Aim: To compare switching off 3 different immunosuppressive (IS) regimen 4years after renal transplantation (Tx).

Methods: 802 patients (pts) were included in this prospective, open-label, randomized, controlled multi-center study with observational follow-up (FU) until Mo60 post Tx. After induction therapy with basiliximab all pts received cyclosporine A (CsA), enteric-coated mycophenolate sodium (EC-MPS) and steroids. 3Mo post Tx 499pts were randomized 1:1:1 to either i) continue standard CsA(100-180ng/ml)+EC-MPS(n=166) (STD) or convert ii) to a calcineurin inhibitor (CNI)-free regimen with everolimus (EVR)(5-10ng/ml)+EC-MPS(n=171) or iii) to a CNI-low regimen with EVR(3-8ng/ml) + reduced CsA(50-75ng/ml) (n=162). All pts continued on steroids.

Results: At 48 Mo post Tx 60 (36%) CNI-free, 43 (27%) CNI-low and 83 (51%) STD treated pts were still on their initial assigned treatment and available for Mo48 analysis. Among those pts who completed Mo48 FU visit non-switcher frequencies were 53% for CNI-free, 41% for CNI-low and 81% for STD treated pts. Drop-out frequency among FU ITT pop. from randomization to Mo48 was 17% for STD, 15% for CNI-free and 14% for CNI-low treated pts. Premature discontinuation due to AEs occurred in 5 (3%) of STD, 5 (3%) of CNI-free and 1 (1%) of CNI-low pts (safety-pop) from Mo12 to 48. Renal function (cGFR, Nankivell, LOCF) among those pts, who never switched off their assigned treatment GFR was significantly improved by +13.7ml/min/1.73m² in favor of the CNI-free regimen at Mo48 (ITT;p<0.001).

Conclusions: Mo48 results from HERAKLES show that IS regimen using EVR with low-dose or without CNI-exposure reflect the opportunity for an individualized IS to minimize CNI-exposure. Drop-out rates over 4 years post Tx showed similar adherence rates between groups. Pts that never switched off the assigned CNI-free regimen reached a markedly improved GRF.

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