Impact of Immunosuppressive Regimens on Polyomavirus-related Transplant Nephropathy

NCT ID: NCT00160966

Last Updated: 2017-03-28

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE4

Total Enrollment

108 participants

Study Classification

INTERVENTIONAL

Study Start Date

2004-09-30

Study Completion Date

2010-03-31

Brief Summary

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The aim of this study is to characterize and evaluate risk factors of polyomavirus nephropathy (PVN) including the impact of three immunosuppressive regimens.

Detailed Description

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Polyomavirus nephropathy (PVN) is an emerging cause of renal transplant loss. Until now the risk factors of PVN are poorly understood. Tacrolimus (Tacr) and mycophenolate mofetil (MMF) are thought to be associated with a higher risk of developing PVN. However, the way in which Tacr or MMF might enhance the susceptibility for PVN remains largely unknown. In this prospective study we will analyze whether differences in immune-reactivity patterns (Th1, Th2, B cell and monocyte responses, sCD30, immunoregulatory antibodies) of renal transplant patients induced by different immunosuppressive regimens (cyclosporine A \[CsA\]/MMF, Tacr/MMF, Tacr/MMF with conversion to Tacr/Everolimus \[ERL\]) or by cytokine promoter gene polymorphisms may account for the different risks of developing PVN.

Comparison(s): renal transplant recipients stratified according to their relative immunological risk (group 1: low risk (primary recipients without pre-immunization \[PRA \< 5%\]); group 2: moderate risk (group 2a: primary recipients with low pre-immunization \[PRA 6-20%\]; group 2b: re-transplanted patients); group 3: very high risk (re-transplanted patients with a history of vascular rejection or recipients of a first graft with high pre-immunization \[PRA \> 20%\]) randomized to be treated with one of three immunosuppressive regimens (CsA/MMF, Tacr/MMF, Tacr/MMF with subsequent conversion to Tacr/ERL).

Conditions

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Polyomavirus Infections

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

TREATMENT

Blinding Strategy

NONE

Study Groups

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1

Immunosuppression with Ciclosporin and Mycophenolate-mofetil; Ciclosporin treatment being started at the latest at day 4 after transplantation with 7 mg/kg body weight daily administered every 8 hours until the target trough level of 300 µg/l was reached. Then it was administered twice daily with daily monitoring of trough levels. The target trough level was lowered to 200 µg/l 1 month after transplantation. Thereafter dosage and target trough levels were adjusted at the investigators discretion. Mycophenolate-mofetil was started previous to transplantation procedure with a starting dosage of 3 g/day administered twice daily. Once ciclosporin was entered into the therapy-scheme Mycophenolate-mofetil dosage was reduced to 2 g/daily. The therapy was controlled by measuring of trough levels with a target trough level exceeding 1 µg/ml. The dosage was adjusted at the investigators discretion.

Group Type ACTIVE_COMPARATOR

Ciclosporin and Mycophenolate-mofetil

Intervention Type DRUG

according to the Giessen protocol

2

Immunosuppression with Tacrolimus and Mycophenolate-mofetil Mycophenolate-mofetil was started previous to transplantation procedure with a starting dosage of 3 g/day administered twice daily. Once tacrolimus was entered into the therapy-scheme Mycophenolate-mofetil dosage was reduced to 2 g/daily. The therapy was controlled by measuring of trough levels with a target trough level exceeding 1 µg/ml. The dosage was adjusted to clinical signs of overimmunosuppression (infections) or intolerance (mainly gastrointestinal side effects) or rejections.

Group Type ACTIVE_COMPARATOR

Tacrolimus and Mycophenolate-mofetil

Intervention Type DRUG

according to Giessen protocol

3

Immunosuppression with Tacrolimus and Mycophenolate-mofetil with change from Mycophenolate-mofetil to Everolimus after completion of posttransplant wound healing

Group Type ACTIVE_COMPARATOR

Tacrolimus and Mycophenolate-mofetil with change from Mycophenolate-mofetil to Everolimus

Intervention Type DRUG

according to Giessen protocol

Interventions

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Ciclosporin and Mycophenolate-mofetil

according to the Giessen protocol

Intervention Type DRUG

Tacrolimus and Mycophenolate-mofetil

according to Giessen protocol

Intervention Type DRUG

Tacrolimus and Mycophenolate-mofetil with change from Mycophenolate-mofetil to Everolimus

according to Giessen protocol

Intervention Type DRUG

Eligibility Criteria

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Inclusion Criteria

* Cadaver kidney and living donor kidney transplant recipients
* Primary, secondary, and tertiary transplant recipients
* Pre-immunized and not pre-immunized transplant recipients
* Age \> 18 years

Exclusion Criteria

* Contraindications against administration of one of the four study drugs
* History of severe gastrointestinal morbidity
* Age \< 18 years
* Pregnant or breast feeding women
* Rejection of effective contraceptive methods with young women
* Combined kidney and islet cell transplantation
Minimum Eligible Age

18 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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Heidelberg University

OTHER

Sponsor Role collaborator

Hoffmann-La Roche

INDUSTRY

Sponsor Role collaborator

Astellas Pharma Inc

INDUSTRY

Sponsor Role collaborator

Novartis

INDUSTRY

Sponsor Role collaborator

University of Giessen

OTHER

Sponsor Role lead

Responsible Party

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Prof. Dr. Rolf Weimer

Prof. Dr.

Responsibility Role PRINCIPAL_INVESTIGATOR

Principal Investigators

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Rolf Weimer, Prof., MD

Role: PRINCIPAL_INVESTIGATOR

University Giessen, Internal Medicine

Locations

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Department of Internal Medicine, University of Giessen

Giessen, , Germany

Site Status

Countries

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Germany

References

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Andrews CA, Shah KV, Daniel RW, Hirsch MS, Rubin RH. A serological investigation of BK virus and JC virus infections in recipients of renal allografts. J Infect Dis. 1988 Jul;158(1):176-81. doi: 10.1093/infdis/158.1.176.

Reference Type BACKGROUND
PMID: 2839580 (View on PubMed)

Barri YM, Ahmad I, Ketel BL, Barone GW, Walker PD, Bonsib SM, Abul-Ezz SR. Polyoma viral infection in renal transplantation: the role of immunosuppressive therapy. Clin Transplant. 2001 Aug;15(4):240-6. doi: 10.1034/j.1399-0012.2001.150404.x.

Reference Type BACKGROUND
PMID: 11683817 (View on PubMed)

Nickeleit V, Hirsch HH, Zeiler M, Gudat F, Prince O, Thiel G, Mihatsch MJ. BK-virus nephropathy in renal transplants-tubular necrosis, MHC-class II expression and rejection in a puzzling game. Nephrol Dial Transplant. 2000 Mar;15(3):324-32. doi: 10.1093/ndt/15.3.324.

Reference Type BACKGROUND
PMID: 10692517 (View on PubMed)

Hirsch HH, Knowles W, Dickenmann M, Passweg J, Klimkait T, Mihatsch MJ, Steiger J. Prospective study of polyomavirus type BK replication and nephropathy in renal-transplant recipients. N Engl J Med. 2002 Aug 15;347(7):488-96. doi: 10.1056/NEJMoa020439.

Reference Type BACKGROUND
PMID: 12181403 (View on PubMed)

Hirsch HH. Polyomavirus BK nephropathy: a (re-)emerging complication in renal transplantation. Am J Transplant. 2002 Jan;2(1):25-30. doi: 10.1034/j.1600-6143.2002.020106.x.

Reference Type BACKGROUND
PMID: 12095052 (View on PubMed)

Hirsch HH, Mohaupt M, Klimkait T. Prospective monitoring of BK virus load after discontinuing sirolimus treatment in a renal transplant patient with BK virus nephropathy. J Infect Dis. 2001 Dec 1;184(11):1494-5; author reply 1495-6. doi: 10.1086/324425. No abstract available.

Reference Type BACKGROUND
PMID: 11709797 (View on PubMed)

Binet I, Nickeleit V, Hirsch HH, Prince O, Dalquen P, Gudat F, Mihatsch MJ, Thiel G. Polyomavirus disease under new immunosuppressive drugs: a cause of renal graft dysfunction and graft loss. Transplantation. 1999 Mar 27;67(6):918-22. doi: 10.1097/00007890-199903270-00022.

Reference Type BACKGROUND
PMID: 10199744 (View on PubMed)

Weimer R, Susal C, Yildiz S, Streller S, Pelzl S, Staak A, Renner F, Dietrich H, Daniel V, Feuring E, Kamali-Ernst S, Ernst W, Padberg W, Opelz G. sCD30 and neopterin as risk factors of chronic renal transplant rejection: impact of cyclosporine A, tacrolimus, and mycophenolate mofetil. Transplant Proc. 2005 May;37(4):1776-8. doi: 10.1016/j.transproceed.2005.02.088.

Reference Type BACKGROUND
PMID: 15919463 (View on PubMed)

Weimer R, Staak A, Susal C, Streller S, Yildiz S, Pelzl S, Renner F, Dietrich H, Daniel V, Rainer L, Kamali-Ernst S, Ernst W, Padberg W, Opelz G. ATG induction therapy: long-term effects on Th1 but not on Th2 responses. Transpl Int. 2005 Feb;18(2):226-36. doi: 10.1111/j.1432-2277.2004.00047.x.

Reference Type BACKGROUND
PMID: 15691277 (View on PubMed)

Weimer R, Mytilineos J, Feustel A, Preiss A, Daniel V, Grimm H, Wiesel M, Opelz G. Mycophenolate mofetil-based immunosuppression and cytokine genotypes: effects on monokine secretion and antigen presentation in long-term renal transplant recipients. Transplantation. 2003 Jun 27;75(12):2090-9. doi: 10.1097/01.TP.0000058808.37349.23.

Reference Type BACKGROUND
PMID: 12829918 (View on PubMed)

Weimer R, Streller S, Staak A, Heilke M, Li D, Dietrich H, Daniel V, Feustel A, Rainer L, Zinn S, Friemann S, Ernst W, Grimm H, Padberg W, Zimmermann T, Opelz G. Effects of three immunosuppressive regimens on CD4 helper function, B cell monocyte and cytokine responses in renal transplant recipients: 4-month follow-up of a prospective randomized study. Transplant Proc. 2002 Sep;34(6):2377-8. doi: 10.1016/s0041-1345(02)03278-5. No abstract available.

Reference Type BACKGROUND
PMID: 12270445 (View on PubMed)

Weimer R, Melk A, Daniel V, Friemann S, Padberg W, Opelz G. Switch from cyclosporine A to tacrolimus in renal transplant recipients: impact on Th1, Th2, and monokine responses. Hum Immunol. 2000 Sep;61(9):884-97. doi: 10.1016/s0198-8859(00)00152-x.

Reference Type BACKGROUND
PMID: 11053632 (View on PubMed)

Daniel V, Arzberger J, Melk A, Weimer R, Ruhenstroth A, Carl S, Wiesel M, Opelz G. Predictive indicators of rejection or infection in renal transplant patients. Transplant Proc. 1999 Feb-Mar;31(1-2):1364-5. doi: 10.1016/s0041-1345(98)02030-2. No abstract available.

Reference Type BACKGROUND
PMID: 10083605 (View on PubMed)

Weimer R, Zipperle S, Daniel V, Carl S, Staehler G, Opelz G. Pretransplant CD4 helper function and interleukin 10 response predict risk of acute kidney graft rejection. Transplantation. 1996 Dec 15;62(11):1606-14. doi: 10.1097/00007890-199612150-00014.

Reference Type BACKGROUND
PMID: 8970616 (View on PubMed)

Daniel V, Pasker S, Wiesel M, Carl S, Pomer S, Staehler G, Schnobel R, Weimer R, Opelz G. Cytokine monitoring of infection and rejection in renal transplant recipients. Transplant Proc. 1995 Feb;27(1):884-6. No abstract available.

Reference Type BACKGROUND
PMID: 7879219 (View on PubMed)

Weimer R, Zipperle S, Daniel V, Pomer S, Staehler G, Opelz G. IL-6 independent monocyte/B cell defect in renal transplant recipients with long-term stable graft function. Transplantation. 1994 Jan;57(1):54-9. doi: 10.1097/00007890-199401000-00011.

Reference Type BACKGROUND
PMID: 7507271 (View on PubMed)

Weimer R, Daniel V, Zimmermann R, Schimpf K, Opelz G. Autoantibodies against CD4 cells are associated with CD4 helper defects in human immunodeficiency virus-infected patients. Blood. 1991 Jan 1;77(1):133-40.

Reference Type BACKGROUND
PMID: 1824617 (View on PubMed)

Weimer R, Daniel V, Pomer S, Opelz G. B lymphocyte response as an indicator of acute renal transplant rejection. II. Pretransplant and posttransplant B cell responses of m mitogen and donor cell-stimulated cultures. Transplantation. 1989 Oct;48(4):572-5.

Reference Type BACKGROUND
PMID: 2678634 (View on PubMed)

Weimer R, Daniel V, Pomer S, Opelz G. B lymphocyte response as an indicator of acute renal transplant rejection. I. Immunoglobulin-secreting cells in peripheral blood. Transplantation. 1989 Oct;48(4):569-72.

Reference Type BACKGROUND
PMID: 2572082 (View on PubMed)

Susal C, Dohler B, Opelz G. Graft-protective role of high pretransplantation IgA-anti-Fab autoantibodies: confirmatory evidence obtained in more than 4000 kidney transplants. The Collaborative Transplant Study. Transplantation. 2000 Apr 15;69(7):1337-40. doi: 10.1097/00007890-200004150-00021.

Reference Type BACKGROUND
PMID: 10798750 (View on PubMed)

Pelzl S, Opelz G, Daniel V, Wiesel M, Susal C. Evaluation of posttransplantation soluble CD30 for diagnosis of acute renal allograft rejection. Transplantation. 2003 Feb 15;75(3):421-3. doi: 10.1097/01.TP.0000044702.18327.66.

Reference Type BACKGROUND
PMID: 12589170 (View on PubMed)

Susal C, Pelzl S, Dohler B, Opelz G. Identification of highly responsive kidney transplant recipients using pretransplant soluble CD30. J Am Soc Nephrol. 2002 Jun;13(6):1650-6. doi: 10.1097/01.asn.0000014256.75920.5b.

Reference Type BACKGROUND
PMID: 12039995 (View on PubMed)

Susal C, Opelz G. Kidney graft failure and presensitization against HLA class I and class II antigens. Transplantation. 2002 Apr 27;73(8):1269-73. doi: 10.1097/00007890-200204270-00014.

Reference Type BACKGROUND
PMID: 11981420 (View on PubMed)

Other Identifiers

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NTx-PV-002

Identifier Type: -

Identifier Source: org_study_id

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