Randomized Conversion of Calcineurin-Inhibitors in Renal Allograft Recipients
Condition: Renal Transplant Rejection
Study type: Interventional
Phase: Phase 4

Summary: 
      This study is being done to investigate the impact of changing immunosuppressive medications
      from tacrolimus (Prograf®) to sirolimus (Rapamune®) between 6 and 24 months post transplant.
      The primary purpose of this research study is to evaluate whether the use of mycophenolate
      mofetil(MMF)/Cellcept® and tacrolimus(TAC)/Prograf® (Group 1) or mycophenolate
      mofetil(MMF)/Cellcept® and sirolimus/Rapamune® (Group 2) impacts the incidence of acute
      cellular rejection in post kidney transplant patients. This study will examine whether
      switching from tacrolimus to sirolimus will better preserve long-term kidney function.
    

Detailed description: 
      For this research study, between 6 and 24 Months post-transplant, we plan to prospectively
      randomize 2:1 renal transplant patients to either:

        -  Substitute tacrolimus (TAC) with sirolimus and continue mycophenolate mofetil (MMF) or

        -  Continue with tacrolimus (TAC) and mycophenolate mofetil (MMF)

      A total of 400 patients are expected to be screened for the randomization. We expect to
      randomize 275 renal transplant patients into this protocol (275 donors to be recruited).

      The following data will be collected at the time of randomization:

      Recipient demographics: (i) age at transplantation, (ii) sex, and (iii) race.

      Clinical history: (i) causes of end-stage renal disease, and (ii) past medical history.

      Transplant related information: (i) donor age, (ii) cadaveric versus living kidney
      transplant, (iii) histocompatibility and cross match data, (iv) viral serology, (v) history
      of acute rejection and delayed graft function, (vi) use of induction therapy and
      immunosuppressants, (vii) use of ACEI and/or ARB, and (viii) level of renal allograft
      function-estimated GFR (e-GFR(12) using MDRD formula, proteinuria.

      Peripheral blood leukocytes will be obtained from renal transplant recipients for baseline
      (prior to randomization) lymphocytes functional activity and characterization of lymphocytes
      subpopulations by flow cytometry analysis.

      Peripheral donor leukocytes (from living donor patients) will also be obtained at the time of
      randomization. These donor leukocytes will be used as stimulator cells to study the
      functional activity of the recipient's lymphocytes function.

      The recipients assigned to continue with tacrolimus and MMF will be routinely followed at the
      outpatient Comprehensive Transplant Center (CTC) with monthly labs. In addition to labs at
      baseline pre-randomization, 6, 12 and 24 Months post-randomization, peripheral blood
      leukocytes will be obtained to study lymphocytes functional activity and to characterize
      lymphocytes subpopulations by flow cytometry analysis.

      Post randomization: The recipients assigned to switch from tacrolimus to sirolimus and
      continue with MMF will be routinely followed at the CTC with monthly labs. During the period
      of conversion from tacrolimus to sirolimus, weekly labs will be obtained to monitor renal
      function and bone marrow function. In addition to labs at baseline pre-randomization, 6, 12
      and 24 Months post-randomization, peripheral blood leukocytes will be obtained to study
      lymphocytes functional activity to characterize lymphocytes subpopulations by flow cytometry
      analysis. Urine will be collected to assess tubular toxicity by evaluating urinary
      biomarkers.

      Both groups of patients will be followed for 2 years post-randomization. In addition to
      monitoring renal allograft function, we will evaluate the incidence of acute rejection,
      patient and graft survival, impact of CI conversion on the lipid profile, incidence of
      hypertension, malignancies, opportunistic infections, and post-transplant diabetes mellitus
      (DM). For those willing to undergo an optional kidney biopsy, one will be performed at the
      end of the second year in order to evaluate renal allograft pathology and renal allograft
      tissue gene expression profiles of the two groups.

      With the peripheral leukocytes obtained at baseline prior to randomization and at 6, 12 and
      24 Months post-randomization, we will investigate possible modifications of lymphocytes
      function and the lymphocytes subpopulations that might have occurred as a consequence of the
      switch from tacrolimus to sirolimus.

      Obtaining renal allograft tissue samples at 24 months post randomization can have potential
      important ramifications to help explain the mechanisms of fibrosis and tubular atrophy
      typically associated with CI and the role of CI elimination with the substitution of
      sirolimus (SRL). All data will then be analyzed comparing gene expression profiles of
      peripheral blood (Pax gene tubes are routinely collected at the different time points as part
      of the original study). Based on power analysis, we will perform 24 months post randomization
      biopsies in 70% of the total subjects enrolled in the study (approximately 46 subjects from
      the tacrolimus/MMF group and approximately 93 subjects from the sirolimus/MMF group).

      We plan to obtain renal allograft biopsies at 24 Months for those that consent for this
      additional biopsy. This will be compared to the standard of care 12 months post-transplant
      biopsy to allow us to address the effect of immunosuppressive modifications on renal
      allograft pathology at 24 months post randomization. Renal allograft biopsies will also be
      stored in RNA later to further extend our knowledge on the effect of CI free
      immunosuppression on gene expression profiles.
    

Intervention name(s): Sirolimus; Demographic Data, Medical History, and Donor Data; Blood Draws for Control Group; Blood Draws for Experimental Group; Donor Blood Draws; Donor Information; Kidney Biopsy
Intervention type(s): Drug; Other; Procedure; Procedure; Procedure; Other; Procedure
Intervention description(s): Sirolimus will initially be given at a dose of 2-4 mg orally (PO) daily. The dose will be modified to achieve 24 hours trough concentrations of 6-10 ng/ml by high-performance liquid chromatography (HPLC) assay. This medication will be given in an open label fashion. The first dose of sirolimus will be given at the time of randomization to those patients assigned to have tacrolimus switched to sirolimus.; Age at transplant, sex, race, cause of end-stage renal disease, medical history, donor age, cadaveric vs. living kidney transplant, histocompatibility/cross match data, viral serology, history of acute rejection and delayed graft function, use of induction therapy and immunosuppressants, use of Angiotensin Converting Enzyme Inhibitor (ACEI) and/or Angiotensin Receptor Blockers (ARB) level of renal allograft function-estimated GFR (e-GFR(12) using Modification of Diet in Renal Disease (MDRD) formula, proteinuria.; Subjects maintaining standard of care drug treatment of TAC and MMF will have monthly labs in addition to the baseline pre-randomization labs, at 6, 12, and 24 Months post-randomization. Peripheral blood leukocytes will be obtained.; This group will have monthly labs taken but will also have weekly labs during the period of conversion to monitor renal function and bone marrow function. In addition to the baseline pre-randomization labs, and labs collected at 6, 12, and 24 Months post-randomization, peripheral blood leukocytes will be obtained.; Peripheral blood leukocytes from living donors obtained at the time of randomization. These donor leukocytes will be used as stimulator cells to study the functional activity of the recipient's lymphocytes function.; Donor age, cadaveric vs. living donor, and histocompatibility and cross match to recipient; Kidney biopsy at 24 Months to compare to the standard of care biopsy taken at 12 Months. This information will help evaluate renal allograft pathology and renal allograft tissue gene expression profiles of the two groups. Renal allograft biopsies will be stored in RNA later (preservative) to further extend knowledge on the effect of calcineurin-inhibitors (CI) free immunosuppression on gene expression profiles.
Other intervention name(s): Rapamune
Intervention MeSH terms: Sirolimus
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Prevention
Keywords: Sirolimus; Rapamune; Immunosuppression; Renal allograft function; Lymphocytes function