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

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

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

Study Overview

• Status: Terminated
• Conditions: Kidney Transplant
• Intervention / Treatment: Drug: Sirolimus; Drug: Tacrolimus

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 Type: Interventional
• Enrollment (Actual): 12
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Sirolimus; patients will be switched from Tacrolimus to Sirolimus	Drug: Sirolimus; Tacrolimus to Sirolimus; Drug: Tacrolimus; dosage per trough level
No Intervention: Tacrolimus; Patient will stay on Tacrolimus

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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

Collaborators and Investigators

• Sponsor: The Cleveland Clinic
• Collaborators: Pfizer
• Investigators: Principal Investigator: T Srinivas, MD, The Cleveland Clinic

Study record dates

Study Major Dates

• Study Start: July 1, 2010
• Primary Completion (Actual): December 1, 2014
• Study Completion (Actual): December 1, 2014

Study Registration Dates

• First Submitted: July 20, 2010
• First Submitted That Met QC Criteria: July 20, 2010
• First Posted (Estimate): July 21, 2010

Study Record Updates

• Last Update Posted (Actual): June 7, 2017
• Last Update Submitted That Met QC Criteria: May 9, 2017
• Last Verified: February 1, 2017

More Information

Terms related to this study

• Keywords: Kidney transplant
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antifungal Agents; Calcineurin Inhibitors; Tacrolimus; Sirolimus
• Other Study ID Numbers: 09-702