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

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• 作者：Lionel Rostaing ; MD ; PhD¹ ; ^{rostaing.l@chu-toulouse.fr" class="auth_mail" title="E-mail the corresponding author} ; Suphamai Bunnapradist ; MD² ; Josep M. Grinyó ; MD³ ; Kazimierz Ciechanowski ; MD ; PhD⁴ ; Jason E. Denny ; MD⁵ ; Helio Tedesco Silva Jr. ; MD⁶ ; Klemens Budde ; MD⁷ ; on behalf of the Envarsus Study Group^&lowast ; ; Jason E. Denny ; MD ; Sanjay Kulkarni ; MD ; Donald Hricik ; MD ; 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&rsquo ; Connell ; Peter Hughes ; Graeme Russ ; Grant B. Pidgeon ; Ian D. Dittmer ; Terence Kee ; Anantharaman Vathsala ; Radomir Naumovic ; Igor Mitic ; Randhawa Parmjeet ; MD
• 关键词：Immunosuppression ; tacrolimus ; kidney transplantation ; extended-release ; formulation ; bioavailability ; efficacy ; treatment failure ; safety ; biopsy-proven acute rejection ; Envarsus ; pill burden ; transplant recipient ; end-stage renal disease (ESRD) ; randomized controlled trial (RCT)
• 刊名：American Journal of Kidney Diseases
• 出版年：2016
• 出版时间：April 2016
• 年：2016
• 卷：67
• 期：4
• 页码：648-659
• 全文大小：369 K

文摘

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.