Campath, Calcineurin Inhibitor Reduction and Chronic Allograft Nephropathy

Study Overview
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Brief Summary
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The 3C study is investigating 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.

Detailed Description
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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 were tested. Firstly, Campath-1H (a monoclonal lymphocyte-depleting antibody) was compared to standard basiliximab-based induction. All patients then received tacrolimus-based maintenance therapy for 6-months (using lower doses in the Campath-1H arm). At six months, patients were re-randomized between remaining on tacrolimus and converting to sirolimus (and therefore no longer taking calcineurin inhibitors). Patients were then followed-up in clinic and through routine NHS registries to collect information on relevant outcomes (including graft function, survival, hospitalisations and death).

Official Title
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Open-label, Randomised Multicentre Study of CAMPATH-1H Versus Basiliximab Induction Treatment and Sirolimus Versus Tacrolimus Maintenance Treatment for the Preservation of Renal Function in Patients Receiving Kidney Transplants

Conditions
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Kidney Transplantation

Intervention / Treatment
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* Drug: Alemtuzumab
* Drug: Basiliximab
* Drug: Sirolimus
* Drug: Tacrolimus


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 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: Treatment
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Alemtuzumab/Sirolimus<br>Induction therapy allocation: Alemtuzumab (Campath-1H). Maintenance therapy allocation (at 6-months post-transplant): Sirolimus | Drug: Alemtuzumab<br>* Alemtuzumab 30 mg intravenously or subcutaneously, two doses 24 hours apart<br>* Other names: Campath-1H;Drug: Sirolimus<br>* Sirolimus: target trough levels 6-12 ng/mL for first 6-months after maintenance therapy randomization, then 5-10 ng/mL<br>* Other names: Rapamune;|
| Experimental: Alemtuzumab/Tacrolimus<br>Induction therapy allocation: Alemtuzumab (Campath-1H). Maintenance therapy allocation (at 6-months post-transplant): Tacrolimus | Drug: Alemtuzumab<br>* Alemtuzumab 30 mg intravenously or subcutaneously, two doses 24 hours apart<br>* Other names: Campath-1H;Drug: Tacrolimus<br>* Tacrolimus: target trough levels 5-7 ng/mL after maintenance therapy randomization.<br>* Other names: Prograf;|
| Active Comparator: Basiliximab/Tacrolimus<br>Induction therapy allocation: Basiliximab. Maintenance therapy allocation (at 6-months post-transplant): Tacrolimus | Drug: Basiliximab<br>* 20 mg intravenously, two doses 96 hours apart<br>* Other names: Simulect;Drug: Tacrolimus<br>* Tacrolimus: target trough levels 5-7 ng/mL after maintenance therapy randomization.<br>* Other names: Prograf;|
| Active Comparator: Basiliximab/Sirolimus<br>Induction therapy allocation: Basiliximab. Maintenance therapy allocation (at 6-months post-transplant): Sirolimus | Drug: Basiliximab<br>* 20 mg intravenously, two doses 96 hours apart<br>* Other names: Simulect;Drug: Sirolimus<br>* Sirolimus: target trough levels 6-12 ng/mL for first 6-months after maintenance therapy randomization, then 5-10 ng/mL<br>* Other names: Rapamune;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Biopsy-proven Acute Rejection at 6-months After Randomization to Induction Therapy | Occurence of biopsy-proven acute rejection events at 6-months after transplantation during Period 1 (randomization to induction therapy (Campath-1H and Tacrolimus, or Basiliximab and Tacrolimus)) | 6 months post-transplantation | 
| Graft Function (at 18-months After Randomization to Maintenance Therapy) | Estimated glomerular filtration rate (estimated using MDRD formula) at 18-months after maintenance therapy randomization to either Sirolimus or Tacrolimus. | 2 years post-transplantation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Graft Failure (at 6-months After Randomization to Induction Therapy) | Return to dialysis or re-transplantation by 6-months after randomization to induction therapy. | 6 months post-transplantation | 
| Number of Participants With Graft Failure (at 18-Months After Randomization to Maintenance Therapy) | Return to dialysis or re-transplantation by 18-months after randomization to maintenance therapy. | 2 years post-transplantation | 
| Number of Participants With Serious Infection (at 6-months After Randomization to Induction Therapy) | Occurrence of any serious infection (opportunistic or requiring admission to hospital) reported within Period 1 (randomization to induction therapy of either Alemtuzumab (Campath-1H) and Tacrolimus, or Basiliximab and Tacrolimus). | 6-months post-transplantation | 
| Number of Participants With Serious Infection (at 18-months After Randomization to Maintenance Therapy) | Occurrence of any serious infection (opportunistic or requiring admission to hospital) reported during Period 2 (maintenance therapy randomization to either Sirolimus or Tacrolimus). | 2 years post-transplantation | 
| Number of Participants With Cancer (at 18-months After Randomization to Maintenance Therapy) | Occurrence of any cancer reported during Period 2 (maintenance therapy randomization to either Sirolimus or Tacrolimus). | 2 years post-transplantation | 
| Number of Participants With Major Vascular Event (at 18-months After Randomization to Maintenance Therapy) | Composite of non-fatal myocardial infarction, non-fatal stroke, cardiovascular death or arterial revascularization | 2 years post-transplantation | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Kidney transplantation, Alemtuzumab, Sirolimus, Basiliximab, Tacrolimus, Campath-1H