Tacrolimus/Everolimus Versus Tacrolimus/Enteric-Coated Mycophenolate Sodium
Condition: Transplant; Failure, Kidney
MeSH terms: Renal Insufficiency
Study type: Interventional
Phase: Phase 3

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
    

Detailed description: 
      A. Primary Objectives:

        1. The percentage of patients who develop chronic allograft injury (CAI) progression during
           the first 12 months post-transplant protocol biopsy (i.e., higher grade of IF/TA at
           either the 6 or 12 month protocol biopsy in comparison with the baseline biopsy).

        2. The incidence rate of biopsy-proven acute rejection (BPAR) during the first 12 months
           post-transplant.

      B. Secondary Objectives:

        1. Adverse events including graft loss (death-censored and death-uncensored), and death at
           12 months post-transplant.

        2. Incidence rate and severity (severity of CAI at 12 months as well), based upon careful
           review of all clinically indicated and protocol biopsies.

        3. Renal function as determined by serum creatinine and estimated glomerular filtration
           rate (eGFR) (calculated using the abbreviated MDRD formula) at 12, months
           post-transplant. Use of multivariable analysis to compare renal function as well as BPAR
           and CAI progression will also be performed (particularly, after adjusting for the
           significant effects of donor age, recipient age, race/ethnicity, and any other
           predictors).

      5. Adverse events including withholding (for ≥ 28 days) or discontinuance of study
      medications (and reasons why), new onset diabetes mellitus after transplantation (NODAT),
      infections requiring hospitalization, and requirement of anti-lipid medication at 12 months
      post-transplant.

      6. Avoidance of the requirement for maintenance corticosteroid therapy after renal
      transplantation.

      7. Allowance of reduced maintenance tacrolimus dosing (rTd).
    

Intervention name(s): Tacrolimus; Everolimus; Enteric Coated Mycophenolate Sodium (EC-MPS); Corticosteroids
Intervention type(s): Drug; Drug; Drug; Drug
Intervention description(s): 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.
Other intervention name(s): Prograf (brand name); Zortress (brand name); Myfortic (brand name); Methylprednisolone
Intervention MeSH terms: Mycophenolic Acid; Methylprednisolone; Everolimus; Tacrolimus
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Kidney transplant patients