Everolimus with Reduced Calcineurin Inhibitor Exposure in Renal Transplantation

Abstract

Background Everolimus permits reduced calcineurin inhibitor (CNI) exposure, but the efficacy and safety outcomes of this treatment after kidney transplant require confirmation.Methods In a multicenter noninferiority trial, we randomized 2037 de novo kidney transplant recipients to receive, in combination with induction therapy and corticosteroids, everolimus with reduced-exposure CNI (everolimus arm) or mycophenolic acid (MPA) with standard-exposure CNI (MPA arm). The primary end point was treated biopsy-proven acute rejection or eGFR<50 ml/min per 1.73 m² at post-transplant month 12 using a 10% noninferiority margin.Results In the intent-to-treat population (everolimus n=1022, MPA n=1015), the primary end point incidence was 48.2% (493) with everolimus and 45.1% (457) with MPA (difference 3.2%; 95% confidence interval, -1.3% to 7.6%). Similar between-treatment differences in incidence were observed in the subgroups of patients who received tacrolimus or cyclosporine. Treated biopsy-proven acute rejection, graft loss, or death at post-transplant month 12 occurred in 14.9% and 12.5% of patients treated with everolimus and MPA, respectively (difference 2.3%; 95% confidence interval, -1.7% to 6.4%). De novo donor-specific antibody incidence at 12 months and antibody-mediated rejection rate did not differ between arms. Cytomegalovirus (3.6% versus 13.3%) and BK virus infections (4.3% versus 8.0%) were less frequent in the everolimus arm than in the MPA arm. Overall, 23.0% and 11.9% of patients treated with everolimus and MPA, respectively, discontinued the study drug because of adverse events.Conclusions In kidney transplant recipients at mild-to-moderate immunologic risk, everolimus was noninferior to MPA for a binary composite end point assessing immunosuppressive efficacy and preservation of graft function.

Trial registration: ClinicalTrials.gov NCT01950819.

Keywords: calcineurin inhibitor; efficacy graft; everolimus; function; kidney transplantation; randomized.

Figure 1.

In total, 2037 patient were transplanted and randomized and comprised the intention-to-treat (ITT) population. The month 12 study visit was completed by more than 90% of patients in both treatment groups. *One misrandomized patient received study medication and was included in the ITT population. **Six of these patients completed their month 12 visit after day 450. ***Four of these patients completed their month 12 visit after day 450.

Figure 2.

The Kaplan-Meier estimate of the key secondary endpoint of tBPAR, graft loss or death at month 12 post-transplant was 14.9% versus 12.5% in the everolimus versus MPA groups, respectively; difference 2.3% with 95% CI [–1.7% to 6.4%], supporting the non-inferiority of everolimus to MPA (ITT population). ITT, intention-to-treat.

Figure 3.

All efficacy endpoints at month 12 occurred at a similar rate in the everolimus and MPA groups (ITT population). Difference was defined as everolimus − MPA. 95% CI and P values test for no difference. The primary end point is shown in bold text. *P=0.001 for noninferiority; ^‡P<0.001 for noninferiority; ^†compared using raw incidence rates (other end points are compared using Kaplan–Meier incidence rates). AMR, antibody-mediated rejection; AR, acute rejection; ITT, intention-to-treat; KM, Kaplan-Meier; tAR, treated acute rejection.