Study of PD/PK/PG Relationships of Tacrolimus and Cyclosporin in Liver Transplant Patients

NCT01760356 | Terminated

• 1 other identifier: 3PIGREF- 2009 -1165
• Study Type: observational
• Target: 141
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

End Stage Liver Disease; Rejection; Infection; Malignancy; Toxicity; Diabetes

Keywords

Liver transplantation; Calcineurin inhibitors; Pharmacodynamic biomarkers; Calcineurin pathway; Tacrolimus; interindividual variability

Outcome Measures

Primary Outcomes (5)

• Change in Percentage of expression of CD25High in CD3, CD4 and CD8 T Lymphocytes.

  Related to T lymphocyte activation

  All subjects at the inclusion. Patients from the longitudinal cohort: at 0, 30, 90, 180 and 360 days post transplantation.

• Pharmacogenetic investigations

  Related to the influence of genetic variants in anticalcineurin drug pharmacodynamics

  At the moment of the inclusion for all cohorts.

• Anticalcineurin drug concentration through levels

  Related to whole blood target calcineurin inhibitor concentration values

  At the moment of the inclusion and at each regular office visit during check up.

• Change in Mean Fluorescence Intensity of NFAT1 Nuclear Translocation Inhibition in PMBC nuclei.

  Related to calcineruin activation/inhibition (enzyme target of this group of drugs).

  All subjects at the inclusion. Patients from the longitudinal cohort: at 0, 30, 90, 180 and 360 days post transplantation.

• Change in the Percentage of expression of IL-2 in CD4 and CD8 subsets of T lymphocytes.

  Related to T cell function and the maintenance of T cell response.

  All subjects at the inclusion. Patients from the longitudinal cohort: at 0, 30, 90, 180 and 360 days post transplantation.

Secondary Outcomes (9)

• Acute Cellular Rejection Mild, Moderate and Severe

  Within the year of follow up.

• Infection Episodes which requiere anmicrobials treament

  Within the year of follow up

• Neurotoxicity to CNIs

  Within the year of follow up

• Nephrotoxicity to CNIs

  Within the year of follow up

• Malignancies

  Within the year of follow up

Study Arms (5)

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.

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)
• 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

You may qualify if:

• Healthy volunteers:
• Age: 18 to 70 years.
• Ethnicity: Hispanic, African American.
• Gender: male and female.
• Condition: healthy.
• 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
• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• UDA Centro Nacional Hepato-Bilio-Pancreático: lead
• INSERM UMR-S850, Limoges, France: collaborator
• University Hospital, Limoges: collaborator
• PEDECIBA, Uruguay: collaborator
• Universidad de la Republica: collaborator
• ANII (Agencia Nacional de Investigación e Innovación), Uruguay: collaborator
• Scientific Cooperation Service, French Embassy, Uruguay: collaborator
• Hospital Central de las Fuerzas Armadas, Uruguay: collaborator
• ECOS Sud Program France-Uruguay: collaborator
• National Center for Liver Transplantation, Uruguay: collaborator

Study Sites (1)

National Center for Liver Transplantation and Liver Diseases Department, Hospital Central de las Fuerzas Armadas

Montevideo, 11600, Uruguay

Location

Related Publications (1)

• Noceti O, Pouche L, Esperon P, Lens D, Vital M, Tourino C, Gerona S, Woillard JB, Marquet P. Activity of the Calcineurin Pathway in Patients on the Liver Transplantation Waiting List: Factors of Variability and Response to Tacrolimus Inhibition. Clin Chem. 2017 Nov;63(11):1734-1744. doi: 10.1373/clinchem.2017.272534.

  PMID: 29054923 DERIVED

Biospecimen

Retention: SAMPLES WITH DNA

Samples from whole blood: PBMC,DNA, RNA

MeSH Terms

Conditions

End Stage Liver Disease; Rejection, Psychology; Infections; Neoplasms; Diabetes Mellitus

Condition Hierarchy (Ancestors)

Liver Failure; Hepatic Insufficiency; Liver Diseases; Digestive System Diseases; Social Behavior; Behavior; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases

Study Officials

• Ofelia M Noceti, PhD, PharmD

  National Center for Liver Transplantation and Liver Diseases Department, Hospital Central de las Fuerzas Armadas

  PRINCIPAL INVESTIGATOR

• Solange Gerona, MD

  National Center for Liver Transplantation and Liver Diseases Department, Hospital Central de las Fuerzas Armadas

  STUDY CHAIR

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Target Duration: 12 Months
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 1, 2012
• First Posted: January 4, 2013
• Study Start: May 1, 2011
• Primary Completion: February 28, 2015
• Study Completion: May 17, 2021
• Last Updated: May 19, 2021

Record last verified: 2021-05

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Time Frame: Once the trial concludes
• Access Criteria: On request

Locations

UR (1)