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

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  1 , Klemens Budde  2 , Oliver Witzke  3 , Claudia Sommerer  4 , Thomas Vogel  5 , Peter Schenker  6 , Rainer Peter Woitas  7 , Mirian Opgenoorth  8 , Evelyn Trips  9 , Eva Schrezenmeier  2   10 , Christian Hugo  1 ; German S&L Study
Collaborators, Affiliations

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 et al. EClinicalMedicine. .

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.

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Conflict of interest statement

CH received grants from Astellas Pharma GmbH during the conduct of the study as well as grants and other from Novartis, other from Astellas, other from Chiesi, grants and other from AstraZeneca, grants and other from Hansa Biopharma, other from Alexion, grants and other from Boehringer Ingelheim, other from Takeda, other from Vifor Pharma, grants and other from Otsuka, other from Stadapharm, other from GlaxoSmithKline, other from Bayer Vital, other from MSD, grants from Calliditas, grants from Vera Therapeutics outside the submitted work. OW has received research grants for clinical studies, speaker's fees, honoraria and travel expenses from Amgen, Alexion, Astellas, Basilea, Biotest, Bristol-Myers Squibb, Correvio, Chiesi, Gilead, Hexal, Janssen, Dr. F. Köhler Chemie, MSD, Novartis, Roche, Pfizer, Sanofi, TEVA, AstraZeneca, GSK and UCB. KB received grants from Astellas during the conduct of the study; grants from Astellas, Chiesi, Alexion, CSL-Behring, MSD, personal fees from MSD, Takeda, Natera, Aicuris, CareDx, Stada, CSL-Behring, Paladin, Veloxis, Alexion, Pirche, Vifor, Carealytics, Neovii, outside the submitted work. TV received personal fees from Astellas Pharma GmbH outside the submitted work. ET received grants from University Hospital Carl Gustav Carus at the Technische Universität Dresden, Department of Internal Medicine III, Division of Nephrology during the conduct of the study. All other authors of this manuscript have no conflicts of interest to be disclosed.

Figures

Fig. 1
Fig. 1
Study flow chart. The per-protocol population comprises all patients who received the allocated treatment without severe protocol violation during the complete study follow up period of 6 months (see Supplemetary Material). Multiple severe protocol violations may have occurred in one patient. PPS = per protocol set.
Fig. 2
Fig. 2
Mean tacrolimus levels during different time periods after renal transplantation. In case, more than one measurement per patient was documented, mean tacrolimus trough level per period was calculated. The groups shown differ in the immunosuppressive regimen which consisted of basiliximab induction, mycophenolate and steroids, and either standard extended-release tacrolimus (according to the dosing recommendation by the manufacturer; Standard Care arm) or a 7-day fixed initial dose of 5 mg/day extended-release tacrolimus followed by lower tacrolimus predose levels (trough levels: 5–7 ng/ml; Slow & Low arm). The colored highlighted areas show the target ranges of the corresponding treatment arms over time. Filled diamond = median, filled circle = mean, strokes = interquartile range (Q1/Q3), if several tacrolimus through values were available between the former and illustrated time point, individual mean values were calculated and used for the graph.
Fig. 3
Fig. 3
Kaplan-Meier diagram of the primary endpoint (panel A) and allograft survival (panel B) and cumulative incidence function of biopsy-proven acute rejections (panel C) according to treatment arm in the intent to treat population.
Fig. 4
Fig. 4
Kaplan-Meier diagram of post transplant diabetes mellitus (PTDM) (panel A) and prediabetes or PTDM (panel B) in the intent-to-treat population according to treatment arm. Patients with preexisting diabetes mellitus were excluded.
Fig. 5
Fig. 5
Forest plot of risk differences in different populations (intent to treat, per protocol set), in various sensitivity analyses (counting of events: excluding borderline rejections or rejections detected in protocol biopsies), or subgroups. The non-inferiority criterion defined for intent-to-treat population is not met if the upper limit of the 90 percent two-sided confidence intervall is higher than 0.1250.
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