Efficacy and safety of concentration-controlled everolimus with reduced-dose cyclosporine in Japanese de novo renal transplant patients: 12-month results

Abstract

Background: No study to date has evaluated the efficacy and safety of everolimus with reduced-exposure cyclosporine in Japanese de-novo renal transplant (RTx) patients.

Methods: This 12-month, multicenter, open-label study randomized (1:1) 122 Japanese de-novo RTx patients to either an everolimus regimen (1.5 mg/day starting dose (target trough: 3 to 8 ng/ml) + reduced-dose cyclosporine) or a mycophenolate mofetil (MMF) regimen (2 g/day + standard dose cyclosporine). All patients received basiliximab and corticosteroids. Key endpoints at month 12 were composite efficacy failure (treated biopsy-proven acute rejection, graft loss, death, or loss to follow-up) and renal function (estimated glomerular filtration rate; Modification of Diet in Renal Disease-4).

Results: Clear cyclosporine exposure reduction was achieved in the everolimus group throughout the study (52% reduction at month 12). Month 12 efficacy failure rates showed everolimus 1.5 mg to be non-inferior to MMF (11.5% vs. 11.5%). The median estimated glomerular filtration rate at month 12 was 58.00 ml/minute/1.73 m2 in the everolimus group versus 55.25 ml/minute/1.73 m2 in the MMF group (P = 0.063). Overall, the incidence of adverse events was comparable between the groups with some differences in line with the known safety profile of the treatments. The everolimus group had a higher incidence of wound healing events and edema, whereas a higher rate of cytomegalovirus infections was reported in the MMF group.

Conclusions: This study confirmed the efficacy of everolimus 1.5 mg/day (target trough: 3 to 8 ng/ml) in Japanese RTx patients for preventing acute rejection, while allowing for substantial cyclosporine sparing. Renal function and safety findings were comparable with previous reports from other RTx populations.

Trial registration: ClinicalTrials.gov number: NCT00658320.

Figure 1

Patient disposition. MMF, mycophenolate mofetil.

Figure 2

Mean everolimus and cyclosporine trough levels over time. (a) Mean everolimus trough levels over time for the everolimus 1.5 mg group (safety population). At each visit the mean is shown and these are joined with horizontal lines. Whiskers are the 5th and 95th percentiles. Target levels are displayed. (b) Mean cyclosporine trough levels for all treatment groups over time (safety population). At each visit the mean is shown and these are joined with horizontal lines. Whiskers are the 5th and 95th percentiles. The target ranges are also displayed with solid lines (lower limit) and broken lines (upper limit) for comparison with the values seen. MMF, mycophenolate mofetil.