Everolimus with Reduced Calcineurin Inhibitor Exposure in Renal Transplantation
Julio Pascual, Stefan P Berger, Oliver Witzke, Helio Tedesco, Shamkant Mulgaonkar, Yasir Qazi, Steven Chadban, Federico Oppenheimer, Claudia Sommerer, Rainer Oberbauer, Yoshihiko Watarai, Christophe Legendre, Franco Citterio, Mitchell Henry, Titte R Srinivas, Wen-Lin Luo, AnaMaria Marti, Peter Bernhardt, Flavio Vincenti, TRANSFORM Investigators, Alan Jardine, Tim Friede, Rafael Maldonado, Pablo Massari, Silvina Aleman, Silvia Maurich, Luis E Gaite, Pablo Raffaele, Nora Imperiali, Scott Campbell, Steven Chadban, Peter Hughes, Ashley Irish, John Kanellis, Wai Lim, Philip J O'Connell, Graeme Russ, Zoltan Endre, Peter Mount, Paul Hengster, Peter Neudorfer, Rainer Oberbauer, Johann Pratschke, Dirk Kuypers, Jean-Louis Bosmans, Emine N Broeders, Laurent Weekers, Helio Tedesco Silva Jr, Elias D Neto, Valter D Garcia, Emil P Dimitrov, Alvaro Kompatzki, Carlos Benavides, Johanna Schweineberg, Nikolina Basic Jukic, Mladen Knotek, Sanjin Racki, Ondrej Viklicky, M A Bakr, Christophe Legendre, Elisabeth Cassuto, Vincent Pernin, Vincent Vuiblet, Mathias Buchler, Claudia Sommerer, Peter Weithofer, Thomas Rath, Oliver Witzke, Markus van der Giet, Wolfgang Arns, Lutz Renders, Antje Habicht, Daniel Seehofer, Bernhard Banas, Frank Lehner, Johann Pratschke, Ioannis Boletis, Dimitrios Goumenos, Vasileios Papanikolaou, Spyros Drakopoulos, Dinesh Khullar, Veerbhadra Guptha, Shibu Jacob, Alan Fernandes Almeida, Eytan Mor, Richard Nakache, Mario Carmellini, Paolo Rigotti, Giacomo Colussi, Giuseppe Tisone, Paola Todeschini, Luigi Biancone, Franco Citterio, Vincenzo Cantaluppi, Loreto Gesualdo, Umberto Maggiore, Yoshihiko Watarai, Naotake Akutsu, Takashi Kenmochi, Duck Jong Han, Myoung Soo Kim, Sung Joo Kim, Torki AlOtaibi, Dania Chelala, Hilal Abou Zeinab, Khalil Jaber, Ghazali Ahmad Kutty, Hin Seng Wong, Francisco Javier Monteon Ramos, J W de Fijter, Stefan P Berger, F J Bemelman, A D van Zuilen, L Hilbrands, M H L Christiaans, Anders Hartmann, Romina Danguilan, Angel Joaquin Amante, Kazimierz Ciechanowski, Maciej Glyda, Marek Karczewski, Alicja Debska-Slizien, Fernando Nolasco, Jose Guerra, Joana Santos, Patricia Joao Matias, Arnaldo Figueiredo, Yan G Moysyuk, Aleksey V Pinchuk, Ilya V Aleksandrov, Vladimir E Zagainov, Elena I Boretskaya, Vladimir L Medvedev, Ashraf Attia, Wael Habhab, Meteb Bugami, Neven Vavic, Igor Mitic, Goran Paunovic, Terence Kee, Tatiana Baltesova, Eva Lackova, Zuzana Zilinska, Ivana Dedinska, Miha Arnol, Elmi Muller, Julio Pascual, Federico Oppenheimer, Asuncion Sancho, Alex Gutierrez Dalmau, Domingo Marrero, Josep M Cruzado, Amado Andres Belmonte, Juan Carlos Ruiz San Millan, Antonio Osuna, Ana Fernandez, Lars Wennberg, Bengt von Zur Muhlen, Bengt Gustafsson, Uyen Huynh-Do, Meng-Kun Tsai, Ming Ju Wu, Tsung Ching Chou, Prajej Ruangkanchanasetr, Sakarn Bunnag, Atiporn Ingsathit, Aydin Turmen, Ahmet V Celik, Huseyin Kocak, Alexander Wiseman, Phillippe Gauthier, Fuad Shihab, Stevenson Bynon, Bernard Fischbach, Goran B Klintmalm, Richard Knight, Kenneth L Brayman, Jason Wellen, Stanley J Jordan, Yasir Qazi, Ronald Cotton, Venkat Peddi, David Leeser, Mohamed E Akoad, Shamkant Mulgaonkar, Martha Pavlakis, Reginald Gohh, Charles Bratton, Nahel Elias, Debra Sudan, Mary Waybill, Johnny Hong, Silas Norman, Ivo Tzvetanov, Dean Kim, Mitchell Henry, Jeffrey Rogers, Chandrasekar Santhanakrishnan, Nicolae Leca, Tomasz Kozlowski, Flavio Vincenti, Enver Akalin, Clifton E Kew, David Shaffer, Liise K Kayler, Steven Steinberg, Stuart M Flechner, Donald Hricik, Michael de Vera, Didier Mandelbrot, Julio Pascual, Stefan P Berger, Oliver Witzke, Helio Tedesco, Shamkant Mulgaonkar, Yasir Qazi, Steven Chadban, Federico Oppenheimer, Claudia Sommerer, Rainer Oberbauer, Yoshihiko Watarai, Christophe Legendre, Franco Citterio, Mitchell Henry, Titte R Srinivas, Wen-Lin Luo, AnaMaria Marti, Peter Bernhardt, Flavio Vincenti, TRANSFORM Investigators, Alan Jardine, Tim Friede, Rafael Maldonado, Pablo Massari, Silvina Aleman, Silvia Maurich, Luis E Gaite, Pablo Raffaele, Nora Imperiali, Scott Campbell, Steven Chadban, Peter Hughes, Ashley Irish, John Kanellis, Wai Lim, Philip J O'Connell, Graeme Russ, Zoltan Endre, Peter Mount, Paul Hengster, Peter Neudorfer, Rainer Oberbauer, Johann Pratschke, Dirk Kuypers, Jean-Louis Bosmans, Emine N Broeders, Laurent Weekers, Helio Tedesco Silva Jr, Elias D Neto, Valter D Garcia, Emil P Dimitrov, Alvaro Kompatzki, Carlos Benavides, Johanna Schweineberg, Nikolina Basic Jukic, Mladen Knotek, Sanjin Racki, Ondrej Viklicky, M A Bakr, Christophe Legendre, Elisabeth Cassuto, Vincent Pernin, Vincent Vuiblet, Mathias Buchler, Claudia Sommerer, Peter Weithofer, Thomas Rath, Oliver Witzke, Markus van der Giet, Wolfgang Arns, Lutz Renders, Antje Habicht, Daniel Seehofer, Bernhard Banas, Frank Lehner, Johann Pratschke, Ioannis Boletis, Dimitrios Goumenos, Vasileios Papanikolaou, Spyros Drakopoulos, Dinesh Khullar, Veerbhadra Guptha, Shibu Jacob, Alan Fernandes Almeida, Eytan Mor, Richard Nakache, Mario Carmellini, Paolo Rigotti, Giacomo Colussi, Giuseppe Tisone, Paola Todeschini, Luigi Biancone, Franco Citterio, Vincenzo Cantaluppi, Loreto Gesualdo, Umberto Maggiore, Yoshihiko Watarai, Naotake Akutsu, Takashi Kenmochi, Duck Jong Han, Myoung Soo Kim, Sung Joo Kim, Torki AlOtaibi, Dania Chelala, Hilal Abou Zeinab, Khalil Jaber, Ghazali Ahmad Kutty, Hin Seng Wong, Francisco Javier Monteon Ramos, J W de Fijter, Stefan P Berger, F J Bemelman, A D van Zuilen, L Hilbrands, M H L Christiaans, Anders Hartmann, Romina Danguilan, Angel Joaquin Amante, Kazimierz Ciechanowski, Maciej Glyda, Marek Karczewski, Alicja Debska-Slizien, Fernando Nolasco, Jose Guerra, Joana Santos, Patricia Joao Matias, Arnaldo Figueiredo, Yan G Moysyuk, Aleksey V Pinchuk, Ilya V Aleksandrov, Vladimir E Zagainov, Elena I Boretskaya, Vladimir L Medvedev, Ashraf Attia, Wael Habhab, Meteb Bugami, Neven Vavic, Igor Mitic, Goran Paunovic, Terence Kee, Tatiana Baltesova, Eva Lackova, Zuzana Zilinska, Ivana Dedinska, Miha Arnol, Elmi Muller, Julio Pascual, Federico Oppenheimer, Asuncion Sancho, Alex Gutierrez Dalmau, Domingo Marrero, Josep M Cruzado, Amado Andres Belmonte, Juan Carlos Ruiz San Millan, Antonio Osuna, Ana Fernandez, Lars Wennberg, Bengt von Zur Muhlen, Bengt Gustafsson, Uyen Huynh-Do, Meng-Kun Tsai, Ming Ju Wu, Tsung Ching Chou, Prajej Ruangkanchanasetr, Sakarn Bunnag, Atiporn Ingsathit, Aydin Turmen, Ahmet V Celik, Huseyin Kocak, Alexander Wiseman, Phillippe Gauthier, Fuad Shihab, Stevenson Bynon, Bernard Fischbach, Goran B Klintmalm, Richard Knight, Kenneth L Brayman, Jason Wellen, Stanley J Jordan, Yasir Qazi, Ronald Cotton, Venkat Peddi, David Leeser, Mohamed E Akoad, Shamkant Mulgaonkar, Martha Pavlakis, Reginald Gohh, Charles Bratton, Nahel Elias, Debra Sudan, Mary Waybill, Johnny Hong, Silas Norman, Ivo Tzvetanov, Dean Kim, Mitchell Henry, Jeffrey Rogers, Chandrasekar Santhanakrishnan, Nicolae Leca, Tomasz Kozlowski, Flavio Vincenti, Enver Akalin, Clifton E Kew, David Shaffer, Liise K Kayler, Steven Steinberg, Stuart M Flechner, Donald Hricik, Michael de Vera, Didier Mandelbrot
Abstract
Background Everolimus permits reduced calcineurin inhibitor (CNI) exposure, but the efficacy and safety outcomes of this treatment after kidney transplant require confirmation.Methods In a multicenter noninferiority trial, we randomized 2037 de novo kidney transplant recipients to receive, in combination with induction therapy and corticosteroids, everolimus with reduced-exposure CNI (everolimus arm) or mycophenolic acid (MPA) with standard-exposure CNI (MPA arm). The primary end point was treated biopsy-proven acute rejection or eGFR<50 ml/min per 1.73 m2 at post-transplant month 12 using a 10% noninferiority margin.Results In the intent-to-treat population (everolimus n=1022, MPA n=1015), the primary end point incidence was 48.2% (493) with everolimus and 45.1% (457) with MPA (difference 3.2%; 95% confidence interval, -1.3% to 7.6%). Similar between-treatment differences in incidence were observed in the subgroups of patients who received tacrolimus or cyclosporine. Treated biopsy-proven acute rejection, graft loss, or death at post-transplant month 12 occurred in 14.9% and 12.5% of patients treated with everolimus and MPA, respectively (difference 2.3%; 95% confidence interval, -1.7% to 6.4%). De novo donor-specific antibody incidence at 12 months and antibody-mediated rejection rate did not differ between arms. Cytomegalovirus (3.6% versus 13.3%) and BK virus infections (4.3% versus 8.0%) were less frequent in the everolimus arm than in the MPA arm. Overall, 23.0% and 11.9% of patients treated with everolimus and MPA, respectively, discontinued the study drug because of adverse events.Conclusions In kidney transplant recipients at mild-to-moderate immunologic risk, everolimus was noninferior to MPA for a binary composite end point assessing immunosuppressive efficacy and preservation of graft function.
Trial registration: ClinicalTrials.gov NCT01950819.
Keywords: calcineurin inhibitor; efficacy graft; everolimus; function; kidney transplantation; randomized.
Copyright © 2018 by the American Society of Nephrology.
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Source: PubMed