Ignite Creation Date:
2024-05-06 @ 8:18 PM
Last Modification Date:
2024-10-26 @ 3:25 PM
Study NCT ID:
NCT06338306
Status:
RECRUITING
Last Update Posted:
2024-04-09
First Post:
2024-03-21
Brief Title:
Tacrolimus and Personalized Therapy to Prevent Acute Rejection Episodes
Sponsor:
Fondazione IRCCS Policlinico San Matteo di Pavia
Organization:
Fondazione IRCCS Policlinico San Matteo di Pavia
Study Overview
Official Title:
Therapeutic Drug Monitoring of Tacrolimus Personalized Therapy in Heart Transplantation New Strategies
Status:
RECRUITING
Status Verified Date:
2024-03
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:
None
Brief Summary:
Heart transplant is the only effective treatment for people with advanced heart failure
Post-transplant pharmacological therapies are of fundamental importance for the survival of individuals after surgery although considerable progress has been made for combined immunosuppressive therapies acute cellular and especially non-cellular rejection still represents a great challenge for doctors
To verify the absence of the first signs of acute rejection the analysis of numerous cardiac biopsies EMB endomyocardial biopsies is necessary during the first 12 months following the transplant
Thanks to these scheduled checks doctors are able to identify the first symptoms of possible chronic rejection and reduce its episodes
Since the analysis of biopsies is also based on subjective interpretations cases of erroneous conclusions are frequent
The researchers of this study aim not only to analyze the biopsies according to the current best clinical practice but also to evaluate how much anti-rejection drug is actually contained within them
This is an analysis that is still little used for this type of transplant which could provide very useful information to doctors
The researchers will focus their attention on one drug in particular tacrolimus abbreviated to TAC
The amount of drug measured in biopsies will be compared with that measured in whole blood samples and in particular blood cells peripheral blood mononuclear cells PBMC
The genetic characteristics of each person play an important role in the success of treatment with the drug To best interpret the results all participants will be asked to take a blood sample to identify some characteristics of their DNA that could influence the outcome of tacrolimus therapy
Post-transplant pharmacological therapies are of fundamental importance for the survival of individuals after surgery although considerable progress has been made for combined immunosuppressive therapies acute cellular and especially non-cellular rejection still represents a great challenge for doctors
To verify the absence of the first signs of acute rejection the analysis of numerous cardiac biopsies EMB endomyocardial biopsies is necessary during the first 12 months following the transplant
Thanks to these scheduled checks doctors are able to identify the first symptoms of possible chronic rejection and reduce its episodes
Since the analysis of biopsies is also based on subjective interpretations cases of erroneous conclusions are frequent
The researchers of this study aim not only to analyze the biopsies according to the current best clinical practice but also to evaluate how much anti-rejection drug is actually contained within them
This is an analysis that is still little used for this type of transplant which could provide very useful information to doctors
The researchers will focus their attention on one drug in particular tacrolimus abbreviated to TAC
The amount of drug measured in biopsies will be compared with that measured in whole blood samples and in particular blood cells peripheral blood mononuclear cells PBMC
The genetic characteristics of each person play an important role in the success of treatment with the drug To best interpret the results all participants will be asked to take a blood sample to identify some characteristics of their DNA that could influence the outcome of tacrolimus therapy
Detailed Description:
Heart transplant is the only effective treatment for people with advanced heart failure Major advances in allograft protection such as improved combined immunosuppressive therapies have led to progressive increases in post-transplant survival but acute cellular and especially non-cellular rejection still represents a challenge for clinicians Endomyocardial biopsy EMB is the current standard of care used to identify rejection after HTx with at least 13 biopsies scheduled within the twelve months following transplantation
The mortality rate after this period is approximately 35 per year and the causes of death range from primary graft failure and multiorgan failure to neoplasms renal failure and cardiac allograft vasculopathy Although acute rejection can be well managed in most cases episodes of cumulative rejection and chronic rejection are likely to contribute to long-term graft failure and graft vasculopathy The current ISHLT International Society for Heart and Lung Transplantation classification system provides categories of severity of rejection for both cellular and antibody-mediated rejection It describes the degree of tissue damage and infiltration by inflammatory cells and states that the greater the infiltrate the worse the rejection The purpose of the evaluation is to guide doctors in treating rejection before symptoms appear However histological reading like any diagnostic technique is subject to false positives and false negatives
The researchers propose to monitor TAC trough concentrations directly in EMBs during the first year after transplantation 5 scheduled biopsies from at least 25 de novo heart transplant recipients The results will be analyzed and correlated with whole blood and with the minimum concentrations of PBMC peripheral blood mononuclear cells detected for each patient in the same 5 scheduled follow-up visits Pharmacogenetic studies will focus on CYP3A4 CYP3A5 and ABCB1 gene variants The ABCB1 gene encodes P-glycoprotein Pg-p an ATP-driven transmembrane transporter that acts as an efflux pump and transports TAC out of PBMCs and tissues These researchers hypothesize that elevated cardiac expression of P-gp may reduce TAC uptake into cardiac donor tissue may act as an important modulator of immunosuppressive effects and thus have important therapeutic implications
Main objectives
Tacrolimus is a critically dosed drug and therapeutic drug monitoring is mandatory to avoid under- and overexposure However rejection and drug-related toxicity occur despite pre-dose whole blood blood TAC tacrolimus concentrations being on target Monitoring tacrolimus concentrations at the target site within peripheral blood mononuclear cells TAC cells and directly in endomyocardial biopsies TAC EMB may better correlate with treatment efficacy
The objectives of this study are
1 study TAC trough concentrations in whole blood blood TAC PBMC cells TAC and EMB TACEMB simultaneously across 5 scheduled follow-up visits of 25 HTx recipients
2 identify genetic characteristics that influence the metabolism and distribution of tacrolimus in whole blood cells and EMBs
3 study the relationships between the three concentration profiles TACblood TACcells TACEMB and clinical outcomes during the first year after heart transplantation
The mortality rate after this period is approximately 35 per year and the causes of death range from primary graft failure and multiorgan failure to neoplasms renal failure and cardiac allograft vasculopathy Although acute rejection can be well managed in most cases episodes of cumulative rejection and chronic rejection are likely to contribute to long-term graft failure and graft vasculopathy The current ISHLT International Society for Heart and Lung Transplantation classification system provides categories of severity of rejection for both cellular and antibody-mediated rejection It describes the degree of tissue damage and infiltration by inflammatory cells and states that the greater the infiltrate the worse the rejection The purpose of the evaluation is to guide doctors in treating rejection before symptoms appear However histological reading like any diagnostic technique is subject to false positives and false negatives
The researchers propose to monitor TAC trough concentrations directly in EMBs during the first year after transplantation 5 scheduled biopsies from at least 25 de novo heart transplant recipients The results will be analyzed and correlated with whole blood and with the minimum concentrations of PBMC peripheral blood mononuclear cells detected for each patient in the same 5 scheduled follow-up visits Pharmacogenetic studies will focus on CYP3A4 CYP3A5 and ABCB1 gene variants The ABCB1 gene encodes P-glycoprotein Pg-p an ATP-driven transmembrane transporter that acts as an efflux pump and transports TAC out of PBMCs and tissues These researchers hypothesize that elevated cardiac expression of P-gp may reduce TAC uptake into cardiac donor tissue may act as an important modulator of immunosuppressive effects and thus have important therapeutic implications
Main objectives
Tacrolimus is a critically dosed drug and therapeutic drug monitoring is mandatory to avoid under- and overexposure However rejection and drug-related toxicity occur despite pre-dose whole blood blood TAC tacrolimus concentrations being on target Monitoring tacrolimus concentrations at the target site within peripheral blood mononuclear cells TAC cells and directly in endomyocardial biopsies TAC EMB may better correlate with treatment efficacy
The objectives of this study are
1 study TAC trough concentrations in whole blood blood TAC PBMC cells TAC and EMB TACEMB simultaneously across 5 scheduled follow-up visits of 25 HTx recipients
2 identify genetic characteristics that influence the metabolism and distribution of tacrolimus in whole blood cells and EMBs
3 study the relationships between the three concentration profiles TACblood TACcells TACEMB and clinical outcomes during the first year after heart transplantation
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None