Phase IV - Study of PK,PD,PG Relationships of Anticalcineurin Drugs: Cyclosporin and Tacrolimus in Liver Transplant Recipients.
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.
The cohorts are formed by its own nature:healthy volunteers, transplant patients and
patients on the liver waiting list for transplantation. Each member, shall belong to them
once consented to participate in the study and has been found to meet the inclusion criteria
of the study.
Once the information stage was completed, and after obtaining signed informed consent, each
volunteer was evaluated to ensure that he meets all inclusion criteria and none of the
exclusion ones. 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 will be used to estimate the impact of bias due to potential missing data, and if
applicable will be complemented with a sensibility analysis.SPSS and ACCESS are the proposed
softwares to carry out this type of analysis.
The loading of data will be conducted electronically. The data will be validated according
to the data management plan, jointly defined by the principal investigator and the
methodologist, in charge of the data managing and the statistics. The software to be used to
test consistency will be: ACCESS ®.
The freezing and thawing process data will be held in accordance with the procedure
established in the methodology and data management.
The pharmacokinetic and pharmacodynamic modeling will be done using the program NONMEM
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 eill occur,those will be documented and the reasons
The calculation of sample size includes the percentage of occurrence of rejection and side
effects to consider, as reported by the National Liver Transplant Program and the possible
rates of abandonment or premature retirement of the in study volunteers.
Under national rates, will be studied at least 30 healthy volunteers, 50 patients and 10
patients transplanted from the instance of pretransplant liver waiting list, 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 and research
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 standard deviation or median and 25th and 75th percentiles,
minimum and maximum. Variables developed over time will be presented by Kaplan-Meier curves.
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
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
The program used will be R.
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.
Observational [Patient Registry]
Observational Model: Cohort, Time Perspective: Prospective
Change in Percentage of CD25 (IL2RA) in CD3 Lymphocytes. Flow Cytometry Measurement.
Related to the activation of T lymphocytes.
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.
Ofelia M Noceti
UDA Centro Nacional Hepato-Bilio-Pancreático
Uruguay: Ministry of Health
3PIGREF- 2009 -1165