Efficacy, Safety and Tolerability of Everolimus in Combination With Reduced Exposure Cyclosporine or Tacrolimus in Paediatric Liver Transplant Recipients.

Study Overview
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Brief Summary
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This study was designed to assess the evolution of renal function and to collect efficacy, safety, and tolerability data of everolimus in co-exposure with reduced CNI in paediatric liver transplant recipients.

Detailed Description
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Study is completed (was active and ongoing but no longer recruiting since December 2014). The study Data Monitoring Committee meeting communicated to Novartis the following safety findings in the study population: high rate of premature discontinuation of study medication, high rate of post-transplant lymphoproliferative disease and high rate of related serious infections leading to hospitalization. In light of the safety findings, Novartis followed the DMC recommendation to discontinue the study medication in this age group and to stop enrolling new patients in this study (regardless of age).

Official Title
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A 24-month, Multi-center, Single Arm, Prospective Study to Evaluate Renal Function, Efficacy, Safety and Tolerability of Everolimus in Combination With Reduced Exposure Cyclosporine or Tacrolimus in Paediatric Liver Transplant Recipients.

Conditions
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Renal Function, Liver Transplant

Intervention / Treatment
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* Drug: Introduction of everolimus with reduced cyclosporine or tacrolimus dose, the earliest 1 month and the latest 6 months after liver transplantation.


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Signed informed consent from both parents or legal guardian(s) prior to patient participation in the study. Paediatric liver transplant recipients aged greater than or equal to 1 month and younger than 18 years of age. Paediatric recipients at the earliest 1 month and latest 6 month after liver transplantation. Key Exclusion Criteria: Patients with hepato-biliary malignancies and/or patients transplanted due to fulminant hepatitis /acute liver failure. Presence of thrombosis of any major hepatic arteries, major/reconstructed hepatic veins, portal vein or inferior vena cava at any time prior to the start of study drug. Patients with serum creatinine value >2 times age-related ULN at Baseline or who received renal replacement therapy within one week prior to the start of study drug and patients with a confirmed spot urine protein/creatinine ratio indicating a urinary protein excretion >500 mg/m2/24 hrs, at Baseline. Patients with clinically significant systemic infection and/or in a critical care setting requiring life support measures such as mechanical ventilation, dialysis, or vasopressor agents. Patients with a known hypersensitivity to the drugs used on study or their class, or to any of the excipients. Pregnant or nursing (lactating) female patients, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive βHCG laboratory test (>9 mIU/mL) at Baseline. Female patients of child-bearing potential, defined as all women physiologically capable of becoming pregnant, UNLESS they agree for abstinence from sexual activity.

Ages Eligible for Study
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Minimum Age: 1 Month
Maximum Age: 17 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: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Everolimus based regimen<br>Conversion at Baseline from an immunosuppressive regimen which contains either cyclosporine (CsA) or tacrolimus (TAC) with or without mycophenolic acid (MPA), with or without corticosteroids in a regimen which contains everolimus combined reduced dose of either cyclosporine (CsA) or tacrolimus (TAC). The dosing schedule was twice daily, 12 hours apart. | Drug: Introduction of everolimus with reduced cyclosporine or tacrolimus dose, the earliest 1 month and the latest 6 months after liver transplantation.<br>* Immunosuppression after liver transplantation. Pediatric transplant recipients received a starting dose of 0.8 mg/m^2/dose in combination wit Cyclosporine A or 2.0 mg/m^2/dose in combination with tacrolimus, twice-daily. Thereafter, doses were adjusted to achieve everolimus C-0h blood trough level between 3 to 8 ng/ml.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Estimated Glomerular Filtration Rate - Month 12 | Evolution of renal function assessed by estimated Glomerular Filtration Rate (eGFR) calculated by the Chronic Kidney Disease in Children (CKiD) Schwartz formula (Schwartz 2009), expressed in mean change in eGFR of CKiD between start of study (baseline assessment) and Month 12. | Baseline, Month 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Kaplan-Meier Estimates for Failure Rates of Efficacy Endpoints | The proportion of patients with composite efficacy failure (treated biopsy proven acute rejection[tBPAR], graft loss [GL] , death [D]) before/at Month 12 and Month 24, estimated with Kaplan-Meier (KM) methods and the proportion of patients who experienced any of the components of composite efficacy failure (tBPAR, GL, D) before/at Month 12 and Month 24, separately for each component. AR: acute rejection; BPAR: biopsy proven acute rejection. Rate = Kaplan-Meier estimate for failure in %; CI = confidence interval for failure rate. | At 12-month and 24-month after start of study drug | 
| Change From Baseline in Estimated Glomerular Filtration Rate - Month 24 | Evolution of renal function assessed by estimated Glomerular Filtration Rate (eGFR) calculated by the Chronic Kidney Disease in Children (CKiD) Schwartz formula (Schwartz 2009), expressed in mean change in eGFR of CKiD between start of study (baseline assessment) and Month 24. | Baseline, Month 24 | 
| Growth Development - Height at Baseline and Month 12 | Individual growth measurements were compared with the gender and age-specific growth percentiles in the CDC growth charts for the US population. Each value observed is thus represented by the (approximated) percentage of subjects with a lower value in the reference population. Changes were calculated on this scale and thus express the change in growth measurements relative to the percentiles in the CDC growth charts. Patients were classified into growth percentile categories (<=5, >5-25, >25-50, >50-75, >75-95 and >95% percentile). | Baseline, Month 12 | 
| Growth Development - Weight at Baseline and Month 12 | Individual growth measurements were compared with the gender and age-specific growth percentiles in the CDC growth charts for the US population. Each value observed is thus represented by the (approximated) percentage of subjects with a lower value in the reference population. Changes were calculated on this scale and thus express the change in growth measurements relative to the percentiles in the CDC growth charts. Patients were classified into growth percentile categories (<=5, >5-25, >25-50, >50-75, >75-95 and >95% percentile). | Baseline, Month 12 | 
| Growth Development - Weight at Baseline and Month 24 | Individual growth measurements were compared with the gender and age-specific growth percentiles in the CDC growth charts for the US population. Each value observed is thus represented by the (approximated) percentage of subjects with a lower value in the reference population. Changes were calculated on this scale and thus express the change in growth measurements relative to the percentiles in the CDC growth charts. Patients were classified into growth percentile categories (<=5, >5-25, >25-50, >50-75, >75-95 and >95% percentile). | Baseline, Month 24 | 
| Growth Development - Height at Baseline and Month 24 | Individual growth measurements were compared with the gender and age-specific growth percentiles in the CDC growth charts for the US population. Each value observed is thus represented by the (approximated) percentage of subjects with a lower value in the reference population. Changes were calculated on this scale and thus express the change in growth measurements relative to the percentiles in the CDC growth charts. Patients were classified into growth percentile categories (<=5, >5-25, >25-50, >50-75, >75-95 and >95% percentile). | Baseline, Month 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Paediatric liver transplantation, Everolimus, Reduced calcineurin inhibitor, Cyclosporine, tacrolimus, Renal function, Composite efficacy endpoint (treated biopsy proven acute rejection death, graft loss), Liver transplant