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

This study is currently recruiting participants. (see Contacts and Locations)
Verified June 2014 by Novartis
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier:
NCT01544491
First received: June 9, 2011
Last updated: June 6, 2014
Last verified: June 2014
  Purpose

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.


Condition Intervention Phase
Prevention of Acute Rejection in Paediatric Recipients of a Renal Transplant
Drug: RAD001
Drug: MMF
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment

Resource links provided by NLM:


Further study details as provided by Novartis:

Primary Outcome Measures:
  • Composite efficacy endpoint of biopsy-proven acute rejection [ Time Frame: 12 months post transplantation ] [ Designated as safety issue: Yes ]
    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.

  • Renal function. [ Time Frame: 12 months post-transplantation ] [ Designated as safety issue: Yes ]
    To evaluate renal function assessed by Glomerular Filtration Rate (eGFR) estimated by the Schwartz Formula (abbreviated and extended) (Schwartz, 2009).


Secondary Outcome Measures:
  • Composite efficacy endpoint [ Time Frame: at 12 and 36 months post-transplantation ] [ Designated as safety issue: No ]
    To evaluate the proportion of patients with the following efficacy events: Biopsy Proven Acute Rejection (BPAR), graft loss or death. The efficacy events will be descriptively summarized by treatment group.

  • Incidence of biopsy proven antibody mediated rejection. [ Time Frame: at 12 and 36 months post-transplantation ] [ Designated as safety issue: No ]
    To evaluate the proportion of patients with the following efficacy events: biopsy proven antibody mediated rejection/Steroid resistant BPAR and BPAR treated with T cell depleting therapy.

  • Chronic allograft nephropathy [ Time Frame: at 12 and 36 months post-transplantation. ] [ Designated as safety issue: No ]
    To evaluate the proportion of patients with chronic allograft nephropathy (interstitial fibrosis and tubular atrophy, IF/TA) by histopathology and its progression.

  • Proteinuria (urinary protein/creatinine ratio) [ Time Frame: at 12 and 36 months post-transplantation ] [ Designated as safety issue: No ]
    The urinary protein/creatinine ratio will be descriptively summarized by treatment group at each visit. The incidence rate of patients with proteinuria will be categorized in <0.2 mg/mg, 0.2<2.0 mg/mg and ≥ 2.0 mg/mg and summarized by treatment groups at each visit.

  • Growth/development [ Time Frame: at 12 and 36 months post-transplantation. ] [ Designated as safety issue: No ]
    evaluation of the potential effects upon the gonadal axis and bone growth.


Estimated Enrollment: 106
Study Start Date: August 2012
Estimated Study Completion Date: December 2018
Estimated Primary Completion Date: December 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Investigational arm
Conversion from MMF to everolimus plus reduced dose tacrolimus and steroids withdrawal at 6 months after transplant
Drug: RAD001
Everolimus (C0 trough level of 3-8 ng/mL) in combination with reduced dose tacrolimus and steroids withdrawal at 6 months after transplant
Active Comparator: Control arm
MMF continuation (in combination with tacrolimus and standard dose steroids)
Drug: MMF
MMF (Cellcept®): 600mg/m2/dose twice daily (1200 mg/m2/day) in combination with tacrolimus (Prograf) and standard dose steroids

  Eligibility

Ages Eligible for Study:   up to 18 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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).
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01544491

Contacts
Contact: Novartis Pharmaceuticals 1-888-669-6682
Contact: Novartis Pharmaceuticals

  Show 43 Study Locations
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
  More Information

No publications provided

Responsible Party: Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier: NCT01544491     History of Changes
Other Study ID Numbers: CRAD001A2314, 2010-024381-21
Study First Received: June 9, 2011
Last Updated: June 6, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by Novartis:
Paediatric kidney transplantation
Early MMF to everolimus conversion
Composite efficacy (biopsy-proven acute rejection, graft loss or death)
Renal function

Additional relevant MeSH terms:
Mycophenolate mofetil
Everolimus
Sirolimus
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Anti-Bacterial Agents
Anti-Infective Agents
Therapeutic Uses
Antibiotics, Antineoplastic
Antineoplastic Agents
Antifungal Agents

ClinicalTrials.gov processed this record on August 21, 2014