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Safety of Everolimus With Reduced Calcineurin Inhibitor Exposure in De Novo Kidney Transplants

An Analysis From the Randomized TRANSFORM Study

Tedesco-Silva, Helio MD1; Pascual, Julio MD2; Viklicky, Ondrej MD3; Basic-Jukic, Nikolina MD4; Cassuto, Elisabeth MD5; Kim, Dean Y. MD6; Cruzado, Josep M. MD7; Sommerer, Claudia MD8; Adel Bakr, Mohamed MD9; Garcia, Valter D. MD10; Uyen, Huynh-Do MD11; Russ, Graeme MD12; Soo Kim, Myoung MD13; Kuypers, Dirk MD14,15; Buchler, Matthias MD16; Citterio, Franco MD17; Hernandez Gutierrez, Maria Pilar MSc18; Bernhardt, Peter PhD18; Chadban, Steve MD19 on behalf of the TRANSFORM Investigators

doi: 10.1097/TP.0000000000002626
Original Clinical Science—General
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Background. The safety profiles of standard therapy versus everolimus with reduced-exposure calcineurin inhibitor (CNI) therapy using contemporary protocols in de novo kidney transplant recipients have not been compared in detail.

Methods. TRANSFORM was a randomized, international trial in which de novo kidney transplant patients were randomized to everolimus with reduced-exposure CNI (N = 1014) or mycophenolic acid (MPA) with standard-exposure CNI (N = 1012), both with induction and corticosteroids.

Results. Within the safety population (everolimus 1014, MPA 1012), adverse events with a suspected relation to study drug occurred in 62.9% versus 59.2% of patients given everolimus or MPA, respectively (P = 0.085). Hyperlipidemia, interstitial lung disease, peripheral edema, proteinuria, stomatitis/mouth ulceration, thrombocytopenia, and wound healing complications were more frequent with everolimus, whereas diarrhea, nausea, vomiting, leukopenia, tremor, and insomnia were more frequent in the MPA group. The incidence of viral infections (17.2% versus 29.2%; P < 0.001), cytomegalovirus (CMV) infections (8.1% versus 20.1%; P < 0.001), CMV syndrome (13.6% versus 23.0%, P = 0.044), and BK virus (BKV) infections (4.3% versus 8.0%, P < 0.001) were less frequent with everolimus. CMV infection was less common with everolimus versus MPA after adjusting for prophylaxis therapy in the D+/R− subgroup (P < 0.001). Study drug was discontinued more frequently due to rejection or impaired healing with everolimus, and more often due to BKV infection or BKV nephropathy with MPA.

Conclusions. De novo everolimus with reduced-exposure CNI yielded a comparable incidence, though a distinctly different pattern, of adverse events versus current standard of care. Both regimens are safe and effective, yet their distinct profiles may enable tailoring for individual kidney transplant recipients.

1 Division of Nephrology, Hospital do Rim, Universidade Federal de São Paulo, São Paulo, Brazil.

2 Department of Nephrology, Hospital del Mar, Barcelona, Spain.

3 Department of Nephrology, Transplant Centre, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.

4 Department of Nephrology, Arterial Hypertension, Dialysis and Transplantation, University Hospital Centre Zagreb, School of Medicine, University of Zagreb, Zagreb, Croatia.

5 Department of Nephrology and Renal Transplantation, Hôpital Pasteur, Nice, France.

6 Division of Transplant and Hepatobiliary Surgery, Henry Ford Hospital, Detroit, MI.

7 Department of Nephrology, Hospital Universitari de Bellvitge, Barcelona, Spain.

8 Department of Nephrology, Heidelberg University Hospital, Heidelberg, Germany.

9 Mansoura Urology and Nephrology Center, Mansoura, Egypt.

10 Department of Renal Transplantation, Santa Casa de Misericórdia de Porto Alegre, Porto Alegre, Brazil.

11 Department of Nephrology and Hypertension, Inselspital Bern, Bern, Switzerland.

12 Central and Northern Adelaide Renal and Transplantation Services, Royal Adelaide Hospital, Adelaide, Australia.

13 Department of Transplantation Surgery, Severance Hospital Yonsei University Health System, Seoul, Republic of Korea.

14 Department of Nephrology and Renal Transplantation, Gasthuisberg University Hospital, University of Leuven, Leuven, Belgium.

15 Department of Microbiology and Immunology, University of Leuven, Leuven, Belgium.

16 Department of Nephrology and Renal Transplantation, CHRU de Tours, Hôpital Bretonneau, Tours, France.

17 Policlinico Foundation, A Gemelli University, IRCCS, Catholic University of the Sacred Heart, Rome, Italy.

18 Research and Development, Novartis Pharma AG, Basel, Switzerland.

19 Department of Renal Medicine, Royal Prince Alfred Hospital, University of Sydney, Sydney, Australia.

Received 1 October 2018. Revision received 2 January 2019.

Accepted 5 January 2019.

H.T.-S. and J.P. are joint lead authors.

* The list of TRANSFORM Investigators is given in Appendix 1.

The TRANSFORM study was funded by Novartis Pharma AG, Basel, Switzerland. Medical writing support was funded by Novartis.

H.T-S. has received consulting honoraria and travel grants from Novartis, Pfizer, BMS, and Roche, and his institution has received research grants from Novartis, Pfizer, BMS, Roche, Veloxis, and Teraclone. J.P. has received consulting honoraria from Novartis and Chiesi, travel grants from Novartis and Chiesi, and his institution has received research grants from Novartis, Astellas, Chiesi, and Amgen. O.V. has received consulting honoraria from Alexion, Chiesi, travel grants from Sanofi, and his institution has received research grants from Novartis, Alexion, and Teva. N.B-J. has received honoraria from Novartis, Astellas, Chiesi, Roche, Amgen, Abbvie, Fresenius Medical Care, and Teva. E.C. has received travel grants from Novartis, Roche, Astellas, Chiesi, and Amgen. J.M.C. has received honoraria from Sandoz and Novartis and travel grants from Chiesi. The institution of C.S. has received research grants from Novartis and Astellas. V.D.G. has received consulting honoraria from Pfizer and travel grants from Pfizer and EMS. H-D.U. has received advisory board and speaker’s honoraria from Amgen, Astellas, Shire, and Vifor. G.R. has received honoraria from Astellas and Novartis. D.K. has received consulting and speaker’s honoraria from Astellas and Novartis, travel grants from Astellas and Novartis, and research grants from Astellas. M.B. has received travel grants from Novartis. F.C. has received consulting honoraria and travel grants from Novartis, Astellas, Pfizer, and Bristol Myers Squibb. M.P.H.G. and P.B. are employees of Novartis. S.C. has received institutional research funding, travel support, or consulting honoraria from Novartis, Astellas, and Alexion. D.Y.K., M.A.B., and M.S.K. declare no conflicts of interest.

All authors except P.B. and M.P.H.G. recruited patients and collected data. M.P.H.G. provided statistical support. P.B. provided medical input. All authors critically reviewed the manuscript and approved the final version for publication.

Supplemental digital content (SDC) is available for this article. Direct URL citations appear in the printed text, and links to the digital files are provided in the HTML text of this article on the journal’s Web site (www.transplantjournal.com).

Correspondence: Helio Tedesco-Silva, MD, Division of Nephrology, Hospital do Rim e da Hipertensao, Sao Paulo 04038-002, Brazil. (heliotedesco@medfarm.com.br).

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