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
Lionel Rostaing, Suphamai Bunnapradist, Josep M Grinyó, Kazimierz Ciechanowski, Jason E Denny, Helio Tedesco Silva Jr, Klemens Budde, Envarsus Study Group, Jason E Denny, Sanjay Kulkarni, Donald Hricik, Barbara A Bresnahan, Suphamai Bunnapradist, Rafik A El-Sabrout, Laurence K Chan, Gaetano Ciancio, Mohamed A El-Ghoroury, Michael J Goldstein, Robert S Gaston, Reginald Y Gohh, Mary T Killackey, Anne King, Richard J Knight, Arputharaj H Kore, Debra L Sudan, Javier Chapochnick Friedmann, Shamkant P Mulgaonkar, Charles Nolan, Oleh G Pankewycz, John D Pirsch, Heidi M Schaefer, Steven M Steinberg, Bruce E Gelb, Karin A True, Patricia M West-Thielke, Mary M Waybill, Joshua H Wolf, Beverley L Ketel, Robert C Harland, Fuad S Shihab, Elisabeth Cassuto, Yannick Le Meur, Lionel Rostaing, Christophe Mariat, Josep Maria Grinyó, Jose Puig, Daniel Seron, Giuseppe Tisone, Kazimierz Ciechanowski, Bartosz Foroncewicz, Zbigniew Wlodarczyk, Klemens Budde, Oliver Witzke, Guillermo A Mondragon, Eduardo Mancilla Urrea, Josefina Alberu Gomez, Rafael Reyes Acevedo, Maria Del Carmen Rial, Pablo A Novoa, Helio T Silva Jr, Valter D Garcia, Deise D Carvalho, Luciana T Santamaria Saber, Fabiana L Contieri, Marcos G Bastos, Roberto C Manfro, John Kanellis, Josette Eris, Philip O'Connell, Peter Hughes, Graeme Russ, Grant B Pidgeon, Ian D Dittmer, Terence Kee, Anantharaman Vathsala, Radomir Naumovic, Igor Mitic, Randhawa Parmjeet, Lionel Rostaing, Suphamai Bunnapradist, Josep M Grinyó, Kazimierz Ciechanowski, Jason E Denny, Helio Tedesco Silva Jr, Klemens Budde, Envarsus Study Group, Jason E Denny, Sanjay Kulkarni, Donald Hricik, Barbara A Bresnahan, Suphamai Bunnapradist, Rafik A El-Sabrout, Laurence K Chan, Gaetano Ciancio, Mohamed A El-Ghoroury, Michael J Goldstein, Robert S Gaston, Reginald Y Gohh, Mary T Killackey, Anne King, Richard J Knight, Arputharaj H Kore, Debra L Sudan, Javier Chapochnick Friedmann, Shamkant P Mulgaonkar, Charles Nolan, Oleh G Pankewycz, John D Pirsch, Heidi M Schaefer, Steven M Steinberg, Bruce E Gelb, Karin A True, Patricia M West-Thielke, Mary M Waybill, Joshua H Wolf, Beverley L Ketel, Robert C Harland, Fuad S Shihab, Elisabeth Cassuto, Yannick Le Meur, Lionel Rostaing, Christophe Mariat, Josep Maria Grinyó, Jose Puig, Daniel Seron, Giuseppe Tisone, Kazimierz Ciechanowski, Bartosz Foroncewicz, Zbigniew Wlodarczyk, Klemens Budde, Oliver Witzke, Guillermo A Mondragon, Eduardo Mancilla Urrea, Josefina Alberu Gomez, Rafael Reyes Acevedo, Maria Del Carmen Rial, Pablo A Novoa, Helio T Silva Jr, Valter D Garcia, Deise D Carvalho, Luciana T Santamaria Saber, Fabiana L Contieri, Marcos G Bastos, Roberto C Manfro, John Kanellis, Josette Eris, Philip O'Connell, Peter Hughes, Graeme Russ, Grant B Pidgeon, Ian D Dittmer, Terence Kee, Anantharaman Vathsala, Radomir Naumovic, Igor Mitic, Randhawa Parmjeet
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.
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<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 IR-Tac. Lower TDD reflects LCPT's improved bioavailability and absorption.
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.
Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.
Source: PubMed