Ignite Creation Date:
2025-12-24 @ 11:14 PM
Ignite Modification Date:
2026-01-18 @ 3:17 PM
Study NCT ID:
NCT01760356
Status:
TERMINATED
Last Update Posted:
2021-05-19
First Post:
2012-12-01
Is Gene Therapy:
True
Has Adverse Events:
False
Brief Title:
Study of PD/PK/PG Relationships of Tacrolimus and Cyclosporin in Liver Transplant Patients
Sponsor:
Organization:
Raw JSON
{'hasResults': False, 'derivedSection': {'miscInfoModule': {'versionHolder': '2025-12-24'}, 'conditionBrowseModule': {'meshes': [{'id': 'D058625', 'term': 'End Stage Liver Disease'}, {'id': 'D012059', 'term': 'Rejection, Psychology'}, {'id': 'D007239', 'term': 'Infections'}, {'id': 'D009369', 'term': 'Neoplasms'}, {'id': 'D003920', 'term': 'Diabetes Mellitus'}], 'ancestors': [{'id': 'D017093', 'term': 'Liver Failure'}, {'id': 'D048550', 'term': 'Hepatic Insufficiency'}, {'id': 'D008107', 'term': 'Liver Diseases'}, {'id': 'D004066', 'term': 'Digestive System Diseases'}, {'id': 'D012919', 'term': 'Social Behavior'}, {'id': 'D001519', 'term': 'Behavior'}, {'id': 'D044882', 'term': 'Glucose Metabolism Disorders'}, {'id': 'D008659', 'term': 'Metabolic Diseases'}, {'id': 'D009750', 'term': 'Nutritional and Metabolic Diseases'}, {'id': 'D004700', 'term': 'Endocrine System Diseases'}]}}, 'protocolSection': {'designModule': {'bioSpec': {'retention': 'SAMPLES_WITH_DNA', 'description': 'Samples from whole blood: PBMC,DNA, RNA'}, 'studyType': 'OBSERVATIONAL', 'designInfo': {'timePerspective': 'PROSPECTIVE', 'observationalModel': 'COHORT'}, 'enrollmentInfo': {'type': 'ACTUAL', 'count': 141}, 'targetDuration': '12 Months', 'patientRegistry': True}, 'statusModule': {'overallStatus': 'TERMINATED', 'startDateStruct': {'date': '2011-05-01', 'type': 'ACTUAL'}, 'expandedAccessInfo': {'hasExpandedAccess': False}, 'statusVerifiedDate': '2021-05', 'completionDateStruct': {'date': '2021-05-17', 'type': 'ACTUAL'}, 'lastUpdateSubmitDate': '2021-05-17', 'studyFirstSubmitDate': '2012-12-01', 'studyFirstSubmitQcDate': '2012-12-27', 'lastUpdatePostDateStruct': {'date': '2021-05-19', 'type': 'ACTUAL'}, 'studyFirstPostDateStruct': {'date': '2013-01-04', 'type': 'ESTIMATED'}, 'primaryCompletionDateStruct': {'date': '2015-02-28', 'type': 'ACTUAL'}}, 'outcomesModule': {'primaryOutcomes': [{'measure': 'Change in Percentage of expression of CD25High in CD3, CD4 and CD8 T Lymphocytes.', 'timeFrame': 'All subjects at the inclusion. Patients from the longitudinal cohort: at 0, 30, 90, 180 and 360 days post transplantation.', 'description': 'Related to T lymphocyte activation'}, {'measure': 'Pharmacogenetic investigations', 'timeFrame': 'At the moment of the inclusion for all cohorts.', 'description': 'Related to the influence of genetic variants in anticalcineurin drug pharmacodynamics'}, {'measure': 'Anticalcineurin drug concentration through levels', 'timeFrame': 'At the moment of the inclusion and at each regular office visit during check up.', 'description': 'Related to whole blood target calcineurin inhibitor concentration values'}, {'measure': 'Change in Mean Fluorescence Intensity of NFAT1 Nuclear Translocation Inhibition in PMBC nuclei.', 'timeFrame': 'All subjects at the inclusion. Patients from the longitudinal cohort: at 0, 30, 90, 180 and 360 days post transplantation.', 'description': 'Related to calcineruin activation/inhibition (enzyme target of this group of drugs).'}, {'measure': 'Change in the Percentage of expression of IL-2 in CD4 and CD8 subsets of T lymphocytes.', 'timeFrame': 'All subjects at the inclusion. Patients from the longitudinal cohort: at 0, 30, 90, 180 and 360 days post transplantation.', 'description': 'Related to T cell function and the maintenance of T cell response.'}], 'secondaryOutcomes': [{'measure': 'Acute Cellular Rejection Mild, Moderate and Severe', 'timeFrame': 'Within the year of follow up.', 'description': "Recipients's Immune response to his graft"}, {'measure': 'Infection Episodes which requiere anmicrobials treament', 'timeFrame': 'Within the year of follow up'}, {'measure': 'Neurotoxicity to CNIs', 'timeFrame': 'Within the year of follow up'}, {'measure': 'Nephrotoxicity to CNIs', 'timeFrame': 'Within the year of follow up'}, {'measure': 'Malignancies', 'timeFrame': 'Within the year of follow up'}, {'measure': 'Post transplant Diabetes', 'timeFrame': 'Within the year of follow up'}, {'measure': 'Cardiovascular disease, post transplant blood pressure augmentation', 'timeFrame': 'Within the year of follow up'}, {'measure': 'Death', 'timeFrame': 'Within the year of follow up'}, {'measure': 'Post transplant surgical complications', 'timeFrame': 'Within the year of follow up'}]}, 'oversightModule': {'oversightHasDmc': False}, 'conditionsModule': {'keywords': ['Liver transplantation', 'Calcineurin inhibitors', 'Pharmacodynamic biomarkers', 'Calcineurin pathway', 'Tacrolimus', 'interindividual variability'], 'conditions': ['End Stage Liver Disease', 'Rejection', 'Infection', 'Malignancy', 'Toxicity', 'Diabetes']}, 'referencesModule': {'availIpds': [{'id': 'PMID: 25142246', 'url': 'http://www.ncbi.nlm.nih.gov/pubmed/25142246', 'type': 'Clinical Study Report', 'comment': 'Tacrolimus pharmacodynamics and pharmacogenetics along the calcineurin pathway in human lymphocytes.'}, {'id': 'PMID: 29054923', 'url': 'https://www.ncbi.nlm.nih.gov/pubmed/29054923', 'type': 'Clinical Study Report', 'comment': 'Activity of the Calcineurin Pathway in Patients on the Liver Transplantation Waiting List: Factors of Variability and Response to Tacrolimus Inhibition.'}], 'references': [{'pmid': '29054923', 'type': 'DERIVED', 'citation': '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.'}]}, 'descriptionModule': {'briefSummary': '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.\n\nIn 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.', 'detailedDescription': 'The research will be conducted under the rules of Good Clinical Practice, Good Laboratory Practice of the International Conference on Harmonisation (ICH)and the Principles of Declaration of Helsinki.\n\nGroups of study are included once inclusion/exclusion criteria were verified and after written informed consent was given: healthy volunteers, patients of the waiting list for liver transplantation, liver transplant recipients on tacrolimus and cyclosporine and a longitudinal cohort of patients enrolled since the waiting list for transplantation.\n\nFrom this instance proceed the sampling plan. Considering potential dropouts or withdrawals during the study, the intention is to recruit an additional 10% to compensate for the cohorts, as they allow.\n\nThe study design does not suppose applying masking methods, since it is an open study.\n\nAll data required in the registration forms will be recorded, however in case of persistent failure, will be properly documented the reasons for the absence. Each instance will merit a particular analysis, dated and signed.\n\nModels could be used to estimate the impact of bias due to potential missing data, and if applicable will be complemented with a sensibility analysis.\n\nLoading data will be conducted electronically. Data will be validated according to the data management plan, jointly defined by the principal investigator and the biostatistician, including freezing and thawing processes.\n\nPharmacokinetic, pharmacogenetic and pharmacodynamic modeling will be done using R software.\n\nData back ups will be run everyday, and will be archived on tape and a USB storage drive.\n\nBesides self monitoring procedures, the study may be audited by the health authority (during the course of the study or even when it is completed), to assess compliance with the standards of Good Clinical Practice.\n\nAtypical results if any, will be handled according to the criteria of results outside of specification. If re-analysis of samples will occur, they will be properly documented.\n\nSample size calculation includes the percentage of occurrence of acute cellular rejection and adverse events, as reported by the National Liver Transplant Program and the possible rates of abandonment or premature retirement of the in study subjects.\n\nUnder national rates, will be studied at least 30 healthy volunteers, 50 patients and 12 patients with end stage liver disease enlisted for liver transplantation, with serial follow-up during the first year.\n\nStatistical analysis will be performed according to the principle of "intention to treat", and will be the responsible for at least one specialist in biostatistics.\n\nIt will be developed a descriptive analysis of all variables collected. Categorical variables will be expressed in percentages and number of observations. Continuous variables will be expressed as mean and coefficient of variation or median and 25th and 75th percentiles, minimum and maximum. Lof transformations will be held whenever needed.\n\nThe variables will be compared between groups according to the patient\'s original listing (intention to treat). They will be calculated and presented the estimated relative risks and their effect with 95% confidence intervals.\n\nFor comparison of categorical variables, it will be used the Chi-square test or Fisher\'s exact test as appropriate.\n\nFor comparison of continuous variables, it will be used the test "t" of Student.\n\nFor variables that develop with time, they will be represented by Kaplan-Meier curves and compared using the "log-rank" test. Their relative risk with 95% confidence interval will be calculated.\n\nTo identify variables associated with different responses multivariate linear analysis, logistic or Cox proportional will be used.\n\nAll analyzes will be performed with hypothesis testing and a 2-tailed significance level of 5%.\n\nThe program used will be R. Multivariate analysis will be held corrected according Bonferroni\'s criteria.\n\nWe have established standard operating procedures to describe blood collection instances, biological fluids sampling circuit, evaluation of the candidates to include in the study, verification of the inclusion criteria, monitoring of patients during the study, record of undesirable events and report of adverse drug reactions, terminating tracking.'}, 'eligibilityModule': {'sex': 'ALL', 'stdAges': ['ADULT', 'OLDER_ADULT'], 'maximumAge': '70 Years', 'minimumAge': '18 Years', 'samplingMethod': 'NON_PROBABILITY_SAMPLE', 'studyPopulation': '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', 'healthyVolunteers': True, 'eligibilityCriteria': 'Inclusion Criteria:\n\nHealthy volunteers:\n\n* Age: 18 to 70 years.\n* Ethnicity: Hispanic, African American.\n* Gender: male and female.\n* Condition: healthy.\n* Informed consent: granted and signed informed consent at the time of inclusion and agreement to comply with all the procedures included in the protocol.\n\nWaiting List Patients:\n\n* Age: 18 to 70 years.\n* Ethnicity: Hispanic, African American.\n* Gender: male and female.\n* Being active on the waiting list for liver transplantation\n* Informed consent: granted and signed at the time of inclusion and agreement to comply with all the procedures included in the protocol.\n\nTransplant Patients:\n\n* Age: 18 to 70 years.\n* Ethnicity: Hispanic, African American.\n* Gender: male and female.\n* Drug therapy: cyclosporine or tacrolimus, with or without mycophenolic acid derivatives and/or corticosteroids.\n* Informed consent: granted and signed at the time of inclusion and agreement to comply with all the procedures included in the protocol.\n\nExclusion Criteria:\n\nHealthy volunteers:\n\n* pregnancy\n* breastfeeding\n* chronic drug treatment\n* non healthy\n\nWaiting List Patients:\n\n* Patients with previous transplant.\n* Patients with more of one transplanted organ.\n* Patients on anticalcineurin drugs.\n* Patients with impaired renal function - creatinine clearance ≤ 20 ml/min.\n\nTransplant Patients:\n\n* Pregnant or breastfeeding.\n* Patients with prior retransplantation.\n* Patients with more of one transplanted organ.\n* Patients with impaired renal function - creatinine clearance ≤ 20 ml/min.\n* Everolimus indication at any time during treatment.'}, 'identificationModule': {'nctId': 'NCT01760356', 'acronym': '3PIGREF', 'briefTitle': 'Study of PD/PK/PG Relationships of Tacrolimus and Cyclosporin in Liver Transplant Patients', 'organization': {'class': 'OTHER', 'fullName': 'UDA Centro Nacional Hepato-Bilio-Pancreático'}, 'officialTitle': 'Study of Pharmacodynamic, Pharmacokinetic and Pharmacogenetic Relationships of Anticalcineurin Drugs: Tacrolimus and Cyclosporin in Liver Transplant Recipients.', 'orgStudyIdInfo': {'id': '3PIGREF- 2009 -1165'}}, 'armsInterventionsModule': {'armGroups': [{'label': 'Healthy Volunteers No treatment', 'description': '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.'}, {'label': 'Liver Transplant Patients on Tacrolimus', 'description': 'To explore PD/PG/PK relationships of TAC residual PD activities ex-vivo in stimulated and non-stimulated conditions in liver recipients.\n\nThe number proposed is 50.'}, {'label': 'Waiting List for Liver Transplantation', 'description': '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.\n\nThe number proposed is 12.'}, {'label': 'Liver Transplant Patients on Cyclosporine', 'description': 'To explore PD/PG/PK relationships of CsA residual PD activities ex-vivo in stimulated and non-stimulated conditions in liver recipients.\n\nThe number proposed is 10.'}, {'label': 'Longitudinal Cohort', 'description': '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.\n\nThe number proposed is 20.'}]}, 'contactsLocationsModule': {'locations': [{'zip': '11600', 'city': 'Montevideo', 'country': 'Uruguay', 'facility': 'National Center for Liver Transplantation and Liver Diseases Department, Hospital Central de las Fuerzas Armadas', 'geoPoint': {'lat': -34.90328, 'lon': -56.18816}}], 'overallOfficials': [{'name': 'Ofelia M Noceti, PhD, PharmD', 'role': 'PRINCIPAL_INVESTIGATOR', 'affiliation': 'National Center for Liver Transplantation and Liver Diseases Department, Hospital Central de las Fuerzas Armadas'}, {'name': 'Solange Gerona, MD', 'role': 'STUDY_CHAIR', 'affiliation': 'National Center for Liver Transplantation and Liver Diseases Department, Hospital Central de las Fuerzas Armadas'}]}, 'ipdSharingStatementModule': {'infoTypes': ['STUDY_PROTOCOL', 'SAP', 'ICF', 'CSR'], 'timeFrame': 'Once the trial concludes', 'ipdSharing': 'YES', 'description': 'Through scientific publications and congresses', 'accessCriteria': 'On request'}, 'sponsorCollaboratorsModule': {'leadSponsor': {'name': 'UDA Centro Nacional Hepato-Bilio-Pancreático', 'class': 'OTHER'}, 'collaborators': [{'name': 'INSERM UMR-S850, Limoges, France', 'class': 'UNKNOWN'}, {'name': 'University Hospital, Limoges', 'class': 'OTHER'}, {'name': 'PEDECIBA, Uruguay', 'class': 'UNKNOWN'}, {'name': 'Universidad de la Republica', 'class': 'OTHER'}, {'name': 'ANII (Agencia Nacional de Investigación e Innovación), Uruguay', 'class': 'UNKNOWN'}, {'name': 'Scientific Cooperation Service, French Embassy, Uruguay', 'class': 'UNKNOWN'}, {'name': 'Hospital Central de las Fuerzas Armadas, Uruguay', 'class': 'UNKNOWN'}, {'name': 'ECOS Sud Program France-Uruguay', 'class': 'UNKNOWN'}, {'name': 'National Center for Liver Transplantation, Uruguay', 'class': 'UNKNOWN'}], 'responsibleParty': {'type': 'SPONSOR'}}}}