Campath, Calcineurin Inhibitor Reduction and Chronic Allograft Nephropathy (3C)

• Biopsy-proven acute rejection [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]
  Primary outcome for induction therapy comparison
• Graft function [ Time Frame: 2 and 5 years post-transplantation ] [ Designated as safety issue: No ]
  Primary outcome for maintenance therapy comparison

• Graft survival [ Time Frame: 6 months, 2 and 5 years ] [ Designated as safety issue: No ]
• Serious infection [ Time Frame: 2 and 5 years ] [ Designated as safety issue: Yes ]
• Malignancy [ Time Frame: 2 and 5 years ] [ Designated as safety issue: Yes ]
• Major vascular event [ Time Frame: 2 and 5 years ] [ Designated as safety issue: No ]
  Composite of non-fatal myocardial infarction, non-fatal stroke, cardiovascular death or arterial revascularization

The 3C study will investigate whether reducing exposure to calcineurin inhibitors (by using more potent antibody induction treatment and/or an elective switch to sirolimus) can improve the function and survival of kidney transplants.

The long-term survival of kidney transplants has not improved over the past decade despite reductions in the rate of acute rejection. The commonest cause of late graft loss is chronic allograft nephropathy which is frequently caused by calcineurin inhibitor toxicity. Therefore, it may be possible to improve long-term graft outcomes by reducing the amount of calcineurin inhibitor exposure.

Two possible strategies to do this will be tested. Firstly, Campath-1H (a monoclonal lymphocyte-depleting antibody) will be compared to standard basiliximab-based induction. All patients will then receive tacrolimus-based maintenance therapy for 6 months (using lower doses in the Campath-1H arm).

At six months, patients will be re-randomised between remaining on tacrolimus and converting to sirolimus (and therefore no longer take calcineurin inhibitors). Patients will then be followed-up in clinic and through routine NHS registries to collect information on relevant outcomes (including graft function, survival, hospitalisations and death).

• Drug: Alemtuzumab
  Alemtuzumab 30 mg intravenously or subcutaneously Two doses 24 hours apart
  Other Name: Campath-1H
• Drug: Basiliximab
  20 mg intravenously Two doses 96 hours apart
  Other Name: Simulect
• Drug: Sirolimus
  Sirolimus: target trough levels 5-10 ng/mL for first 6 months, then 5-8 ng/mL
  Other Name: Rapamune
• Drug: Tacrolimus
  Target trough level 5-12 ng/mL for first 6 months after basiliximab; 5-7 ng/mL for first six months after basiliximab. 5-7 ng/mL for all participants after 6 months.
  Other Name: Prograf

• Experimental: Campath-1H/Sirolimus
  Induction therapy allocation: Campath-1H Maintenance therapy allocation (at 6 months post-transplant): Sirolimus
  Interventions:

  • Drug: Alemtuzumab
  • Drug: Sirolimus
• Experimental: Campath-1H/Tacrolimus
  Induction therapy allocation: Campath-1H Maintenance therapy allocation (at 6 months post-transplant): Tacrolimus
  Interventions:

  • Drug: Alemtuzumab
  • Drug: Tacrolimus
• Active Comparator: Basliximab/Tacrolimus
  Induction therapy allocation: Basiliximab Maintenance therapy allocation (at 6 months post-transplant): Tacrolimus
  Interventions:

  • Drug: Basiliximab
  • Drug: Tacrolimus
• Active Comparator: Basliximab/Sirolimus
  Induction therapy allocation: Basiliximab Maintenance therapy allocation (at 6 months post-transplant): Sirolimus
  Interventions:

  • Drug: Basiliximab
  • Drug: Sirolimus

Inclusion Criteria:

• men or women aged over 18 years
• recipient of kidney transplant (planned in next 24 hours)

Exclusion Criteria:

• recipients of multi-organ transplant
• previous treatment with Campath-1H
• active infection (including HIV, hepatitis B or C)
• history of anaphylaxis to humanized monoclonal antibody
• history of malignancy (except adequately treated non-melanoma skin cancer)
• loss of kidney transplant within 6 months not due to technical reasons
• medical history that might limit the individual's ability to take trial treatments for the duration of the study

• National Health Service, United Kingdom
• Pfizer
• Novartis