Fixed low dose versus concentration-controlled initial tacrolimus dosing with reduced target levels in the course after kidney transplantation: results from a prospective randomized controlled non-inferiority trial (Slow & Low study)

Julian Stumpf; Klemens Budde; Oliver Witzke; Claudia Sommerer; Thomas Vogel; Peter Schenker; Rainer Peter Woitas; Mirian Opgenoorth; Evelyn Trips; Eva Schrezenmeier; Christian Hugo; German S&L Study

doi:10.1016/j.eclinm.2023.102381

Fixed low dose versus concentration-controlled initial tacrolimus dosing with reduced target levels in the course after kidney transplantation: results from a prospective randomized controlled non-inferiority trial (Slow & Low study)

EClinicalMedicine. 2023 Dec 22:67:102381. doi: 10.1016/j.eclinm.2023.102381. eCollection 2024 Jan.

Authors

Collaborators

German S&L Study:
Matthias Girndt, Gunter Wolf, Christine Kurschat, Kai Lopau, Jens Lutz

Affiliations

¹ Division of Nephrology, Department of Internal Medicine III, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Dresden, Germany.
² Department of Nephrology and Medical Intensive Care, Charité Universitätsmedizin Berlin, Berlin, Germany.
³ Department of Infectious Diseases, West German Centre of Infectious Diseases, University Hospital Essen, University Duisburg-Essen, Germany.
⁴ Department of Nephrology, Kidney Center, University Hospital Heidelberg, Heidelberg, Germany.
⁵ Department of General, Visceral and Transplant Surgery, University Hospital Münster, Münster, Germany.
⁶ Department of Surgery, University Hospital Knappschaftskrankenhaus Bochum, Ruhr-University Bochum, Bochum, Germany.
⁷ Department of Internal Medicine I, University of Bonn, Bonn, Germany.
⁸ Department of Nephrology and Hypertension, University Hospital of Erlangen, Erlangen, Germany.
⁹ Coordination Centre for Clinical Trials, Faculty of Medicine Carl Gustav Carus, Dresden University of Technology, Dresden, Germany.
¹⁰ Berlin Institute of Health at Charité-Universitätsmedizin Berlin, BIH Academy, Clinician Scientist Program Universitätsmedizin Berlin, Berlin, Germany.

Abstract

Background: Optimal initial tacrolimus dosing and early exposure of tacrolimus after renal transplantation is not well studied.

Methods: In this open-label, 6 months, multicenter, randomized controlled, non-inferiority study, we randomly assigned 432 renal allograft recipients to receive basiliximab induction, mycophenolate and steroids and either standard prolonged-release tacrolimus (trough levels: 7-9 ng/ml; Standard Care arm), or an initial 7-day fixed 5 mg/day dose of prolonged-release tacrolimus followed by lower tacrolimus predose levels (trough levels: 5-7 ng/ml; Slow & Low arm). The primary end point was the combined incidence rate of biopsy-proven acute rejections (BPAR; including borderline), graft failure, or death at 6 months with a non-inferiority margin of 12.5%. (EudraCT-Nr: 2013-001770-19.

Findings: The combined primary endpoint in the Slow & Low arm was non-inferior compared to the Standard Care arm (22.1% versus 20.7%; difference: 1.4%, 90% CI -5.5% to 8.3%). The overall rate of BPAR including borderlines was similar (Slow & Low 17.4% versus Standard Care 16.6%). Safety parameters such as delayed graft function, kidney function, donor specific HLA-antibodies, infections, or post-transplantation diabetes mellitus did not differ.

Interpretation: This is the first study to show that an initial fixed dose of 5 mg per day followed by lower tacrolimus exposure is non-inferior compared to standard tacrolimus therapy and equally efficient and safe within 6 months after renal transplantation. These data suggest that therapeutic drug monitoring for prolonged release tacrolimus can be abandoned until start of the second week after transplantation.

Funding: Investigator-initiated trial, financial support by Astellas Pharma GmbH.

Keywords: Fixed low dose; Immunosuppression; Renal transplantation; Tacrolimus monitoring.