Clinical Study of the Pharmacogenetic / Pharmacokinetic / Pharmacodynamic Relationships of Calcineurin Inhibitors Cyclosporine and Tacrolimus in Liver Transplant Recipients (3PIGREF)

This study is enrolling participants by invitation only.
Sponsor:
Collaborators:
INSERM UMR-S850, Limoges, France
University Hospital, Limoges
PEDECIBA Química,University of the Republic,Uruguay
Facultad de Química,University of the Republic, Uruguay
ANII (Agencia Nacional de Investigación e Innovación), Uruguay
Servicio de Cooperación Científica y Técnica de la Embajada de Francia, Uruguay
Hospital Central de las Fuerzas Armadas, Uruguay
Information provided by (Responsible Party):
UDA Centro Nacional Hepato-Bilio-Pancreático
ClinicalTrials.gov Identifier:
NCT01760356
First received: December 1, 2012
Last updated: February 16, 2014
Last verified: February 2014
  Purpose

The purpose of the study aims to contribute to the safety and efficacy of individual immunosuppressive treatment.

Its principal objective is to investigate biochemical and physiological effects of calcineurin inhibitors on the body, go in depth of their mechanisms of action and to see if there is a correlation between drug concentration, outcomes and genetics. This will be able to explain the variability of the response observed, and correlated with rejection episodes or drug adverse effects.

As an approach to pharmacodynamic monitoring of calcineurin it has been proposed to measure indirectly calcineurin activity in peripheral blood lymphocytes, through the measure of the Nuclear Factor of activated T Cells nuclear translocation inhibition, the intracytosolic expression of interleukin 2, and the expression of activation markers as CD25 in T lymphocytes.

Once the biomarkers selected can be validated, it is expected to contribute to a better understanding of the steps associated with lymphocyte activation and response resulting from exposure of calcineurin, fine-tune the levels of these immunosuppressants, and alert in prematurely about a possible episode of rejection and / or occurrence of side effects - immediate or delayed - as a result of immunosuppressive therapy.

The study on healthy volunteers, would help to determine the baseline for these patients.

Tracking patients from inclusion on the transplant waiting list, will reveal the profile of the patient prior to initiating chronic treatment and closely monitor the evolution of the changes that occur at the molecular level, so as to warn clinicians on the basis of the evidence, to act accordingly.


Condition
Liver Transplantation
Graft Versus Host Disease
Infection
Cardiovascular Diseases
Malignancy

Study Type: Observational [Patient Registry]
Study Design: Observational Model: Cohort
Time Perspective: Prospective
Target Follow-Up Duration: 12 Months
Official Title: Phase IV - Study of PK,PD,PG Relationships of Anticalcineurin Drugs: Cyclosporin and Tacrolimus 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 CD25 (IL2RA) in CD3 Lymphocytes. Flow Cytometry Measurement. [ Time Frame: All the cohorts at the inclusion. Afterwards, Transplant patients: if there is acute rejection, infection or toxicity episodes related to anticalcineurin drugs; Patients in the liver waiting list: at 30, 90, 180 and 360 days post transplantation. ] [ Designated as safety issue: No ]
    Related to the activation of T lymphocytes.

  • SNP genotyping. Taqman Technique. [ Time Frame: At the moment of the inclusion for all cohorts. ] [ Designated as safety issue: No ]
  • Blood through levels of anticalcineurin drug Concentration. Chemiluminescent microparticle immunoassay. [ Time Frame: At the moment of the inclusion and at each office visit during regular check up. ] [ Designated as safety issue: Yes ]
    Related to blood target concentration ranges

  • Change in Mean Fluorescence Intensity of NFAT Nuclear Translocation Inhibition in PMBC nuclei. Flow Cytometry Measurement [ Time Frame: All the cohorts at the inclusion. Afterwards, Transplant patients: if there is acute rejection, infection or toxicity episodes related to anticalcineurin drugs; Patients in the liver waiting list: at 30, 90, 180 and 360 days post transplantation. ] [ Designated as safety issue: No ]
    Related to Calcineruin activity (enzyme target of this group of drugs).

  • Change in the Percentage of IL-2 in CD4 and CD8 subsets of T lymphocytes. Flow Cytometry Measurement. [ Time Frame: All the cohorts at the inclusion. Afterwards, Transplant patients: if there is acute rejection, infection or toxicity episodes related to anticalcineurin drugs; Patients in the liver waiting list: at 30, 90, 180 and 360 days post transplantation. ] [ Designated as safety issue: No ]
    Related to the maintenance of the immune response.


Secondary Outcome Measures:
  • Acute and Chronic Cellular Rejection. Percutaneous biopsy. [ Time Frame: Within the year of follow up. ] [ Designated as safety issue: Yes ]
  • Infection events. Clinical, biochemical, microbiological, endoscopic, radiological, echocardiographic, serological, imaging, evolution criteria. [ Time Frame: Within the year of follow up ] [ Designated as safety issue: Yes ]
  • Toxicity: renal, hematological, neurological. clinical, biochemical, imaging, nerve conduction, electromyography, CBC criteria. [ Time Frame: Within the year of follow up ] [ Designated as safety issue: Yes ]
  • Cardiovascular disease. Blood pressure measurements, biochemical tests, BMI and waist circumference, myocardial revascularization, angioplastic, CTP, ischemia testing, echocardiographic imaging, ultrasound, bone densitometry, radiology. [ Time Frame: Within the year of follow up ] [ Designated as safety issue: Yes ]
  • Malignancies. Tissue or lymph biopsy. [ Time Frame: Within the year of follow up ] [ Designated as safety issue: Yes ]
  • Re transplantation - Loss of the graft. Biopsy and functional tests. [ Time Frame: Within the year of follow up ] [ Designated as safety issue: Yes ]
  • Rehospitalization. Hospital admission. [ Time Frame: Within the year of follow up ] [ Designated as safety issue: Yes ]
  • Death. Absence of vital signs. [ Time Frame: Within the year of follow up ] [ Designated as safety issue: Yes ]

Biospecimen Retention:   Samples With DNA

Genetic analysis is carried out from whole blood samples,from which DNA is extracted for the study of relevant polymorphisms.


Enrollment: 46
Study Start Date: May 2011
Primary Completion Date: February 2014 (Final data collection date for primary outcome measure)
Groups/Cohorts
No treatment

Healthy Volunteers. In the design of the trial 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 drug contact prior all cell incubations.

Number proposed 30.

Liver Transplant Patients

About the cohort treated with immunosuppressive calcineurin drugs, it will be studied the behavior of pharmacodynamic markers ruled, their drug plasma concentration achieved before next dose and the clinical response.

The number proposed is 50.

Waiting LiverTransplantation List

Biomarkers determination, plasma concentrations of calcineurin and monitoring of the clinical response, will be done before transplantation (time 0), and then at 30, 60, 90, 180 and 365 days after transplantation.

The number proposed is 12.


  Show Detailed Description

  Eligibility

Ages Eligible for Study:   18 Years to 70 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Sampling Method:   Non-Probability Sample
Study Population

Transplant Patients on anticalcineurin drugs and Transplant Waiting List Patients comprising the National Program of Liver Transplantation in Uruguay.

Healthy Volunteers belonging to the Hospital payroll.

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 agree 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 agree 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 agree 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
Hospital Central de las Fuerzas Armadas
Montevideo, Uruguay, 11300
Sponsors and Collaborators
UDA Centro Nacional Hepato-Bilio-Pancreático
INSERM UMR-S850, Limoges, France
University Hospital, Limoges
PEDECIBA Química,University of the Republic,Uruguay
Facultad de Química,University of the Republic, Uruguay
ANII (Agencia Nacional de Investigación e Innovación), Uruguay
Servicio de Cooperación Científica y Técnica de la Embajada de Francia, Uruguay
Hospital Central de las Fuerzas Armadas, Uruguay
Investigators
Principal Investigator: Ofelia M Noceti UDA Centro Nacional Hepato-Bilio-Pancreático
Study Director: Solange Gerona, MD National Liver Transplantation Program
  More Information

No publications provided

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: February 16, 2014
Health Authority: Uruguay: Ministry of Health

Keywords provided by UDA Centro Nacional Hepato-Bilio-Pancreático:
Liver organ transplantation
Anticalcineurin drugs
Pharmacodynamic biomarkers
Calcineurin pathway

Additional relevant MeSH terms:
Neoplasms
Cardiovascular Diseases
Graft vs Host Disease
Immune System Diseases
Cyclosporins
Cyclosporine
Tacrolimus
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antifungal Agents
Anti-Infective Agents
Therapeutic Uses
Dermatologic Agents
Antirheumatic Agents

ClinicalTrials.gov processed this record on August 01, 2014