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

Phase 4

Completed

Conditions: Renal Function

Interventions: Drug: cyclosporine A
Drug: everolimus
Drug: Enteric Coated Mycophenolate Sodium (EC-MPS)
Drug: corticosteroids
Drug: Basiliximab

Registration Number: NCT00634920

Lead Sponsor: Novartis Pharmaceuticals

Brief Summary: 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

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 204

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Everolimus (CNI-free)	Enteric Coated Mycophenolate Sodium (EC-MPS)	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.
Control (CsA)	Enteric Coated Mycophenolate Sodium (EC-MPS)	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.
Everolimus (CNI-free)	corticosteroids	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.
Control (CsA)	corticosteroids	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.
Control (CsA)	cyclosporine A	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.
Everolimus (CNI-free)	everolimus	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.
Everolimus (CNI-free)	Basiliximab	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.
Control (CsA)	Basiliximab	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.

Primary Outcome Measures

Name	Time	Method
Measured Glomerular Filtration Rate	Month 12	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.

Secondary Outcome Measures

Name	Time	Method
Time to First Malignancy	Months 12, 24, 36	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.
Percentage of Participants Who Developed CAN (Chronic Allograft Nephropathy)	Month 12, Month 36	Assessed by protocol biopsies findings (Banff 1997 lesion scores and morphometry of the interstitial space)
Lipid Profile for Apolipoprotein	Months 12, 24, 36	Blood lipid levels of patients in both groups for Apolipoprotein (Apo) A1 and B.
Percentage of Participants Who Had Donor Specific Antibodies (DSA)	Month 36	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.
Lipid Profile for HDL-C, LDL-C,Total Cholesterol, and Triglycerides	Months 12, 24, 36	Blood lipid levels of patients in both groups: HDL-C, LDL-C,Total cholesterol, and triglycerides.
Number of Antihypertensive Drugs Taken	Months 12, 24, 36
Proteinuria (Measured as Urine Albumin/Creatinine Ratio (mg/mmol))	Months 12, 24, 36	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.
Health-related Quality of Life (QoL) as Measured by EuroQoL EQ-5D	Before randomization, Months 12, 36	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.
Measured Glomerular Filtration Rate	Month 36	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.
Percentage of Participants With Biopsy Proven Acute Rejection (BPAR)	Months 12, 24, 36	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.
Percentage of Participants on Antihypertensive Drugs	Months 12, 24, 36
Percentage of Participants With Graft Loss or Death	Months 12, 24, 36	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).
Percentage of Participants With Treatment Failures	Months 12, 24, 36	Treatment failure was defined as graft loss or death.
Calculated Glomerular Filtration Rate	Months 12, 36	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.
Progression of Measured Glomerular Filtration Rate	Week 7, Week 52, Month 36	Change in renal progression measured by mean mGFR from week 7 to Month 36
Time to Treatment Failure	Months 12, 24, 36	Treatment failure was defined as graft loss or death.Time to treatment failure is shown as mean time to treatment failure.
Number of Lipid-lowering Drugs Taken	Months 12, 24, 36
Percentage of Participants on Lipid-lowering Drugs	Months 12, 24, 36