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

Phase 3

Terminated

• Conditions: Kidney Transplant
• Interventions: Drug: Sirolimus; Drug: Tacrolimus

• Registration Number: NCT01166724
• Lead Sponsor: The Cleveland Clinic

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

Study Timeline

• Study Start: 2010-07
• Study First Submitted: 2010-07-20
• Study First Submitted QC: 2010-07-20
• Study First Posted: 2010-07-21
• Primary Completion: 2014-12
• Study Completion: 2014-12
• Status Verified: 2017-02
• Results First Submitted: 2017-02-14
• Results First Submitted QC: 2017-05-09
• Last Update Submitted: 2017-05-09
• Results First Posted: 2017-06-07
• Last Update Posted: 2017-06-07

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 12

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Sirolimus	Sirolimus	patients will be switched from Tacrolimus to Sirolimus
Sirolimus	Tacrolimus	patients will be switched from Tacrolimus to Sirolimus

Primary Outcome Measures

Name	Time	Method
Biopsy-derived Measures of Fibrosis	12 months	The primary analyses will compare biopsy-derived measures of fibrosis in the Tac-maintenance and SRL groups using the t-test.

Secondary Outcome Measures

Name	Time	Method
Change in iGFR	12 months	We will also compare the change in iGFR (as well as estimated GFR) from time of conversion to 12 and 24 months of follow up by paired t-test between groups.

Trial Locations

Locations (1)

Cleveland Clinic; 🇺🇸 Cleveland, Ohio, United States