Progression of Renal Interstitial Fibrosis / Tubular Atrophy (IF/TA) According to Epithelial-mesenchymal Transition (EMT) and Immunosuppressive Regimen (Everolimus Based Versus CNI Based) in de Novo Renal Transplant Recipients

• Status: Completed
• Trial end date: 2012-06-01
• Target enrollment: 0
• Participant gender: All

Summary

Recently, early biomarkers of renal interstitial fibrosis have been identified, amongst them de novo expression of vimentin by tubular epithelial cells, which is an intermediate filament, and the translocation of beta-catenin into their cytoplasm. These markers, when present, suggest that the epithelial cell undergoes a phenomenon well known as "epithelial to mesenchymal transition" (EMT) and could behaves like a myo-fibroblast. EMT is highly instrumental in several models of tissue fibrosis, including in the kidney. Actually, it has not only been demonstrated that these markers are detectable in the renal graft at an early time point post-transplant (i.e. as soon as three months), but also that the intensity of their expression correlates with the progression of interstitial fibrosis of the graft between 3 and 12 months

• Phase: Phase 3
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Novartis Pharmaceuticals
• Treatments: Basiliximab; Cyclosporine; Cyclosporins; Everolimus; Immunosuppressive Agents; Mycophenolate mofetil; Mycophenolic Acid; Sirolimus

Criteria

Inclusion Criteria:

• Recipient of a primary or secondary deceased or living (related or not) donor kidney transplant and who requires basiliximab induction therapy.

• Cold ischemia time < 30 hours.

• Women of child-bearing age, even those with a history of infertility, must have had a negative pregnancy test during the 7 days before screening or at the time of screening, and must use a recognized and reliable method of contraception throughout the study and for 2 months after discontinuing the study treatment.

• Patients who want and are able to take part in the entire study, and have given their written consent.

• Patients who are registered with a French national health insurance scheme or are covered by such a scheme.

Exclusion Criteria:

• Recipient of multi-organ transplantation, including dual kidneys, or who have previously received non renal transplant organ.

• Patients receiving a graft from a non-heart-beating donor.

• Anti-HLA antibody levels ≥ 20% in the last 3 months before the inclusion.

• ABO incompatible graft or with positive cross match T.

• Severe hyperlipidemia: total cholesterol ≥ 9.1 mmol/L (≥ 350 mg/dL) and/or triglycerides ≥ 8.5 mmol/L (≥ 750 mg/dL) despite appropriate lipid-lowering therapy.

• Known hypersensitivity or contraindications to mycophenolic acid, cyclosporine or lactose.

• Known hypersensitivity or contraindications to macrolides or drugs of the mTOR inhibitor class.

• HIV seropositive, or active chronic hepatitis B (HBs Ab) or C. Results obtained during the 6 months before the inclusion are accepted. Recipients from donors with hepatitis B or C will be excluded.

• Patients with thrombocytopenia (≤ 75000/mm3), absolute neutrophil count (≤ 1500/mm3), leukocytopenia (≤ 2500/mm3) and/or hemoglobin < 8g/dL at the inclusion visit.

• ASAT, ALAT or total bilirubin ≥ 3 UNL.

• Uncontrolled severe infection, severe allergy requiring an acute or chronic treatment.

• Patients with a malignant disease or previous malignancy in the past 5 years, with the exception of excised basal cell or squamous cell carcinoma and in situ cervical cancer treated.

• Medical or surgical condition, with the exception of the transplantation, which in the investigator's opinion could exclude the patient.

• Women who are pregnant, breastfeeding or of reproductive age and refuse or are unable to use a recognized and reliable method of contraception.

• Patients with symptoms of significant mental or somatic disease. Inability to cooperate or communicate with the investigator.

• Patients under supervision or guardianship or any patient subject to legal protection

Randomization criteria:

Eligibility criteria (no later than 4 months post-transplantation:

• Renal graft biopsy performed at M3 and adequate histological material sent within the deadline for the determination of EMT.

• Woman of child-bearing potential, even in case of a history of infertility, must use a recognized and reliable method of contraception throughout the study and for 2 months after discontinuing the study treatment.

Non-eligibility criteria (no later than 4 months post-transplantation):

• Acute rejection histologically proven between transplantation and randomization (local reading).

• Acute subclinical rejection diagnosed on the M3 biopsy (except borderline lesions) (local reading).

• Positive anti-donor antibodies at M3.

• Estimated glomerular filtration rate (eGFR) < 30 ml/min/1.73 m2 (MDRDa).

• Proteinuria ≥ 1 g/24h.

• Severe hyperlipidemia: total cholesterol ≥ 9.1 mmol/L (≥ 350 mg/dL) and/or triglycerides ≥ 8.5 mmol/L (≥ 750 mg/dL) despite appropriate lipid-lowering therapy.

• Thrombocytopenia (≤ 75000/mm3), absolute neutrophil count (≤ 1500/mm3), leukocytopenia (≤ 2500/mm3) and/or hemoglobin < 8 g/dL.

• ASAT, ALAT or total bilirubin ≥ 3 UNL.

• Medical or surgical condition which in the investigator's opinion might exclude the patient.

Other protocol-defined inclusion/exclusion criteria may apply.