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

NCT01544491 | Completed Phase 3 Results DMC

• 2 other identifiers: CRAD001A23142010-024381-21
• Study Type: interventional
• Target: 106
• Locations: 13 countries
• Sites: 31

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.

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

Outcome Measures

Primary Outcomes (2)

• Number of Participants Having Reached the Composite Efficacy Endpoint of Biopsy-proven Acute Rejection

  To estimate the rate of the composite efficacy endpoint of biopsy-proven acute rejection (BPAR), graft loss or death at 12 months post transplantation in primary paediatric kidney transplant recipients converted at 4-6 weeks post-transplantation from MMF + standard TAC regimen and steroids, to everolimus + reduced dose TAC regimen and steroid withdrawal at 6 months, versus continuation of MMF + standard TAC regimen and steroids.

  12 months, 36 months

• To Evaluate Renal Function, Assessed by Glomerular Filtration Rate (eGFR) and Estimated by the Schwartz Formula (Abbreviated), at Month 12 and 36

  To evaluate renal function assessed by Glomerular Filtration Rate (eGFR) estimated by the Schwartz Formula (abbreviated) (Schwartz, 2009).

  12 months and 36 months post-transplantation

Secondary Outcomes (9)

• Composite Efficacy Endpoint

  at 12 and 36 months post-transplantation

• To Evaluate the Severity of BPAR (Acute T-cell Mediated Rejection Only) (Banff 2009)

  month 12, month 36

• To Evaluate the Time to Event of BPAR

  36 months

• Incidence of Biopsy Proven Antibody Mediated Rejection.

  at 12 and 36 months post-transplantation

• Chronic Allograft Nephropathy / Interstitial Fibrosis and Tubular Atrophy

  at 12 and 36 months post-transplantation.

Study Arms (2)

Investigational arm

EXPERIMENTAL

Conversion from MMF to everolimus plus reduced dose tacrolimus and steroids withdrawal at 6 months after transplant

Drug: RAD001

Control arm

ACTIVE COMPARATOR

MMF continuation (in combination with tacrolimus and standard dose steroids)

Drug: MMF

Interventions

RAD001 DRUG

Everolimus (C0 trough level of 3-8 ng/mL) in combination with reduced dose tacrolimus and steroids withdrawal at 6 months after transplant

Investigational arm

MMF DRUG

MMF (Cellcept®): 600mg/m2/dose twice daily (1200 mg/m2/day) in combination with tacrolimus (Prograf) and standard dose steroids

Control arm

Eligibility Criteria

• Age: 1 Year - 18 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Written informed consent/assent must be obtained from the parent(s) or legal guardian before any assessment is performed.
• 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.
• Patients on TAC + MMF + steroids.
• Renal function with eGFR \> 40 ml/min/1.73 m2 (Schwartz formula - abbreviated).

You may not qualify if:

• Recipients of kidneys from donors with known renal disease (such as diabetes nephropathy, nephrosclerosis), at the time of transplant.
• Recipients of a kidney with a cold ischemia time \> 24 hours.
• History of hypersensitivity or contraindications to any of the study drugs or to drugs of similar chemical classes, or to any of the excipients.
• History of malignancy of any organ system treated or untreated, carrying possible risk of recurrence according to current guidelines (Appendix 10 of protocol).
• Use of other investigational drugs at the time of randomization, or within 30 days or 5 half-lives prior randomization, whichever is longer.
• 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.
• 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).
• Patients with ongoing wound healing problems, clinically significant wound infection requiring continued therapy or other severe surgical complication in the opinion of the investigator.
• 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).
• Patients with nephrotic range proteinuria (protein to creatinine ratio ≥2.0 mg/mg or 200 mg/mmol (Hogg, 2003).

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (31)

Novartis Investigative Site

Los Angeles, California, 90095-1752, United States

Location

Novartis Investigative Site

Ann Arbor, Michigan, 48109-0331, United States

Location

Novartis Investigative Site

St Louis, Missouri, 63110, United States

Location

Novartis Investigative Site

Santa Fe, S3000EPV, Argentina

Location

Novartis Investigative Site

Porto Alegre, Rio Grande do Sul, 90020-090, Brazil

Location

Novartis Investigative Site

São Paulo, São Paulo, 04038-002, Brazil

Location

Novartis Investigative Site

Bron, 69677, France

Location

Novartis Investigative Site

Lille, 59000, France

Location

Novartis Investigative Site

Paris, 75015, France

Location

Novartis Investigative Site

Paris, 75019, France

Location

Novartis Investigative Site

Berlin, 13353, Germany

Location

Novartis Investigative Site

Essen, 45147, Germany

Location

Novartis Investigative Site

Hamburg, 20246, Germany

Location

Novartis Investigative Site

Hanover, 30625, Germany

Location

Novartis Investigative Site

Heidelberg, 69120, Germany

Location

Novartis Investigative Site

Münster, 48149, Germany

Location

Novartis Investigative Site

Tübingen, 72076, Germany

Location

Novartis Investigative Site

Budapest, 1082, Hungary

Location

Novartis Investigative Site

Bologna, BO, 40138, Italy

Location

Novartis Investigative Site

Genova, GE, 16147, Italy

Location

Novartis Investigative Site

Roma, ITA, 00165, Italy

Location

Novartis Investigative Site

Padua, PD, 35128, Italy

Location

Novartis Investigative Site

Torino, TO, 10126, Italy

Location

Novartis Investigative Site

Oslo, 0424, Norway

Location

Novartis Investigative Site

Warsaw, 04 730, Poland

Location

Novartis Investigative Site

Esplugues de Llobregat, Barcelona, 08950, Spain

Location

Novartis Investigative Site

Stockholm, 14186, Sweden

Location

Novartis Investigative Site

Antalya, 07070, Turkey (Türkiye)

Location

Novartis Investigative Site

London, WC1N 1EH, United Kingdom

Location

Novartis Investigative Site

Manchester, M13 9WL, United Kingdom

Location

Novartis Investigative Site

Nottingham, NG7 2UH, United Kingdom

Location

Related Publications (2)

• 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.

  PMID: 36264431 DERIVED

• 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.

  PMID: 32406111 DERIVED

MeSH Terms

Conditions

Death

Interventions

Everolimus

Condition Hierarchy (Ancestors)

Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Sirolimus; Macrolides; Lactones; Organic Chemicals

Results Point of Contact

• Title: Study Director
• Organization: Novartis Pharmaceuticals

novartis.email@novartis.com

862-778-8300

Study Officials

• Novartis Pharmaceuticals

  Novartis Pharmaceuticals

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 9, 2011
• First Posted: March 6, 2012
• Study Start: August 17, 2012
• Primary Completion: October 3, 2016
• Study Completion: September 24, 2018
• Last Updated: May 31, 2019
• Results First Posted: May 31, 2019

Record last verified: 2019-05

Locations

PL (1); ES (1); SE (1); FR (4); IT (5); DE (7); GB (3); TU (1); AR (1); US (3); NO (1); HU (1); BR (2)