Renal Allograft Function and Histology Following Switching From A Tacrolimus to Sirolimus (SRL)-Based Immunosuppression-

NCT ID: NCT01166724

Last Updated: 2017-06-07

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE3
• Total Enrollment: 12 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2010-07-31
• Study Completion Date: 2014-12-31

Brief Summary

The investigators hypothesize that Tacrolimus (Tac) withdrawal from a Tac, MMF and steroid based triple therapy regimen leads to long term improved/stabilized graft function (glomerular filtration rate, GFR) primarily as a consequence of halting CNI-induced fibrogenetic processes that mediate loss of functioning renal tissue. The investigators further hypothesize that the underlying fibrotic mechanism is mediated by pathophysiologic processes that promote epithelial to mesenchymal transition (EMT) (mediated by TGF- ƒÒ) and that early therapeutic intervention may reverse this process (mediated by BMP-7)4.

To address these hypotheses the investigators propose the following clinical and mechanistic aims:

The investigators will test the hypothesis that switching from Tac to SRL in a Tac based triple therapy regimen with MMF and steroids in living and or deceased donor renal transplant recipients leads to improvement in allograft structure and function at 2 years post-transplantation.

The investigators will test this hypothesis in an open label controlled trial where stable renal allograft recipients on Tac, MMF, prednisone maintenance immunosuppression will undergo renal biopsy at 3-4 months post-transplantation and will be randomized to either a) Remain on Tac, MMF and prednisone (CNI-maintenance) or b) switch the Tac to SRL and continue MMF and prednisone. The investigators will then compare biopsy derived measures of allograft fibrosis (CADI, Sirius Red, Banff Chronicity Index) and GFR in the two groups

Detailed Description

We will test this hypothesis in an open label controlled trial where stable renal allograft recipients on Tac, MMF, prednisone maintenance immunosuppression will undergo renal biopsy at 3-4 months post-transplantation and will be randomized to either a) Remain on Tac, MMF and prednisone (CNI-maintenance) or b) switch the Tac to SRL and continue MMF and prednisone. We will then compare biopsy derived measures of allograft fibrosis (CADI, Sirius Red, Banff Chronicity Index) and GFR in the two groups

Conditions

Kidney Transplant

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Sirolimus

patients will be switched from Tacrolimus to Sirolimus

Group Type: ACTIVE_COMPARATOR

Sirolimus

Intervention Type: DRUG

Tacrolimus to Sirolimus

Tacrolimus

Intervention Type: DRUG

dosage per trough level

Tacrolimus

Patient will stay on Tacrolimus

Group Type: NO_INTERVENTION

No interventions assigned to this group

Interventions

Sirolimus

Tacrolimus to Sirolimus

Intervention Type: DRUG

Tacrolimus

dosage per trough level

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

1. Absence of clinical acute rejection in post-transplant period preceding randomization

2. HLA-mismatched solitary first and second kidney transplant recipients

3. Absence of any degree of rejection (Banff 2007) on renal biopsy at 3-6 months(+/- 2 months) post-transplant.

4. Absence of post-transplant donor-specific antibody

Exclusion Criteria

1. HLA-identical transplants

2. Contraindication or inability to undergo renal biopsy, like previous complications due to biopsies, anticoagulation, active infection, etc.

3. Positive flow cross match, sensitized recipient, presence of donor-specific antibody.

4. Rejection episode after transplantation, either cellular or humoral on for cause or renal biopsy.

5. Rejection present on pre-randomization renal biopsy.

6. Proteinuria greater than 0.3 gram/day

7. Native kidney disease biopsy proven or likely glomerulonephritis, primary or recurrent FSGS, MPGN or primary or recurrent membranous GN.

8. Hypertriglyceridemia > 400 mg/dL (treated), LDL cholesterol > 160 mg/dL while on optimal treatment.

9. WBC < 2000/mm3, ANC < 1000 mm3, Platelet count < 100,000 mm3

10. Active wound issues.

11. Primary non-function.

12. Active BKV or CMV disease.

13. Evidence of recurrent disease.

14. Active infection

15. Pregnancy

16. Women of childbearing potential unable or unwilling to use birth control during the study.

17. e GFR ≤ 40 ml/ min at screening

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Pfizer

INDUSTRY

Sponsor Role: collaborator

The Cleveland Clinic

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

T Srinivas, MD

Role: PRINCIPAL_INVESTIGATOR

The Cleveland Clinic

Locations

Cleveland Clinic

Cleveland, Ohio, United States

Countries

United States

Other Identifiers

09-702

Identifier Type: -

Identifier Source: org_study_id