Impact of Immunosuppressive Regimens on Polyomavirus-related Transplant Nephropathy

Prospective Randomized Study to Characterize Risk Factors of Polyomavirus-related Transplant Nephropathy and the Impact of Three Immunosuppressive Regimens on Nephropathy Incidence

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

Study Overview

• Status: Completed
• Conditions: Polyomavirus Infections
• Intervention / Treatment: Drug: Ciclosporin and Mycophenolate-mofetil; Drug: Tacrolimus and Mycophenolate-mofetil; Drug: Tacrolimus and Mycophenolate-mofetil with change from Mycophenolate-mofetil to Everolimus

Detailed Description

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).

• Study Type: Interventional
• Enrollment (Actual): 108
• Phase: Phase 4

Contacts and Locations

Study Locations

• Germany
  • Giessen, Germany, 35392
    • Department of Internal Medicine, University of Giessen

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: 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.	Drug: Ciclosporin and Mycophenolate-mofetil; according to the Giessen protocol
ACTIVE_COMPARATOR: 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.	Drug: Tacrolimus and Mycophenolate-mofetil; according to Giessen protocol
ACTIVE_COMPARATOR: 3; Immunosuppression with Tacrolimus and Mycophenolate-mofetil with change from Mycophenolate-mofetil to Everolimus after completion of posttransplant wound healing	Drug: Tacrolimus and Mycophenolate-mofetil with change from Mycophenolate-mofetil to Everolimus; according to Giessen protocol

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
incidence of polyomavirus associated transplant nephropathy (PVN)	2 years posttransplant
incidence of polyoma viremia	2 years posttransplant
urine polyomavirus concentration within the first two years post-transplant	2 years posttransplant

Secondary Outcome Measures

Outcome Measure	Time Frame
patients' and grafts' survival	2 years posttransplant
incidence of acute rejections	2 years posttransplant
transplant function 1 and 2 years post-transplant	2 years posttransplant
comparison of urine cytology and polymerase chain reaction (PCR) quantitative data regarding diagnosis of PVN	2 years posttransplant
predictive value of immune parameters prognostically relevant for acute or chronic rejection	2 years posttransplant
side effects of immunosuppressive drugs	2 years posttransplant

Collaborators and Investigators

• Sponsor: University of Giessen
• Collaborators: Novartis; Hoffmann-La Roche; Astellas Pharma Inc; Heidelberg University
• Investigators: Principal Investigator: Rolf Weimer, Prof., MD, University Giessen, Internal Medicine

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start: September 1, 2004
• Primary Completion (ACTUAL): March 1, 2010
• Study Completion (ACTUAL): March 1, 2010

Study Registration Dates

• First Submitted: September 8, 2005
• First Submitted That Met QC Criteria: September 8, 2005
• First Posted (ESTIMATE): September 12, 2005

Study Record Updates

• Last Update Posted (ACTUAL): March 28, 2017
• Last Update Submitted That Met QC Criteria: March 27, 2017
• Last Verified: January 1, 2017

More Information

Terms related to this study

• Keywords: BK polyomavirus; immunosuppression; kidney transplantation; everolimus; mycophenolate mofetil; tacrolimus; polyoma virus associated transplant nephropathy; cyclosporin A; BK virus PCR; viruria screening
• Additional Relevant MeSH Terms: Virus Diseases; Infections; Urologic Diseases; DNA Virus Infections; Kidney Diseases; Polyomavirus Infections; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Dermatologic Agents; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antifungal Agents; Antitubercular Agents; Antibiotics, Antitubercular; Calcineurin Inhibitors; Tacrolimus; Mycophenolic Acid; Everolimus; Cyclosporine; Cyclosporins
• Other Study ID Numbers: NTx-PV-002

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: De-identified data of all participants will be made available within 1 year of study completion.