Clinical trial NCT01166724: Renal Allograft Function and Histology Following Switching From A Tacrolimus to Sirolimus (SRL)-Based Immunosuppression-
Official title: Renal Allograft Function and Histology Following Switching From A Tacrolimus to Sirolimus (SRL)-Based Immunosuppression- Clinical and Mechanistic Impact
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Kidney Transplant
Keywords: Kidney transplant
Lead sponsor: The Cleveland Clinic
Sponsor class: OTHER
Collaborators: name: Pfizer
First posted: 2010-07-21
Enrollment: 12
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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

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

Primary outcomes:
measure: Biopsy-derived Measures of Fibrosis
timeFrame: 12 months
Secondary outcomes:
measure: Change in iGFR
timeFrame: 12 months
Other outcomes:
Locations:
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
Study officials:
affiliation: The Cleveland Clinic
name: T Srinivas, MD
role: PRINCIPAL_INVESTIGATOR
References: