Novel Once-Daily Extended-Release Tacrolimus Versus Twice-Daily Tacrolimus in De Novo Kidney Transplant Recipients: Two-Year Results of Phase 3, Double-Blind, Randomized Trial

Background: 1-year data from this trial showed the noninferiority of a novel once-daily extended-release tacrolimus (LCPT; Envarsus XR) to immediate-release tacrolimus (IR-Tac) twice daily after kidney transplantation. Study Design: Final 24-month analysis of a 2-armed, parallel-group, randomized, double-blind, double dummy, multicenter, phase 3 trial. Setting & Participants: 543 de novo kidney recipients randomly assigned to LCPT (n = 268) or IR-Tac (n = 275); 507 (93.4%) completed the 24-month study. Intervention: LCPT tablets once daily at 0.17 mg/kg/d or IR-Tac twice daily at 0.1 mg/kg/d; subsequent doses were adjusted to maintain target trough ranges (first 30 days, 6-11 ng/mL; thereafter, 4-11 ng/mL). The intervention was 24 months; the study was double blinded for the entirety. Outcomes & Measurements: Treatment failure (death, transplant failure, biopsy-proven acute rejection, or loss to follow up) within 24 months. Safety end points included adverse events, serious adverse events, new onset diabetes, kidney function, opportunistic infections, and malignancies. Pharmacokinetic measures included total daily dose (TDD) of study drugs and tacrolimus trough levels. Results: 24-month treatment failure was LCPT, 23.1%; I R-Tac, 27.3% (treatment difference, -4.14% [95% CI, -11.38% to +3.17%], well below the +10% noninferiority criterion defined for the primary 12-month end point). Subgroup analyses showed fewer treatment failures for LCPT versus I R-Tac among black, older, and female recipients. Safety was similar between groups. From month 1, TDD was lower for LCPT; the difference increased over time. At month 24, mean TDD for LCPT was 24% lower than for the IR-Tac group (P < 0.001), but troughs were similar (means at 24 months: LCPT, 5.47 +/- 0.17 ng/mL; IR-Tac, 5.8 +/- 0.30 ng/mL; P = 0.4). Limitations: Trial participant eligibility criteria may limit the generalizability of results to the global population of de novo kidney transplant recipients. Conclusions: Results suggest that once-daily LCPT in de novo kidney transplantation has comparable efficacy and safety profile to that of I R-Tac. Lower TDD reflects LCPT's improved bioavailability and absorption. (C) 2016 The Authors. Published by Elsevier Inc. on behalf of the National Kidney Foundation, Inc.