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

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.

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.

Study Overview

• Status: Completed
• Conditions: Renal Function; Liver Transplant
• Intervention / Treatment: Drug: Introduction of everolimus with reduced cyclosporine or tacrolimus dose, the earliest 1 month and the latest 6 months after liver transplantation.

Detailed Description

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).

• Study Type: Interventional
• Enrollment (Actual): 56
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • Victoria
    • Parkville, Victoria, Australia, 3052
      • Novartis Investigative Site
• Belgium
  • Bruxelles, Belgium, 1200
    • Novartis Investigative Site
• Canada
  • Alberta
    • Edmonton, Alberta, Canada, T6G 2B7
      • Novartis Investigative Site
• Denmark
  • København Ø, Denmark, DK-2100
    • Novartis Investigative Site
• France
  • Bron, France, 69677
    • Novartis Investigative Site
• Germany
  • Bonn, Germany, 53105
    • Novartis Investigative Site
  • Essen, Germany, 45147
    • Novartis Investigative Site
  • Hamburg, Germany, 20246
    • Novartis Investigative Site
  • Hannover, Germany, 30625
    • Novartis Investigative Site
  • Regensburg, Germany, 93053
    • Novartis Investigative Site
  • Tübingen, Germany, 72076
    • Novartis Investigative Site
• Hungary
  • Budapest, Hungary, 1082
    • Novartis Investigative Site
  • Budapest, Hungary, 1083
    • Novartis Investigative Site
• Italy
  • BG
    • Bergamo, BG, Italy, 24128
      • Novartis Investigative Site
  • ITA
    • Roma, ITA, Italy, 00165
      • Novartis Investigative Site
  • PD
    • Padova, PD, Italy, 35128
      • Novartis Investigative Site
  • TO
    • Torino, TO, Italy, 10126
      • Novartis Investigative Site
• Spain
  • Madrid, Spain, 28046
    • Novartis Investigative Site
  • Catalunya
    • Barcelona, Catalunya, Spain, 08035
      • Novartis Investigative Site
• Sweden
  • Stockholm, Sweden, SE-141 86
    • Novartis Investigative Site
• United Kingdom
  • Leeds, United Kingdom, LS1 3EX
    • Novartis Investigative Site
  • London, United Kingdom, SE5 9RS
    • Novartis Investigative Site
  • Birmingham
    • West Midlands, Birmingham, United Kingdom, B4 6NH
      • Novartis Investigative Site
• United States
  • California
    • Los Angeles, California, United States, 90027
      • Novartis Investigative Site
  • Connecticut
    • New Haven, Connecticut, United States, 06520
      • Novartis Investigative Site
  • Illinois
    • Chicago, Illinois, United States, 60637
      • Novartis Investigative Site
  • Missouri
    • St Louis, Missouri, United States, 63110
      • Novartis Investigative Site
  • New York
    • New York, New York, United States, 110032
      • Novartis Investigative Site
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Novartis Investigative Site
  • Texas
    • Houston, Texas, United States, 77030-2400
      • Novartis Investigative Site
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • Novartis Investigative Site
  • Wisconsin
    • Madison, Wisconsin, United States, 53792
      • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 month to 17 years (CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NON_RANDOMIZED
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

EXPERIMENTAL: Everolimus based regimen; 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.; 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.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Study record dates

Study Major Dates

• Study Start: October 1, 2012
• Primary Completion (ACTUAL): June 1, 2016
• Study Completion (ACTUAL): June 1, 2016

Study Registration Dates

• First Submitted: March 1, 2012
• First Submitted That Met QC Criteria: May 11, 2012
• First Posted (ESTIMATE): May 15, 2012

Study Record Updates

• Last Update Posted (ACTUAL): May 16, 2017
• Last Update Submitted That Met QC Criteria: April 13, 2017
• Last Verified: April 1, 2017

More Information

Terms related to this study

• Keywords: Everolimus; Liver transplant; Renal function; Paediatric liver transplantation; Reduced calcineurin inhibitor; Cyclosporine, tacrolimus; Composite efficacy endpoint (treated biopsy proven acute rejection death, graft loss)
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Dermatologic Agents; Antifungal Agents; Calcineurin Inhibitors; Tacrolimus; Everolimus; Cyclosporine; Cyclosporins
• Other Study ID Numbers: CRAD001H2305; 2011-003069-14