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

Kidney Transplant Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01166724
• Other study ID #: 09-702
• Status: Completed
• Phase: Phase 3
• First received: July 20, 2010
• Last updated: October 26, 2016
• Start date: July 2010
• Est. completion date: December 2014

Study information

• Verified date: October 2016
• Source: The Cleveland Clinic
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Institutional Review Board
• Study type: Interventional

Clinical Trial 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

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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 25
• Est. completion date: December 2014
• Est. primary completion date: December 2014
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Kidney Transplant

Intervention

Drug:
• Sirolumus
Tacrolimus to Sirolimus
• Tacrolimus
dosage per trough level

Locations

Country	Name	City	State
United States	Cleveland Clinic	Cleveland	Ohio

Sponsors (1)

Lead Sponsor	Collaborator
The Cleveland Clinic

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	biopsy-derived measures of fibrosis	The primary analyses will compare biopsy-derived measures of fibrosis in the Tac-maintenance and SRL groups using the t-test.	12 months	No
Secondary	change in iGFR	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.	12 months	No