Clinical trial NCT01544491: 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
Official title: 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.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Prevention of Acute Rejection in Paediatric Recipients of a Renal Transplant
Keywords: Paediatric kidney transplantation
Early MMF to everolimus conversion
Composite efficacy (biopsy-proven acute rejection, graft loss or death)
Renal function
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2012-03-06
Enrollment: 106
Sex: ALL
Minimum age (years): 1
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: Inclusion Criteria:

Inclusion criteria at baseline:

1. Written informed consent/assent must be obtained from the parent(s) or legal guardian before any assessment is performed.
2. 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:

1. Patients on TAC + MMF + steroids.
2. Renal function with eGFR \> 40 ml/min/1.73 m2 (Schwartz formula - abbreviated).

Exclusion Criteria:

Exclusion criteria at baseline:

1. Recipients of kidneys from donors with known renal disease (such as diabetes nephropathy, nephrosclerosis), at the time of transplant.
2. Recipients of a kidney with a cold ischemia time \> 24 hours.
3. History of hypersensitivity or contraindications to any of the study drugs or to drugs of similar chemical classes, or to any of the excipients.
4. 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:

1. Use of other investigational drugs at the time of randomization, or within 30 days or 5 half-lives prior randomization, whichever is longer.
2. 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.
3. 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).
4. Patients with ongoing wound healing problems, clinically significant wound infection requiring continued therapy or other severe surgical complication in the opinion of the investigator.
5. 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).
6. Patients with nephrotic range proteinuria (protein to creatinine ratio ≥2.0 mg/mg or 200 mg/mmol (Hogg, 2003).

Primary outcomes:
measure: Number of Participants Having Reached the Composite Efficacy Endpoint of Biopsy-proven Acute Rejection
timeFrame: 12 months, 36 months
measure: To Evaluate Renal Function, Assessed by Glomerular Filtration Rate (eGFR) and Estimated by the Schwartz Formula (Abbreviated), at Month 12 and 36
timeFrame: 12 months and 36 months post-transplantation
Secondary outcomes:
measure: Composite Efficacy Endpoint
timeFrame: at 12 and 36 months post-transplantation
measure: To Evaluate the Severity of BPAR (Acute T-cell Mediated Rejection Only) (Banff 2009)
timeFrame: month 12, month 36
measure: To Evaluate the Time to Event of BPAR
timeFrame: 36 months
measure: Incidence of Biopsy Proven Antibody Mediated Rejection.
timeFrame: at 12 and 36 months post-transplantation
measure: Chronic Allograft Nephropathy / Interstitial Fibrosis and Tubular Atrophy
timeFrame: at 12 and 36 months post-transplantation.
measure: Proteinuria (Urinary Protein/Creatinine Ratio)
timeFrame: at 12 and 36 months post-transplantation
measure: Growth/Development : Weight, Height, BMI : Change From Baseline
timeFrame: month 12 , month 36 post transplantation.
measure: Evaluation of Evolution of Renal Allograft Function Over Time
timeFrame: baseline, 6 months, 12 months , 24 months, 36 months
measure: To Evaluate Renal Function, Assessed by Glomerular Filtration Rate (eGFR) and Estimated by the Schwartz Formula (Extended), at Month 12
timeFrame: 12 months post-transplantation
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Novartis Investigative Site
state: California
city: Ann Arbor
country: United States
facility: Novartis Investigative Site
state: Michigan
city: Saint Louis
country: United States
facility: Novartis Investigative Site
state: Missouri
city: Santa Fe
country: Argentina
facility: Novartis Investigative Site
city: Porto Alegre
country: Brazil
facility: Novartis Investigative Site
state: RS
city: São Paulo
country: Brazil
facility: Novartis Investigative Site
state: SP
city: Bron Cedex
country: France
facility: Novartis Investigative Site
city: Lille
country: France
facility: Novartis Investigative Site
city: Paris cedex 15
country: France
facility: Novartis Investigative Site
city: Paris
country: France
facility: Novartis Investigative Site
city: Berlin
country: Germany
facility: Novartis Investigative Site
city: Essen
country: Germany
facility: Novartis Investigative Site
city: Hamburg
country: Germany
facility: Novartis Investigative Site
city: Hannover
country: Germany
facility: Novartis Investigative Site
city: Heidelberg
country: Germany
facility: Novartis Investigative Site
city: Muenster
country: Germany
facility: Novartis Investigative Site
city: Tübingen
country: Germany
facility: Novartis Investigative Site
city: Budapest
country: Hungary
facility: Novartis Investigative Site
city: Bologna
country: Italy
facility: Novartis Investigative Site
state: BO
city: Genova
country: Italy
facility: Novartis Investigative Site
state: GE
city: Roma
country: Italy
facility: Novartis Investigative Site
state: ITA
city: Padova
country: Italy
facility: Novartis Investigative Site
state: PD
city: Torino
country: Italy
facility: Novartis Investigative Site
state: TO
city: Oslo
country: Norway
facility: Novartis Investigative Site
city: Warsaw
country: Poland
facility: Novartis Investigative Site
city: Esplugues de Llobregat
country: Spain
facility: Novartis Investigative Site
state: Barcelona
city: Stockholm
country: Sweden
facility: Novartis Investigative Site
city: Antalya
country: Turkey
facility: Novartis Investigative Site
city: London
country: United Kingdom
facility: Novartis Investigative Site
city: Manchester
country: United Kingdom
facility: Novartis Investigative Site
city: Nottingham
country: United Kingdom
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References:
citation: Patry C, Sauer LD, Sander A, Krupka K, Fichtner A, Brezinski J, Geissbuhler Y, Aubrun E, Grinienko A, Strologo LD, Haffner D, Oh J, Grenda R, Pape L, Topaloglu R, Weber LT, Bouts A, Kim JJ, Prytula A, Konig J, Shenoy M, Hocker B, Tonshoff B. Emulation of the control cohort of a randomized controlled trial in pediatric kidney transplantation with Real-World Data from the CERTAIN Registry. Pediatr Nephrol. 2023 May;38(5):1621-1632. doi: 10.1007/s00467-022-05777-x. Epub 2022 Oct 20.
citation: Tonshoff B, Tedesco-Silva H, Ettenger R, Christian M, Bjerre A, Dello Strologo L, Marks SD, Pape L, Veldandi U, Lopez P, Cousin M, Pandey P, Meier M. Three-year outcomes from the CRADLE study in de novo pediatric kidney transplant recipients receiving everolimus with reduced tacrolimus and early steroid withdrawal. Am J Transplant. 2021 Jan;21(1):123-137. doi: 10.1111/ajt.16005. Epub 2020 Jun 27.