Nutritional and Metabolic Diseases

Gland and Hormone Related Diseases

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Liver Diseases

Gastrointestinal Diseases

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All Drugs and Chemicals

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Tacrolimus

Triamcinolone

Triamcinolone Acetonide

Triamcinolone hexacetonide

Triamcinolone diacetate

Cyclosporine

Cyclosporins

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Mitogens

Calcineurin Inhibitors

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.

To explore PD/PG/PK relationships of TAC residual PD activities ex-vivo in stimulated and non-stimulated conditions in liver recipients.

The number proposed is 50.

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.

The number proposed is 12.

To explore PD/PG/PK relationships of CsA residual PD activities ex-vivo in stimulated and non-stimulated conditions in liver recipients.

The number proposed is 10.

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.

The number proposed is 20.

Ofelia M Noceti, PhD, PharmD

Solange Gerona, MD

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.

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.

Study of PD/PK/PG Relationships of Tacrolimus and Cyclosporin in Liver Transplant Patients

Study of Pharmacodynamic, Pharmacokinetic and Pharmacogenetic Relationships of Anticalcineurin Drugs: Tacrolimus and Cyclosporin in Liver Transplant Recipients.

Through scientific publications and congresses

Related to the influence of genetic variants in anticalcineurin drug pharmacodynamics

Related to whole blood target calcineurin inhibitor concentration values

Related to calcineruin activation/inhibition (enzyme target of this group of drugs).

Related to T cell function and the maintenance of T cell response.

Recipients's Immune response to his graft

INSERM UMR-S850, Limoges, France

University Hospital, Limoges

PEDECIBA, Uruguay

Universidad de la Republica

ANII (Agencia Nacional de Investigación e Innovación), Uruguay

Scientific Cooperation Service, French Embassy, Uruguay

Hospital Central de las Fuerzas Armadas, Uruguay

ECOS Sud Program France-Uruguay

National Center for Liver Transplantation, Uruguay

UDA Centro Nacional Hepato-Bilio-Pancreático

Neoplasms

Blood and Lymph Conditions

Immune System Diseases

Rare Diseases

Syndrome

Leukemia

Preleukemia

Myelodysplastic Syndromes

Hematologic Neoplasms

Graft vs Host Disease

Homologous Wasting Disease

Antineoplastic Agents

Reproductive Control Agents

Micronutrients

Vitamins

Methotrexate

Mycophenolic Acid

Sirolimus

KRN 7000

Antimetabolites

Enzyme Inhibitors

Folic Acid

Vitamin B Complex

Folic Acid Antagonists

Immunosuppressive Agents

Immunologic Factors

Anti-Bacterial Agents

Antibiotics, Antitubercular

Antitubercular Agents

Clotrimazole

Miconazole

Antifungal Agents

Adjuvants, Immunologic

Folinic Acid

Folate

Vitamin B9

RGI-2001 will be add to standard treatment with a calcineurin inhibitor, in combination with either methotrexate, mycophenolate mofetil, or sirolimus all at doses as per the institutional protocols

Dose escalation cohort 1 in part 1 of this study will include 2-6 patients

RGI-2001 will be add to standard treatment with a calcineurin inhibitor, in combination with either methotrexate, mycophenolate mofetil, or sirolimus all at doses as per the institutional protocols

Cohort 2 in part 1 of this study will include 2-6 patients

RGI-2001 will be add to standard treatment with a calcineurin inhibitor, in combination with either methotrexate, mycophenolate mofetil, or sirolimus all at doses as per the institutional protocols

Cohort 3 in part 1 of this study will include 2-6 patients

RGI-2001 will be add to standard treatment with a calcineurin inhibitor, in combination with either methotrexate, mycophenolate mofetil, or sirolimus all at doses as per the institutional protocols

Cohort 4 in part 1 of this study will include 2-6 patients

RGI-2001 will be add to standard treatment with a calcineurin inhibitor, in combination with either methotrexate, mycophenolate mofetil, or sirolimus all at doses as per the institutional protocols

Cohort 5 in part 1 of this study will include 2-6 patients

RGI-2001 will be add to standard treatment with a calcineurin inhibitor, in combination with either methotrexate, mycophenolate mofetil, or sirolimus all at doses as per the institutional protocols

Cohort 6 in part 1 of this study will include 2-6 patients

RGI-2001 will be add to standard treatment with a calcineurin inhibitor, in combination with either methotrexate, mycophenolate mofetil, or sirolimus all at doses as per the institutional protocols

Cohort 7 in part 1 of this study will include 2-6 patients (optional)

RGI-2001 will be add to standard treatment with a calcineurin inhibitor, in combination with either methotrexate, mycophenolate mofetil, or sirolimus all at doses as per the institutional protocols

In part 2 of this study the best dose or doses determined from part 1 will be administered in up to 30 persons.

A single administration of RGI-2001 on Day 0 post AHSCT.

RGI-2001

GVHD prophylaxis according to institutional guidelines. Subjects could have received any number/combinations of treatments.

Allogeneic Hematopoietic Stem Cell Transplantation

Myeloablative preparative treatment according to institutional guidelines. Subjects could have received any number/combinations of treatments.

Conditioning Regimen

Allogeneic Bone Marrow Transplantation

Mofetil Mycophenolate

Administered for GVHD prophylaxis as per institutional guidelines

sirolimus

The clinical trial is a Phase 1/2a, open-label, multi-center, dose-escalation study to evaluate the safety, tolerability and pharmacokinetic profile of RGI-2001 in patients undergoing AHSCT, with radiation or non-radiation myeloablative preparative treatment.

The study will be separated into two parts; a dose escalation phase to assess safety, followed by a large expansion phase to further evaluate the pharmacologic effects of either a Maximum Tolerated Dose, Maximum Feasible Dose or optimal pharmacologically active dose of RGI-2001. The initial dose escalation safety portion of the study (Part 1) will include higher risk patients and limit the unrelated donor transplants. After safety is established in part 1 of the study, the second portion of the study will expand the enrollment criteria and allow transplantation by either related or unrelated donors.

This study will endeavor to identify the dose range at which RGI-2001 has an acceptable safety profile, at which biologic activity is observed, and to guide possible dose levels to utilize in later phase studies based on biological activity.

The clinical trial is a Phase 1/2a, open-label, multi-center, dose-escalation study to evaluate the safety, tolerability and pharmacokinetic profile of RGI-2001 in patients undergoing AHSCT, with radiation or non-radiation myeloablative preparative treatment.

In Part 1 (Phase 1: Dose Escalation Phase), patients will receive a single intravenous administration of RGI-2001 approximately 30 minutes after completion of the transplant (either allogeneic PBSCs or allogenic bone marrow transplantation (unmodified)) with the dosage based upon the assigned treatment cohort. Eligible patients will be enrolled in five to seven centers in the United States. Patients who are undergoing AHSCT will be enrolled in a sequential group dose-escalating fashion to determine the safety, tolerability, pharmacokinetic profile, and the MTD or MFD of RGI-2001. It is anticipated that up to six dose levels will be evaluated in Part 1, with an option for an additional cohort (Cohort 7) if the MTD is not reached and pharmacodynamic markers suggest higher doses are warranted.

In Part 2 (Expansion Phase), one or more doses below the MTD or MFD will be selected based on a potential correlation between GvHD and biological activity to further assess safety and biologic activity. Approximately 30 patients who are undergoing either allogeneic PBSCs or allogenic bone marrow transplantation (unmodified) will be enrolled in Part 2 of the study.

Patients will be monitored for safety for 29 days after the transplant procedure.

All patients will be followed for 100 days following transplant procedure for the incidence of acute GvHD, according to the Modified Keystone Criteria for grading acute GvHD (Przepiorka D, et al)

Intravenous Administration of RGI-2001 in Patient Undergoing Allogenic Hematopoietic Stem Cell Transplantation (AHSCT)

A Phase 1/2a, Open-Label, Multicenter, Dose-Escalation Study to Evaluate the Safety and Tolerability of Intravenous Administration of RGI-2001 in Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation (AHSCT)

The primary outcome measures are:

* The incidence and severity of adverse events
* The maximum tolerated dose (MTD) or maximum feasible dose (MFD) of RGI-2001, administered as a single intravenous infusion approximately 30 minutes after AHSCT

Evaluate biomarkers to assess the potential pharmacodynamic effects of RGI-2001 through biomarkers and cytokine assessments. Exploratory biomarkers for efficacy in reducing GvHD include IL-2R, TNFR1, HGF. Cytokines will be evaluated for both safety and for evidence of mechanism of action and include IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, MIG, TNF-α and IFN-γ.

Obtain pharmacokinetic parameters such as Cmax, Cmin, Tmax, AUC and half-life of the study drug in plasma.

The time to onset, peak intensity and course of GvHD after the AHSCT procedure will be monitored according to the Modified Keystone Criteria for Acute Graft-Versus-Host Disease.

Determine optimal doses of RGI-2001 for further evaluation based on pharmacodynamic response and effectiveness in reducing the intensity of GvHD

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Study of PD/PK/PG Relationships of Tacrolimus and Cyclosporin in Liver Transplant Patients	NCT01760356	End Stage Liver... Rejection Infection Malignancy Toxicity Diabetes		18 Years - 70 Years	UDA Centro Nacional Hepato-Bilio-Pancreático
Intravenous Administration of RGI-2001 in Patient Undergoing Allogenic Hematopoietic Stem Cell Transplantation (AHSCT)	NCT01379209	Graft Versus Ho...	RGI-2001 Calcineurin Inh... Allogeneic Hema... Conditioning Re... Allogeneic Bone... Methotrexate Mofetil Mycophe... sirolimus	18 Years -	Regimmune Corporation

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