title: Everolimus versus mycophenolate mofetil in the prevention of rejection in de novo renal transplant recipients: a 3-year randomized, multicenter, phase III study.
abstract: 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.
authors.affiliation: Yale University School of Medicine, New Haven, CT 06520, USA. Marc.Lorber@yale.edu
authors.forename: Marc I
authors.initials: MI
authors.lastname: Lorber
authors.forename: Shamkant
authors.initials: S
authors.lastname: Mulgaonkar
authors.forename: Khalid M H
authors.initials: KM
authors.lastname: Butt
authors.forename: Elmahdi
authors.initials: E
authors.lastname: Elkhammas
authors.forename: Robert
authors.initials: R
authors.lastname: Mendez
authors.forename: P R
authors.initials: PR
authors.lastname: Rajagopalan
authors.forename: Barry
authors.initials: B
authors.lastname: Kahan
authors.forename: Hans
authors.initials: H
authors.lastname: Sollinger
authors.forename: Yulan
authors.initials: Y
authors.lastname: Li
authors.forename: Nathalie
authors.initials: N
authors.lastname: Cretin
authors.forename: Helio
authors.initials: H
authors.lastname: Tedesco
mesh_terms: 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
chemical_list: D007166:Immunosuppressive Agents; D000068338:Everolimus; D009173:Mycophenolic Acid; D020123:Sirolimus