Clinical trial NCT00978965: Identification of Patients With High Probability of Poorly Responding to Therapy With Mycophenolic Acid Prodrugs
Official title: Identification of Patients With High Probability of Not or Poorly Responding to Mycophenolate-mofetil (Cellcept®) or Mycophenolate-natrium (Myfortic®) Therapy
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Renal Transplantation
Keywords: kidney transplantation
immunosuppression
single nucleotide polymorphism
IMPDH
Lead sponsor: Medical University of Vienna
Sponsor class: OTHER
Collaborators: name: Novartis
First posted: 2009-09-17
Enrollment: 277
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Patients with a de novo kidney transplantation

Brief summary: This study is designed to define groups of patients (among patients with a heart or kidney graft or a glomerular disease and nephrotic range proteinuria) who would either not profit from a therapy with mycophenolate-mofetil (MMF) or need a higher than conventional dose to respond.

Mainly there are 2 possible explanations for inter-patient differences in responsiveness to MMF therapy:

1. Based on a mutation (in this study single nucleotide polymorphisms-SNPs-) in the inosine monophosphate dehydrogenase 2 (IMPDH 2) transcript as the target enzyme of mycophenolic acid (MPA) pathway, MMF cannot exert its effect.
2. Based on a high enzyme activity of IMPDH 2 a higher MMF dose than in the conventional regimens is needed.

To study the significance of these possible explanations there are 4 objectives in this study:

Objective 1: Since there are no data on SNPs with functional relevance in IMPDH 2 transcript, we will first sequence all 14 exons of this gene in their entirety in 100 gender and age matched healthy individuals.

Objective 2: The functional relevance of a detected SNP will be tested in vitro in a lymphocyte proliferation assay using various MPA concentrations.

Objective 3: These functionally relevant SNPs will be searched in patients with kidney graft in a retrospective as well as prospective manner.

Objective 4: Parallel to the genotyping experiments, IMPDH 2 activity and MPA plasma levels will be measured in all patients recruited in the study prospectively.

An association between these SNPs or various IMPDH 2 activity / MPA plasma levels with MMF responsiveness will be examined.

Objective 5: Strongyloides IgG titers are screened to evaluate the prevalence of helminth carriers in patients with immunosuppressive therapy.


Eligibility criteria: Inclusion Criteria:

* patients with a de novo kidney graft and age \>18 and \< 75

Exclusion Criteria:

* pregnancy
* panel of antigens reactivity \> 40%

Primary outcomes:
measure: Detection of functionally relevant SNPs in IMPDH 2 gene.
timeFrame: 6 months
measure: The association of detected SNPs in inosine monophosphate dehydrogenase-2 transcript or high IMPDH 2 activity with the lack of response to MPA therapy defined as - number of biopsy proven acute rejections in the first year after transplantation
timeFrame: 12 months per patient
Secondary outcomes:
measure: Screening for strongyloides IgG titers
timeFrame: 12 months
Other outcomes:
Locations:
city: Vienna
country: Austria
facility: Department of Medicine III, Division of Nephrology
Study officials:
affiliation: Medical University of Vienna
name: Gürkan Sengölge, MD
role: PRINCIPAL_INVESTIGATOR
References: