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

This study is currently recruiting participants. (see Contacts and Locations)
Verified July 2013 by The Cleveland Clinic
Sponsor:
Information provided by (Responsible Party):
The Cleveland Clinic
ClinicalTrials.gov Identifier:
NCT01166724
First received: July 20, 2010
Last updated: July 29, 2013
Last verified: July 2013
  Purpose

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


Condition Intervention Phase
Kidney Transplant
Drug: Sirolumus
Drug: Tacrolimus
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Renal Allograft Function and Histology Following Switching From A Tacrolimus to Sirolimus (SRL)-Based Immunosuppression- Clinical and Mechanistic Impact

Resource links provided by NLM:


Further study details as provided by The Cleveland Clinic:

Primary Outcome Measures:
  • biopsy-derived measures of fibrosis [ Time Frame: 12 months ] [ Designated as safety issue: No ]
    The primary analyses will compare biopsy-derived measures of fibrosis in the Tac-maintenance and SRL groups using the t-test.


Secondary Outcome Measures:
  • change in iGFR [ Time Frame: 12 months ] [ Designated as safety issue: No ]
    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.


Estimated Enrollment: 25
Study Start Date: July 2010
Estimated Study Completion Date: December 2014
Estimated Primary Completion Date: December 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Sirolimus
patients will be switched from Tacrolimus to Sirolimus
Drug: Sirolumus
Tacrolimus to Sirolimus
Drug: Tacrolimus
dosage per trough level
No Intervention: Tacrolimus
Patient will stay on 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

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01166724

Contacts
Contact: Titte Srinvas, MD 216 445 0034
Contact: Emilio Poggio, MD 216 444 5383

Locations
United States, Ohio
Cleveland Clinic Recruiting
Cleveland, Ohio, United States, 44195
Contact: Jennifer Czerr    216-444-3256      
Contact: Leslie Iosue, RN    216 444 2991      
Principal Investigator: Titte Srinivas, MD         
Sponsors and Collaborators
The Cleveland Clinic
Investigators
Principal Investigator: T Srinivas, MD The Cleveland Clinic
  More Information

No publications provided

Responsible Party: The Cleveland Clinic
ClinicalTrials.gov Identifier: NCT01166724     History of Changes
Other Study ID Numbers: 09-702
Study First Received: July 20, 2010
Last Updated: July 29, 2013
Health Authority: United States: Institutional Review Board

Keywords provided by The Cleveland Clinic:
Kidney transplant

Additional relevant MeSH terms:
Sirolimus
Everolimus
Tacrolimus
Antibiotics, Antineoplastic
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Antifungal Agents
Anti-Infective Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Anti-Bacterial Agents

ClinicalTrials.gov processed this record on July 23, 2014