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 0.17mg/kg/d or IR-Tac twice daily at 0.1mg/kg/d; subsequent doses were adjusted to maintain target trough ranges (first 30 days, 6-11ng/mL; thereafter, 4-11ng/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%; IR-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 IR-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 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 IR-Tac. Lower TDD reflects LCPT's improved bioavailability and absorption.