title: 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.
abstract: 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.
  
  
  METHODS
  Final 24-month analysis of a 2-armed, parallel-group, randomized, double-blind, double-dummy, multicenter, phase 3 trial.
  
  
  METHODS
  543 de novo kidney recipients randomly assigned to LCPT (n=268) or IR-Tac (n=275); 507 (93.4%) completed the 24-month study.
  
  
  METHODS
  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.
  
  
  METHODS
  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<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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: University Hospital Toulouse-Rangueil, Toulouse, France. Electronic address: rostaing.l@chu-toulouse.fr.
authors.forename: Lionel
authors.initials: L
authors.lastname: Rostaing
authors.affiliation: David Geffen School of Medicine at UCLA, Los Angeles, CA.
authors.forename: Suphamai
authors.initials: S
authors.lastname: Bunnapradist
authors.affiliation: Hospital Universitari de Bellvitge, Catalunya, Spain.
authors.forename: Josep M
authors.initials: JM
authors.lastname: Grinyó
authors.affiliation: Pomeranian Medical University, Szczecin, Poland.
authors.forename: Kazimierz
authors.initials: K
authors.lastname: Ciechanowski
authors.affiliation: Henry Ford Hospital, Detroit, MI.
authors.forename: Jason E
authors.initials: JE
authors.lastname: Denny
authors.affiliation: Hospital do Rim e Hipertensao, Sao Paulo, Brazil.
authors.forename: Helio Tedesco
authors.initials: HT
authors.lastname: Silva
authors.affiliation: Department of Nephrology, Charité Universitätsmedizin, Berlin, Germany.
authors.forename: Klemens
authors.initials: K
authors.lastname: Budde
mesh_terms: D000328:Adult; D000368:Aged; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D016559:Tacrolimus / Q000008:administration & dosage*; D013997:Time Factors
chemical_list: D007166:Immunosuppressive Agents; D016559:Tacrolimus
keywords: Envarsus; Immunosuppression; bioavailability; biopsy-proven acute rejection; efficacy; end-stage renal disease (ESRD); extended-release; formulation; kidney transplantation; pill burden; randomized controlled trial (RCT); safety; tacrolimus; transplant recipient; treatment failure