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

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ClinicalTrials.gov Identifier: NCT01598987

Recruitment Status : Completed

First Posted : May 15, 2012

Results First Posted : January 24, 2017

Last Update Posted : May 16, 2017

Sponsor:

Information provided by (Responsible Party):

Novartis ( Novartis Pharmaceuticals )

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Renal Function Liver Transplant	Drug: Introduction of everolimus with reduced cyclosporine or tacrolimus dose, the earliest 1 month and the latest 6 months after liver transplantation.	Phase 3

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 Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	56 participants
Allocation:	Non-Randomized
Intervention Model:	Single Group Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	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.
Study Start Date :	October 2012
Actual Primary Completion Date :	June 2016
Actual Study Completion Date :	June 2016

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Children's Health Kidney Tests Liver Transplantation

Drug Information available for: Cyclosporine Tacrolimus Everolimus

U.S. FDA Resources

Arms and Interventions

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.

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.

Outcome Measures

Primary Outcome Measures :

Change From Baseline in Estimated Glomerular Filtration Rate - Month 12 [ Time Frame: Baseline, 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.

Secondary Outcome Measures :

Kaplan-Meier Estimates for Failure Rates of Efficacy Endpoints [ Time Frame: At 12-month and 24-month after start of study drug ]
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.
Change From Baseline in Estimated Glomerular Filtration Rate - Month 24 [ Time Frame: Baseline, 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.
Growth Development - Height at Baseline and Month 12 [ Time Frame: Baseline, 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).
Growth Development - Weight at Baseline and Month 12 [ Time Frame: Baseline, 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).
Growth Development - Weight at Baseline and Month 24 [ Time Frame: Baseline, 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).
Growth Development - Height at Baseline and Month 24 [ Time Frame: Baseline, 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).

Eligibility Criteria

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Ages Eligible for Study:	1 Month to 17 Years (Child)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

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.

Contacts and Locations

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To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01598987

Locations

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

Sponsors and Collaborators

Novartis Pharmaceuticals

Investigators

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Study Director:	Novartis Pharmaceuticals	Novartis Pharmaceuticals

More Information

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Responsible Party:	Novartis Pharmaceuticals
ClinicalTrials.gov Identifier:	NCT01598987
Other Study ID Numbers:	CRAD001H2305 2011-003069-14
First Posted:	May 15, 2012 Key Record Dates
Results First Posted:	January 24, 2017
Last Update Posted:	May 16, 2017
Last Verified:	April 2017

Keywords provided by Novartis ( Novartis Pharmaceuticals ):


Paediatric liver transplantation Everolimus Reduced calcineurin inhibitor Cyclosporine, tacrolimus	Renal function Composite efficacy endpoint (treated biopsy proven acute rejection death, graft loss) Liver transplant

Additional relevant MeSH terms:

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Cyclosporine Everolimus Tacrolimus Cyclosporins Immunosuppressive Agents Immunologic Factors Physiological Effects of Drugs Calcineurin Inhibitors	Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action Antifungal Agents Anti-Infective Agents Dermatologic Agents Antirheumatic Agents Antineoplastic Agents

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