title: Efficacy of everolimus with reduced-exposure cyclosporine in de novo kidney transplant patients at increased risk for efficacy events: analysis of a randomized trial.
abstract: The efficacy of de novo everolimus with reduced-exposure calcineurin inhibitor (CNI) was examined in kidney transplant subpopulations from the A2309 study that were identified to be at increased risk for efficacy events. A2309 was a 24-month, multicenter, open-label trial in which 833 de novo kidney transplant recipients were randomized to everolimus targeting 3-8 or 6-12 ng/ml with reduced-exposure cyclosporine (CsA), or mycophenolic acid (MPA) with standard-exposure CsA, all with basiliximab induction. The composite efficacy endpoint was treated biopsy-proven acute rejection (BPAR), graft loss, death, or loss to follow-up. Cox proportional hazard modeling showed male gender, younger recipient age, black race, delayed graft function, human leukocyte antigen (HLA) mismatch ≥3 and increasing donor age to be significantly predictive for the composite efficacy endpoint at months 12 or 24 post-transplant. CsA exposure was 53-75 % lower, and 46-75 % lower, in patients receiving everolimus 3-8 ng/ml or receiving everolimus 6-12 ng/ml, respectively, versus MPA-treated patients. The incidence of the composite endpoint was similar in all three treatment groups within each subpopulation analyzed. The incidence of treated BPAR was similar with everolimus 3-8 ng/ml or MPA in all subpopulations, but less frequent with everolimus 6-12 ng/ml versus MPA in patients with HLA mismatch ≥3 (p = 0.049). This post hoc analysis of a large, randomized trial suggests that a de novo regimen of everolimus with reduced-exposure CsA maintains immunosuppressive efficacy even in kidney transplant patients at increased risk for efficacy events despite substantial reductions in CsA exposure.
authors.affiliation: Department of Surgery and Bioengineering, University of Siena, Siena, Italy. mario.carmellini@unisi.it.|Centro Trapianti di Rene, Az. Osped Universitaria Senese Ospedale S Maria alle Scotte, U.O.C. Chirugira dei Trpianti-Dip. Chirugria Gen. e Spec, Viale Bracci 1, 53100, Siena, Italy. mario.carmellini@unisi.it.
authors.forename: Mario
authors.initials: M
authors.lastname: Carmellini
authors.affiliation: Hospital Don Vicente Scherer, Santa Casa de Misericordia do Porto Alegre, Porto Alegre, Brazil.
authors.forename: Valter
authors.initials: V
authors.lastname: Garcia
authors.affiliation: Novartis Pharma AG, Basel, Switzerland.
authors.forename: Zailong
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
authors.forename: Marcela
authors.initials: M
authors.lastname: Vergara
authors.affiliation: Renal Unit, The Queen Elizabeth Hospital, Woodville, Australia.
authors.forename: Graeme
authors.initials: G
authors.lastname: Russ
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001706:Biopsy; D016572:Cyclosporine / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D000068338:Everolimus / Q000008:administration & dosage*; D005260:Female; D005500:Follow-Up Studies; D006084:Graft Rejection / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D007165:Immunosuppression Therapy / Q000379:methods*; D007166:Immunosuppressive Agents / Q000008:administration & dosage; D007668:Kidney / Q000473:pathology; D007676:Kidney Failure, Chronic / Q000601:surgery; D016030:Kidney Transplantation / Q000009:adverse effects*; D008297:Male; D008875:Middle Aged; D012307:Risk Factors; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D007166:Immunosuppressive Agents; D016572:Cyclosporine; D000068338:Everolimus
keywords: Calcineurin inhibitor; Cyclosporine; Efficacy; Everolimus; High risk; Kidney transplantation; Rejection; Sparing