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Open Access Study protocol

A multicenter, randomized, open-labeled study to steer immunosuppressive and antiviral therapy by measurement of virus (CMV, ADV, HSV)-specific T cells in addition to determination of trough levels of immunosuppressants in pediatric kidney allograft recipients (IVIST01-trial): study protocol for a randomized controlled trial

Thurid Ahlenstiel-Grunow12, Armin Koch23, Anika Großhennig23, Cornelia Frömke234, Martina Sester5, Urban Sester6, Christoph Schröder27 and Lars Pape12*

Author Affiliations

1 Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Carl-Neuberg-Straße 1, D-30625 Hannover, Germany

2 Integrated Research and Treatment Center Transplantation (IFB-Tx), Hannover Medical School, Carl-Neuberg-Straße 1, D-30625 Hannover, Germany

3 Department of Biostatistics, Hannover Medical School, Carl-Neuberg-Straße 1, D-30625 Hannover, Germany

4 Insitute for Biometry, Empidemiology and Information processing, University of Veterinary Medicine Hannover, Bünteweg 2, D-30559 Hannover, Germany

5 Department of Transplant and Infection Immunology, Saarland University, Kirrberger Straße Geb. 57, D_ 66421 Homburg/Saar, Germany

6 Department of Nephrology and Hypertension, Saarland University, Kirrberger Straße Geb. 57, D_ 66421 Homburg/Saar, Germany

7 Institute for Clinical Pharmacology, Hannover Medical School, Carl-Neuberg-Straße 1, D-30625, Hannover, Germany

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Trials 2014, 15:324  doi:10.1186/1745-6215-15-324

Published: 15 August 2014

Abstract

Background

After kidney transplantation, immunosuppressive therapy causes impaired cellular immune defense leading to an increased risk of viral complications. Trough level monitoring of immunosuppressants is insufficient to estimate the individual intensity of immunosuppression. We have already shown that virus-specific T cells (Tvis) correlate with control of virus replication as well as with the intensity of immunosuppression. The multicentre IVIST01-trial should prove that additional steering of immunosuppressive and antiviral therapy by Tvis levels leads to better graft function by avoidance of over-immunosuppression (for example, viral infections) and drug toxicity (for example, nephrotoxicity).

Methods/design

The IVIST-trial starts 4 weeks after transplantation. Sixty-four pediatric kidney recipients are randomized either to a non-intervention group that is only treated conservatively or to an intervention group with additional monitoring by Tvis. The randomization is stratified by centre and cytomegalovirus (CMV) prophylaxis. In both groups the immunosuppressive medication (cyclosporine A and everolimus) is adopted in the same target range of trough levels. In the non-intervention group the immunosuppressive therapy (cyclosporine A and everolimus) is only steered by classical trough level monitoring and the antiviral therapy of a CMV infection is performed according to a standard protocol. In contrast, in the intervention group the dose of immunosuppressants is individually adopted according to Tvis levels as a direct measure of the intensity of immunosuppression in addition to classical trough level monitoring. In case of CMV infection or reactivation the antiviral management is based on the individual CMV-specific immune defense assessed by the CMV-Tvis level. Primary endpoint of the study is the glomerular filtration rate 2 years after transplantation; secondary endpoints are the number and severity of viral infections and the incidence of side effects of immunosuppressive and antiviral drugs.

Discussion

This IVIST01-trial will answer the question whether the new concept of steering immunosuppressive and antiviral therapy by Tvis levels leads to better future graft function. In terms of an effect-related drug monitoring, the study design aims to realize a personalization of immunosuppressive and antiviral management after transplantation. Based on the IVIST01-trial, immunomonitoring by Tvis might be incorporated into routine care after kidney transplantation.

Trial Registration

EudraCT No: 2009-012436-32, ISRCTN89806912 (17 June 2009).

Keywords:
Kidney transplantation; Immunosuppression; Virus-specific T cells; Personalized immunosuppressive therapy; Viral infections; Pediatric transplantation; Cytomegalovirus; Antiviral therapy; Over-immunosuppression; Immunomonitoring; Drug-monitoring