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Everolimus plus early tacrolimus minimization: a phase III, randomized, open-label, multicentre trial in renal transplantation

  1. Robert M Langer1,
  2. Ronald Hené2,
  3. Stefan Vitko3,
  4. Maarten Christiaans4,
  5. Helio Tedesco-Silva Jr5,
  6. Kazimierz Ciechanowski6,
  7. Elisabeth Cassuto7,
  8. Lionel Rostaing8,
  9. Mario Vilatoba9,
  10. Uwe Machein10,
  11. Bettina Ulbricht10,
  12. Guido Junge10,
  13. Gaohong Dong11,
  14. Julio Pascual12

Article first published online: 26 MAR 2012

DOI: 10.1111/j.1432-2277.2012.01465.x

Issue

Transplant International

Transplant International

Volume 25, Issue 5, pages 592–602, May 2012

Additional Information

How to Cite

Langer, R. M., Hené, R., Vitko, S., Christiaans, M., Tedesco-Silva, H., Ciechanowski, K., Cassuto, E., Rostaing, L., Vilatoba, M., Machein, U., Ulbricht, B., Junge, G., Dong, G. and Pascual, J. (2012), Everolimus plus early tacrolimus minimization: a phase III, randomized, open-label, multicentre trial in renal transplantation. Transplant International, 25: 592–602. doi: 10.1111/j.1432-2277.2012.01465.x

Author Information

  1. 1

     Department of Transplantation and Surgery, Semmelweis University, Budapest, Hungary

  2. 2

     Department of Nephrology, University Medical Centre, Utrecht, The Netherlands

  3. 3

     Institute of Clinical and Experimental Medicine, Transplant Centre, Prague, Czech Republic

  4. 4

     Division of Nephrology, Department of Internal Medicine, Academisch Ziekenhuis Maastricht, Maastricht, The Netherlands

  5. 5

     Division of Nephrology, Hospital do Rim e Hipertensâo, São Paulo, Brazil

  6. 6

     Department of Nephrology, Transplantology and Internal Medicine, Szczecin, Poland

  7. 7

     Service de Néphrologie, Hôpital Pasteur, CHU Nice, France

  8. 8

     Department of Nephrology-Dialysis-Organ Transplantation, Hôpital Rangueil, Toulouse, France

  9. 9

     Departamento de Trasplantes, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico

  10. 10

     Novartis Pharma AG, Basel, Switzerland

  11. 11

     Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA

  12. 12

     Servicio de Nefrología, Hospital del Mar, Barcelona, Spain

*Dr Robert M Langer, Department of Transplantation and Surgery, Semmelweis University, Baross u. 23. H-1082, Budapest, Hungary. Tel.: +36-20-825-8639; fax: +36-1-317-2166; e-mail: roblanger@hotmail.com

  1. Conflicts of Interest The authors of this manuscript have no conflicts of interest to disclose.

Publication History

  1. Issue published online: 4 APR 2012
  2. Article first published online: 26 MAR 2012
  3. Received: 28 October 2011 Revision requested: 21 November 2011 Accepted: 22 February 2012

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Keywords:

  • calcineurin inhibitor minimization;
  • everolimus;
  • mammalian target of rapamycin inhibitor;
  • proliferation signal inhibitors;
  • tacrolimus

Summary

There is increasing interest in tacrolimus-minimization regimens. ASSET was an open-label, randomized, 12-month study of everolimus plus tacrolimus in de-novo renal-transplant recipients. Everolimus trough targets were 3–8 ng/ml throughout the study. Tacrolimus trough targets were 4–7 ng/ml during the first 3 months and 1.5–3 ng/ml (n = 107) or 4–7 ng/ml (n = 117) from Month 4. All patients received basiliximab induction and corticosteroids. The primary objective was to demonstrate superior estimated glomerular filtration rate (eGFR; MDRD-4) at Month 12 in the tacrolimus 1.5–3 ng/ml versus the 4–7 ng/ml group. Secondary endpoints included incidence of biopsy-proven acute rejection (BPAR; Months 4–12) and serious adverse events (SAEs; Months 0–12). Statistical significance was not achieved for the primary endpoint (mean eGFR: 57.1 vs. 51.7 ml/min/1.73 m2), potentially due to overlapping of achieved tacrolimus exposure levels (Month 12 mean ± SD, tacrolimus 1.5–3 ng/ml: 3.4 ± 1.4; tacrolimus 4–7 ng/ml: 5.5 ± 2.0 ng/ml). BPAR (months 4–12) and SAE rates were comparable between groups (2.7% vs. 1.1% and 58.7% vs. 51.3%; respectively). Everolimus-facilitated tacrolimus minimization, to levels lower than previously investigated, achieved good renal function, low BPAR and graft-loss rates, and an acceptable safety profile in renal transplantation over 12 months although statistically superior renal function of the 1.5–3 ng/ml tacrolimus group was not achieved. (ClinicalTrials.gov: NCT00369161) is registered at http://www.clinicaltrials.gov.

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