ASCERTAIN: Assessment of Everolimus in Addition to Calcineurin Inhibitor Reduction in the Maintenance of Renal Transplant Recipients

Study Overview
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Brief Summary
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The study is designed to evaluate whether the initiation of everolimus together with the reduction or discontinuation of calcineurin inhibitors (CNIs) will improve graft function in the maintenance of renal transplant recipients with renal impairment by reducing the progression of chronic allograft nephropathy. The development of atherosclerosis in the native arteries of the patients will also be explored.

Official Title
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Assessment of Everolimus in Addition to Calcineurin Inhibitors Reduction in Maintenance Renal Transplant Recipients

Conditions
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Renal Transplantation

Intervention / Treatment
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* Drug: Everolimus (RAD001)
* Drug: Calcineurin Inhibitors (CNI)
* Drug: Mycophenolate acid (MPA)/Azathioprine (AZA)
* Drug: Steroids


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female patient at least 18 years of age. Patient who has undergone a primary or secondary renal transplant 12-96 months ago from a living related or unrelated donor or a cadaveric donor. Patient receiving cyclosporine microemulsion with a C2-h level ≥ 400 ng/mL or tacrolimus with a C0-h level ≥ 4 ng/mL with or without mycophenolic acid or azathioprine plus or minus steroids. The immunosuppressive regimen must remain unchanged within the last 3 months. Patient with renal impairment defined as GFR between 30 and 70 mL/min/1.73 m^2 by Cockcroft-Gault formula. Exclusion Criteria: Patient who is recipient of multiple organ transplants. Patient with protein/creatinine ratio ≥ 150 (mg/mmol). Patient with a treated acute rejection episode within the last 3 months. Patient with any past or present BK-polyomavirus nephropathy. Patient with de novo or recurrent glomerular nephritis. Other protocol defined inclusion/exclusion criteria may apply.

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: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Group A: No RAD<br>Calcineurin Inhibitors (CNI) ± Mycophenolate Acid (MPA)/Azathioprine (AZA) ± Steroids | Drug: Calcineurin Inhibitors (CNI)<br> <br> Drug: Mycophenolate acid (MPA)/Azathioprine (AZA)<br> <br> Drug: Steroids<br> <br> |
| Experimental: Group B : CNI Withdrawal<br>Initiation of everolimus (8-12 ng/mL) with discontinuation of CNI. Everolimus(RAD001) 4 mg initial daily dose. | Drug: Everolimus (RAD001)<br> <br> Drug: Mycophenolate acid (MPA)/Azathioprine (AZA)<br> <br> Drug: Steroids<br> <br> |
| Experimental: Group C: CNI Reduction<br>Initiation of everolimus (3-8 ng/mL) with reduction by 70-90% in CNI blood levels. Everolimus (RAD001) 3 mg initial daily dose. | Drug: Everolimus (RAD001)<br> <br> Drug: Calcineurin Inhibitors (CNI)<br> <br> Drug: Mycophenolate acid (MPA)/Azathioprine (AZA)<br> <br> Drug: Steroids<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Renal Function Assessed by Measured GFR (mGFR) | The acceptable methods for GFR measurement were Chromium 51-Ethylenediaminetetra acetic acid (Cr-EDTA), Technetium 99-Diethylenetriaminepentacetic acid (Tc-DTPA), Iohexol clearance Inuline clearance and Iothalamate clearance. The method should have been consistent for a given patient at every time point. | 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Safety Parameters | The selected safety parameters (such as hypertension, hyperlipidemia, diabetes mellitus, anemia, malignancies ) were derived based on adverse events preferred terms defined in the analysis plan. | 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Renal transplantation, everolimus, calcineurin inhibitors, GFR