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

Novartis Pharmaceuticals204 enrolled

Overview

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

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

204

Conditions

Renal Function

Interventions

everolimusDRUG

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.

cyclosporine ADRUG

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

Enteric Coated Mycophenolate Sodium (EC-MPS)DRUG

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)

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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.

Locations (8)

Novartis Investigative Site

Aarhus N, Denmark

Novartis Investigative Site

Copenhagen, Denmark

Novartis Investigative Site

Herlev, Denmark

Novartis Investigative Site

Odense C, Denmark

Outcomes

Primary Outcomes

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.

Time frame: Month 12

Secondary Outcomes

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.

Time frame: 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.

Time frame: Months 12, 36

Progression of Measured Glomerular Filtration Rate

Change in renal progression measured by mean mGFR from week 7 to Month 36

Time frame: 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)

Time frame: 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.

Data from ClinicalTrials.gov

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corticosteroidsDRUG

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.

BasiliximabDRUG

Induction therapy 20 mg basiliximab on Day 0 prior to reperfusion and 20 mg on Day 4 post-TX.

Novartis Investigative Site

Oslo, Norway

Novartis Investigative Site

Gothenburg, Sweden

Novartis Investigative Site

Malmo, Sweden

Novartis Investigative Site

Uppsala, Sweden

Time frame: 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).

Time frame: 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.

Time frame: Months 12, 24, 36

Percentage of Participants With Treatment Failures

Treatment failure was defined as graft loss or death.

Time frame: 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.

Time frame: Months 12, 24, 36

Lipid Profile for Apolipoprotein

Blood lipid levels of patients in both groups for Apolipoprotein (Apo) A1 and B.

Time frame: 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.

Time frame: Months 12, 24, 36

Number of Lipid-lowering Drugs Taken

Time frame: Months 12, 24, 36

Percentage of Participants on Lipid-lowering Drugs

Time frame: Months 12, 24, 36

Number of Antihypertensive Drugs Taken

Time frame: Months 12, 24, 36

Percentage of Participants on Antihypertensive Drugs

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: Before randomization, Months 12, 36