Everolimus and Low Dose CNI Compared With MMF and Full CNI Dose in Heart Transplanted Patients: One Year Follow up

Phase IV: Effect of Everolimus and CNI Minimalization on Renal Function.

The different mechanisms of action of Everolimus and cyclosporine suppress immune function in synergistic manner. Thus it is postulated that the use of Everolimus in combination with cyclosporine permits a significant cyclosporine dose reduction without loss of immunosuppressive activity in the clinical setting.

The aim of the present study is to evaluate the evolution of renal function after initiation of Everolimus and minimalisation of CNI dose.

Everolimus is a new proliferation signal inhibitor with immunosuppressive and antiproliferative activity.

The mechanism of action of Everolimus is distinct from that of calcineurin inhibitors.

Cardiac allograft vasculopathy is the major cause of late death in cardiac transplant patients.

The different mechanisms of action of Everolimus and cyclosporine suppress immune function in synergistic manner. Thus it is postulated that the use of Everolimus in combination with cyclosporine permits a significant cyclosporine dose reduction without loss of immunosuppressive activity in the clinical setting.

The aim of the present study is to evaluate the evolution of renal function after initiation of Everolimus and minimalisation of CNI dose.

Inclusion Criteria:

• Age ≥ 18 year
• Signed informed consent
• 6 months to 15 year after heart transplantation
• Stable heart allograft function without rejection for at least 12 months
• Same immunusuppressive drugs for at least 3 months
• CNI based immunusuppression, with Cyclosporin levels C0 100-200 ng/ml FK levels of 5-10 ng/ml for preserved CNI levels.
• Poor renal function: creatinine > 1.5 mg%.

Exclusion Criteria:

• Suspected non-compliance
• Intolerance to Everolimus
• Life expectancy < 1year
• Proteinuria > 1.5 g/24u/1.73m2
• Previous sirolimus treatment
• Patients who received any other investigational drug
• Patients with platelet count <50,000/mm³ before baseline.
• Presence of severe hypercholesterolemia (≥350 mg/dL; ≥9 mmol/L) or hypertriglyceridemia (≥750 mg/dL; ≥8.5 mmol/L)
• Patients with an absolute neutrophil count of ≤ 1,500/mm3 or white blood cell count of ≤ 4000/mm³ at baseline
• Patients with a known hypersensitivity to similar drugs and to the components of the formulations
• Patients being treated with terfenadine, astemizole, or cisapride.
• Patients who are treated with drugs strong inducers or inhibitors of cytochrome P450 3A4.
• Patients with any past (within the past 5 years) or present malignancy (other than excised basal cell carcinoma)
• Patients with clinically significant systemic infection.
• Existence of any surgical or medical condition, which in the opinion of the investigator, might significantly alter the absorption, distribution, metabolism and excretion of study medication, and/or the presence of severe diarrhea or active peptic ulcer.
• Females of childbearing potential who are planning to become pregnant, who are pregnant and/or lactating, who are unwilling to use effective means of contraception.