Fibrosis in Renal Allografts

NCT ID: NCT00493194

Last Updated: 2008-11-26

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

UNKNOWN

Clinical Phase

PHASE4

Total Enrollment

100 participants

Study Classification

INTERVENTIONAL

Study Start Date

2005-05-31

Study Completion Date

2007-07-31

Brief Summary

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This prospective, randomized study, comparing sirolimus to cyclosporine in renal transplant recipients, has two major objectives:

1. -To determine the incidence and the degree of interstitialfibrosis and arteriosclerosis, as wel as the glomerular volume in protocol biopsies at 6 months in sirolimus-and in cyclosporine-treated renal allograft recipients, by means of quantitative computerized image analysis.

* To determine the prognostic implication of these morphologic changes.
2. To study the expression of genes, involved in inflammation and fibrosis, in protocol biopsies at 6 months in sirolimus-and cyclosporine-treated renal allograft recipients.

Detailed Description

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Calcineurin inhibitors have significantly improved the one-year graft survival of renal allografts. However, chronic nephrotoxicity caused by calcineurin inhibitors contributes to the long-term decline in renal function in kidney transplant recipients. Approximately ninety percent of the protocol biopsies of renal allografts, performed at 18 months post transplantation, show histological lesions of chronic calcineurin nephrotoxicity . In recent years, two new non-nephrotoxic immunosuppressive drugs, i.e. mycophenolate mofetil and sirolimus, have become available for the prophylaxis of graft rejection in renal transplantation.

Three randomized clinical trials, comparing cyclosporine with sirolimus in combination with mycophenolate mofetil, reported a superior graft function at one year in sirolimus treated renal allograft recipients. However, data on long-term graft survival and histological lesions of protocol biopsies in sirolimus-treated renal transplant recipients, are currently lacking.

In analogy with previous observations in native kidney disease, Grimm et al. recently reported that interstitial fibrosis in protocol biopsies of renal allografts, at 6 months post transplantation, significantly inversely correlates with the subsequent graft survival One hundred recipients of a first renal allograft will be randomized to an immunosuppressive protocol based on cyclosporine (50 patients) or sirolimus (50 patients). Concommittant immunosuppression will be similar in both groups, and consists of Daclizumab as induction treatment (five iv gifts every two weeks), and mycophenolate mophetil and steroids as maintenance immunosuppression.

Randomization will be performed by centre to avoid centre-related bias. All patients will complete a follow-up of 12 months. Two core biopsies of the graft will be obtained in each recipient, at implantation and at 6 months. Serum creatinine and the estimated creatinine clearance (by the Nankivell and the Jellife method) will be monthly recorded.

Conditions

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Kidney Failure, Chronic Transplantation Immunosuppression Interstitial Fibrosis

Keywords

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Cyclosporine toxicity Interstitial Fibrosis Chronic allograft nephropathy Sirolimus

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

TREATMENT

Blinding Strategy

NONE

Interventions

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sirolimus

Intervention Type DRUG

cyclosporine

Intervention Type DRUG

daclizumab

Intervention Type DRUG

Eligibility Criteria

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Inclusion Criteria

1. Recipients of a renal allograft, with a minimum age of 18 years.
2. Male or female recipients. Women of child-bearing age must practice adequate contraception
3. For renal allografts from living donors, at least one HLA-mismatch is required.
4. Written informed consent, compliant with local regulations.

Exclusion Criteria

1. Recipients of a second or third renal allograft, with a past history of graft failure due to rejection.
2. Recipients of a renal allograft from a haplotype-identical living donor or a non-heart beating donor.
3. Cold ischemia time \> 24 hours
4. Recipients of a kidney from donors ≥ 65 years of age
5. Recipients of multiple organs.
6. Pregnant women.
7. Immunological high-risk recipients, defined as current or historical PRA \> 50 %
8. Recipients with focal segmental sclerosis as primary renal disease.
9. Recipients with leucopenia (WBC \< 3000/mm³), thrombocytopenia (Thr \< 100.000/mm³),or hyperlipidemia (Tot Chol \> 300 mg/dl or Triglycerides \> 300 mg/dl)
10. Previous history of malignancy, except completely excised basocellular skin tumor
11. Chronic active infection.
12. Inadequate compliance to treatment.
13. Use of specific drugs: Terfenadine, pimozide, astemizole, fluconazole, ketoconazole and cimetidine.
Minimum Eligible Age

18 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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Wyeth is now a wholly owned subsidiary of Pfizer

INDUSTRY

Sponsor Role collaborator

Hoffmann-La Roche

INDUSTRY

Sponsor Role collaborator

University Hospital, Antwerp

OTHER

Sponsor Role lead

Principal Investigators

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Jean-Louis Bosmans, M.D. Ph.D.

Role: PRINCIPAL_INVESTIGATOR

University Hospital, Antwerp

Locations

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University Hospital Antwerp

Edegem, Antwerp, Belgium

Site Status RECRUITING

University Hospital Brussels

Brussels (Jette), Brabant, Belgium

Site Status RECRUITING

University Hospital Gent

Ghent, Oost-Vlaanderen, Belgium

Site Status RECRUITING

Countries

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Belgium

Central Contacts

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Jean-Louis Bosmans, MD Ph.D

Role: CONTACT

Phone: ..32/3/821 37 92

Email: [email protected]

Angelika Jurgens, Coordinator

Role: CONTACT

Phone: ..32/3/821.34.68

Email: [email protected]

Facility Contacts

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Jean-Louis Bosmans, M.D. Ph.D.

Role: primary

Angelika Jurgens, Coordinator

Role: backup

Jacques Sennesael, M.D.

Role: primary

Katrien Van Bever, Study-nurse

Role: backup

Patrick Peeters, M.D.

Role: primary

Cathy Vandermeulen, Study-Nurse

Role: backup

References

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Flechner SM, Goldfarb D, Modlin C, Feng J, Krishnamurthi V, Mastroianni B, Savas K, Cook DJ, Novick AC. Kidney transplantation without calcineurin inhibitor drugs: a prospective, randomized trial of sirolimus versus cyclosporine. Transplantation. 2002 Oct 27;74(8):1070-6. doi: 10.1097/00007890-200210270-00002.

Reference Type RESULT
PMID: 12438948 (View on PubMed)

Groth CG, Backman L, Morales JM, Calne R, Kreis H, Lang P, Touraine JL, Claesson K, Campistol JM, Durand D, Wramner L, Brattstrom C, Charpentier B. Sirolimus (rapamycin)-based therapy in human renal transplantation: similar efficacy and different toxicity compared with cyclosporine. Sirolimus European Renal Transplant Study Group. Transplantation. 1999 Apr 15;67(7):1036-42. doi: 10.1097/00007890-199904150-00017.

Reference Type RESULT
PMID: 10221490 (View on PubMed)

Kreis H, Cisterne JM, Land W, Wramner L, Squifflet JP, Abramowicz D, Campistol JM, Morales JM, Grinyo JM, Mourad G, Berthoux FC, Brattstrom C, Lebranchu Y, Vialtel P. Sirolimus in association with mycophenolate mofetil induction for the prevention of acute graft rejection in renal allograft recipients. Transplantation. 2000 Apr 15;69(7):1252-60. doi: 10.1097/00007890-200004150-00009.

Reference Type RESULT
PMID: 10798738 (View on PubMed)

Grimm PC, Nickerson P, Gough J, McKenna R, Stern E, Jeffery J, Rush DN. Computerized image analysis of Sirius Red-stained renal allograft biopsies as a surrogate marker to predict long-term allograft function. J Am Soc Nephrol. 2003 Jun;14(6):1662-8. doi: 10.1097/01.asn.0000066143.02832.5e.

Reference Type RESULT
PMID: 12761269 (View on PubMed)

Other Identifiers

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2004-004115-38

Identifier Type: -

Identifier Source: org_study_id