Early Conversion of Calcineurin Inhibitor to Everolimus in De Novo Paediatric Renal Transplant Recipients and Its Impact on Efficacy and Renal Function; Design of An Open-Label, Randomised, Multi-Centre Study

Abstract

Introduction:Immunosuppression with both calcineurin inhibitors (CNIs) and steroids is associated with adverse effects in paediatric renal transplant (pRTx) recipients. Exposure to CNIs and steroids can be reduced or eliminated by introduction of the mTOR inhibitor everolimus (EVR). The present study assesses the efficacy and safety of the early introduction of EVR combined with reduced exposure tacrolimus (TAC) and corticosteroid withdrawal in pRTx recipients. Method:A2314 is a 12-month (M) multi-centre, randomised, open-label study with 24M additional safety follow-up in two parallel groups of pRTx recipients (≥1 and < 18 years). After a 4-6 weeks run-in period with TAC, mycophenolate mofetil and steroids, pRTx recipients (eGFR >50ml/min/1.73m2) will be randomised (1:1) to either continue the TAC regimen or start EVR with reduced dose TAC (EVR+rTAC) and steroid withdrawal at M6 (figure). Main analysis will be performed at M12 to investigate the efficacy and safety variables while M36 analysis will be a follow-up assessing the durability of 12M outcomes. The co-primary objectives at M12 are to estimate the rate of composite efficacy endpoint (biopsyproven acute rejection [BPAR], graft loss or death) and to evaluate renal function (eGFR by abbreviated Schwartz formula). Key secondary objectives at both M12 and M36 include: components of composite efficacy endpoint, time to event and severity of BPAR, incidence of antibody mediated rejection, evolution of renal allograft function over time, incidence of proteinuria, incidence/progression of interstitial fibrosis/tubular atrophy, assessment of growth and development, and overall safety. Enrolment of approximately 106 pRTx recipients will take place in 2012 and 2013 with M12 results expected in 2014.Figure: [Study design]Conclusion: This controlled multi-centre trial aims to provide evidence on the potential efficacy and safety benefits of an EVR-based regimen in pRTx recipients up to 36M post-RTx.