Efficacy, Tolerability and Safety of Early Introduction of Everolimus, Reduced Calcineurin Inhibitors and Early Steroid Elimination Compared to Standard CNI, Mycophenolate Mofetil and Steroid Regimen in Paediatric Renal Transplant Recipients
Condition: Prevention of Acute Rejection in Paediatric Recipients of a Renal Transplant
Intervention: RAD001; MMF
Intervention description: Everolimus (C0 trough level of 3-8 ng/mL) in combination with reduced dose tacrolimus and steroids withdrawal at 6 months after transplant; MMF (Cellcept®): 600mg/m2/dose twice daily (1200 mg/m2/day) in combination with tacrolimus (Prograf) and standard dose steroids
Intervention MeSH terms: Everolimus
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 106.0
Sex: All
Minimum age: 1 Year
Maximum age: 18 Years
Healthy volunteers: No
Keywords: Paediatric kidney transplantation; Early MMF to everolimus conversion; Composite efficacy (biopsy-proven acute rejection, graft loss or death); Renal function

Summary:

      The purpose of this study is to determine if everolimus combined with reduced exposure CNI
      (TAC) is efficacious and safe and will support corticosteroid elimination compared to a
      standard exposure CNI (TAC) + MMF + steroid regimen after paediatric kidney transplantation.
      An additional purpose of the study is to assess the effect of the combination of EVR and
      reduced exposure CNI (TAC) on renal function.

      This study is part of the requirements of the Paediatric Investigational Plan approved by
      Paediatric Committee at the European Medicines Agency (PDCO/EMA) on September 10, 2010, and
      is intended to support the indication of everolimus in the prevention of acute rejection in
      paediatric recipients of a renal transplant.
    

Eligibility criteria:

        Inclusion Criteria:

        Inclusion criteria at baseline:

          1. Written informed consent/assent must be obtained from the parent(s) or legal guardian
             before any assessment is performed.

          2. Primary or secondary paediatric kidney transplant recipient aged greater than or equal
             to 1 year and younger than 18 years receiving a deceased donor or non-HLA identical
             living donor (related or unrelated) renal transplant.

        Inclusion criteria at randomization:

          1. Patients on TAC + MMF + steroids.

          2. Renal function with eGFR > 40 ml/min/1.73 m2 (Schwartz formula - abbreviated).

        Exclusion Criteria:

        Exclusion criteria at baseline:

          1. Recipients of kidneys from donors with known renal disease (such as diabetes
             nephropathy, nephrosclerosis), at the time of transplant.

          2. Recipients of a kidney with a cold ischemia time > 24 hours.

          3. History of hypersensitivity or contraindications to any of the study drugs or to drugs
             of similar chemical classes, or to any of the excipients.

          4. History of malignancy of any organ system treated or untreated, carrying possible risk
             of recurrence according to current guidelines (Appendix 10 of protocol).

        Exclusion criteria at randomization:

          1. Use of other investigational drugs at the time of randomization, or within 30 days or
             5 half-lives prior randomization, whichever is longer.

          2. Patients with ongoing or recently (within 2 weeks prior to randomization) treated
             episodes of acute rejection (any grade) or a steroid resistant acute rejection at the
             time of randomization.

          3. Patients who experienced acute cellular rejection (Banff ≥1B) or any antibody mediated
             acute rejection or patients considered at high risk of antibody mediated acute
             rejection by the investigator assessment (e.g. presence of newly formed DSA,
             histological suspicion) at any time before randomization (as the DSA quantitative
             threshold to define high risk is not fully established, the assessment of the risk
             will be made after discussion between the laboratory expert and the investigator who
             will take into account all information available and apply best judgment).

          4. Patients with ongoing wound healing problems, clinically significant wound infection
             requiring continued therapy or other severe surgical complication in the opinion of
             the investigator.

          5. Patients who are treated with drugs that are strong inducers or inhibitors of
             cytochrome P450 3A4 (CYP3A4) and can not discontinue the treatment (see Appendix 6 for
             list of medications).

          6. Patients with nephrotic range proteinuria (protein to creatinine ratio ≥2.0 mg/mg or
             200 mg/mmol (Hogg, 2003).