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Study of PD/PK/PG Relationships of Tacrolimus and Cyclosporin in Liver Transplant Patients (3PIGREF)

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborators:
INSERM UMR-S850, Limoges, France
CHU Limoges, France
PEDECIBA, Uruguay
Universidad de la República, Uruguay
ANII (Agencia Nacional de Investigación e Innovación), Uruguay
Scientific Cooperation Service, French Embassy, Uruguay
Hospital Central de las Fuerzas Armadas, Uruguay
ECOS Sud Program France-Uruguay
National Center for Liver Transplantation, Uruguay
Information provided by (Responsible Party):
UDA Centro Nacional Hepato-Bilio-Pancreático
ClinicalTrials.gov Identifier:
NCT01760356
First received: December 1, 2012
Last updated: October 7, 2016
Last verified: October 2016
  Purpose

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
End Stage Liver Disease
Rejection
Infection
Malignancy
Toxicity
Diabetes

Study Type: Observational [Patient Registry]
Study Design: Observational Model: Cohort
Time Perspective: Prospective
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.

Resource links provided by NLM:


Further study details as provided by UDA Centro Nacional Hepato-Bilio-Pancreático:

Primary Outcome Measures:
  • 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. ] [ Designated as safety issue: Yes ]
    Related to T lymphocyte activation

  • Pharmacogenetic investigations [ Time Frame: At the moment of the inclusion for all cohorts. ] [ Designated as safety issue: Yes ]
    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. ] [ Designated as safety issue: Yes ]
    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. ] [ Designated as safety issue: Yes ]
    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. ] [ Designated as safety issue: Yes ]
    Related to T cell function and the maintenance of T cell response.


Secondary Outcome Measures:
  • Acute Cellular Rejection Mild, Moderate and Severe [ Time Frame: Within the year of follow up. ] [ Designated as safety issue: Yes ]
    Recipients's Immune response to his graft

  • Infection Episodes which requiere anmicrobials treament [ Time Frame: Within the year of follow up ] [ Designated as safety issue: Yes ]
  • Neurotoxicity to CNIs [ Time Frame: Within the year of follow up ] [ Designated as safety issue: Yes ]
  • Nephrotoxicity to CNIs [ Time Frame: Within the year of follow up ] [ Designated as safety issue: Yes ]
  • Malignancies [ Time Frame: Within the year of follow up ] [ Designated as safety issue: Yes ]
  • Post transplant Diabetes [ Time Frame: Within the year of follow up ] [ Designated as safety issue: Yes ]
  • Cardiovascular disease, post transplant blood pressure augmentation [ Time Frame: Within the year of follow up ] [ Designated as safety issue: No ]
  • Death [ Time Frame: Within the year of follow up ] [ Designated as safety issue: Yes ]
  • Post transplant surgical complications [ Time Frame: Within the year of follow up ] [ Designated as safety issue: Yes ]

Biospecimen Retention:   Samples With DNA
Samples from whole blood: PBMC,DNA, RNA

Enrollment: 141
Study Start Date: May 2011
Estimated Study Completion Date: December 2018
Primary Completion Date: February 2015 (Final data collection date for primary outcome measure)
Groups/Cohorts
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.

Longitudinal Cohort

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.


  Show Detailed Description

  Eligibility

Ages Eligible for Study:   18 Years to 70 Years   (Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Sampling Method:   Non-Probability Sample
Study Population
Healthy Volunteers Patients of the Waiting List for Liver Transplantation Liver Transplant recipients on Tacrolimus Liver Transplant Recipients on Cyclosporine Longitudinal Cohort of Patients since their pretransplant condition up 1 year posttransplantation
Criteria

Inclusion Criteria:

Healthy volunteers:

  • Age: 18 to 70 years.
  • Ethnicity: Hispanic, African American.
  • Gender: male and female.
  • Condition: healthy.
  • Informed consent: granted and signed informed consent at the time of inclusion and agreement to comply with all the procedures included in the protocol.

Waiting List Patients:

  • Age: 18 to 70 years.
  • Ethnicity: Hispanic, African American.
  • Gender: male and female.
  • Being active on the waiting list for liver transplantation
  • Informed consent: granted and signed at the time of inclusion and agreement to comply with all the procedures included in the protocol.

Transplant Patients:

  • Age: 18 to 70 years.
  • Ethnicity: Hispanic, African American.
  • Gender: male and female.
  • Drug therapy: cyclosporine or tacrolimus, with or without mycophenolic acid derivatives and/or corticosteroids.
  • Informed consent: granted and signed at the time of inclusion and agreement to comply with all the procedures included in the protocol.

Exclusion Criteria:

Healthy volunteers:

  • pregnancy
  • breastfeeding
  • chronic drug treatment
  • non healthy

Waiting List Patients:

  • Patients with previous transplant.
  • Patients with more of one transplanted organ.
  • Patients on anticalcineurin drugs.
  • Patients with impaired renal function - creatinine clearance ≤ 20 ml/min.

Transplant Patients:

  • Pregnant or breastfeeding.
  • Patients with prior retransplantation.
  • Patients with more of one transplanted organ.
  • Patients with impaired renal function - creatinine clearance ≤ 20 ml/min.
  • Everolimus indication at any time during treatment.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01760356

Locations
Uruguay
National Center for Liver Transplantation and Liver Diseases Department, Hospital Central de las Fuerzas Armadas
Montevideo, Uruguay, 11600
Sponsors and Collaborators
UDA Centro Nacional Hepato-Bilio-Pancreático
INSERM UMR-S850, Limoges, France
CHU Limoges, France
PEDECIBA, Uruguay
Universidad de la República, Uruguay
ANII (Agencia Nacional de Investigación e Innovación), Uruguay
Scientific Cooperation Service, French Embassy, Uruguay
Hospital Central de las Fuerzas Armadas, Uruguay
ECOS Sud Program France-Uruguay
National Center for Liver Transplantation, Uruguay
Investigators
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
  More Information

Study Data/Documents: Clinical Study Report  This link exits the ClinicalTrials.gov site
Identifier: PMID: 25142246
Tacrolimus pharmacodynamics and pharmacogenetics along the calcineurin pathway in human lymphocytes

Responsible Party: UDA Centro Nacional Hepato-Bilio-Pancreático
ClinicalTrials.gov Identifier: NCT01760356     History of Changes
Other Study ID Numbers: 3PIGREF- 2009 -1165 
Study First Received: December 1, 2012
Last Updated: October 7, 2016
Health Authority: Uruguay: Ministry of Health
Individual Participant Data  
Plan to Share IPD: Yes
Plan Description: Through scientific publications and congresses

Keywords provided by UDA Centro Nacional Hepato-Bilio-Pancreático:
Liver transplantation
Calcineurin inhibitors
Pharmacodynamic biomarkers
Calcineurin pathway
Tacrolimus
interindividual variability

Additional relevant MeSH terms:
Liver Diseases
End Stage Liver Disease
Digestive System Diseases
Liver Failure
Hepatic Insufficiency
Liver Extracts
Tacrolimus
Cyclosporins
Cyclosporine
Hematinics
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Calcineurin Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antifungal Agents
Anti-Infective Agents
Dermatologic Agents
Antirheumatic Agents

ClinicalTrials.gov processed this record on December 05, 2016