Clinical trial NCT00663455: Randomized Study to Reduce Calcineurininhibitor Toxicity in Pediatric and Adolescent Kidney Transplant Recipients
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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE4
Conditions: Kidney Transplant
Keywords: kidney transplant recipients
children and adolescents with kidney transplants
Lead sponsor: University of Erlangen-Nürnberg Medical School
Sponsor class: OTHER
First posted: 2008-04-22
Enrollment: 50
Sex: ALL
Minimum age (years): 3
Maximum age (years): 16
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

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

1. the evaluation of the health-related Quality of life and psychosocial burden in the two treatment arms.
2. 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.
3. 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 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

Primary outcomes:
measure: 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)
timeFrame: 24 months
Secondary outcomes:
measure: 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
timeFrame: 24 months
measure: Health-related Quality of life evaluation using validated questionnaires (TACQoL) to determine differences between the two study arms
timeFrame: 24 months
Other outcomes:
Locations:
city: Erlangen
country: Germany
facility: Dept. of Pediatric Nephrology, University Hospital Erlangen
city: Freiburg
country: Germany
facility: Dept. of Pediatric Nephrology, University Hospital Freiburg
city: Hamburg
country: Germany
facility: Dept. of Pediatric Nephrology, University Hospital Hamburg
city: Hannover
country: Germany
facility: Dept. of Pediatric Nephrology, University Hospital Hannover
city: Heidelberg
country: Germany
facility: Dept. of Pediatric Nephrology, University Hospital Heidelberg
city: Jena
country: Germany
facility: Dept. of Pediatric Nephrology, University Hospital Jena
city: Memmingen
country: Germany
facility: Dept. of Pediatric Nephrology, Community Hospital Memmingen
city: Muenster
country: Germany
facility: Dept. of Pediatric Nephrology, University Hospital Muenster
city: Munich
country: Germany
facility: Dept. of Pediatric Nephrology, University Hospital München
city: Rostock
country: Germany
facility: Dept. of Pediatric Nephrology, University Hospital Rostock
Study officials:
affiliation: Dept. of Pediatric Nephrology, University Hospital Erlangen, Germany
name: Jörg Dötsch, MD
role: PRINCIPAL_INVESTIGATOR
References: