The use of everolimus in renal-transplant patients

Figures & data

Table 1 Summary of clinical studies of everolimus in renal-transplant patients

Study	Design	Number of patients	Treatments	Summary of main findings
B201^Citation6	36-month, Phase III, multicenter, randomized, parallel-group, double-blind (12 months), then open-label (24 months)	588 de novo Renal-amendment population: 236 patients	Everolimus (1.5 or 3 mg/day) vs MMF (2 g/day), in addition to CsA and steroids	At 36 months, efficacy failure rates were similar for all groups (p = NS) At 36 months, patient survival, graft survival and rejection rates were similar for everolimus 1.5 mg/day vs MMF; everolimus 3 mg/day demonstrated inferior graft survival (p = 0.0048 for everolimus 1.5 vs 3 mg/day)
B251^Citation5	36-month, Phase III, multicenter, randomized, parallel-group, double-blind for ≥12 months, then open-label	583 de novo	Everolimus (1.5 or 3 mg/day) vs MMF (2 g/day), in addition to CsA and steroids	At 36 months, efficacy failure rates were similar for all groups (p = NS) At 36 months, antibody-treated acute rejection was significantly lower for everolimus 1.5 mg/day vs MMF (p = 0.014)
B156^Citation17	36-month, Phase II, multicenter, randomized, open-label, parallel-group	111 de novo	Everolimus 3 mg/day in combination with basiliximab, steroids and either full-dose or reduced-dose CsA	Efficacy failure was significantly lower in the reduced-dose vs full-dose CsA group at 6, 12 and 36 months (p < 0.05 for all) Mean creatinine clearance was higher in the reduced-dose vs full-dose CsA group at 6 months (p = 0.009), 12 months (p = 0.007) and 36 months (p = 0.436)
US09^Citation18	6-month, exploratory, multicenter, randomized, open-label	92 de novo	Everolimus in combination with steroids, basiliximab and either low- or standard-exposure tacrolimus	Efficacy was similar between groups, with BPAR occurring in 14% of patients in each group Renal function (mean serum creatinine level and estimated GFR) was similar between groups (p = NS)
A2306^Citation7	12-month, Phase III, randomized, open-label, parallel-group	237 de novo	Everolimus 1.5 vs 3 mg/day, in combination with steroids and low-exposure CsA (C2 monitoring)	After 6 months, median serum creatinine levels were 133 and 132 μmol/L in the everolimus 1.5 and 3 mg/day groups, respectively After 6 months, there were no significant differences between groups for any efficacy parameter
A2307^Citation7	12-month, Phase III, randomized, open-label, parallel-group	256 de novo	Everolimus 1.5 vs 3 mg/day, in combination with steroids, low-exposure CsA (C2 monitoring) and basiliximab induction therapy (Days 0 and 4)	After 6 months, median serum creatinine levels were 130 μmol/L in both everolimus groups After 6 months, there were no significant differences between groups for any efficacy parameter
CENTRAL^Citation27	6-month, single-center, pilot	20 recipients of a first or second single renal transplant from a deceased or living donor	Patients were converted from CsA to everolimus 7 weeks post-transplant; all received basiliximab induction therapy with maintenance EC-MPS and steroids	Calculated GFR improved significantly following conversion from CsA to everolimus (p = 0.001) BPAR occurred in 3/20 (15.0%) patients during the 7 weeks post-conversion to everolimus, but all episodes were mild and reversible, with subsequent recovery of renal function Abrupt conversion from CsA to everolimus was well tolerated

Abbreviations: BPAR, biopsy-proven acute refection; CsA, cyclosporine; CNI, calcineurin inhibitor; EC-MPS, enteric-coated mycophenolate sodium; GFR, glomerular filtration rate; IL-2, interleukin-2; MMF, mycophenolate mofetil; NS, not significant.

Table 2 Summary of ongoing Phase III–IV studies with everolimus in renal-transplant patients

Study	Design	Patient population	Treatments	Primary outcome	Secondary outcomes
MECANO^Citation61	24-month, prospective, multicenter, randomized, open-label	255 patients undergoing first or second renal transplant	6 months treatment with basiliximab, CsA, EC-MPS and prednisolone, followed by randomization to 18 months treatment with CsA + prednisolone, EC-MPS + prednisolone, or everolimus + prednisolone	Degree of inflammation, fibrosis and arteriolar hyalinosis in renal biopsies taken at Months 6 and 24	Vascular assessments by IMT and M-mode of carotis interna Blood pressure and number of anti-hypertensive drugs Lipid profile Renal allograft survival and function Patient survival Incidence of malignancies Infectious complications
CALLISTO A2420^Citation62	12-month, Phase III, multicenter, open-label	139 de novo with risk of developing DGF	Immediate vs delayed everolimus after 1 month of EC-MPS treatment. All patients also received anti-IL-2 receptor induction therapy and steroids	To compare the incidence of the composite of BPAR, graft loss, death, DGF and wound healing complications with immediate vs delayed administration of everolimus at 3 months	Renal function at 3 months (creatinine clearance; Nankivell) at 6 and 12 months (serum creatinine, creatinine clearance [Nankivell and Cockcroft Gault]) and proteinuria Wound healing complications To assess efficacy (BPAR, graft loss/re-transplantation, death or lost to follow-up) at 6 and 12 months post transplantation Safety based on adverse event reporting
EVEREST AIT02^Citation21	6-month, Phase III, multicenter, randomized, open-label	285 de novo	Higher everolimus target trough levels (C0 8 to 12 ng/mL) with very low-dose CsA (C2 600 ng/mL, tapered to 300 ng/mL at Month 3) or standard everolimus target trough levels (C0 3 to 8 ng/mL) with low-dose CsA (C2 600 ng/mL, tapered to 500 ng/mL at Month 3)	To assess if higher target everolimus trough levels and very-low-dose CsA improves the 6-month creatinine clearance, in comparison with the standard everolimus regimen with low-dose CsA To assess if the optimized new regimen is equally effective in preventing acute rejection, compared with the standard regimen	Incidence of BPAR, graft loss, death or lost to follow-up Efficacy parameters: BPAR, antibody-treated acute rejection and clinically-confirmed acute rejection Evaluate the percentage of patients with a stable serum creatinine increase of more than 30% from the previous nadir after transplantation Incidence of graft loss or death Safety and tolerability
A2309^Citation22	24-month, Phase III, multicenter, randomized, parallel-group, open-label	833 de novo	Everolimus (1.5 or 3 mg/day) + reduced-exposure CsA vs EC-MPS + standard-exposure CsA	Treated biopsy acute rejection, graft loss and survival within 12 months	Graft loss, survival and renal function at 12 months
ZEUS A2418^Citation63	12-month, Phase IV, multicenter, randomized, open-label study with additional 4-year follow-up	300 de novo renal transplant patients	Following basiliximab induction therapy, all patients were treated with CsA, EC-MPS and steroids for 4.5 months, then randomized to either continue the same treatment or switch from CsA to everolimus	Renal function assessed as GFR (Nankivell) 12 months after transplantation	To assess renal function by GFR (Cockcroft-Gault and MDRD) at Month 12 post transplant To assess efficacy (BPAR, graft loss, death) at Month 6 and 12 Occurrence of treatment failures up to or at Month 12 To assess evolution of renal function between Month 4.5 and 12 (creatinine slope) To assess safety and tolerability at Month 4.5 and 12 Changes in cardiovascular risk (Framingham Score) between Month 4.5 and 12
A2426^Citation23	12-month, Phase IV, multicenter, randomized, open-label, parallel-group	230 de novo	Everolimus + IL-2 receptor antagonist + steroids, in combination with one of two tacrolimus doses	Renal function, assessed as GFR (MDRD), at Month 12	BPAR incidence from Month 4 to Month 12 Efficacy (BPAR, graft loss, death) Renal function Incidence of AEs and SAEs and new onset diabetes mellitus
HERAKLES (ADE13)^Citation24	12-month, Phase III, multicenter, randomized, open-label, parallel-group	450 de novo	Everolimus in combination with low-dose CNI vs CNI-free vs EC-MPS with standard-dose CNI	Renal function, assessed as GFR (Nankivell), at Month 12	Renal function (GFR) assessed by Cock-croft Gault and MDRD at Month 12 Efficacy (BPAR, graft loss, death) at Months 6 and 12 Treatment failure up to Month 12 To assess efficacy (BPAR, graft loss, death, renal function [creatinine, GFR]) safety and tolerability (CMV, tumor incidence, cardiovascular risk, proteinuria) at follow up visits at Month 18, 24, 36, 48, and 60
SOCRATES (A2421)^Citation64	12-month, Phase IV, multicenter, randomized, open-label, parallel-group	177 de novo	Initial treatment with CsA, EC-MPS and steroids, followed after 2 weeks by everolimus and EC-MPS with either CsA or steroids (ie, either steroid withdrawal or CsA withdrawal). These two groups will be compared with a third control group that will receive CsA, EC-MPS and steroids	Renal function, assessed as estimated GFR (Nankivell), at Month 12	BPAR incidence at Month 12 Histology (CAN, subclinical acute rejection) at Month 12 Proteinuria at Month 12 Patient graft survival at Month 12 Incidence of wound problems Prevalence of post-transplant diabetes mellitus at Month 12 Effect on cardiovascular health Incidence of anemia, leucopenia, thrombocytopenia and erythropoietin usage Quality of life at Month 12 Effect on healthcare resource utilization (hospital events) and employment status Influence of parameters on safety and efficacy outcomes
A2423^Citation65	12-month, Phase IV, multicenter, randomized, open-label, parallel-group	51 de novo	Everolimus in combination with basiliximab and steroids, in a maintained vs discontinued CsA regimen	Renal function, assessed as calculated GFR, at Month 12	Serum creatinine and calculated serum creatinine at Months 6 and 12 Incidence of composite of BPAR, graft loss, death, or loss to follow-up at Months 6 and 12 Incidence of graft loss, death, BPAR, antibody-treated acute rejection, clinically confirmed acute rejection and clinically confirmed chronic rejection at Months 6 and 12 Safety based on adverse event reporting
A2419^Citation25	12-month, Phase IV, multicenter, randomized, open-label, parallel-group	119 de novo	Everolimus + basiliximab, in combination with CsA, either discontinued after 3 months or minimized	Renal function, assessed as calculated GFR, serum creatinine and calculated creatinine clearance at Month 12	Incidence of composite of BPAR, graft loss, death, or loss to follow-up at Month 12 Incidence of graft loss, death, BPAR, antibody-treated acute rejection, clinically confirmed acute rejection and clinically confirmed chronic rejection at Month 12 Safety based on adverse event reporting
ASCERTAIN (A2413)^Citation26	Phase IV, randomized, open-label, parallel-group	398 maintenance patients	Patients are randomized to one of three groups: Continuation of current immunosuppressive regimen without everolimus Initiation of everolimus with discontinuation of CNI, or Initiation of everolimus with reduction of CNI blood levels by 70% to 90%	Renal function evaluated by measured GFR at Month 24	Patient and graft survival and BPAR at 24 months Other renal function data Progression of CAN Progression of atherosclerosis Safety based on adverse eventreporting

Abbreviations: BPAR, biopsy-proven acute refection; CAN, chronic allograft nephropathy; CsA, cyclosporine; CNI, calcineurin inhibitor; DGF, delayed graft function; EC-MPS, enteric-coated mycophenolate sodium; GFR, glomerular filtration rate; IL-2, interleukin-2; IMT, intima-media thickness; MDRD, modification of diet in renal disease.

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