Study of PD/PK/PG Relationships of Tacrolimus and Cyclosporin in Liver Transplant Patients (3PIGREF)
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|ClinicalTrials.gov Identifier: NCT01760356|
Recruitment Status : Active, not recruiting
First Posted : January 4, 2013
Last Update Posted : April 6, 2020
To search for suitable pharmacodynamic biomarkers, i.e., with high specificity for calcineurin inhibition and most affected by inter-individual variability, our works aimed at exploring the pharmacodynamics of CNI, the strength and variability of signal translation along the calcineurin pathway, as well as the steps where sources of internal (genetic) or external variability are the most influential.
In order to achieve this, we assessed simultaneously NFAT1 translocation into the nucleus of peripheral blood mononuclear cells (PBMC) (NFTA1 being the main NAFT isoform in resting and activated lymphocytes), the intracellular expression of IL-2 in CD3+, CD4+ and CD8+ T cell subsets and the membrane expression of CD25 (IL-2Rα), a surface marker of T cells activation, in T cells at large. A non-interventional clinical trial was set up in healthy volunteers, patients registered on a liver transplantation waiting list (WLP) and liver transplant recipients (LTR). A different question was addressed in each group: The healthy volunteer study (n=35): explored TAC PD along the calcineurin pathway by exposing PBMC ex-vivo; modelled signal translation along this cascade; examined the interindividual variability of TAC PD parameters; and investigated the sources of the variability observed and their contribution at each step of the calcineurin pathway. Furthermore, it allowed us to evaluate the analytical variability of our techniques as well as the intra-individual variability of TAC PD parameters. WLP (n=19) were enrolled to confirm in patients with liver diseases the results obtained in healthy volunteers, as well as to test the potential influence of their initial disease on the ex-vivo pharmacodynamics of TAC. The aims of the transversal study of LTR on CNI (n=80) were to further explore the interindividual variability in the PD of CNI in realistic clinical conditions, i.e. in situations of residual PD activities under tacrolimus or cyclosporine exposure, and the potential pharmacogenetic (PG) sources of such variability. The (still small) group of liver transplant patients (n=9) enrolled immediately before transplantation and followed-up with serial monitoring along the first year post-transplantation was intended to explore the relationships between CNI PD and clinical responses.
|Condition or disease|
|End Stage Liver Disease Rejection Infection Malignancy Toxicity Diabetes|
|Study Type :||Observational [Patient Registry]|
|Actual Enrollment :||141 participants|
|Target Follow-Up Duration:||12 Months|
|Official Title:||Study of Pharmacodynamic, Pharmacokinetic and Pharmacogenetic Relationships of Anticalcineurin Drugs: Tacrolimus and Cyclosporin in Liver Transplant Recipients.|
|Actual Study Start Date :||May 1, 2011|
|Actual Primary Completion Date :||February 28, 2015|
|Estimated Study Completion Date :||December 2020|
Healthy Volunteers No treatment
This is set as reference a cohort of untreated healthy volunteers, over which will be measured the biomarkers to determine the baseline. Implies PBMC ex-vivo exposure to Tacrolimus prior all cell incubations to study ex-vivo PD in stimulated conditions with mitogens to identify potential genetic sources of interindividual variability in physiological conditions Number proposed 30.
Liver Transplant Patients on Tacrolimus
To explore PD/PG/PK relationships of TAC residual PD activities ex-vivo in stimulated and non-stimulated conditions in liver recipients.
The number proposed is 50.
Waiting List for Liver Transplantation
To study the ex-vivo PD response to TAC in stimulated and non-stimulated conditions and the potential genetic sources of PD variability in pathological conditions.
The number proposed is 12.
Liver Transplant Patients on Cyclosporine
To explore PD/PG/PK relationships of CsA residual PD activities ex-vivo in stimulated and non-stimulated conditions in liver recipients.
The number proposed is 10.
Patients form the waiting list for liver transplantation will be enrolled and monitored at different times after transplantation to study the relationships between TAC PD and the clinical responses.
The number proposed is 20.
- Change in Percentage of expression of CD25High in CD3, CD4 and CD8 T Lymphocytes. [ Time Frame: All subjects at the inclusion. Patients from the longitudinal cohort: at 0, 30, 90, 180 and 360 days post transplantation. ]Related to T lymphocyte activation
- Pharmacogenetic investigations [ Time Frame: At the moment of the inclusion for all cohorts. ]Related to the influence of genetic variants in anticalcineurin drug pharmacodynamics
- Anticalcineurin drug concentration through levels [ Time Frame: At the moment of the inclusion and at each regular office visit during check up. ]Related to whole blood target calcineurin inhibitor concentration values
- Change in Mean Fluorescence Intensity of NFAT1 Nuclear Translocation Inhibition in PMBC nuclei. [ Time Frame: All subjects at the inclusion. Patients from the longitudinal cohort: at 0, 30, 90, 180 and 360 days post transplantation. ]Related to calcineruin activation/inhibition (enzyme target of this group of drugs).
- Change in the Percentage of expression of IL-2 in CD4 and CD8 subsets of T lymphocytes. [ Time Frame: All subjects at the inclusion. Patients from the longitudinal cohort: at 0, 30, 90, 180 and 360 days post transplantation. ]Related to T cell function and the maintenance of T cell response.
- Acute Cellular Rejection Mild, Moderate and Severe [ Time Frame: Within the year of follow up. ]Recipients's Immune response to his graft
- Infection Episodes which requiere anmicrobials treament [ Time Frame: Within the year of follow up ]
- Neurotoxicity to CNIs [ Time Frame: Within the year of follow up ]
- Nephrotoxicity to CNIs [ Time Frame: Within the year of follow up ]
- Malignancies [ Time Frame: Within the year of follow up ]
- Post transplant Diabetes [ Time Frame: Within the year of follow up ]
- Cardiovascular disease, post transplant blood pressure augmentation [ Time Frame: Within the year of follow up ]
- Death [ Time Frame: Within the year of follow up ]
- Post transplant surgical complications [ Time Frame: Within the year of follow up ]
Biospecimen Retention: Samples With DNA
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Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01760356
|National Center for Liver Transplantation and Liver Diseases Department, Hospital Central de las Fuerzas Armadas|
|Montevideo, Uruguay, 11600|
|Principal Investigator:||Ofelia M Noceti, PhD, PharmD||National Center for Liver Transplantation and Liver Diseases Department, Hospital Central de las Fuerzas Armadas|
|Study Chair:||Solange Gerona, MD||National Center for Liver Transplantation and Liver Diseases Department, Hospital Central de las Fuerzas Armadas|