Everolimus versus mycophenolate mofetil in the prevention of rejection in de novo renal transplant recipients: a 3-year randomized, multicenter, phase III study.
BACKGROUND
This 36-month, randomized, parallel-group study compared safety and efficacy of two doses of everolimus with mycophenolate mofetil (MMF) in de novo renal-transplant recipients.


METHODS
Renal-allograft recipients received 1.5 mg/day or 3 mg/day of everolimus or 2 g/day of MMF, plus full-dose cyclosporine (CsA) and corticosteroids after randomization. For at least their first year, patients received study medication according to a double-blinded, double-dummy design. Concerns over nephrotoxicity led to a protocol amendment to an open-label design with reduced CsA troughs.


RESULTS
Incidences of primary efficacy failure at 36 months (biopsy-proven acute rejection, graft loss, death, or loss to follow-up) were everolimus 1.5 mg/day, 33.7% (65/193); everolimus 3 mg/day, 34.0% (66/194); and MMF, 31.1% (61/196) (P=0.810). Antibody-treated acute rejection at 36 months was significantly lower with everolimus 1.5 mg (9.8%) than MMF (18.4%, P=0.014). Discontinuation for adverse events was more frequent with everolimus and hemolytic uremic syndrome, lymphoproliferative disease, and proteinuria, and higher serum creatinine occurred at increased frequency relative to the MMF arm. Creatinine levels in the everolimus arms were stable in follow-up: the mean rise in creatinine over the first 6 months of the open-label phase was 3 micromol/L or greater with everolimus and 7 micromol/L with MMF. However, serum creatinine levels were lower in the MMF group throughout. Death and graft loss were higher in the everolimus arms (not significant).


CONCLUSIONS
As part of triple-drug immunosuppression, everolimus (1.5 or 3 mg/day) was as efficacious as MMF, although the side-effect profile featured increased adverse events. Nephrotoxicity/calcineurin-inhibitor-related adverse events will require judicious lowering of CsA exposure with monitoring of everolimus troughs.
Lorber
Marc I
MI
Yale University School of Medicine, New Haven, CT 06520, USA. Marc.Lorber@yale.edu
Mulgaonkar
Shamkant
S
Butt
Khalid M H
KM
Elkhammas
Elmahdi
E
Mendez
Robert
R
Rajagopalan
P R
PR
Kahan
Barry
B
Sollinger
Hans
H
Li
Yulan
Y
Cretin
Nathalie
N
Tedesco
Helio
H
D000293:Adolescent; D000328:Adult; D000368:Aged; D004359:Drug Therapy, Combination; D000068338:Everolimus; D005260:Female; D006084:Graft Rejection / Q000517:prevention & control*; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D016030:Kidney Transplantation / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000627:therapeutic use; D012449:Safety; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000627:therapeutic use; D014019:Tissue Donors / Q000706:statistics & numerical data
D007166:Immunosuppressive Agents; D000068338:Everolimus; D009173:Mycophenolic Acid; D020123:Sirolimus