Improving Immunosuppressive Therapy in Heart Transplantation

Study Overview
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Brief Summary
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Cardiac allograft rejection (CAR) occurs in 30% to 40% of transplant recipients within the first year post-transplant, and carries an increased risk of both acute graft failure and reduced graft longevity. Because of the high morbidity of CAR when diagnosed after symptoms develop, surveillance endomyocardial biopsy (EMB) has been included in heart transplantation guidelines since 1990. Although EMB is the established gold standard for the diagnosis of CAR, the clinical utility of EMB using standard hematoxylin and eosin (H&E) histologic analysis is limited by marked inter-observer variability and significant discordance between the histologic grade and clinical impression of CAR severity. On the other hand, Tacrolimus (TAC), one of the most important immunosuppressant drug and widely used for the prevention of rejection after solid organ transplantation (SOT), is considered a critical dose drug: too low exposure to TAC may result in under-immunosuppression and acute rejection, whereas overexposure puts patients at risk for toxicity. Tac concentrations, in whole-blood, are considered therapeutic when maintained in the range 5 and 20 ng/mL. In addition to being highly variable inter-individually, TAC pharmacokinetics can also be variable within individual patients. Although in recent years significant decrease of rejection post SOT has been observed, there is space for further modulation of immunosuppressive therapy, in order to reduce the most common adverse side effects (nephrotoxicity, diabetes, osteoporosis, cardiovascular disease, infections and malignancies), to improve the patients quality of life and to better individualize their therapies. Tac. Unfortunately, a clear correlation between TAC whole blood concentration and acute rejection risk has not yet been defined.

Detailed Description
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Monocentric and Observational Study - Longitudinal Prospective The study considers the collection of the following samples: a single whole blood sample, 3-5 mL in EDTA for Pharmacogenetics, 10 mL whole blood sample in lithium-heparin for Tac quantification in PBMC collected at each time-point scheduled for routine follow-up visits: day +15 and month 1, 3, 6, 12 post transplant About 1 mg cardiac tissue samples (from cardiac biopsies), collected by standard procedure adopted at the Transplant Center of CardiacSurgery at each time-point scheduled for routine follow-up visits: day +15 and month 1, 3, 6, 12 post transplant Each blood sample and biopsy specimen will be identified and labeled with an alphanumeric code, whose decoding matrix will be kept by dedicated personnel at the U.O.C. Cardiac Surgery, Department of Intensive Medicine. In general, each patient will be defined as TAC + progressive enrollment number (example: TAC1, TAC2, TAC3 ...). Each sample sent to the laboratories for the analyzes in the different matrices and for the different activities foreseen by the protocol (measurements of tacrolimus and pharmacogenetic concentrations) must always contain the identification code assigned to the patient followed by the type of analysis + sampling time. For example, patient collection # 2 for tacrolimus assay to be performed in PBMC, whole blood and EMB at month 3, will be identified as: TAC2-PBMC-M3 TAC2-WB-M3 TAC2-BEM-M3 The storage of the codes that will allow the patients' identification will be kept by dr. Carlo Pellegrini and dr. Barbara Cattadori (U.O.C. Cardiosurgery). All samples will be investigated within the Foundation: blood samples for the quantification of Tacrolimus in blood mononuclear cells (PBMC) and in whole blood will be transferred to the Clinical and Experimental Pharmacokinetic Laboratory. Blood samples for pharmacogenetic investigations will be transferred to the Biochemical and Genetic Laboratory of Respiratory Diseases. The proponents of the study will keep any residual samples at the investigations planned by the study in a safe place with limited access, ie in a freezer -80 °C located in a locked room (room n.11a, Lab Clinical and Experimental Pharmacokinetics, Pavilion 13). These samples can be used for scientific purposes directly related to those of the main study

Official Title
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New Strategies to Improve Immunosuppressive Therapy Management in Heart Transplantation: a Pilot Study

Conditions
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Rejection Heart Transplant, Immunosuppression

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: de-novo heart transplant recipients Male and female (18-70 years) Receiving TAC in combination with steroids, antiproliferative drugs, Everolimus, Sirolimus. Exclusion Criteria: Age < 18 years Intolerance of the drug object of the present study (Tacrolimus) or at any of the excipients contained therein Intolerance to glucose Diabetes mellitus

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Twenty-five de-novo heart transplant recipients<br>Twenty-five de-novo heart transplant recipients will be enrolled, male and female, aging 18-70 years, receiving TAC in combination with steroids and antiproliferative drugs, either Everolimus or Sirolimus. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| TAC concentration in whole blood | To detect if a correlation exists between the concentration of tacrolimus in whole blood and the acute transplanted heart rejection. TAC concentration in whole-blood samples will be measured in ng/mL | 2 years | 
| TAC concentration in peripheral blood mononuclear cell (PBMC) | To detect if a correlation exists between the concentration of tacrolimus in PBMC and the acute transplanted heart rejection. TAC concentration will be measured in PBMC (pg/million of cells) | 2 years | 
| TAC concentration in endomyocardial biopsy (EMB) | To detect if a correlation exists between the concentration of tacrolimus in EMB and the acute transplanted heart rejection. TAC concentration will be measured in pg/mg of biopsy | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacogenetic analysis | Different single nucleotide polymorphisms (SNPs) will be analyzed in ABCB1 (P-gp) and CYP3A4/CYP3A5 genes | 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Immunosuppressive therapy, Tacrolimus, Heart transplantation, Pharmacokinetics, Pharmacogenetics, Acute rejection