Efficacy, Safety and Evolution of Cardiovascular Parameters in Renal Transplant Recipients

Study Overview
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Brief Summary
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The purpose of this study was to determine whether an early Calcineurin Inhibitor (CNI) to everolimus conversion at 10-14 weeks post transplantation improves renal allograft function without compromising efficacy compared to standard CNI treatment in de novo renal allograft recipients. In addition, the study was designed to evaluate the impact of a CNI-free regimen on evolution of cardiovascular parameters in de novo renal allograft recipients

Detailed Description
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This was a 24-month, multi-center, randomized, open-label trial with two parallel arms in adult de novo renal allograft recipients. The study consisted of a run-in period from transplantation to Randomization and a treatment period from Randomization until Month 24. At baseline visit, patients were transplanted and entered the run-in period from transplantation (Baseline) to Randomization (week 10-14 post-transplantation). At Week 10-14, eligible patients were randomized into one of the 2 treatment arms: standard CNIs and Myfortic versus everolimus and Myfortic and entered the treatment period of the study from Randomization to Month 24. Patients in both arms received steroids as per center practice and in any caseat least 5 mg/Day. At Randomization, patients were stratified according to their renal allograft function and previous cardiovascular events. The main analysis was performed at Month 12 and the follow-up analysis was performed at Month 24.

Official Title
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A 24-month, Multi-center, Open-label, Randomized, Controlled Trial to Investigate Efficacy, Safety and Evolution of Cardiovascular Parameters in de Novo Renal Transplant Recipients After Early Calcineurin Inhibitor to Everolimus Conversion

Conditions
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Kidney Transplantation

Intervention / Treatment
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* Drug: Everolimus
* Drug: Prograf or Neoral


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria at Baseline: Male or female renal allograft recipients at least 18 years old. Written informed consent. Patient receiving a primary or secondary kidney transplant from a cadaveric or living unrelated-/related donor. Cold ischemia time (CIT) < 24 hours. Negative pregnancy test for female patients. Inclusion Criteria at Randomization: Patients on CNI (TAC or CsA) + Myfortic + steroids. Serum creatinine < 2.8 mg/dL (250 µmol/L) and an actual eGFR (MDRD4) ≥ 25 mL/min/1.73m exp2 (without renal replacement therapy). Exclusion Criteria at Baseline: Patients fulfilling any of the following criteria are not eligible for inclusion in this study: Recipient of multiple organ transplants. Recipient of ABO incompatible allograft or a positive cross-match. Panel Reactive Antibodies (PRA) level ≥ 30 %. Positive test for human immunodeficiency virus (HIV). Patient receiving an allograft from a Hepatitis B surface Antigen (HBsAg) or a Hepatitis C Virus (HCV) positive donor. HBsAg and/or a HCV positive patient with evidence of elevated LFTs (ALT/AST levels ≥ 2.5 times ULN). Severe restrictive or obstructive pulmonary disorders. Patient with severe allergy requiring acute or chronic treatment or hypersensitivity to any of the study drugs or similar drugs. Severe hypercholesterolemia or hypertriglyceridemia. Low platelet count. Low white blood cell count. History of malignancy of any organ system Exclusion Criteria at Randomization: Graft loss. Patient on renal replacement therapy. Patient who experienced severe humoral and/or cellular rejection (BANFF ≥ IIb). Patient with ≥ 2 episodes of AR or an AR episode that needed antibody treatment. Patient with ongoing or currently treated AR (2 weeks prior to randomization). Proteinuria > 1 g/day. Patients with recurrence of Focal Segmental Glomerulosclerosis (FSGS). Low platelet count; Low white blood cell count; Low absolute neutrophil count; Low hemoglobin. Severe liver disease. Systemic infection requiring continued therapy that would interfere with the objectives of the study. Severe hypercholesterolemia or hypertriglyceridemia. Patients with ongoing wound healing problems, clinically significant infection requiring continued therapy. Presence of intractable immunosuppressant complications or side effects. Patients on anticoagulants that prevents renal allograft biopsy. Use of prohibited medication. Use of immunosuppressive agents not utilized in the protocol. Pregnant or nursing (lactating) women. Women of child-bearing potential not using a highly effective method of birth control.

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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Everolimus<br>Conversion from CNI to everolimus in combination with Myfortic and steroids | Drug: Everolimus<br>* Early CNI to everolimus conversion<br>* Other names: Certican, Zortress, RAD001;|
| Active Comparator: Calcineurin inhibitor, Prograf or Neoral<br>Control arm: CNI continuation, either Prograf or Neoral in combination with Myfortic and steroids | Drug: Prograf or Neoral<br>* Active CNI-based control (Prograf or Neoral)<br>* Other names: Tacrolimus or Cyclosporine;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Estimated Glomerular Filtration Rate (eGFR) | Assessment of renal function by comparing change from randomization to Month 12 in eGFR (MDRD4) between treatment arms (Full analysis set). Renal function was assessed by estimated Glomerular Filtration Rate (eGFR) using the Modification of Diet in Renal Disease (MDRD) formula. MDRD formula: GFR [mL/min/1.73m˄2] = 186.3*(C˄-1.154)*(A˄-0.203)*G*R. DEFINITIONS: C = serum concentration of creatinine [mg/dL]; A = age [years]; G = 0.742 when gender is female, otherwise G = 1; R = 1.21 when race is black, otherwise R = 1 | Month 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Composite Efficacy Endpoint for Each Arm at Month 12 and Month 24 | Efficacy failure rate used the composite endpoint of: (1) treated biopsy-proven acute rejection (BPAR)*, (2) graft loss**, or (3) death . *A treated BPAR was defined as a biopsy graded IA, IB, IIA, IIB, or III and which was treated with anti-rejection therapy. **Graft loss is defined as when the allograft was presumed lost on the day the participant started dialysis and was not able to subsequently be removed from dialysis or re-transplanted. | at 12 months and month 24 post-transplantation | 
| Change in Left Ventricular Mass Index (LVMi) From Randomization to Month 12 and Month 24 | Evolution of left ventricular mass and hypertrophy were evaluated by left ventricular mass index (LVMi) assessed by echocardiography. LVMi is derived using a standard formula from dimensional measurements on the echocardiogram. Analysis of covariance was applied with treatment, center (as a random effect), and donor type as factors and LVMi at Randomization as covariate. | Randomization, Month 12 and Month 24 | 
| Comparison of Incidence Rates of Efficacy Endpoints Between Treatment Arms (Full Analysis Set - 24 Month Analysis) | (treated BPAR ≥ IB, graft loss or death)A comparison of the incidence rates for the individual components of the composite efficacy endpoint between treatment arms | at 24 months post-transplantation | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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de novo renal allograft recipients, renal allograft function, CNI-free regimen