Randomized trial of everolimus-facilitated calcineurin inhibitor minimization over 24 months in renal transplantation

Diane Cibrik, Helio Tedesco Silva, Anantharaman Vathsala, Eva Lackova, Catherine Cornu-Artis, Rowan G. Walker, Zailong Wang, Gazi B. Zibari, Fuad Shihab, Yu S. Kim

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Abstract

BACKGROUND: Strategies allowing calcineurin inhibitor minimization while maintaining efficacy may improve renal transplant outcomes. METHODS: A2309 was a 24-month, phase IIIb, open-label trial of 833 de novo renal transplant recipients randomized to everolimus, targeting trough concentrations of 3-8 or 6-12 ng/mL plus reduced-exposure cyclosporine A (CsA) or to mycophenolic acid (MPA) 1.44 g per day plus standard-exposure CsA. All patients received basiliximab±corticosteroids. The incidence of the primary composite efficacy endpoint and its components (treated biopsy-proven acute rejection, graft loss, death, or loss to follow-up), renal function (serum creatinine and estimated glomerular filtration rate), and adverse events (AEs) were compared at 24 months; as per the protocol, these analyses were not noninferiority. RESULTS: Composite efficacy failure rates (95% confidence interval for difference vs. MPA) were 32.9% (-2.2%, 13.0%), 26.9% (-7.9%, 6.8%), and 27.4% at month 24 in the everolimus 3-8 and 6-12 ng/mL and MPA groups, respectively. Mean estimated glomerular filtration rate (Modification of Diet in Renal Disease) at month 24 was 52.2 (-2.1, 5.5 mL/min/1.73 m), 49.4 (-4.8, 2.7 mL/min/1.73 m), and 50.5 mL/min/1.73 m, respectively. AEs were generally mild to moderate in severity and comparable between the groups. AEs leading to discontinuation were reported in 28.5% (P=0.03 vs. MPA), 30.6% (P=0.007 vs. MPA), and 20.5% of patients receiving everolimus 3-8 and 6-12 ng/mL and MPA, respectively. CONCLUSIONS: Everolimus trough concentrations targeted to 3-8 ng/mL, along with a greater than 60% reduction in CsA exposure, was associated with comparable efficacy and renal function versus MPA plus standard-exposure CsA over the 2-year period. A significantly higher incidence of AEs led to discontinuation in the everolimus groups compared with the MPA group.

Original languageEnglish
Pages (from-to)933-942
Number of pages10
JournalTransplantation
Volume95
Issue number7
DOIs
Publication statusPublished - 2013 Apr 15

All Science Journal Classification (ASJC) codes

  • Transplantation

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    Cibrik, D., Silva, H. T., Vathsala, A., Lackova, E., Cornu-Artis, C., Walker, R. G., Wang, Z., Zibari, G. B., Shihab, F., & Kim, Y. S. (2013). Randomized trial of everolimus-facilitated calcineurin inhibitor minimization over 24 months in renal transplantation. Transplantation, 95(7), 933-942. https://doi.org/10.1097/TP.0b013e3182848e03