Identification of Patients With High Probability of Poorly Responding to Therapy With Mycophenolic Acid Prodrugs
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Purpose
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.
| Condition | Intervention | Phase |
|---|---|---|
|
Renal Transplantation |
Genetic: MPA SNP |
Phase 2 |
| Study Type: | Observational |
| 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 ]
| Estimated Enrollment: | 250 |
| 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) |
| Groups/Cohorts | Assigned Interventions |
|---|---|
| All patients |
Genetic: MPA SNP
Functional relevant MPA SNP will be sought in patients DNA isolated from leucocytes
|
Eligibility| Ages Eligible for Study: | 18 Years to 75 Years |
| Genders Eligible for Study: | Both |
| Accepts Healthy Volunteers: | Yes |
| Sampling Method: | Non-Probability Sample |
Patients with a de novo kidney transplantation
Inclusion Criteria:
- patients with a de novo kidney graft and age >18 and < 75
Exclusion Criteria:
- pregnancy
- panel of antigens reactivity > 40%
Contacts and Locations| Contact: Gürkan Sengölge, MD | ++43-1-40400 ext 4389 | guerkan.sengoelge@meduniwien.ac.at |
| Contact: Wolfgang Winnicki, MD | ++43-1-40400 ext 2125 | winnicki_wolfgang@gmx.at |
| Austria | |
| Department of Medicine III, Division of Nephrology | Recruiting |
| Vienna, Austria, A-1090 | |
| Contact: Gürkan Sengölge, MD ++43-1-40400 ext 4389 guerkan.sengoelge@meduniwien.ac.at | |
| Principal Investigator: Gürkan Sengölge, MD | |
| Principal Investigator: | Gürkan Sengölge, MD | Medical University of Vienna |
More Information
No publications provided
| Responsible Party: | Guerkan SENGOELGE, Assoc. Prof. Priv.-Doz. Dr., Medical University of Vienna |
| ClinicalTrials.gov Identifier: | NCT00978965 History of Changes |
| Other Study ID Numbers: | MPASNPVienna |
| Study First Received: | September 14, 2009 |
| Last Updated: | April 23, 2012 |
| Health Authority: | Austria: Agency for Health and Food Safety |
Keywords provided by Medical University of Vienna:
|
kidney transplantation immunosuppression single nucleotide polymorphism IMPDH |
Additional relevant MeSH terms:
|
Mycophenolic Acid Mycophenolate mofetil Antibiotics, Antineoplastic Antineoplastic Agents Therapeutic Uses Pharmacologic Actions |
Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action Immunosuppressive Agents Immunologic Factors Physiological Effects of Drugs |
ClinicalTrials.gov processed this record on May 21, 2013