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

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ClinicalTrials.gov Identifier: NCT01166724
Recruitment Status : Terminated (Collaborator stopped study)
First Posted : July 21, 2010
Results First Posted : June 7, 2017
Last Update Posted : June 7, 2017
Sponsor:
Collaborator:
Pfizer
Information provided by (Responsible Party):
The Cleveland Clinic

Tracking Information
First Submitted Date  ICMJE July 20, 2010
First Posted Date  ICMJE July 21, 2010
Results First Submitted Date  ICMJE February 14, 2017
Results First Posted Date  ICMJE June 7, 2017
Last Update Posted Date June 7, 2017
Study Start Date  ICMJE July 2010
Actual Primary Completion Date December 2014   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 20, 2010)
Biopsy-derived Measures of Fibrosis [ Time Frame: 12 months ]
The primary analyses will compare biopsy-derived measures of fibrosis in the Tac-maintenance and SRL groups using the t-test.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: July 20, 2010)
Change in iGFR [ Time Frame: 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.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Renal Allograft Function and Histology Following Switching From A Tacrolimus to Sirolimus (SRL)-Based Immunosuppression-
Official Title  ICMJE Renal Allograft Function and Histology Following Switching From A Tacrolimus to Sirolimus (SRL)-Based Immunosuppression- Clinical and Mechanistic Impact
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 Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Kidney Transplant
Intervention  ICMJE
  • Drug: Sirolimus
    Tacrolimus to Sirolimus
  • Drug: Tacrolimus
    dosage per trough level
Study Arms  ICMJE
  • Active Comparator: Sirolimus
    patients will be switched from Tacrolimus to Sirolimus
    Interventions:
    • Drug: Sirolimus
    • Drug: Tacrolimus
  • No Intervention: Tacrolimus
    Patient will stay on Tacrolimus
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Terminated
Actual Enrollment  ICMJE
 (submitted: May 9, 2017)
12
Original Estimated Enrollment  ICMJE
 (submitted: July 20, 2010)
25
Actual Study Completion Date  ICMJE December 2014
Actual Primary Completion Date December 2014   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01166724
Other Study ID Numbers  ICMJE 09-702
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party The Cleveland Clinic
Study Sponsor  ICMJE The Cleveland Clinic
Collaborators  ICMJE Pfizer
Investigators  ICMJE
Principal Investigator: T Srinivas, MD The Cleveland Clinic
PRS Account The Cleveland Clinic
Verification Date February 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP