Effects of the De Novo use of Everolimus with Reduced Calcineurin Inhibitor on Wound Healing Events in the TRANSFORM Study
Franco Citterio1, Yoshihiko Watarai2, Shamkant Mulgaonkar3, Uyen Huynh-Do4, Peter Bernhardt5, Mitchell Henry6.
1Università Cattolica del Sacro Cuore, Rome, Italy; 2Nagoya Daini Red Cross Hospital, Nagoya City, Japan; 3Saint Barnabas Medical Centre, New Jersey, NJ, United States; 4University Hospital of Bern, Bern, Switzerland; 5Novartis Pharma AG, Basel, Switzerland; 6The Ohio State University, Ohio, OH, United States
Introduction: Anti-proliferative properties of mammalian target of rapamycin inhibitors (mTORi) may interfere with the wound healing process post-transplantation (Tx) and as such, some are hesitant to incorporate mTORi into immunosuppressive regimens immediately post-Tx. Several studies with everolimus (EVR) have shown comparable wound healing events (WHE) vs mycophenolic acid (MPA)-based regimen. Here, we evaluate the effect of EVR in combination with reduced-exposure calcineurin inhibitor (rCNI) vs MPA with standard-exposure CNI (sCNI) on WHE from the TRANSFORM study.
Methods: TRANSFORM (NCT01950819) is a 24-month (M), multicentre, open-label study in which de novo adult kidney transplant recipients were randomised within 24 hours of Tx to receive either EVR+rCNI (N=1022; EVR trough level [C0]: 3-8 ng/mL; tacrolimus [TAC] C0: 4-7, 2-5, and 2-4 ng/mL or cyclosporine [CsA] C0: 100-150, 50-100, and 25-50 ng/mL from Day 1(D1)-M2, M3-M6, and M7-M24, respectively) or MPA+sCNI (N=1015; MPA [1.44 g/day of enteric-coated mycophenolate sodium or 2 g/day of mycophenolate mofetil]; TAC C0: 8-12, 6-10, and 5-8 ng/mL or CsA C0: 200-300, 150-200, and 100-200 ng/mL from D1-M2, M3-M6, and M7-M24, respectively). All patients received basiliximab or rabbit antithymocyte globulin induction and steroids. The WHE by treatment groups at M12 are summarised here.
Results: Overall baseline characteristics, including mean body mass index (25.6 kg/m2 in both groups) and proportion of patients with diabetes (EVR+rCNI vs MPA+sCNI: 27.3% vs 26.5%), were comparable between the groups. Up to 86% of patients were within the target EVR C0 over M12. The overall incidence of WHE at M12 was comparable between the groups (EVR+rCNI vs MPA+sCNI: 39.0% vs 33.7%). Procedural pain, lymphocele, and incision site pain were the most commonly reported WHE in both the groups and were majorly of mild to moderate severity (Table). Patients in the EVR+rCNI vs MPA+sCNI group reported significantly, but slightly, higher incidence of wound dehiscence (3.8% vs 1.8%) and impaired healing (3.5% vs 0.8%). Impaired healing and lymphoceles were the most frequent adverse events leading to study drug discontinuation/dose adjustment/drug interruption in the EVR+rCNI group (Table).
Conclusion: The results from the TRANSFORM study show that in spite of EVR initiation within 24 hours of Tx, the increased risk of WHE was limited between the EVR+rCNI and MPA+sCNI groups.
