title: The MANDELA study: A multicenter, randomized, open-label, parallel group trial to refine the use of everolimus after heart transplantation.
abstract: In recent years a series of trials has sought to define the optimal protocol for everolimus-based immunosuppression in heart transplantation, with the goal of minimizing exposure to calcineurin inhibitors (CNIs) and harnessing the non-immunosuppressive benefits of everolimus. Randomized studies have demonstrated that immunosuppressive potency can be maintained in heart transplant patients receiving everolimus despite marked CNI reduction, although very early CNI withdrawal may be inadvisable. A potential renal advantage has been shown for everolimus, but the optimal time for conversion and the adequate reduction in CNI exposure remain to be defined. Other reasons for use of everolimus include a substantial reduction in the risk of cytomegalovirus infection, and evidence for inhibition of cardiac allograft vasculopathy, a major cause of graft loss. The ongoing MANDELA study is a 12-month multicenter, randomized, open-label, parallel-group study in which efficacy, renal function and safety are compared in approximately 200 heart transplant patients. Patients receive CNI therapy, steroids and everolimus or mycophenolic acid during months 3 to 6 post-transplant, and are then randomized at month 6 post-transplant (i) to convert to CNI-free immunosuppression with everolimus and mycophenolic acid or (ii) to continue reduced-exposure CNI, with concomitant everolimus. Patients are then followed to month 18 post-transplant The rationale and expectations for the trial and its methodology are described herein.
authors.affiliation: Department of Cardiovascular Surgery, University Heart Center Hamburg, Martinistr 52, 20246 Hamburg, Germany. Electronic address: t.deuse@uke.de.
authors.forename: Tobias
authors.initials: T
authors.lastname: Deuse
authors.affiliation: Division of Cardiovascular, Thoracic and Transplantation Surgery, Hannover Medical School, Carl-Neuberg-Straße 1, 30625 Hannover, Germany. Electronic address: bara.christoph@mh-hannover.de.
authors.forename: Christoph
authors.initials: C
authors.lastname: Bara
authors.affiliation: Department of Cardiovascular Surgery, University Heart Center Hamburg, Martinistr 52, 20246 Hamburg, Germany; Department of Cardiac Surgery, University Hospital Leipzig, Heart Center, Strümpellstraße 39, Leipzig, Germany. Electronic address: m.barten@uke.de.
authors.forename: Markus J
authors.initials: MJ
authors.lastname: Barten
authors.affiliation: Department of Cardiothoracic Surgery, University Hospital Regensburg, Franz-Josef-Strauß-Allee 11, 93053 Regensburg, Germany. Electronic address: Stephan.Hirt@klinik.uni-regensburg.de.
authors.forename: Stephan W
authors.initials: SW
authors.lastname: Hirt
authors.affiliation: Department of Cardiology, University Hospital Heidelberg, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany. Electronic address: Andreas.Doesch@med.uni-heidelberg.de.
authors.forename: Andreas O
authors.initials: AO
authors.lastname: Doesch
authors.affiliation: Department of Cardiovascular and Thoracic Surgery, German Heart Institute Berlin, Augustenburger Platz 1, 13353 Berlin, Germany. Electronic address: knosalla@dhzb.de.
authors.forename: Christoph
authors.initials: C
authors.lastname: Knosalla
authors.affiliation: Department of Cardiac Surgery, Munich Transplantation Center, Klinikum Großhadern LMU, Marchioninistraße 15, 81377 Munich, Germany. Electronic address: Carola.Grinninger@med.uni-muenchen.de.
authors.forename: Carola
authors.initials: C
authors.lastname: Grinninger
authors.affiliation: Department of Cardiovascular Medicine, Division of Cardiology, University Hospital Münster, Albert-Schweitzer-Straße 33, 48149 Münster, Germany. Electronic address: stypmann@ukmuenster.de.
authors.forename: Jörg
authors.initials: J
authors.lastname: Stypmann
authors.affiliation: Department of Cardiac Surgery, University Hospital Leipzig, Heart Center, Strümpellstraße 39, Leipzig, Germany. Electronic address: Jens.Garbade@herzzentrum-leipzig.de.
authors.forename: Jens
authors.initials: J
authors.lastname: Garbade
authors.affiliation: Novartis Pharma GmbH, Roonstraße 25, 90429 Nuremberg, Germany. Electronic address: peter.wimmer@novartis.com.
authors.forename: Peter
authors.initials: P
authors.lastname: Wimmer
authors.affiliation: Novartis Pharma GmbH, Roonstraße 25, 90429 Nuremberg, Germany. Electronic address: christoph.may@novartis.com.
authors.forename: Christoph
authors.initials: C
authors.lastname: May
authors.affiliation: Novartis Pharma GmbH, Roonstraße 25, 90429 Nuremberg, Germany. Electronic address: martina.porstner@novartis.com.
authors.forename: Martina
authors.initials: M
authors.lastname: Porstner
authors.affiliation: Department of Thoracic and Cardiovascular Surgery, Heart and Diabetes Center NRW, Ruhr University Bochum, Georgstrasse 11, 32545 Bad Oeynhausen, Germany. Electronic address: uschulz@hdz-nrw.de.
authors.forename: Uwe
authors.initials: U
authors.lastname: Schulz
mesh_terms: D000305:Adrenal Cortex Hormones / Q000008:administration & dosage; D065095:Calcineurin Inhibitors / Q000008:administration & dosage / Q000009:adverse effects; D003586:Cytomegalovirus Infections / Q000453:epidemiology; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D000068338:Everolimus / Q000008:administration & dosage / Q000627:therapeutic use*; D006084:Graft Rejection / Q000517:prevention & control; D016027:Heart Transplantation / Q000379:methods*; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D007674:Kidney Diseases / Q000139:chemically induced; D009173:Mycophenolic Acid / Q000008:administration & dosage / Q000627:therapeutic use*; D012107:Research Design
chemical_list: D000305:Adrenal Cortex Hormones; D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D000068338:Everolimus; D009173:Mycophenolic Acid
keywords: Everolimus; Heart; MANDELA; Randomized; Transplantation