Everolimus in paediatric liver transplant recipients

Overview

Status: Not yet recruiting
Keywords: Everolimus , Cyclosporine , Tacrolimus , Pediatric liver transplant recipients , Renal function
IRB Number: 00063664
Specialty: Gastroenterology, Pediatric Gastroenterology
Sub Specialties: Liver Transplant,

Brief Summary

Purpose and rationale:

This study is part of the Paediatric Investigational Plan (PIP): EMEA-000019-PIP06-09-M02 and is intended to support the indication of everolimus with reduced CNI exposure in the prevention of acute rejection in paediatric liver transplant recipients.

 

As the main benefit expected from the combination of everolimus and reduced CNI exposure is an improvement in renal function without compromising efficacy, this study will assess the evolution of renal function, the rate of efficacy failure events and the overall safety of this regimen.

 

Primary Objective:

 

To evaluate the evolution of renal function assessed by Glomerular Filtration Rate (eGFR) estimated by the Chronic Kidney Disease in Children (CKiD) Schwartz formula (Schwartz 2009) from start to Month 12 of an everolimus based regimen.

 

Other Objectives:

 

Efficacy objectives at 12 and 24 months after start of everolimus

 

To assess:

 

  • Rate of composite efficacy failure of treated biopsy proven acute rejection (BPAR), graft loss (GL) or death (D).

 

  • Each component of the composite efficacy failure endpoint.

 

  • Time to event and severity of tBPAR.

 

  • Incidence and severity of all acute rejection.

 

Renal function related objectives

 

To evaluate:

 

  • Renal function over time assessed by mean change in eGFR by the CKiD Schwartz formula (Schwartz 2009) from the start of everolimus.

 

  • Evolution of renal function over time assessed by various other formulae from the time of transplantation and start of everolimus.

 

  • Evolution of renal function over time by chronic kidney disease (CKD) categories (<15, 15<30, 30<60, 60<90, ≥90 mL/min/1.73 m2).

 

  • Incidence of patients experiencing a change in eGFR of <10, 10<15, 15<20, 20<25 and ≥25 mL/min/1.73 m2 from the start of everolimus to Months 6, 12 and 24.

 

  • Renal function and change in eGFR from the start of everolimus to Months 6, 12 and 24 in the following subgroups: age (0<2 and 2<18 years), body weight (<20 and ≥20 kg), gender, race, region, renal  function categories (<15,  15<30, 30<60,  60<90,  ≥90  mL/min/1.73  m2) and diagnosis leading to transplantation.

 

  • Urinary protein/creatinine ratio at various time points.

 

  • Incidence of urinary protein excretion of (1) <500 mg/m2/24 hrs; (2) 500<1000 mg/m2/24 hrs;  

(3) ≥1000 mg/m2/24 hrs at various time points.

 

  • Incidence and time to renal replacement therapy.

 

Development objectives

To evaluate growth and development that includes linear growth, sexual maturation, and hormonal

gonadal axis (estradiol, testosterone, LH, FSH, Inhibin B, TSH, T3 and T4).

 

Safety objectives

To evaluate:

  • All AE/SAEs as per preferred term and system organ class (SOC), especially viral infections

and reactivation (CMV, EBV, HIV, Hepatitis B and Hepatitis C), hematological and metabolic

laboratory parameters, gastrointestinal side effects and malignancies.

  • Incidence of post-transplant lymphoproliferative disorder (PTLD).
  • Incidence of treatment-related side effects including incidence of new onset diabetes mellitus

(NODM), serum/blood lipid panel, neurotoxicity and hypertension.

  • Incidence and reason (e.g. AE) for premature discontinuation of study medication, and

premature withdrawal from the study.

  • Incidence and reason (e.g. AE) for dose interruption and dose adjustment of study medication.

 

Other objective

To assess the progression rate of allograft fibrosis over time (routine biopsies by local practice)

 

Pharmacokinetic sub-study

This sub-study will characterize the pharmacokinetics of everolimus in combination with reduced CNI

in a total of at least 16 male and female paediatric full-size or technically modified liver allograft

recipients. Group I will consist of at least 8 patients with a body weight <20 kg and Group II of patients

with a body weight ≥20 kg. An attempt will be made to enroll equal proportion of full-size or technically

modified liver allograft recipients into each body weight group. Venous blood samples will be collected

at the following times after the morning dose on Day 1 (first dose of everolimus): 1, 2, 5, 8, and 12

hours post-dose.

Detailed Description

This study is part of the Paediatric Investigational Plan (PIP): EMEA-000019-PIP06-09-M02 and is intended to support the indication of everolimus with reduced CNI exposure in the prevention of acute rejection in paediatric liver transplant recipients. As the main benefit expected from the combination of everolimus and reduced CNI exposure is an improvement in renal function without compromising efficacy, this study will assess the evolution of renal function, the rate of efficacy failure events and the overall safety of this regimen. Primary Objective: To evaluate the evolution of renal function assessed by Glomerular Filtration Rate (eGFR) estimated by the Chronic Kidney Disease in Children (CKiD) Schwartz formula (Schwartz 2009) from start to Month 12 of an everolimus based regimen.

Principal Investigator: Jeffrey Campsen
Department: General Surgery
Co Investigator:

Contact Information

Name:Priscilla Cowan
Phone: 801-213-3401
Email: priscilla.rosen@hsc.utah.edu

Inclusion Criteria

Patients eligible for inclusion in this study have to fulfill at baseline all of the following criteria:

  • A signed informed consent/assent must have been obtained from the parent(s) or legal guardian (s) prior to patient participation in the study and before any assessment is performed.
  • Paediatric liver transplant recipients aged greater than or equal to 1 month and younger than18 years of age and with a body weight greater than 5 kg and treated with a CNI-based immunosuppressive regimen with/without mycophenolic acid and corticosteroids.
  • Paediatric recipients of a full-size or technically modified liver allograft will be eligible at the earliest 1 month and latest 6 month after liver transplantation.
  • Paediatric liver transplant allograft recipients with an acceptable liver graft function as assessed by AST, ALT, total bilirubin levels ≤3 times ULN and INR <1.5.
  • Patients who are able to take oral medication or through nasogastric tube.

Exclusion Criteria

Patients fulfilling any of the following criteria are not eligible in this study. No additional exclusions may be applied by the investigator, in order to ensure that the study population will be representative of all eligible patients.

 

  • Patients who experienced more than two episodes of treated biopsy proven acute rejection or who received T-cell depleting induction agents or acute rejection therapy.

 

  • Patients with hepato-biliary malignancies.

 

  • Patients transplanted due to fulminant hepatitis/acute hepatic failure.

 

  • Presence of thrombosis of any major hepatic arteries, major/reconstructed hepatic veins, portal vein and vena cava at any time  prior  to  the  start  of  everolimus  treatment (graft vessel patency by Doppler ultrasound confirmed and documented).

 

  • 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 everolimus treatment.

 

  • Patients with a confirmed spot urine protein/creatinine ratio indicating a urinary protein excretion >500 mg/m2/24 hrs, at Baseline.

 

  • Patients who are recipients of multiple solid organ transplants (e.g. multivisceral or combined liver-kidney transplants), or have previously received an organ or tissue transplanted, or who received an ABO incompatible transplant.

 

  • Patients who have severe hypercholesterolemia (>350 mg/dL; >9.1 mmol/L) or hypertriglyceridemia (>500 mg/dL; >5.6 mmol/L) at Baseline.

 

  • Patients with platelet count <35.000/mm3 and/or absolute neutrophil count <1.000/mm3 or white blood cell count of <2.000/mm3 at Baseline.

 

  • Patients who have any surgical or medical condition, which in the opinion of the investigator, might significantly alter the absorption, distribution, metabolism and excretion of study drug.

 

  • Patients with a known hypersensitivity to the drugs used on study or their class, or to any of the excipients.

 

  • 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.

 

  • Pregnant or nursing (lactating) female patients, where pregnancy is defined as the state of a female after conception and until 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.