Evaluation of Early Conversion to Everolimus From Cyclosporine in de Novo Renal Transplant Recipients

Study Overview
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Brief Summary
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This study is designed to evaluate if early conversion to everolimus from cyclosporine in de novo renal transplant recipients can improve long-term renal function and slow down the progression of chronic allograft nephropathy

Official Title
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A Controlled Randomized Open-label Multicenter Study Evaluating if Early Conversion to Everolimus (Certican) From Cyclosporine (Neoral) in de Novo Renal Transplant Recipients Can Improve Long-term Renal Function and Slow Down the Progression of Chronic Allograft Nephropathy

Conditions
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Renal Function

Intervention / Treatment
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* Drug: everolimus
* Drug: cyclosporine A
* Drug: Enteric Coated Mycophenolate Sodium (EC-MPS)
* Drug: corticosteroids
* Drug: Basiliximab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: First or second single renal transplant from deceased or living donor Exclusion criteria Recipient of organs other than a renal transplant Present malignancy (within the last 2 years) other than excised basal cell or squamous cell carcinoma of the skin Severe liver disease At the time of randomization 7 weeks after transplantation In addition to the above criteria the following must be met at time of randomization: Inclusion Criteria: Patients maintained on a triple immunosuppressive regime consisting of cyclosporine, Enteric coated mycophenolate, and corticosteroids Patients completed the first 7 weeks without experiencing any rejection Exclusion Criteria: Graft loss Low hemoglobin value, low number of white blood cells or platelets High cholesterol values Proteinuria Wound healing problems Current severe major local or systemic infection Renal insufficiency 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 |
| --- | --- |
| Experimental: Everolimus (CNI-free)<br>Patients in this group were converted to everolimus immunosuppressive therapy. The patients in the everolimus group were treated with everolimus, off-label (CNI-free) use, and EC-MPS and corticosteroids in accordance with local practice and approved label. Conversion to everolimus was as follows: Day 1: begin everolimus 3 mg in the evening. Usual morning dose of CsA and 50% reduced evening dose of CsA Day 2: everolimus 2 mg in the morning and 2 mg in the evening, complete discontinuation of CsA Day 3 or 4, and onwards: everolimus according to trough level 6-10 ng/mL.The given total daily dose of the immunosuppressive drugs (everolimus) was divided into two (equal) doses, applied 12 hours apart. | Drug: everolimus<br>* Everolimus (Certican®) tablets administered orally in two divided doses (b.i.d.) at a starting dose of 4 mg/day adjusted to target a trough blood concentration between 6 and 10 ng/mL in period 2.<br>* Other names: Certican;Drug: Enteric Coated Mycophenolate Sodium (EC-MPS)<br>* Target dose 1440 mg in the control group, target dose 1080 in the everolimus group (higher dose in the CsA group because of interactions of CsA on gastric reabsorption of mycophenolate)<br>* Other names: Myfortic;Drug: corticosteroids<br>* For both groups: minimum corticosteroid dose of 10 mg until week 12, 5-10 mg until month 12, month 12-36 corticosteroid treatment on investigator's descretion.<br>* Other names: Prednisolone;Drug: Basiliximab<br>* Induction therapy 20 mg basiliximab on Day 0 prior to reperfusion and 20 mg on Day 4 post-TX.<br>* Other names: Simulect;|
| Active Comparator: Control (CsA)<br>Patients in the control group continued on an immunosuppressive regimen. The patients in this Control group were treated with CsA, EC-MPS and corticosteroids in accordance with local practice and approved label. The given total daily dose of the immunosuppressive drugs (CsA and EC-MPS) was divided into two (equal) doses, applied 12 hours apart. | Drug: cyclosporine A<br>* CsA (Sandimmun Neoral), based on C0-h levels 75-200 ng/mL or C2-h levels 700 900 ng/mL from randomization to Month 6, or C0-h levels 50-150 ng/mL or C2-h levels 600 800 ng/mL from Month 6 to Month 36, according to local method<br>* Other names: Sndimmun Neoral;Drug: Enteric Coated Mycophenolate Sodium (EC-MPS)<br>* Target dose 1440 mg in the control group, target dose 1080 in the everolimus group (higher dose in the CsA group because of interactions of CsA on gastric reabsorption of mycophenolate)<br>* Other names: Myfortic;Drug: corticosteroids<br>* For both groups: minimum corticosteroid dose of 10 mg until week 12, 5-10 mg until month 12, month 12-36 corticosteroid treatment on investigator's descretion.<br>* Other names: Prednisolone;Drug: Basiliximab<br>* Induction therapy 20 mg basiliximab on Day 0 prior to reperfusion and 20 mg on Day 4 post-TX.<br>* Other names: Simulect;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Measured Glomerular Filtration Rate | To compare the efficacy between treatment regimens by assessing the difference in renal function evaluated by mean measured glomerular filtration rate (mGFR) 12 months after renal transplantation (TX). The mGFR was measured using Iohexol or Cr-EDTA clearance according to local practice. | Month 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Measured Glomerular Filtration Rate | Progression of renal function measured by mean mGFR at 36 months after renal TX. The mGFR was measured using Iohexol or Cr-EDTA clearance according to local practice. | Month 36 | 
| Calculated Glomerular Filtration Rate | The GFR was calculated according to the Modification of Diet in Renal Disease Study Group (MDRD) method, the Cockcroft-Gault method, and the Nankivell formula. cGFR was calculated from blood samples collected at predefined time points. | Months 12, 36 | 
| Progression of Measured Glomerular Filtration Rate | Change in renal progression measured by mean mGFR from week 7 to Month 36 | Week 7, Week 52, Month 36 | 
| Percentage of Participants Who Developed CAN (Chronic Allograft Nephropathy) | Assessed by protocol biopsies findings (Banff 1997 lesion scores and morphometry of the interstitial space) | Month 12, Month 36 | 
| Percentage of Participants With Biopsy Proven Acute Rejection (BPAR) | A BPAR was defined as a biopsy graded IA, IB, IIA, IIB, or III (Banff 97 classification). Biopsy graded IA: Significant interstitial infiltration (> 25% of parenchyma) and foci of moderate tubulitis (> 4 mononuclear cells/tubular cross section or group of 10 tubular cells). Biopsy grade IB: Significant interstitial infiltration (> 25% of parenchyma) and foci of severe tubulitis (> 10 mononuclear cells/tubular cross section or group of 10 tubular cells). Biopsy grade IIA: Mild to moderate intimal arteritis. Biopsy graded IIB: Severe intimal arteritis comprising > 25% of the lumenal area. | Months 12, 24, 36 | 
| Percentage of Participants With Graft Loss or Death | The allograft was presumed to be lost on the day the patient started dialysis and was not able to subsequently be removed from dialysis. If the patient underwent a graft nephrectomy, the day of nephrectomy was the day of graft loss. Graft loss was considered an SAE (serious adverse event). | Months 12, 24, 36 | 
| Time to Treatment Failure | Treatment failure was defined as graft loss or death.Time to treatment failure is shown as mean time to treatment failure. | Months 12, 24, 36 | 
| Percentage of Participants With Treatment Failures | Treatment failure was defined as graft loss or death. | Months 12, 24, 36 | 
| Time to First Malignancy | This is the time to first diagnosed malignancy. Malignancies (skin- or solid cancer) were listed whether they reoccurred in situ, were metastatic or de novo. This is shown as mean time. | Months 12, 24, 36 | 
| Lipid Profile for Apolipoprotein | Blood lipid levels of patients in both groups for Apolipoprotein (Apo) A1 and B. | Months 12, 24, 36 | 
| Lipid Profile for HDL-C, LDL-C,Total Cholesterol, and Triglycerides | Blood lipid levels of patients in both groups: HDL-C, LDL-C,Total cholesterol, and triglycerides. | Months 12, 24, 36 | 
| Number of Lipid-lowering Drugs Taken |  | Months 12, 24, 36 | 
| Percentage of Participants on Lipid-lowering Drugs |  | Months 12, 24, 36 | 
| Number of Antihypertensive Drugs Taken |  | Months 12, 24, 36 | 
| Percentage of Participants on Antihypertensive Drugs |  | Months 12, 24, 36 | 
| Proteinuria (Measured as Urine Albumin/Creatinine Ratio (mg/mmol)) | Proteinuria is when a large amount of protein, that should remain circulating in a person's blood, is spilled into their urine and eliminated from the body. | Months 12, 24, 36 | 
| Percentage of Participants Who Had Donor Specific Antibodies (DSA) | Venous blood was drawn for donor specific (DSA) measurements prior to transplantation and at the final visit (36 months). The blood sample was first screened for the presence of PRA i.e. donor specific Immunoglobulin-G antibodies against specific HLA antigens. If PRA antibodies were detected, the blood sample was tested for specific DSAs on single antigen Luminex beads (coated with single HLA class I or II molecules). In this way, the specificity of these antibodies could be determined. | Month 36 | 
| Health-related Quality of Life (QoL) as Measured by EuroQoL EQ-5D | Health-related QoL was assessed using the EQ-5D questionnaire. The EQ-5D self-report questionnaire consists of the EQ-5D descriptive system that measures health-related quality of life on 5 dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) each of which can take one of three responses. The responses record three levels of severity (no problems/moderate problems/severe problems) within a particular EQ-5D dimension. Scores are transformed to a range of 0-1, in which higher scores reflect better health status. | Before randomization, Months 12, 36 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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De novo renal transplantation