advagraf-based immunosuppressive regimen in de novo renal transplantation. Non inferiority will be assessed by a combined study endpoint consisting of the development of biopsy-proven rejection of BANFF class Ia or higher and/or graft loss and/or patient death within the first six months after renal transplantation.

Detailed description

The most widely used immunosuppressive regimen, in adult kidney transplant recipients, consists of an induction therapy accompanied by maintenance with tacrolimus, mycophenolate and steroids. In the long term, tacrolimus is the single most effective immunosuppressive agent. For adult kidney transplant recipients maintenance of therapeutic levels remains crucial regarding the prevention of allograft rejections. Greater blood levels variability is associated with inferior graft survival as well as non-adherence. Lower variability of tacrolimus blood levels after conversion to extended release tacrolimus formulations has been shown. In addition, once-daily administration promotes patient adherence. The latter is one of the major causes for allograft loss. In the first week after kidney transplantation stable tacrolimus blood levels are hardly achievable. Especially extended release tacrolimus formulations often yield high tacrolimus blood levels. High blood levels are a known risk factor for delayed graft function, which leads to a prolonged hospitalization and a reduced graft survival. Additionally high blood levels are associated with polyomavirus infections and may increase the incidence of new-onset diabetes after renal transplantation. Taking this into consideration, authors demand for calcineurin inhibitor (CNI)-free immunosuppression or the delayed onset of CNI therapy after a stable graft function is reached. This would inevitably lead to a higher rate of acute allograft rejections in the early phase after kidney transplantation. Avoiding high tacrolimus levels, especially early after transplantation, to minimize delayed graft function as well as long term undesirable side effects, seems particularly necessary. For early dose adjustments of extended release tacrolimus formulations, more medical experience is needed compared to immediate release formulations. More stable tacrolimus blood levels can be seen after the first week of administration. To avoid high blood levels of tacrolimus, especially early after transplantation, the investigators aim to demonstrate in this study a non-inferiority of a low dose extended release tacrolimus regimen compared to a standard extended release tacrolimus-based immunosuppressive regimen in de novo renal transplantation. Given inclusion criteria and excluding the exclusion criteria, participants will be randomized into two groups, a standard tacrolimus administration group with daily dose adjustments within the first week after transplantation and a fixed dose tacrolimus administration group, without dose adjustments within the first week after transplantation. In the first 6 months after renal transplantation different blood levels of tacrolimus shall be reached. In the case of the standard tacrolimus administration group the investigators aim at tacrolimus blood levels of 7-9 ng/ml in the first 2 months after transplantation and 6-8 ng/ml for days 61 to 180. In the fixed dose tacrolimus administration group, the low extended release tacrolimus dose of 5mg per day well no be changed in the first week after transplantation. For safety reasons blinded measurements will take place in the first week and study officials will be alerted in case of repeated tacrolimus levels \> 20 ng/ml. On days 7 to 60 the investigators aim at tacrolimus blood levels of 5-7 ng/ml and from days 61 to 180 4-6 ng/ml. Non inferiority will be assessed by a combined study endpoint consisting of the development of biopsy-proven rejection of BANFF class Ia or higher and/or graft loss and/or patient death within the first six months after renal transplantation.

Conditions

• Renal Failure
• Renal Insufficiency
• Renal Disease
• Renal Insufficiency, Chronic

Interventions

Type	Name	Description
DRUG	Advagraf	intervention: different advagraf dosing in the study compared to the control arm, see above

Timeline

• Start date: 2014-09-01
• Primary completion: 2020-02-01
• Completion: 2025-12-01
• First posted: 2018-09-14
• Last updated: 2022-08-03

Locations

1 site across 1 country: Germany