Tacrolimus/Everolimus Versus Tacrolimus/Enteric-Coated Mycophenolate Sodium
Condition: Transplant; Failure, Kidney
MeSH terms: Renal Insufficiency
Intervention: Tacrolimus; Everolimus; Enteric Coated Mycophenolate Sodium (EC-MPS); Corticosteroids
Intervention description: Tacrolimus dosing (rTd) is planned, 0.1 mg/kg PO BID - beginning when serum Cr decreases to a level of <4 mg/dl (i.e., acceptable renal transplant function) postoperatively. Target tacrolimus trough levels during the first year post-transplant and thereafter will be 5-8 ng/ml.; Everolimus initiated at 0.75 PO BID and will be adjusted in order to achieve target everolimus trough levels of 3-8 ng/ml.; EC-MPS 720 mg PO BID - beginning on 1st postoperative day.; Corticosteroids will be given as per our center protocol, i.e., a bolus of 500 mg of Methylprednisolone intravenously at surgery and daily x2, followed by 1.0 mg/kg, then 0.5 mg/kg orally until weaned off completely by 7-10 days postoperatively - the plan is for corticosteroids to be discontinued by 7-10 days postoperatively in both groups.
Intervention MeSH terms: Mycophenolic Acid; Methylprednisolone; Everolimus; Tacrolimus
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 32.0
Sex: All
Minimum age: 18 Years
Maximum age: 75 Years
Healthy volunteers: No
Keywords: Kidney transplant patients

Summary:

      A recent therapeutic strategy following renal transplantation includes simultaneous use of
      reduced calcineurin inhibitor (CNI) dosing and maximized use of a non-nephrotoxic,
      antiproliferative drug (inosine monophosphate dehydrogenase (IMPDH) or TOR inhibitor), with
      the goals of reducing/avoiding CNI nephrotoxicity, the incidence of acute rejection, and
      chronic allograft injury (CAI) (i.e., interstitial fibrosis/tubular atrophy), leading to more
      favorable longer-term patient and graft survival.1-7 Early corticosteroid withdrawal has also
      been used in the attempt to avoid well-known side effects while maintaining favorable patient
      and graft survival.8-10 While the investigators center and numerous other centers have also
      included single agent, antibody induction utilizing the lymphodepleting polyclonal antibody
      rabbit anti-human thymocyte globulin (ATG), nondepleting human anti-interleukin-2 receptor
      (CD25) monoclonal antibody daclizumab (Dac) or basiliximab, or lymphodepleting humanized
      anti-CD52 monoclonal antibody alemtuzumab,11-17 evidence now suggests that an even more
      effective induction strategy may include the combined use of more than one induction agent
      (each with fewer doses than if used alone), with the goal of bringing the kidney transplant
      recipient even closer (through more effectively timed lymphodepletion) to an optimally
      immunosuppressed state, allowing further reduction in long-term maintenance drug dosing.18-25
      The investigators have now successfully used dual ATG/Dac induction therapy in both
      kidney-alone23-24 and simultaneous kidney-pancreas (SPK) transplantation,18-20 and a recent
      report from the investigators center of kidney-alone and SPK recipients shows that the
      addition of anti-CD25 to ATG for induction therapy more effectively delays the return of
      peripheral blood CD25+ cells.25 In the kidney-alone recipient study 3 doses of ATG were
      combined with 2 doses of Dac for induction,23-24 vs. the investigators previous studies
      utilizing single agent induction with 7 doses of ATG or 5 doses of Dac.4,16,17 Successful
      combination of ATG/basiliximab as dual induction in kidney transplantation has also been
      reported elsewhere,21-22 along with equivalency in clinical outcomes using daclizumab vs.
      basiliximab.13
    

Eligibility criteria:

        Inclusion Criteria:

          -  Weight > 40 kg.

          -  Deceased donor (SCD) or LD.

          -  Donor-recipient 1 haplotype matched pairs with a minimum matching of 1 HLA DR antigen.

          -  Negative standard cross match for T cells.

          -  Pretransplant panel reactive antibodies of < 30%.

          -  Graft required to be functional, producing at least 100ml of urine within 24hr after
             transplantation.

        Exclusion Criteria:

          -  Previously received or is receiving an organ transplant other than a kidney.

          -  Donor organ with a cold ischemic time > 48 hours.

          -  ABO incompatible donor kidney.

          -  Recipients of T cell, or B cell crossmatch positive transplant.

          -  Panel reactive antibody (PRA) >30%

          -  HIV or Hepatitis C virus, or Hepatitis B virus antigenemia.

          -  Current malignancy or a history of malignancy

          -  Liver disease

          -  Uncontrolled concomitant infections and/or severe diarrhea, vomiting, active upper
             gastro-intestinal tract malabsorption or an active peptic ulcer

          -  Use of warfarin, fluvastatin, or herbal supplements during the study.

          -  Use of astemizole, pimozide, cisapride, terfenadine, or ketoconazole.

          -  Hypersensitivity to thymoglobulin, IL-2 receptor inhibitor monoclonal antibodies,
             tacrolimus, everolimus, MPA, or corticosteroids.

          -  Pregnant or lactating.

          -  Abnormal screening/baseline labs WBC, platelet count, triglycerides, and cholesterol
             Double kidneys,ECD, pediatric en-block, and donation after cardiac death (DCD)