Randomized Study to Reduce Calcineurininhibitor Toxicity in Pediatric and Adolescent Kidney Transplant Recipients - Full Text View

Purpose

The purpose of this study is to determine if a safe reduction of cyclosporine A in pediatric and adolescent patients with stable renal graft function, reduces signs of calcineurin-inhibitor toxicity.

Condition	Intervention	Phase
Kidney Transplant	Drug: Reduction of cyclosporine A (CSA)-dosing	Phase 4

Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Parallel Assignment Masking: Open Label Primary Purpose: Treatment
Official Title:	A Multicenter, Randomized, Parallel-group, Trial to Reduce Toxicity of Calcineurininhibitor-therapy in Steroid-free Longterm Immunosuppression in Pediatric and Adolescent Kidney Transplant Recipients

Resource links provided by NLM:

MedlinePlus related topics: Kidney Transplantation

Drug Information available for: Cyclosporine

U.S. FDA Resources

Further study details as provided by University of Erlangen-Nürnberg Medical School:

Primary Outcome Measures:

Mean decline per month in glomerular filtration rate (calculated acc. to Schwartz' formula) during the clinical trial - comparison between the two study arms (CSA-dose reduction group and group with constant CSA-dosing) [ Time Frame: 24 months ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:

Evaluation of the NFAT-regulated gene expression (nuclear factor of activated t-cells) of intracellular cytokines [Interleukin-2, TNF-alpha, Interferon-gamma and GMCSF) by quantitative PCR as measurement of CSA activity [ Time Frame: 24 months ] [ Designated as safety issue: Yes ]
Health-related Quality of life evaluation using validated questionnaires (TACQoL) to determine differences between the two study arms [ Time Frame: 24 months ] [ Designated as safety issue: No ]

Estimated Enrollment:	50
Study Start Date:	December 2008
Estimated Study Completion Date:	June 2013
Estimated Primary Completion Date:	December 2012 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
A Reduction of CSA-dosing over 4 months. Therapy control by safety parameters (serum creatinine, C2-monitoring, renal biopsy).	Drug: Reduction of cyclosporine A (CSA)-dosing Reduction of CSA-dosing over 4 months. Therapy control by safety parameters (serum creatinine, C2-monitoring, renal biopsy).
No Intervention: B Standard CSA-dosing without reduction. Therapy control by C2-monitoring.

Detailed Description:

Chronic transplant nephropathy is one of the major causes of graft loss after renal transplantation. Toxicity of calcineurin-inhibitors is suspected to be one cause for loss of graft function. Therefore reduction of cyclosporine A dosing can result in longer graft survival and better graft function in patients after renal-transplantation. However, reduction of immunosuppression can result in acute rejection episodes, although it is less likely in patients with stable graft function 12 months or longer after successful renal transplantation.

Therefore the aim of this randomized, controlled study in pediatric and adolescent renal transplant recipients, is to compare the impact of reduced cyclosporine A-dosing to standard CSA-dosing on renal graft function. Therapy monitoring in both groups will be performed by obtaining CSA blood levels two hours after intake, as they provide an individual insight in pharmacokinetics in comparison to conventional trough level (C0)-measurements.

Secondary objectives to evaluate are

the evaluation of the health-related Quality of life and psychosocial burden in the two treatment arms.
measurement of the NFAT-regulated gene expression (nuclear factor of activated t-cells) of intracellular cytokines [Interleukin-2, TNF-alpha, Interferon-gamma and GMCSF) by quantitative PCR as measurement of CSA activity.
To obtain new insights by screening for metabolites conjunct with clinic features of nephrotoxicity or graft rejections a metabolomic screening and a targeted analysis (trimethylamine-N-oxide, neopterin and kynurenine/tryptophan ratio) will be performed.

Eligibility

Ages Eligible for Study:	3 Years to 16 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

age at inclusion 3-16 years
male or female patients
recipient of first or second renal transplant
graft age > 24 months
last acute rejection episode > 6 months ago
Immune suppression comedication Mycophenolatmofetil (MMF) in a dose range of 1200 +/- 200 mg/m² BSA/d within at least 6 months or minimal MPA-AUC ≥ 45 mg x h/l. If MPA-AUC < 45 mg x h/l adjustment of dosage with re-screening in ≥ 4 weeks is possible.
Application of CSA in stable dosing within the last 3 months before study inclusion and CSA-C2-level > 500 ng/ml. If CSA-C2-level < 500 ng/ml adjustment of dosage with re-screening in ≥ 4 weeks is possible.
steroid-free immunosuppression for at least 6 months before enrollment
biopsy of the renal graft without any signs of acute rejection (def. according to BANFF classification), within 3 months before enrollment
written informed consent of parents/legal guardians and, if applicable, patient's consent

Exclusion Criteria:

glomerular filtration rate < 40 ml/min/1.73 m2 BSA (acc. to Schwartz' formula) at time of enrollment
> 2 episodes of acute graft rejection within 12 months prior to enrollment
condition after steroid-resistant graft rejection
actual participation in another clinical trial
Recurrence of primary renal disease in the graft
proven infection with EBV and/ or CMV and antiviral therapy within 3 months prior to enrollment
proven infection with polyoma virus within 3 months prior to enrolment
pregnant or nursing women
hemoglobin < 8 g/dl at screening visit
non-treated arterial hypertension
uncontrolled infectious disease
history of malignancy of any organ system, treated or non-treated

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00663455

Locations

Germany
Dept. of Pediatric Nephrology, University Hospital Erlangen
Erlangen, Germany
Dept. of Pediatric Nephrology, University Hospital Freiburg
Freiburg, Germany
Dept. of Pediatric Nephrology, University Hospital Hamburg
Hamburg, Germany
Dept. of Pediatric Nephrology, University Hospital Hannover
Hannover, Germany
Dept. of Pediatric Nephrology, University Hospital Heidelberg
Heidelberg, Germany
Dept. of Pediatric Nephrology, University Hospital Jena
Jena, Germany
Dept. of Pediatric Nephrology, Community Hospital Memmingen
Memmingen, Germany
Dept. of Pediatric Nephrology, University Hospital Muenster
Muenster, Germany
Dept. of Pediatric Nephrology, University Hospital München
Munich, Germany
Dept. of Pediatric Nephrology, University Hospital Rostock
Rostock, Germany

Sponsors and Collaborators

University of Erlangen-Nürnberg Medical School

Investigators

Principal Investigator:

Jörg Dötsch, MD

Dept. of Pediatric Nephrology, University Hospital Erlangen, Germany

More Information

No publications provided

Responsible Party:	Professor Dr. Jörg Dötsch, MD, Dep. of Pediatrics, University of Erlangen-Nürnberg
ClinicalTrials.gov Identifier:	NCT00663455 History of Changes
Other Study ID Numbers:	Recaltox-1
Study First Received:	April 21, 2008
Last Updated:	November 9, 2010
Health Authority:	Germany: Federal Institute for Drugs and Medical Devices

Keywords provided by University of Erlangen-Nürnberg Medical School:

kidney transplant recipients
children and adolescents with kidney transplants

Additional relevant MeSH terms:

Cyclosporins
Cyclosporine
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Immunosuppressive Agents
Immunologic Factors

Physiological Effects of Drugs
Antifungal Agents
Anti-Infective Agents
Therapeutic Uses
Dermatologic Agents
Antirheumatic Agents

ClinicalTrials.gov processed this record on May 16, 2013

Randomized Study to Reduce Calcineurininhibitor Toxicity in Pediatric and Adolescent Kidney Transplant Recipients (Recaltox)