MMF vs. AZA for Kidney Transplantation
Condition: Kidney Transplant
Study type: Interventional
Phase: Phase 4

Summary: 
      The Mycophenolate Steroid Sparing (MYSS) study demonstrated that, in the setting of a
      maintenance immunosuppressive regimen without steroids, mycophenolate mofetil (MMF) and
      azathioprine (AZA) provided the same efficacy in preventing acute rejection episodes and
      allograft dysfunction in kidney transplant recipients. Induction therapy with basiliximab
      combined with low-dose thymoglobulin (RATG), through a transient depletion/inhibition of T
      lymphocytes, allows further reducing the need for maintenance immunosuppression.

      Aim of the present study is to assess whether under this induction strategy MMF and AZA are
      equally effective in preventing acute rejection and chronic allograft nephropathy (CAN), even
      after cyclosporine (CsA) withdrawal.

      Two-hundred-twenty-four kidney transplant recipients from deceased donors given induction
      therapy with two 20 mg basiliximab injections 4 days apart and a seven-day course of RATG
      (0.5 mg/kg/day), will be randomly allocated on a 1:1 basis to 3-year treatment with low-dose
      MMF or AZA, added-on CsA maintenance therapy. At 1 year, rejection-free patients with no
      evidence of tubulitis at kidney biopsy will withdraw CsA and will have a kidney biopsy 3 year
      post-transplant for evaluating the presence and severity of CAN. Should the cumulative
      incidence of acute rejection exceed 15% during CsA withdrawal the study will be stopped.
      Should the incidence differ by >30% between the two treatment arms, all patients will be
      given the most effective treatment and the follow up will be continued. A final biopsy will
      be repeated 4 years post-transplant.

      Most patients are expected to be effectively maintained on single drug immunosuppression,
      which implies less steroid- and CsA- related complications and treatment costs. MMF is
      expected to prevent CAN more effectively than AZA. However, should AZA be more or as
      effective compared to MMF, at study end all patients could be shifted to AZA, that is 15-fold
      less expensive than MMF. Extended to clinical practice, these findings should translate in
      improved patient care and major cost-savings for the Health Care System.
    

Detailed description: 
      INTRODUCTION The introduction of triple-therapy regimens that include a calcineurin
      inhibitor, steroids, and azathioprine (AZA) or mycophenolate mofetil (MMF) greatly reduced
      the risk of acute rejection in renal transplantation. However, the long-term use of both
      calcineurin inhibitors and steroids is associated with serious toxicities that ultimately
      impact patient and graft survival. Minimisation of chronic immunosuppression is therefore of
      paramount importance to improve patient and graft survival. Thus, the quest for strategies
      inducing specific immune hyporesponsiveness or even tolerance - ideally via short-term
      interventions that would target only the pathogenic immune response and leave the protective
      host immune response unimpaired - has provided a "holy grail" for transplant immunologists.

      We recently found that induction therapy with basiliximab and lower (about one fourth) than
      conventional doses of Rabbit Anti-human Thymocyte Globulin (RATG), combined to low-dose CsA
      and MMF maintenance therapy, allowed ineffective prevention of acute rejection without
      steroids. Of note, unlike induction protocols with "standard" RATG doses, the above regimen
      was extremely well tolerated, avoided the risk of acute cytolysis reactions, reduced the
      incidence of immuno-hemolytic anemia and the need for red blood cell transfusions. Moreover,
      this approach did not increase the risk of CMV reactivations or lymphoproliferative
      disorders, even as compared to standard triple immunosuppressive regimens without induction
      therapy.

      The doses of CsA employed in the above protocol were about half the doses currently used in
      clinical practice. However, even these very low doses have been reported to have a
      significant toxicity that, in the long-term, may adversely affect the graft function and
      survival. Thus, implementing innovative immunosuppressive strategies allowing to early and
      safely withdraw calcineurin inhibitor therapy might have major clinical implications in term
      of improved kidney function and long term survival. This would also avoid the adverse effects
      of chronic CsA therapy on arterial blood pressure, lipid profile and blood glucose that,
      altogether, remarkably increase the overall cardiovascular risk in these patients.

      To this purpose, induction therapy with basiliximab plus low-dose RATG might help inducing a
      condition of reduced immuno-responsiveness that might allow to sequentially withdraw steroids
      and CsA without adversely affect the outcome of the graft.

      Evidence that MMF suppresses the production of anti-HLA antibodies, inhibits the recruitment
      of mononuclear cells into the allograft, as well as the proliferation of arterial smooth
      muscle cells, has been taken to suggest that MMF might play an important protective effect
      against the development and progression of CAN. Thus, an immunosuppressive regimen based on
      low-dose MMF as sole antirejection drug not only would avoid chronic toxicity of steroids,
      and calcineurin inhibitors, but would also limit the risk of CAN, the main cause of allograft
      loss in the long-term. On the other hand, however, the Mycophenolate Steroid Sparing (MYSS)
      trial found that AZA was as effective as MMF in preventing acute allograft rejection in
      CsA-treated kidney transplant recipients, even after steroid withdrawal. Since acute
      allograft rejection is one of the strongest predictor of CAN, these findings can be taken to
      suggest that, in the long-term, AZA might share with MMF also a similar protective effect
      against the development of CAN. Moreover, it must be emphasized that chronic CsA
      nephrotoxicity is a major component of CAN. Thus, the prevalence and severity of CAN may be
      reduced in patients on CsA-free immunosuppressive regimens. In this clinical setting, the
      benefits of MMF against the development of CAN might not appreciably exceed those of AZA.
      Should this be the case, AZA might confer the same benefits of MMF, but at remarkably lower
      costs since, at equivalent doses, AZA is about 15 times less expensive than MMF.

      Regardless of the above, MMF or AZA monotherapy would avoid or limit most of the
      complications of chronic immunosuppressive regimens including steroids and calcineurin
      inhibitors, such as metabolic, osteomuscular and cardiovascular diseases, cancer and
      opportunistic infections.

      AIMS Primary To compare the incidence of CAN 3 years post-transplantation in patients
      receiving induction therapy with basiliximab and low-dose RATG and randomized to maintenance
      immunosuppression with low-dose MMF or AZA monotherapy.

      Secondary

        1. year

             -  To assess the overall cumulative incidence (regardless of randomization) of acute
                rejections and of tubulitis at 1-year histology evaluation

             -  To compare the cumulative incidence of acute rejections and of tubulitis in the two
                treatment groups

        2. years

             -  To assess the overall cumulative incidence (regardless of randomization) of
                biopsy-proven acute rejections during CsA tapering

             -  To compare the cumulative incidence of biopsy-proven acute rejections in the two
                treatment groups

        3. years

             -  To assess the overall incidence (regardless of treatment randomization) of CAN and
                the possible relationships between the histology changes at 3 years and the
                histology findings at pre-transplant (baseline) kidney evaluation or previous acute
                rejection episodes observed before or after CsA withdrawal

             -  To asses the global (vascular, glomerular and tubular-interstitial) score of
                chronic histology changes compared to baseline in the study group as a whole, in
                the two treatment arms and within the two subgroups completing or not completing
                CsA withdrawal

        4. years

             -  To assess patient and graft survival and function, incidence of CAN, and possible
                relationships between the histology changes at 4 years and the histology findings
                at baseline and at 3 years post-transplant, or previous acute rejection episodes
                observed before or after CsA withdrawal

             -  To compare overall patient and graft survival and function, incidence of CAN and
                the global histology score in the two treatment groups.

      DESIGN Two-hundred-twenty-four kidney transplant recipients from deceased donors given
      induction therapy with two 20 mg basiliximab injections 4 days apart, a seven-day course of
      RATG (0.5 mg/kg/day) and intravenous methylprednisolone for six days, will be randomly
      allocated on a 1:1 basis to 3-year treatment with low-dose MMF or AZA, added-on CsA
      maintenance therapy. At 1 year, rejection-free patients with no evidence of tubulitis at
      kidney biopsy will progressively taper/withdraw CsA and will have a kidney biopsy 3 year
      post-transplant for evaluating the presence and severity of CAN. Should the cumulative
      incidence of acute rejection exceed 15% during CsA withdrawal the study will be stopped.
      Should the incidence differ by >30% between the two treatment arms, all patients will be
      given the most effective treatment and the follow up will be continued. A final biopsy will
      be repeated 4 years post-transplant.
    

Intervention name(s): mycophenolate mofetil; azathioprine
Intervention type(s): Drug; Drug
Intervention description(s): Patients randomized in this group will receive 750 mg of MMF per os twice a day starting on the day of transplant. MMF dose will be reduced in case of white blood cell count lower than 2,000/mm3 and whenever deemed clinically appropriate.; Patients randomized in this group will receive 75 mg of AZA per os (or 125 mg if body weight > 75 kg) once a day starting on the day of transplant. AZA dose will be reduced in case of white blood cell count lower than 2,000/mm3 and whenever deemed clinically appropriate.
Intervention MeSH terms: Mycophenolic Acid; Azathioprine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment