Ignite Creation Date:
2024-05-06 @ 1:13 AM
Last Modification Date:
2024-10-26 @ 11:01 AM
Study NCT ID:
NCT01760356
Status:
TERMINATED
Last Update Posted:
2021-05-19
First Post:
2012-12-01
Brief Title:
Study of PDPKPG Relationships of Tacrolimus and Cyclosporin in Liver Transplant Patients
Sponsor:
UDA Centro Nacional Hepato-Bilio-Pancreático
Organization:
UDA Centro Nacional Hepato-Bilio-Pancreático
Study Overview
Official Title:
Study of Pharmacodynamic Pharmacokinetic and Pharmacogenetic Relationships of Anticalcineurin Drugs Tacrolimus and Cyclosporin in Liver Transplant Recipients
Status:
TERMINATED
Status Verified Date:
2021-05
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
3PIGREF
Brief Summary:
To search for suitable pharmacodynamic biomarkers ie 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 n35 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 n19 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 n80 were to further explore the interindividual variability in the PD of CNI in realistic clinical conditions ie 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 n9 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
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 n35 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 n19 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 n80 were to further explore the interindividual variability in the PD of CNI in realistic clinical conditions ie 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 n9 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
Detailed Description:
The research will be conducted under the rules of Good Clinical Practice Good Laboratory Practice of the International Conference on Harmonisation ICHand the Principles of Declaration of Helsinki
Groups of study are included once inclusionexclusion 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
From 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
The study design does not suppose applying masking methods since it is an open study
All 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
Models could be used to estimate the impact of bias due to potential missing data and if applicable will be complemented with a sensibility analysis
Loading 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
Pharmacokinetic pharmacogenetic and pharmacodynamic modeling will be done using R software
Data back ups will be run everyday and will be archived on tape and a USB storage drive
Besides 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
Atypical 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
Sample 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
Under 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
Statistical analysis will be performed according to the principle of intention to treat and will be the responsible for at least one specialist in biostatistics
It 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
The variables will be compared between groups according to the patients original listing intention to treat They will be calculated and presented the estimated relative risks and their effect with 95 confidence intervals
For comparison of categorical variables it will be used the Chi-square test or Fishers exact test as appropriate
For comparison of continuous variables it will be used the test t of Student
For 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
To identify variables associated with different responses multivariate linear analysis logistic or Cox proportional will be used
All analyzes will be performed with hypothesis testing and a 2-tailed significance level of 5
The program used will be R Multivariate analysis will be held corrected according Bonferronis criteria
We 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
Groups of study are included once inclusionexclusion 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
From 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
The study design does not suppose applying masking methods since it is an open study
All 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
Models could be used to estimate the impact of bias due to potential missing data and if applicable will be complemented with a sensibility analysis
Loading 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
Pharmacokinetic pharmacogenetic and pharmacodynamic modeling will be done using R software
Data back ups will be run everyday and will be archived on tape and a USB storage drive
Besides 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
Atypical 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
Sample 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
Under 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
Statistical analysis will be performed according to the principle of intention to treat and will be the responsible for at least one specialist in biostatistics
It 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
The variables will be compared between groups according to the patients original listing intention to treat They will be calculated and presented the estimated relative risks and their effect with 95 confidence intervals
For comparison of categorical variables it will be used the Chi-square test or Fishers exact test as appropriate
For comparison of continuous variables it will be used the test t of Student
For 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
To identify variables associated with different responses multivariate linear analysis logistic or Cox proportional will be used
All analyzes will be performed with hypothesis testing and a 2-tailed significance level of 5
The program used will be R Multivariate analysis will be held corrected according Bonferronis criteria
We 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
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None