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
Rostaing L, Bunnapradist S, Grinyó JM, Ciechanowski K, Denny JE, Silva HT Jr, Budde K; Envarsus Study Group. 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. Am J Kidney Dis. 2016 Apr;67(4):648-59.
American journal of kidney diseases : the official journal of the National Kidney Foundation
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%; 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
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.
Medical Subject Headings
Adult; Aged; Double-Blind Method; Drug Administration Schedule; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Prospective Studies; Tacrolimus; Time Factors