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Prevention of Acute Rejection in Paediatric Recipients of a Renal TransplantPhase 3NCT01544491

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

A Phase 3 study testing RAD001 and MMF in people with Prevention of Acute Rejection in Paediatric Recipients of a Renal Transplant, run by Novartis Pharmaceuticals at 31 sites in 13 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 1 year to 18 years
What is being tested?
RAD001 and MMF
Could I receive a placebo?
No, everyone receives an active treatment
How many people
106 participants
Where
31 sitesin 13 countries
Study dates
17 Aug 2012to 24 Sep 2018
Phase
Phase 3
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 1 year to 18 years
  • All sexes
  • No healthy volunteers
  • Child, Adult

Who may be able to join

  • 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).

Who cannot join

  • 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.
Show all 10Show fewer
  • 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).

Trial locations and contacts

31 sites in 13 countries.

31 sites in 13 countries

Germany7 sites
  • Novartis Investigative Site

    Berlin, 13353

  • Novartis Investigative Site

    Essen, 45147

  • Novartis Investigative Site

    Hamburg, 20246

  • Novartis Investigative Site

    Hanover, 30625

  • Novartis Investigative Site

    Heidelberg, 69120

  • Novartis Investigative Site

    Münster, 48149

  • Novartis Investigative Site

    Tübingen, 72076

Other trials in Germany

Italy5 sites
  • Novartis Investigative Site

    Bologna, BO, 40138

  • Novartis Investigative Site

    Genova, GE, 16147

  • Novartis Investigative Site

    Padova, PD, 35128

  • Novartis Investigative Site

    Roma, ITA, 00165

  • Novartis Investigative Site

    Torino, TO, 10126

Other trials in Italy

France4 sites
  • Novartis Investigative Site

    Bron, 69677

  • Novartis Investigative Site

    Lille, 59000

  • Novartis Investigative Site

    Paris, 75015

  • Novartis Investigative Site

    Paris, 75019

Other trials in France

United States3 sites
  • Novartis Investigative Site

    Ann Arbor, Michigan, 48109-0331

  • Novartis Investigative Site

    Los Angeles, California, 90095-1752

  • Novartis Investigative Site

    St Louis, Missouri, 63110

Other trials in United States

United Kingdom3 sites
  • Novartis Investigative Site

    London, WC1N 1EH

  • Novartis Investigative Site

    Manchester, M13 9WL

  • Novartis Investigative Site

    Nottingham, NG7 2UH

Other trials in United Kingdom

Brazil2 sites
  • Novartis Investigative Site

    Porto Alegre, Rio Grande do Sul, 90020-090

  • Novartis Investigative Site

    São Paulo, São Paulo, 04038-002

Other trials in Brazil

Argentina1 site
  • Novartis Investigative Site

    Santa Fe, S3000EPV

Other trials in Argentina

Hungary1 site
  • Novartis Investigative Site

    Budapest, 1082

Other trials in Hungary

Norway1 site
  • Novartis Investigative Site

    Oslo, 0424

Other trials in Norway

Poland1 site
  • Novartis Investigative Site

    Warsaw, 04 730

Other trials in Poland

Spain1 site
  • Novartis Investigative Site

    Esplugues de Llobregat, Barcelona, 08950

Other trials in Spain

Sweden1 site
  • Novartis Investigative Site

    Stockholm, 14186

Other trials in Sweden

Turkey (Türkiye)1 site
  • Novartis Investigative Site

    Antalya, 07070

Other trials in Turkey (Türkiye)

About this study

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.

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.

Being tested
RAD001, MMF
Keywords
Paediatric kidney transplantation, Early MMF to everolimus conversion, Composite efficacy (biopsy-proven acute rejection, graft loss or death), Renal function
Medical subject headings
Death

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • RAD001Drug

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

  • MMFDrug

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

Study groups in NCT01544491
Study groupRoleWhat they receive
Investigational armExperimentalConversion from MMF to everolimus plus reduced dose tacrolimus and steroids withdrawal at 6 months after transplant
Receives: Drug: RAD001
Control armActive comparatorMMF continuation (in combination with tacrolimus and standard dose steroids)
Receives: Drug: MMF

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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.

    Measured: 12 months, 36 months

  2. 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).

    Measured: 12 months and 36 months post-transplantation

Secondary outcomes (9)
  1. Composite Efficacy Endpoint

    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.

    Measured: at 12 and 36 months post-transplantation

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

    T-cell mediated rejection severity :

    Type IA - Significant interstitial infiltration (> 25% of parenchyma) and foci of moderate tubulitis (> 4 mononuclear cells/tubular cross section or group of 10 tubular cells).

    Type IB - Significant interstitial infiltration (> 25% of parenchyma) and foci of severe tubulitis (> 10 mononuclear cells/tubular cross section or group of 10 tubular cells).

    Type IIA - Mild to moderate intimal arteritis Type IIB - Severe intimal arteritis comprising > 25% of the lumenal area Type III - Transmural (full vessel wall thickness) arteritis and/or arterial fibrinoid change and necrosis of medial smooth muscle cells (with accompanying lymphocytic inflammation)

    Measured: month 12, month 36

  3. To Evaluate the Time to Event of BPAR

    Time to incidence of Event, given in terms of number of participants with an Event according to time interval up to 36 months

    Measured: 36 months

  4. Incidence of Biopsy Proven Antibody Mediated Rejection.

    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.

    Measured: at 12 and 36 months post-transplantation

  5. Chronic Allograft Nephropathy / Interstitial Fibrosis and Tubular Atrophy

    To evaluate the proportion of patients with chronic allograft nephropathy (interstitial fibrosis and tubular atrophy, IF/TA) by histopathology and its progression.The term chronic allograft nephropathy was used inappropriately in the protocol and therefore, replaced by interstitial fibrosis and tubular atrophy

    Measured: at 12 and 36 months post-transplantation.

  6. Proteinuria (Urinary Protein/Creatinine Ratio)

    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 g/mg/mg, 0.2<2.0 mg/mg and ≥ 2.0 mg/mg and summarized by treatment groups at each visit.

    Measured: at 12 and 36 months post-transplantation

  7. Growth/Development : Weight, Height, BMI : Change From Baseline

    Evaluation of the potential effects upon the bone growth. The Z-score is a statistical tool which helps to assess data (here child growth parameters) relative to a reference or standard population. The Z-score describes the distance and direction of an observation away from the population median (or mean, however, here the median was used). A negative Z-score shows that data are lower than the median of the standard population, a positive Z-score shows that data are higher than the median of the standard population, and a Z-score of zero shows that the data are equal to the median of the standard population. The more the Z-score is distant from 0, the more expressed is for example underweight or overweight.

    Measured: month 12 , month 36 post transplantation.

  8. Evaluation of Evolution of Renal Allograft Function Over Time

    results given as eGFR values by time interval

    Measured: baseline, 6 months, 12 months , 24 months, 36 months

  9. To Evaluate Renal Function, Assessed by Glomerular Filtration Rate (eGFR) and Estimated by the Schwartz Formula (Extended), at Month 12

    To evaluate renal function assessed by Glomerular Filtration Rate (eGFR) estimated by the Schwartz Formula (extended) (Schwartz, 2009). Results given as change from randomization

    Measured: 12 months post-transplantation

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted6 Mar 2012 (estimated)
  2. Study start17 Aug 2012
  3. Primary completion3 Oct 2016
  4. Study completion24 Sep 2018

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
106 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01544491
Sponsor's protocol ID
CRAD001A2314
Other IDs
2010-024381-21
Status last verified
May 2019
First submitted
9 Jun 2011
Last updated
31 May 2019
Data monitoring committee
Yes
Individual data sharing
Undecided: Novartis is committed to sharing access to patient-level data and supporting clinical documents from eligible studies with qualified external researchers. Requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to protect the privacy of patients who have participated in the trial in line with applicable laws and regulations. This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

Publications

  • 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.

    PubMed 36264431
  • 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.

    PubMed 32406111

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing RAD001 and MMF in people with Prevention of Acute Rejection in Paediatric Recipients of a Renal Transplant, run by Novartis Pharmaceuticals at 31 sites in 13 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 4 inclusion and 10 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 31 May 2019. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 31 sites in Germany, Italy, France, United States, United Kingdom and 8 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 31 May 2019). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Number of Participants Having Reached the Composite Efficacy Endpoint of Biopsy-proven Acute Rejection (time frame: 12 months, 36 months). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01544491, which also lists 2 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 31 May 2019.

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