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
Condition: Renal Interstitial Fibrosis
MeSH terms: Lung Diseases, Interstitial; Fibrosis
Intervention: Certican®; Neoral; Myfortic; Simulect®; Corticosteroids
Intervention description: Certican® was supplied to the participating centers by Novartis for the whole duration of the study in the form of tablets containing 0.75, 0.5 and 0.25 mg and packaged in blister packs.; Neoral® was also supplied to participating centers for the entire duration of the study in the form of soft capsules of 10 mg, 25 mg, 50 mg and 100 mg, and packaged in blister packs.; Myfortic ® was supplied to the participating centers for the duration of the study in the form of 180 and 360 mg gastro-resistant, film-coated tablets. Myfortic® treatment was provided to patients preoperatively or within 24 hours post-transplantation according to the practices of the center. The starting dose was generally 1,440 mg/day, in 2 daily oral fractions, administered at 12 hour intervals up to randomization. Depending on the practices of the center and for the first 6 weeks post-transplantation, a maximum daily dose of 2160 mg of Myfortic® could be administered. In the Neoral® group, the daily dose of 1440 mg was maintained throughout the study.
In the Certican® group, the dose was halved (i.e. 720 mg/day) on introducing Certican® and maintained at 720 mg/day until the end of the study.
An increase in the daily dose of Myfortic® (in the Certican® group) was not authorized unless this was a temporary increase that did not exceed a period of 14 consecutive days.; The administration of Simulect® was part of the standard immunosuppressant therapy. This induction therapy was provided to patients in the form of commercial ampoules each containing 20 mg. Simulect® was administered to each patient at the dose of 20 mg on D0 and D4 post-transplantation.; An intravenous steroid treatment could be administered peri or intraoperatively according to local practice at each center. Oral steroid treatment was quickly introduced (in the week following transplantation) at a daily dose of 20 mg and was then reduced and continued throughout the study at a minimum dose of 5 mg/day.
Intervention MeSH terms: Cyclosporine; Mycophenolic Acid; Everolimus; Cyclosporins; Basiliximab
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 194.0
Sex: All
Minimum age: 19 Years
Maximum age: 75 Years
Healthy volunteers: No
Keywords: De Novo renal transplantation

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
    

Eligibility 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.