Incidence of Posttransplantation Diabetes Mellitus in De Novo Kidney Transplant Recipients Receiving Prolonged-Release Tacrolimus-Based Immunosuppression With 2 Different Corticosteroid Minimization Strategies: ADVANCE, A Randomized Controlled Trial

Georges Mourad, Maciej Glyda, Laetitia Albano, Ondrej Viklický, Pierre Merville, Gunnar Tydén, Michel Mourad, Aleksander Lõhmus, Oliver Witzke, Maarten H L Christiaans, Malcolm W Brown, Nasrullah Undre, Gbenga Kazeem, Dirk R J Kuypers, Advagraf-based immunosuppression regimen examining new onset diabetes mellitus in kidney transplant recipients (ADVANCE) study investigators, Georges Mourad, Maciej Glyda, Laetitia Albano, Ondrej Viklický, Pierre Merville, Gunnar Tydén, Michel Mourad, Aleksander Lõhmus, Oliver Witzke, Maarten H L Christiaans, Malcolm W Brown, Nasrullah Undre, Gbenga Kazeem, Dirk R J Kuypers, Advagraf-based immunosuppression regimen examining new onset diabetes mellitus in kidney transplant recipients (ADVANCE) study investigators

Abstract

Background: ADVANCE (NCT01304836) was a phase 4, multicenter, prospectively randomized, open-label, 24-week study comparing the incidence of posttransplantation diabetes mellitus (PTDM) with 2 prolonged-release tacrolimus corticosteroid minimization regimens.

Methods: All patients received prolonged-release tacrolimus, basiliximab, mycophenolate mofetil and 1 bolus of intraoperative corticosteroids (0-1000 mg) as per center policy. Patients in arm 1 received tapered corticosteroids, stopped after day 10, whereas patients in arm 2 received no steroids after the intraoperative bolus. The primary efficacy variable was the diagnosis of PTDM as per American Diabetes Association criteria (2010) at any point up to 24 weeks postkidney transplantation. Secondary efficacy variables included incidence of composite efficacy failure (graft loss, biopsy-proven acute rejection or severe graft dysfunction: estimated glomerular filtration rate (Modification of Diet in Renal Disease-4) <30 mL/min per 1.73 m), acute rejection and graft and patient survival.

Results: The full-analysis set included 1081 patients (arm 1: n = 528, arm 2: n = 553). Baseline characteristics and mean tacrolimus trough levels were comparable between arms. Week 24 Kaplan-Meier estimates of PTDM were similar for arm 1 versus arm 2 (17.4% vs 16.6%; P = 0.579). Incidence of composite efficacy failure, graft and patient survival, and mean estimated glomerular filtration rate were also comparable between arms. Biopsy-proven acute rejection and acute rejection were significantly higher in arm 2 versus arm 1 (13.6% vs 8.7%, P = 0.006 and 25.9% vs 18.2%, P = 0.001, respectively). Tolerability profiles were comparable between arms.

Conclusions: A prolonged-release tacrolimus, basiliximab, and mycophenolate mofetil immunosuppressive regimen is efficacious, with a low incidence of PTDM and a manageable tolerability profile over 24 weeks of treatment. A lower incidence of biopsy-proven acute rejection was seen in patients receiving corticosteroids tapered over 10 days plus an intraoperative corticosteroid bolus versus those receiving an intraoperative bolus only.

Conflict of interest statement

The authors of this manuscript have conflicts of interest to disclose as described by Transplantation. G.M. has received honoraria from Bristol-Myers-Squibb, Fresenius and Sanofi, and an academic grant from Amgen. O.V. has received consultancy and study fees from Astellas. P.M. has received research grants from Astellas. O.W. has received research grants for clinical studies, speaker's fees, honoraria and travel expenses from Amgen, Astellas, Bristol-Myers Squibb, Chiesi, Novartis, Roche, Pfizer and Sanofi. M.C. has received research grants from Astellas and Novartis and has lectured for, and received consultancy fees from Astellas. M.B. and N.U. are employees of Astellas. G.K. is a consultant statistician working on behalf of Astellas and has received support for travel from Astellas. D.K. has received research grants from Alexion, Astellas, Novartis and Roche and honoraria from Alexion, Astellas, BMS, Chiesi, Novartis, Pfizer, Roche and Opsona Therapeutics. All other authors have nothing to disclose.

Figures

FIGURE 1
FIGURE 1
Flow of patients through the study to Week 24. SAF: randomized patients receiving 1 dose or greater of any study medication; ITT: patients randomized, transplanted and receiving 1 dose or greater of any study medication; FAS: patients enrolled in the study, transplanted, received 1 dose or greater of any study medication and 1 or greater postbaseline estimation of primary variable (all other patients were excluded from this population); PPS: all patients from FAS with no major protocol deviation. Patient discontinuations were analyzed using the FAS population; study completers: arm 1, 451; arm 2, 462. FAS, full-analysis set; ITT, intention-to-treat; PPS, per-protocol set; SAF, safety-analysis set.
FIGURE 2
FIGURE 2
Prolonged-release tacrolimus (A) dose and (B) trough levels stratified by treatment arm over 24 weeks of treatment (FAS). Arm 1: prolonged-release tacrolimus + basiliximab + MMF (intraoperative corticosteroid bolus as per center policy and tapered corticosteroids to day 10; discontinued after day 10), arm 2: prolonged-release tacrolimus + basiliximab + MMF (intraoperative corticosteroid bolus as per center policy only); error bars represent standard deviation; dashed vertical line represents change from days to weeks. FAS, full-analysis set; MMF, mycophenolate mofetil.
FIGURE 3
FIGURE 3
Kaplan–Meier analyses of (A) PTDM (FAS) and (B) BPAR (ITT) over 24 weeks of treatment. Arm 1: prolonged-release tacrolimus + basiliximab + MMF (intraoperative corticosteroid bolus as per center policy and tapered corticosteroids to day 10; discontinued after day 10); arm 2: prolonged-release tacrolimus + basiliximab + MMF (intraoperative corticosteroid bolus as per center policy only); aPatients who completed the 24-week follow-up period and discontinued at week 24 with no PTDM events recorded were not included in the “at risk” numbers for week 24+ (n = 61 and n = 63 in arms 1 and 2, respectively); events that occurred on or after week 24 were included in the week 24 timepoint; analyses of PTDM were performed on the FAS, whereas BPAR analyses were performed on the ITT. BPAR, biopsy-proven acute rejection; eGFR, estimated glomerular filtration rate; FAS, full-analysis set; ITT, intention-to-treat; MDRD4, Modification of Diet in Renal Disease-4; MMF, mycophenolate mofetil; PTDM, posttransplantation diabetes mellitus.

References

    1. First MR, Dhadda S, Croy R, et al. New-onset diabetes after transplantation (NODAT): an evaluation of definitions in clinical trials. Transplantation. 2013;96:58–64.
    1. Ghisdal L, Van Laecke S, Abramowicz MJ, et al. New-onset diabetes after renal transplantation: risk assessment and management. Diabetes Care. 2012;35:181–188.
    1. Miller J, Mendez R, Pirsch JD, et al. Safety and efficacy of tacrolimus in combination with mycophenolate mofetil (MMF) in cadaveric renal transplant recipients. FK506/MMF Dose-Ranging Kidney Transplant Study Group. Transplantation. 2000;69:875–880.
    1. Montori VM, Basu A, Erwin PJ, et al. Posttransplantation diabetes: a systematic review of the literature. Diabetes Care. 2002;25:583–592.
    1. Wauters RP, Cosio FG, Suarez Fernandez ML, et al. Cardiovascular consequences of new-onset hyperglycemia after kidney transplantation. Transplantation. 2012;94:377–382.
    1. Kasiske BL, Snyder JJ, Gilbertson D, et al. Diabetes mellitus after kidney transplantation in the United States. Am J Transplant. 2003;3:178–185.
    1. Burroughs TE, Swindle J, Takemoto S, et al. Diabetic complications associated with new-onset diabetes mellitus in renal transplant recipients. Transplantation. 2007;83:1027–1034.
    1. Pham PT, Pham PM, Pham SV, et al. New onset diabetes after transplantation (NODAT): an overview. Diabetes Metab Syndr Obes. 2011;4:175–186.
    1. Rostaing L, Cantarovich D, Mourad G, et al. Corticosteroid-free immunosuppression with tacrolimus, mycophenolate mofetil, and daclizumab induction in renal transplantation. Transplantation. 2005;79:807–814.
    1. Luan FL, Steffick DE, Ojo AO. New-onset diabetes mellitus in kidney transplant recipients discharged on steroid-free immunosuppression. Transplantation. 2011;91:334–341.
    1. Woodle ES, First MR, Pirsch J, et al. A prospective, randomized, double-blind, placebo-controlled multicenter trial comparing early (7 day) corticosteroid cessation versus long-term, low-dose corticosteroid therapy. Ann Surg. 2008;248:564–577.
    1. Vitko S, Klinger M, Salmela K, et al. Two corticosteroid-free regimens-tacrolimus monotherapy after basiliximab administration and tacrolimus/mycophenolate mofetil-in comparison with a standard triple regimen in renal transplantation: results of the Atlas study. Transplantation. 2005;80:1734–1741.
    1. Pascual J, Quereda C, Zamora J, et al. Steroid withdrawal in renal transplant patients on triple therapy with a calcineurin inhibitor and mycophenolate mofetil: a meta-analysis of randomized, controlled trials. Transplantation. 2004;78:1548–1556.
    1. Augustine JJ, Hricik DE. Steroid sparing in kidney transplantation: changing paradigms, improving outcomes, and remaining questions. Clin J Am Soc Nephrol. 2006;1:1080–1089.
    1. Albano L, Banas B, Klempnauer JJL, et al. OSAKA trial: a randomized, controlled trial comparing tacrolimus QD and BD in kidney transplantation. Transplantation. 2013;96:897–903.
    1. Vincenti F, Friman S, Scheuermann E, et al. Results of an international, randomized trial comparing glucose metabolism disorders and outcome with cyclosporine versus tacrolimus. Am J Transplant. 2007;7:1506–1514.
    1. Johnston O, Rose CL, Webster AC, et al. Sirolimus is associated with new-onset diabetes in kidney transplant recipients. J Am Soc Nephrol. 2008;19:1411–1418.
    1. Peddi VR, Wiseman A, Chavin K, et al. Review of combination therapy with mTOR inhibitors and tacrolimus minimization after transplantation. Transplant Rev (Orlando). 2013;27:97–107.
    1. American Diabetes Association. Standards of medical care in diabetes—2010. Diabetes Care. 2010;33(Suppl 1):S11–S61.
    1. Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group. KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant. 2009;9:S1–S155.
    1. Solez K, Colvin RB, Racusen LC, et al. Banff 07 classification of renal allograft pathology: updates and future directions. Am J Transplant. 2008;8:753–760.
    1. Knight SR, Morris PJ. Steroid avoidance or withdrawal after renal transplantation increases the risk of acute rejection but decreases cardiovascular risk. A meta-analysis. Transplantation. 2010;89:1–14.
    1. Krämer BK, Charpentier B, Bäckman L, et al. Tacrolimus once daily (ADVAGRAF) versus twice daily (PROGRAF) in de novo renal transplantation: a randomized phase III study. Am J Transplant. 2010;10:2632–2643.
    1. Dhadda S, Fitzsimmons W, Croy R, et al. Defining new-onset diabetes after transplantation (NODAT). Transplantation. 2010;90(Suppl 2):694.
    1. Bäckman LA. Post-transplant diabetes mellitus: the last 10 years with tacrolimus. Nephrol Dial Transplant. 2004;19(Suppl 6):vi13–vi16.
    1. Zhang X, Huang H, Han S, et al. Is it safe to withdraw steroids within seven days of renal transplantation? Clin Transplant. 2013;27:1–8.

Source: PubMed

Sponsors et collaborateurs

Les conditions médicales

Interventions en matière de drogue

3
S'abonner