Simultaneous Pancreas-kidney Transplantation With Campath Protocol
Condition: Pancreas-Kidney Transplantation
Study type: Interventional
Phase: Phase 3

Summary: 
      The purpose of this study is to determine and compare the efficacy of Campath-1H/Tacrolimus
      versus ATG/Tacrolimus/MMF therapy in conjunction with initial short-term steroids in Type
      1-diabetic patients undergoing simultaneous pancreas-kidney allograft transplantation as well
      as to evaluate the safety of Campath-1H/Tacrolimus versus ATG/Tacrolimus/MMF in terms of
      drug-related complications and immunosuppression-associated complications.
    

Detailed description: 
      Simultaneous pancreas-kidney (SPK) transplantation is a recommended treatment option for type
      1-diabetic patients suffering from end-stage kidney disease.1 Major factors contributing to
      the success of SPK transplantation include improvements in surgical technique and the
      provision of effective immunosuppressive strategies heralded by the introduction of the
      calcineurin inhibitors.2 According to the International Pancreas Transplant Registry (IPTR),
      since the mid-1990s, the most popular maintenance therapy has been with Tacrolimus and
      Mycophenolate Mofetil (MMF), utilized in approximately 66% of SPK transplanted recipients.
      Since 1994, the proportion of pancreas recipients who received induction therapy has exceeded
      70% and by that means induction therapy is used with greatest frequency for pancreas
      recipients than for any other solid organ recipients. That is in accordance with the registry
      analyses and the clinical trials listed below demonstrating the highest graft survival rates
      for recipients given antibody induction therapy and maintained on Tacrolimus.

      A large European multicenter study compared the efficacy and safety of Tacrolimus versus the
      microemulsion formulation of Cyclosporine in 205 SPK recipients. All of the patients received
      additionally rabbit anti-T-cell induction therapy, MMF and short-term corticosteroids. The
      study showed a significantly higher pancreas graft survival rate with Tacrolimus (91%) than
      with Cyclosporine (74%; P<0.0005).3 A second US multicenter study focused on the effect of
      antibody induction therapy in SPK recipients. The trial conducted at 18 US pancreas
      transplant centers, randomized 87 recipients each to antibody induction therapy versus no
      therapy. In the induction group, either T-cell depleting or nondepleting antibodies were
      used. Maintenance therapy in both groups was Tacrolimus, MMF and steroids. At 3 years, actual
      patient survival rates (94% vs. 90%) and pancreas graft survival rates (76% vs. 76%) were
      similar between the two groups, but actual kidney survival rates were significantly higher in
      the induction group (92% vs. 82%; P=0.04).4 A third US-Canadian multicenter study assessed
      the safety and efficacy of two dosing regimens of daclizumab versus no antibody induction in
      185 SPK recipients maintained on Tacrolimus, MMF and steroids. The probability of either
      kidney or pancreas rejection was lowest with two doses of daclizumab (P=0.042). The authors
      concluded that daclizumab is effective in reducing the incidence of acute rejection in SPK
      recipients, as compared with no antibody induction.5

      During the past years increasingly more centers investigated the usage of Campath-1H
      induction therapy in combination with the calcineurin inhibitors, MMF in the absence or with
      a short course of steroids. A recent single-centre, retrospective study of SPK transplant
      recipients involved two treatment arms with Campath (n=50) and Thymoglobuline (n=58). The
      induction dose of Campath was 30mg and 6mg/kg for Thymoglobuline. Additionally all recipients
      received a prednisone-free maintenance immunosuppressive regimen of Tacrolimus and Sirolimus
      or MMF. The 3-year patient and graft survivals were excellent and similar between the
      treatment arms. The mean creatinine value 1-year post-transplant was however lower in the
      Campath subgroup (1.30 vs. 1.44 mg/dL). Furthermore advantages of Campath were shown by a
      trend of decreased rates of CMV infection, PTLD and it was also less expensive.6 The purpose
      of a further study was to evaluate Campath-1H preconditioning and Tacrolimus monotherapy in
      pancreas transplant recipients. Thirty-seven consecutive pancreas transplants (20 SPK, 10 PAK
      and 7 PTA) were followed up for 7 months, utilizing 30mg Campath-1H preconditioning. Two
      grams of intravenous methylprednisolone were administered, one prior to starting the
      Campath-1H and another at reperfusion. Patient survival was 100%. Pancreas and kidney graft
      survivals were 94% and 90%, respectively. Interestingly, all rejection episodes were preceded
      by tacrolimus trough levels <9.0 ng/ml for an extended period of time, while allograft
      rejection was not observed in pancreases or kidneys if the tacrolimus was >10 ng/ml. During
      the study period no infectious complications were seen. Although follow-up was short, these
      results suggest that a regimen of Campath-1H induction and tacrolimus monotherapy represents
      an effective immunosuppressive protocol for pancreas transplant recipients.7

      As demonstrated above, an increasing number of transplant centres have proposed to withdraw
      or avoid steroids, nevertheless calcineurin inhibitors have remained the backbone of most
      immunosuppressive protocols. The use of antibody induction therapy for pancreas transplant
      recipients has been guided by practical experience, in the absence of randomised prospective
      trials.8 A multicenter trial involving 130 kidney transplant recipients has started in our
      center, investigating the safety and efficacy of Campath-1H in combination with Tacrolimus
      monotherapy compared to a standard Tacrolimus/MMF/steroid regimen, demonstrating excellent
      results with virtually no complications or side effects with Tacrolimus monotherapy after
      Campath-1H induction. Based on the existing clinical trials and the experience of Campath-1H
      therapy in our center we would like to investigate the long-term safety and efficacy of
      Campath-1H induction and Tacrolimus monotherapy compared to a standard regimen with ATG
      induction, Tacrolimus, MMF and short term steroids in a controlled, prospective, randomised
      trial.
    

Intervention name(s): Alemtuzumab; Rabbit Anti-Human Thymocyte Globulin
Intervention type(s): Drug; Drug
Intervention description(s): Day 0: Campath 30 mg i.v. infusion over 3-6 hours; Day O: Single shot of a polyclonal antilymphocyte preparation (ATG-Fresenius - 8 mg/kg, or IMTIX-Sangstat ATG 4 mg/kg/day).
Other intervention name(s): MABCAMPATH; ATG-S FRESENIUS
Intervention MeSH terms: Alemtuzumab; Thymoglobulin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Campath 1H; Alemtuzumab; Tacrolimus; Pancreas-kidney transplantation; immunosuppression; prevention of acute rejection