Clinical Trial Details
— Status: Terminated
Administrative data
| NCT number |
NCT01760356 |
| Other study ID # |
3PIGREF- 2009 -1165 |
| Secondary ID |
|
| Status |
Terminated |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
May 1, 2011 |
| Est. completion date |
May 17, 2021 |
Study information
| Verified date |
May 2021 |
| Source |
UDA Centro Nacional Hepato-Bilio-Pancreático |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational [Patient Registry]
|
Clinical Trial 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.
Description:
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.
Groups 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.
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 patient's 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 Fisher's
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
Bonferroni's 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.
