Three-Year Efficacy and Safety Results from a Study of Everolimus Versus Mycophenolate Mofetil in de novo Renal Transplant Patients

C Blackwell Munksgaard 2005 Copyright  American Journal of Transplantation 2005; 5: 2521–2530 Blackwell Munksgaard doi: 10.1111/j.1600-6143.2005.01...
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C Blackwell Munksgaard 2005 Copyright 

American Journal of Transplantation 2005; 5: 2521–2530 Blackwell Munksgaard

doi: 10.1111/j.1600-6143.2005.01063.x

Three-Year Efficacy and Safety Results from a Study of Everolimus Versus Mycophenolate Mofetil in de novo Renal Transplant Patients ˇ Stefan V´ıtkoa, ∗ , Raimund Margreiterb , Willem Weimarc , Jacques Dantald , Dirk Kuyperse , Michael Winklerf , Ole Øyeng , Hendrik G. Viljoenh , Pavel Filiptsevi , Sami Sadekj , Yulan Lik , Nathalie Cretinl and Klemens Buddem , for the RAD B201 Study Group a

Institute of Clinical and Experimental Medicine, Praha, Czech Republic b Universitatsklinik ¨ fur ¨ Chirurgie, Innsbruck, Austria c Erasmus Medisch Centrum, Rotterdam, The Netherlands d Hopital ˆ Hotel-Dieu, ˆ Nantes, France e University Hospital Gasthuisberg, Leuven, Belgium f Kliniken der Medizinischen Hochschule Hannover, Hannover, Germany g Rikshospitalet, Surgical Department, Oslo, Norway h Garden City Hospital, Cape Town, South Africa i City Clinical Hospital No. 7, Moscow, Russia j Queen Alexandra Hospital, Portsmouth, United Kingdom k Novartis Pharmaceuticals Inc., East Hanover, USA l Novartis Pharma AG, Basel, Switzerland m Universitatsklinik ¨ Charite, ´ Berlin, Germany ∗ Corresponding author: Klemens Budde, [email protected] Everolimus 1.5 or 3 mg/day was compared with mycophenolate mofetil (MMF) 2 g/day in a randomized, multicenter 36-month trial in de novo renal allograft recipients (n = 588) receiving cyclosporine microemulsion (CsA) and corticosteroids. The study was doubleblind until all patients had completed 12 months, then open-label. By 36 months, graft loss occurred in 7.2, 16.7 and 10.7% of patients in the everolimus 1.5, 3 mg/day, and MMF groups, respectively (p = 0.0048 for everolimus 1.5 mg/day vs. 3 mg/day); efficacy failure (biopsy-proven acute rejection (BPAR), graft loss, death or lost to follow-up) occurred in 33.0, 38.9 and 37.2% of patients (p = 0.455 overall), respectively. Mortality and incidence of BPAR were comparable in all groups. Creatinine values were higher in everolimus groups, requiring a protocol amendment that recommended lower CsA exposure. Diarrhea, lymphocele, peripheral edema and hyperlipidemia were more common among everolimus-treated patients, whereas viral infections, particularly cytomegalovirus infection, increased in the MMF group. Overall safety and tolerability were better with MMF and everolimus 1.5 mg/day than with everolimus 3 mg/day. In conclusion, at 36 months, an immunosuppressive regimen con-

taining everolimus 1.5 mg/day had equivalent patient, and graft survival and rejection rates compared with MMF in de novo renal transplant recipients, whereas everolimus 3 mg/day had inferior graft survival. Renal dysfunction in everolimus cohorts necessitates close monitoring. Key words: Cytomegalovirus, everolimus, kidney transplant, mycophenolate mofetil, rejection Received 25 October 2004, revised 17 June 2005, accepted for publication 27 June 2005

Introduction The goal of immunosuppressive therapy is to deliver effective protection against rejection with minimal morbidity. Immunosuppressive regimens that combine drugs that act synergistically via complementary mechanisms of action offer the best opportunity to achieve high efficacy while minimizing adverse effects. The proliferation signal inhibitor everolimus exerts its effect at a different physiological target to cyclosporine microemulsion (CsA), raising interest in an immunosuppressive strategy that optimizes exposure of both agents such that the side effects of either everolimus or CsA are reduced. Everolimus inhibits growth-factor-dependent proliferation of cells through a calcium-independent signal (2,3), whereas CsA inhibits T-cell-dependent growth factors through a calcium-dependent signal. In animal models of organ transplantation, combination therapy using 10% of full everolimus dose with 30% of full CsA dose was as effective as administering either drug alone at full dose (4). Everolimus can also decrease vascular remodeling by preventing growth-factor-mediated smooth muscle cell proliferation and attenuating vascular neointimal formation in animal models (3) and humans (5). Chronic allograft dysfunction is the major barrier to long-term patient and graft survival after renal transplantation. This is a multifactorial process in which the primary causes are acute rejection, vascular remodeling, calcineurin inhibitor (CNI)-induced nephrotoxicity and cytomegalovirus (CMV) infection (6,7). Because it can target several of these contributory factors, everolimus has the potential to improve long-term outcomes in renal transplantation (8). 2521

V´ıtko et al.

Mycophenolate mofetil (MMF) has been shown to reduce graft rejection and prolong death-censored graft survival after renal transplantation (9–12). As a consequence, triple therapy comprising CNI, MMF and corticosteroids evolved as the most prevalent immunosuppressive regimen employed in de novo kidney transplant recipients in the late 1990s (13). This combination was therefore selected as the control group for a randomized, prospective 36-month trial that compared the efficacy and safety of two doses of everolimus with that of MMF, each in combination with CsA and steroids, in a population of de novo renal transplant patients. The 12-month findings were reported previously (14); here we present the full 3-year results of the trial.

Methods Study design This was a 36-month, multicenter, randomized, parallel-group equivalence trial of two oral doses of everolimus (1.5 or 3 mg/day) versus MMF in combination with CsA microemulsion (Neoral) and corticosteroids in de novo renal transplant recipients. The primary objective of the trial was to compare the efficacy of two doses of everolimus with that of MMF as measured by the incidence of a composite endpoint of efficacy failure (biopsy-proven acute rejection (BPAR), graft loss or death) in the first 6 months of treatment (14). The objectives of the protocol-prespecified 36-month analysis were (1) to compare allograft and patient survival, (2) to compare the efficacy of everolimus with that of MMF as measured by the incidence of acute and chronic rejection and (3) to assess safety and tolerability of the everolimus regimens versus the MMF regimen. Additionally, two composite endpoints for efficacy failure (graft loss, death and loss to follow-up with or without BPAR), which were not specified in the protocol, were also assessed. Allograft loss was presumed to occur if a patient started dialysis and could not subsequently be removed from dialysis. Safety assessments included the frequency of deaths, serious adverse events, early discontinuations, malignancies, infections and serial laboratory results from a central laboratory. Renal function was assessed with creatinine levels and calculated creatinine clearance (Cockroft–Gault formula). Patient selection and treatment have been described previously (14). In brief, the trial was conducted at 54 centers (4 in Australia, 48 in Europe, and 2 in South Africa), and patients were recruited between August 1998 and August 1999. Within 48 h after transplantation, patients were randomly assigned (ratio of 1:1:1, stratified by center) to receive everolimus 0.75 mg b.i.d., everolimus 1.5 mg b.i.d. or MMF 2 g/day in a double-blind, double-dummy format for 12 months. Both investigators and patients remained blinded until all patients completed the first year of the study. In October 2000, after the last patient had completed the 12-month visit and the database was locked, investigators were unblinded and the remainder of the study was open-label. Patients were randomized according to a computer-generated schedule that ensured equal distribution among the three treatment groups within each center. Patients were 18–68 years old and had received a donor kidney (cadaveric or living related) with an ischemic time

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