Tacrolimus is an immunosuppressant drug available as a twice-daily formulation (Prograf^®, IR-Tac), or as once-daily formulations (Advagraf^®, PR-Tac; Envarsus^®, LCPT). LCPT has shown clinical non-inferiority vs. IR-Tac, and a flatter PK profile with comparable exposure with lower total daily dose (TDD), lower C_max and other significant PK differences as compared to both IR-Tac and PR-Tac; a comparison of clinical efficacy between the three formulations was still missing. This phase IV study was undertaken to compare dosing, efficacy, safety and tolerability of LCPT with the other formulations (either IR-Tac or PR-Tac, depending on the standard of care of each participating centre) following de novo kidney transplant in 51 centres across 10 European countries. The study was conducted according to the Declaration of Helsinki.

Transplant recipients were randomized (1:1) to receive standard triple therapy with either LCPT (n=201) or a conventional formulation (n=202; either IR-Tac [n= 86] or PR-Tac [n=116]). The primary endpoint was tacrolimus TDD from Week 3 (W3) to Month 6 (M6). Secondary endpoints included dosing, treatment failure rates (death, graft failure, BPAR, and loss to follow-up), and safety. Target trough levels were 5-15 ng/mL until Month 3, and 5-10 ng/mL thereafter.

Average TDD from W3 to M6 was 5.135mg for LCPT and 6.243mg for IR/PR-Tac (−1.11mg [95% CI: −1.76, −0.45;p<0.001]), representing a dose reduction of -18%. Conversely, trough levels were 5% higher for LCPT (9.43 ng/mL) as compared to IR/PR-Tac (9.02 ng/mL) (+0.41 ng/mL [95% CI: 0.08, 0.74;p=0.016]). Dose-normalized trough levels (C/D ratio) were significantly higher for LCPT than IR/PR-Tac (+34%;p<0.001). No difference was found in the intra-patient variability in TDD or trough levels across treatments. No statistically significant difference was found in treatment failure rates or safety profile.

The STEADY Study is the first clinical trial comparing LCPT with both conventional formulations (PR-Tac, IR-Tac). LCPT resulted in higher trough levels with a lower TDD, enabling an overall higher C/D ratio. Clinical efficacy and safety were similar for the 6-month duration of the study. The results confirm the improved bioavailability of LCPT, further reinforcing its clinical validity.

CITATION INFORMATION: Budde K., Piotti G., Procaccianti C., Nicolini G., Geraci S., Surace D. MeltDose Prolonged-Release Once-Daily Tacrolimus (LCPT) vs. Conventional Tacrolimus Formulations in the Initial Maintenance of De Novo Kideny Transplant Recipients across Europe: STEADY Study Am J Transplant. 2017;17 (suppl 3).

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