Everolimus-facilitated calcineurin inhibitor reduction in Asian de novo kidney transplant recipients: 2-year results from the subgroup analysis of the TRANSFORM study.

OBJECTIVE: We analyzed the efficacy and safety of an everolimus with reduced-exposure calcineurin inhibitor (EVR+rCNI) versus mycophenolic acid with standard-exposure CNI (MPA+sCNI) regimen in Asian patients from the TRANSFORM study. METHODS: In this 24-month, open-label study, de novo kidney transplant recipients (KTxRs) were randomized (1:1) to receive EVR+rCNI or MPA+sCNI, along with induction therapy and corticosteroids. RESULTS: Of the 2037 patients randomized in the TRANSFORM study, 293 were Asian (EVR+rCNI, N = 136; MPA+sCNI, N = 157). At month 24, EVR+rCNI was noninferior to MPA+sCNI for the binary endpoint of estimated glomerular filtration rate (eGFR) < 50 ml/min/1.73 m2 or treated biopsy-proven acute rejection (27.0% vs. 29.2%, P = .011 for a noninferiority margin of 10%). Graft loss and death were reported for one patient each in both arms. Mean eGFR was higher in EVR+rCNI versus MPA+sCNI (72.2 vs. 66.3 ml/min/1.73 m2 , P = .0414) even after adjusting for donor type and donor age (64.3 vs. 59.3 ml/min/1.73 m2 , P = .0582). Overall incidence of adverse events was comparable. BK virus (4.4% vs. 12.1%) and cytomegalovirus (4.4% vs. 13.4%) infections were significantly lower in the EVR+rCNI arm. CONCLUSION: This subgroup analysis in Asian de novo KTxRs demonstrated that the EVR+rCNI versus MPA+sCNI regimen provides comparable antirejection efficacy, better renal function, and reduced viral infections (NCT01950819).

Wound healing adverse events in kidney transplant recipients receiving everolimus with reduced calcineurin inhibitor exposure or current standard-of-care: insights from the 24-month TRANSFORM study.

OBJECTIVES: In TRANSFORM, de novo kidney transplant recipients received either everolimus in combination with reduced-exposure calcineurin inhibitor (EVR+rCNI) at standard EVR pre-dose concentrations of 3-8 ng/mL or mycophenolic acid plus standard-exposure CNI (MPA+sCNI). The authors analyzed the incidence of wound healing adverse events (WHAEs) over the 2-year study period 15. METHODS: Patients were randomized to either EVR+rCNI or MPA+sCNI, both combined with induction therapy and steroids 19. RESULTS: The safety population consisted of 2,026 patients (EVR+rCNI: 1,014, MPA+sCNI: 1,012). The proportion of patients with at least 1 WHAE was comparable between EVR+rCNI and MPA+sCNI treatment groups [20.6% vs. 17.3%; risk ratio (RR): 1.19; 95% confidence interval (CI): 0.99, 1.43] at month 24. The numerical difference between EVR+rCNI and MPA+sCNI was mainly caused by an increased proportion of EVR patients with lymphocele and wound dehiscence [7.5% vs. 5.1% (RR: 1.46; 95% CI: 1.04, 2.05) and 3.9% vs. 1.8% (RR: 2.22; 95%CI: 1.28, 3.84), respectively] 20. CONCLUSION: The immediate introduction of EVR+rCNI after kidney transplantation was associated with an overall comparable incidence of WHAEs versus current standard-of-care over the 24-month study period. There was an increased relative risk of experiencing lymphocele and wound dehiscence but the absolute risks were rather low in both groups 21. CT.GOV IDENTIFIER: NCT01950819.

Safety of Everolimus With Reduced Calcineurin Inhibitor Exposure in De Novo Kidney Transplants: An Analysis From the Randomized TRANSFORM Study.

BACKGROUND: The safety profiles of standard therapy versus everolimus with reduced-exposure calcineurin inhibitor (CNI) therapy using contemporary protocols in de novo kidney transplant recipients have not been compared in detail. METHODS: TRANSFORM was a randomized, international trial in which de novo kidney transplant patients were randomized to everolimus with reduced-exposure CNI (N = 1014) or mycophenolic acid (MPA) with standard-exposure CNI (N = 1012), both with induction and corticosteroids. RESULTS: Within the safety population (everolimus 1014, MPA 1012), adverse events with a suspected relation to study drug occurred in 62.9% versus 59.2% of patients given everolimus or MPA, respectively (P = 0.085). Hyperlipidemia, interstitial lung disease, peripheral edema, proteinuria, stomatitis/mouth ulceration, thrombocytopenia, and wound healing complications were more frequent with everolimus, whereas diarrhea, nausea, vomiting, leukopenia, tremor, and insomnia were more frequent in the MPA group. The incidence of viral infections (17.2% versus 29.2%; P < 0.001), cytomegalovirus (CMV) infections (8.1% versus 20.1%; P < 0.001), CMV syndrome (13.6% versus 23.0%, P = 0.044), and BK virus (BKV) infections (4.3% versus 8.0%, P < 0.001) were less frequent with everolimus. CMV infection was less common with everolimus versus MPA after adjusting for prophylaxis therapy in the D+/R- subgroup (P < 0.001). Study drug was discontinued more frequently due to rejection or impaired healing with everolimus, and more often due to BKV infection or BKV nephropathy with MPA. CONCLUSIONS: De novo everolimus with reduced-exposure CNI yielded a comparable incidence, though a distinctly different pattern, of adverse events versus current standard of care. Both regimens are safe and effective, yet their distinct profiles may enable tailoring for individual kidney transplant recipients.