CamTac Trial:Campath-Tacrolimus vs IL2R MoAb/Tacrolimus/MMF in Renal Transplantation

Study Overview
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Brief Summary
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The advent of new, potent immunosuppressive (anti-rejection) drugs over the past ten years has substantially reduced the risk of rejection after kidney transplantation, has allowed the development of immuno-suppressive regimens that do not use long-term steroids (steroid avoidance), and has improved transplant success rates both in the short and medium term. The main new agents used in these modern regimens are the calcineurin inhibitor (CNI) tacrolimus; the anti-proliferative agent mycophenolate; and induction agents which are used to provide effective early suppression of the rejection process; these include monoclonal antibodies (MoAb) such as IL-2 receptor blocking antibodies (IL-2R MoAb: basiliximab and daclizumab) and the anti-CD52 antibody Campath-1H (alemtuzumab). Although almost all modern immunosuppressive regimens involve one or more of these agents, it is not known which is the safest and most effective combination. This randomised controlled trial compares two steroid sparing regimens which have been used with very good short and medium term results at St Mary's Hospital Renal and Transplant Unit over the last 5 years. The primary hypothesis is that the alemtuzumab/tacrolimus regimen is as effective and safe as the IL-2R MoAb/tacrolimus/mycophenolate regimen.

Detailed Description
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RECENT EXPERIENCE AT ST MARY'S: The St Mary's Hospital Renal Unit (now combined with the Hammersmith Hospital Renal Unit at the West London Renal and Transplant Centre) introduced Tacrolimus based immunosuppression in 1995, developing a steroid avoidance regimen based on Tacrolimus, Mycophenolate, and IL-2R MoAb between 2000 and 2002, and moving to Campath-1H as an induction agent in 2004. Results over this period have been excellent with five and ten year survivals with functioning graft rates of 82% and 72% for the first 260 cadaveric kidney transplants performed since 1995. The two most recent regimens used at St Mary's have both produced very low (< 10%) rejection rates, and very good (> 90%) short-term rejection-free patient and graft survival rates. Between 2002 and 2004, the regimen consisted of induction with an Interleukin-2 (IL2) -Receptor blocking monoclonal antibody with Tacrolimus and Mycophenolate as long term maintenance therapy. In patients without rejection steroid usage was limited to the first 7 days post-transplant. The current regimen uses Campath-1H (which is now well established as an induction agent in renal transplantation for induction), with Tacrolimus monotherapy maintenance and an identical short-course steroid regimen. CHARACTERISTICS OF THE TWO REGIMENS TO BE COMPARED: The IL2R MoAb/Tacrolimus/Mycophenolate/Short-course steroids regimen (2002-2004 Regimen 1) has the advantage of flexibility in terms of adjusting maintenance therapy to allow clinical response to patients and transplants with different tolerance of the two maintenance agents, but involves increased expense in terms of using and monitoring the blood levels of two modern (and hence expensive) agents. In addition, patients have long-term exposure to the anti-proliferative agent Mycophenolate, which can be associated with increased risk of infection, gastrointestinal side effects, and skin malignancies. The Campath-1H/Tacrolimus/Short-course steroids regimen (2004-current, Regimen 2) has the advantage of highly effective immunosuppression in the initial 3-month period, allowing lower doses of the potentially nephrotoxic Tacrolimus to be used, and simplicity, but exposes patients to a period of several months of lymphopenia (reduced lymphocyte counts in the blood) after Campath administration, and reliance on Tacrolimus monotherapy for maintenance which might lead to greater long term Tacrolimus exposure. PROPOSED STUDY: In order to allow a proper comparison of these two anti-rejection treatment combinations we propose a randomised trial which will enable us to consider the relative merits of the two regimens without the introduction of bias associated with using historical control groups. Transplant recipients will be randomised in a 1:2 ratio to regimen 1 and regimen 2.

Official Title
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A Randomised Controlled Comparison of Campath-Tacrolimus vs IL2R MoAb-Tacrolimus/Mycophenolate Mofetil in Kidney Transplantation

Conditions
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Kidney Transplantation, Kidney Diseases, Kidney Failure

Intervention / Treatment
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* Drug: Campath
* Drug: Daclizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Kidney transplant recipients under the care of the West London Renal and Transplant Centre Exclusion Criteria: Patients who are unable to give written informed consent Simultaneous kidney/pancreas transplant recipients Non-heart beating deceased donor transplant recipients Patients who would not be offered Campath-1H induction under our current protocol (patients with previous malignancy or with previous exposure to cytotoxic or antiproliferative agents)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Campath-Tacrolimus<br>Campath induction with 7-day short-course steroids followed by tacrolimus monotherapy | Drug: Campath<br>* Monoclonal antibody induction therapy<br>* Other names: Alemtuzumab;|
| Experimental: Daclizumab-Tacrolimus-Mycophenolate<br>Daclizumab induction with 7-day short-course steroids followed by Tacrolimus and Mycophenolate mofetil therapy | Drug: Daclizumab<br>* Monoclonal antibody induction therapy<br>* Other names: Zinbryta;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| One Year Survival With a Functioning Graft | One year survival with a functioning graft, defined as transplant recipient remaining alive and dialysis-independent. the functioning graft is a graft still functioning at the time of analysis. Graft function was estimated using the Modification of Diet in Renal Disease four-variable formula and comparison of graft function between arms undertaken with Student'st test. | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Occurrence of Rejection Episodes | Biopsy-proven rejection episodes classified using Banff criteria | 1 year | 
| Occurrence of Significant Episodes of Infection | Occurence of infection of sufficient severity to produce positive cultures or Nucleic-acid test results from blood, urine, or other body fluids | 1 year | 
| Initial Length of Stay in Hospital |  | 1 year | 
| Presence in the Blood of Cells Which Might Trigger Rejection in, or Promote Tolerance to the Graft |  | 3 years | 
| Early Development of Scarring in the Grafts | Biopsy proven Calcineurin Inhibitor (CNI) toxicity free survival | 1 year | 
| Graft Function: Level of Creatinine |  | 2 years | 
| Patient Survival Censored for Death With Function | Cumulative patient survival | 2 years | 
| Graft Survival Censored for Death With Function | Graft survival (defined as grafts maintaining dialysis independence) | 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Kidney Transplantation, Kidney Disease, Kidney Failure, Graft Rejection