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Safety of Everolimus With Reduced Calcineurin Inhibitor Exposure in De Novo Kidney Transplants: An Analysis From the Randomized TRANSFORM Study
H. Tedesco-Silva, J. Pascual, O. Viklicky, N. Basic-Jukic, E. Cassuto, DY. Kim, JM. Cruzado, C. Sommerer, M. Adel Bakr, VD. Garcia, HD. Uyen, G. Russ, M. Soo Kim, D. Kuypers, M. Buchler, F. Citterio, MP. Hernandez Gutierrez, P. Bernhardt, S....
Language English Country United States
Document type Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't
- MeSH
- Time Factors MeSH
- Cyclosporine administration & dosage adverse effects MeSH
- Adult MeSH
- Everolimus administration & dosage adverse effects MeSH
- Immunosuppressive Agents administration & dosage adverse effects MeSH
- Calcineurin Inhibitors administration & dosage adverse effects MeSH
- Drug Therapy, Combination MeSH
- Mycophenolic Acid administration & dosage MeSH
- Middle Aged MeSH
- Humans MeSH
- Graft Survival drug effects MeSH
- Graft Rejection immunology mortality prevention & control MeSH
- Risk Factors MeSH
- Tacrolimus administration & dosage adverse effects MeSH
- Kidney Transplantation * adverse effects mortality MeSH
- Treatment Outcome MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Publication type
- Journal Article MeSH
- Multicenter Study MeSH
- Research Support, Non-U.S. Gov't MeSH
- Randomized Controlled Trial MeSH
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.
Department of Nephrology and Hypertension Inselspital Bern Bern Switzerland
Department of Nephrology and Renal Transplantation CHRU de Tours Hôpital Bretonneau Tours France
Department of Nephrology and Renal Transplantation Hôpital Pasteur Nice France
Department of Nephrology Heidelberg University Hospital Heidelberg Germany
Department of Nephrology Hospital del Mar Barcelona Spain
Department of Nephrology Hospital Universitari de Bellvitge Barcelona Spain
Department of Renal Medicine Royal Prince Alfred Hospital University of Sydney Sydney Australia
Department of Renal Transplantation Santa Casa de Misericórdia de Porto Alegre Porto Alegre Brazil
Division of Nephrology Hospital do Rim Universidade Federal de São Paulo São Paulo Brazil
Division of Transplant and Hepatobiliary Surgery Henry Ford Hospital Detroit MI
Mansoura Urology and Nephrology Center Mansoura Egypt
Policlinico Foundation A Gemelli University IRCCS Catholic University of the Sacred Heart Rome Italy
Research and Development Novartis Pharma AG Basel Switzerland
References provided by Crossref.org
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- $a 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.
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