Identification of Patients With High Probability of Poorly Responding to Therapy With Mycophenolic Acid Prodrugs
Recruitment status was: Recruiting
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:
- 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.
- 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.
|Study Design:||Observational Model: Cohort
Time Perspective: Prospective
|Official Title:||Identification of Patients With High Probability of Not or Poorly Responding to Mycophenolate-mofetil (Cellcept®) or Mycophenolate-natrium (Myfortic®) Therapy|
- Detection of functionally relevant SNPs in IMPDH 2 gene. [ Time Frame: 6 months ] [ Designated as safety issue: No ]
- 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 [ Time Frame: 12 months per patient ] [ Designated as safety issue: No ]
|Study Start Date:||October 2009|
|Estimated Study Completion Date:||June 2013|
|Estimated Primary Completion Date:||March 2013 (Final data collection date for primary outcome measure)|
Genetic: MPA SNP
Functional relevant MPA SNP will be sought in patients DNA isolated from leucocytes
Please refer to this study by its ClinicalTrials.gov identifier: NCT00978965
|Department of Medicine III, Division of Nephrology|
|Vienna, Austria, A-1090|
|Principal Investigator:||Gürkan Sengölge, MD||Medical University of Vienna|