Early conversion of pediatric kidney transplant patients to everolimus with reduced tacrolimus and steroid elimination: Results of a randomized trial

Abstract

In a 12-month, multicenter, open-label study, 106 children were randomized at 4 to 6 weeks after kidney transplantation to switch to everolimus with reduced TAC (EVR/rTAC) and steroid elimination from month 5 posttransplant or to continue standard tacrolimus with mycophenolate mofetil (sTAC/MMF) and steroids. The cumulative incidence of a co-primary efficacy end point (biopsy-proven acute rejection [BPAR], graft loss, or death from randomization to month 12) was 10.3% with EVR/rTAC and 5.8% with sTAC/MMF (difference 4.4%; P = .417). BPAR occurred in 9.6% and 5.6% of patients, respectively. Patient and renal allograft survival were 100%. The co-primary end point of mean estimated glomerular filtration rate at month 12 was 76.2 mL/min/1.73 m with EVR/rTAC and 72.5 mL/min/1.73 m for sTAC/MMF (difference 3.8 mL/min/1.73m ; P = .49). One EVR/rTAC patient developed posttransplant lymphoproliferative disease. Longitudinal growth and sexual maturation were equivalent between groups. The randomized drug regimen was discontinued in 34.6% and 13% of patients in the EVR/rTAC and sTAC/MMF groups, respectively (P = .024), and discontinued due to adverse events/infections in 25.0% and 11.1% of patients (P = .062). In conclusion, early conversion of pediatric kidney transplant patients from TAC, MMF, and steroids to EVR/rTAC and steroid withdrawal maintains immunosuppressive efficacy and preserves renal function.

Three-year outcomes from the CRADLE study in de novo pediatric kidney transplant recipients receiving everolimus with reduced tacrolimus and early steroid withdrawal

“…After randomization, incidence of dnDSAs was lower in the EVR + rTAC group compared with the MMF + sTAC group, similar to that found at month 12 20. Similarly, low and comparable incidences of dnDSAs were reported up to 4-year posttransplant (11.4% vs 17.9%) in pediatric KTRs receiving an EVR-based steroid withdrawal regimen vs sCNI (mostly CsA) 18.…”

“…The study design, methodology, and eligibility criteria of the CRADLE study have been published previously 20 . This 12‐month core, phase 3, multicenter, open‐label study included 106 pediatric KTRs (aged ≥1 to <18 years) who were followed for an additional 24 months (Figure S1).…”

“…The 12-month results from this study achieved primary objectives on efficacy as well as safety and proved that early conversion of pediatric KTRs from MMF + sTAC and steroids to EVR + rTAC with early steroid withdrawal maintained immunosuppressive efficacy and preserved renal function. 20 Following completion of the 12-month core study, 20 KTRs underwent follow-up until month 36 to evaluate the mid-term outcomes of the EVR + rTAC regimen in this population with an additional focus on the secondary outcomes such as statural growth (height, weight, and body mass index [BMI]) and pubertal development.…”

“…The study design, methodology, and eligibility criteria of the CRADLE study have been published previously. 20 This 12-month core, phase 3, multicenter, open-label study included 106 pediatric KTRs (aged ≥1 to <18 years) who were followed for an additional 24 months ( Figure S1). In the EVR + rTAC group, patients were converted at weeks 4 to 6 posttransplant from MMF to EVR overnight, with EVR initiated at a dosage of 2 mg/m 2 /dose twice daily, on the morning after the last evening dose of MMF, adjusted from day 4 after conversion to target a trough level (C 0 ) of 3 to 8 ng/mL.…”

“…KTRs were then randomized to either (1) switch to EVR + rTAC (n = 52) with steroid withdrawal (at 6 months posttransplant) or (2) continue the MMF + sTAC (n = 54) including steroids. 20…”