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

Study Overview
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Brief Summary
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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.

Official Title
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A 12-month, Multicenter, Open Label, Randomized, Controlled Study to Evaluate the Efficacy, Tolerability and Safety of Early Introduction of Everolimus, Reduced CNI, and Early Steroid Elimination Compared to Standard CNI, Mycophenolate Mofetil and Steroid Regimen in Paediatric Renal Transplant Recipients With a 24-month Additional Safety Follow-up.

Conditions
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Prevention of Acute Rejection in Paediatric Recipients of a Renal Transplant

Intervention / Treatment
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* Drug: RAD001
* Drug: MMF


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Inclusion criteria at baseline: Written informed consent/assent must be obtained from the parent(s) or legal guardian before any assessment is performed. 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: Patients on TAC + MMF + steroids. Renal function with eGFR > 40 ml/min/1.73 m2 (Schwartz formula - abbreviated). Exclusion Criteria: Exclusion criteria at baseline: Recipients of kidneys from donors with known renal disease (such as diabetes nephropathy, nephrosclerosis), at the time of transplant. Recipients of a kidney with a cold ischemia time > 24 hours. History of hypersensitivity or contraindications to any of the study drugs or to drugs of similar chemical classes, or to any of the excipients. 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: Use of other investigational drugs at the time of randomization, or within 30 days or 5 half-lives prior randomization, whichever is longer. 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. 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). Patients with ongoing wound healing problems, clinically significant wound infection requiring continued therapy or other severe surgical complication in the opinion of the investigator. 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). Patients with nephrotic range proteinuria (protein to creatinine ratio ≥2.0 mg/mg or 200 mg/mmol (Hogg, 2003).

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Investigational arm<br>Conversion from MMF to everolimus plus reduced dose tacrolimus and steroids withdrawal at 6 months after transplant | Drug: RAD001<br>* Everolimus (C0 trough level of 3-8 ng/mL) in combination with reduced dose tacrolimus and steroids withdrawal at 6 months after transplant<br>|
| Active Comparator: Control arm<br>MMF continuation (in combination with tacrolimus and standard dose steroids) | Drug: MMF<br>* MMF (Cellcept®): 600mg/m2/dose twice daily (1200 mg/m2/day) in combination with tacrolimus (Prograf) and standard dose steroids<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Having Reached the Composite Efficacy Endpoint of Biopsy-proven Acute Rejection | To estimate the rate of the composite efficacy endpoint of biopsy-proven acute rejection (BPAR), graft loss or death at 12 months post transplantation in primary paediatric kidney transplant recipients converted at 4-6 weeks post-transplantation from MMF + standard TAC regimen and steroids, to everolimus + reduced dose TAC regimen and steroid withdrawal at 6 months, versus continuation of MMF + standard TAC regimen and steroids. | 12 months, 36 months | 
| To Evaluate Renal Function, Assessed by Glomerular Filtration Rate (eGFR) and Estimated by the Schwartz Formula (Abbreviated), at Month 12 and 36 | To evaluate renal function assessed by Glomerular Filtration Rate (eGFR) estimated by the Schwartz Formula (abbreviated) (Schwartz, 2009). | 12 months and 36 months post-transplantation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Composite Efficacy Endpoint | To evaluate the proportion of patients with the following efficacy events: Biopsy Proven Acute Rejection (BPAR), graft loss or death. The efficacy events will be descriptively summarized by treatment group. | at 12 and 36 months post-transplantation | 
| To Evaluate the Severity of BPAR (Acute T-cell Mediated Rejection Only) (Banff 2009) | T-cell mediated rejection severity : Type IA - Significant interstitial infiltration (> 25% of parenchyma) and foci of moderate tubulitis (> 4 mononuclear cells/tubular cross section or group of 10 tubular cells). Type IB - Significant interstitial infiltration (> 25% of parenchyma) and foci of severe tubulitis (> 10 mononuclear cells/tubular cross section or group of 10 tubular cells). Type IIA - Mild to moderate intimal arteritis Type IIB - Severe intimal arteritis comprising > 25% of the lumenal area Type III - Transmural (full vessel wall thickness) arteritis and/or arterial fibrinoid change and necrosis of medial smooth muscle cells (with accompanying lymphocytic inflammation) | month 12, month 36 | 
| To Evaluate the Time to Event of BPAR | Time to incidence of Event, given in terms of number of participants with an Event according to time interval up to 36 months | 36 months | 
| Incidence of Biopsy Proven Antibody Mediated Rejection. | To evaluate the proportion of patients with the following efficacy events: biopsy proven antibody mediated rejection/Steroid resistant BPAR and BPAR treated with T cell depleting therapy. | at 12 and 36 months post-transplantation | 
| Chronic Allograft Nephropathy / Interstitial Fibrosis and Tubular Atrophy | To evaluate the proportion of patients with chronic allograft nephropathy (interstitial fibrosis and tubular atrophy, IF/TA) by histopathology and its progression.The term chronic allograft nephropathy was used inappropriately in the protocol and therefore, replaced by interstitial fibrosis and tubular atrophy | at 12 and 36 months post-transplantation. | 
| Proteinuria (Urinary Protein/Creatinine Ratio) | The urinary protein/creatinine ratio will be descriptively summarized by treatment group at each visit. The incidence rate of patients with proteinuria will be categorized in <0.2 g/mg/mg, 0.2<2.0 mg/mg and ≥ 2.0 mg/mg and summarized by treatment groups at each visit. | at 12 and 36 months post-transplantation | 
| Growth/Development : Weight, Height, BMI : Change From Baseline | Evaluation of the potential effects upon the bone growth. The Z-score is a statistical tool which helps to assess data (here child growth parameters) relative to a reference or standard population. The Z-score describes the distance and direction of an observation away from the population median (or mean, however, here the median was used). A negative Z-score shows that data are lower than the median of the standard population, a positive Z-score shows that data are higher than the median of the standard population, and a Z-score of zero shows that the data are equal to the median of the standard population. The more the Z-score is distant from 0, the more expressed is for example underweight or overweight. | month 12 , month 36 post transplantation. | 
| Evaluation of Evolution of Renal Allograft Function Over Time | results given as eGFR values by time interval | baseline, 6 months, 12 months , 24 months, 36 months | 
| To Evaluate Renal Function, Assessed by Glomerular Filtration Rate (eGFR) and Estimated by the Schwartz Formula (Extended), at Month 12 | To evaluate renal function assessed by Glomerular Filtration Rate (eGFR) estimated by the Schwartz Formula (extended) (Schwartz, 2009). Results given as change from randomization | 12 months post-transplantation | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Paediatric kidney transplantation, Early MMF to everolimus conversion, Composite efficacy (biopsy-proven acute rejection, graft loss or death), Renal function