Clinical trial NCT03932539: Improving Immunosuppressive Therapy in Heart Transplantation
Official title: New Strategies to Improve Immunosuppressive Therapy Management in Heart Transplantation: a Pilot Study
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: Rejection Heart Transplant
Immunosuppression
Keywords: Immunosuppressive therapy
Tacrolimus
Heart transplantation
Pharmacokinetics
Pharmacogenetics
Acute rejection
Lead sponsor: Fondazione IRCCS Policlinico San Matteo di Pavia
Sponsor class: OTHER
First posted: 2019-04-30
Enrollment: 25
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: If no contraindications will be observed, and the patient will be able to tolerate the administration of the study drug, the patients will be enrolled within the 5th post-transplant day.

In the case of impossibility to administer the drug within that period, the patient will not have access to the study

Brief summary: 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: 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

Eligibility criteria: 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

Primary outcomes:
measure: TAC concentration in whole blood
timeFrame: 2 years
measure: TAC concentration in peripheral blood mononuclear cell (PBMC)
timeFrame: 2 years
measure: TAC concentration in endomyocardial biopsy (EMB)
timeFrame: 2 years
Secondary outcomes:
measure: Pharmacogenetic analysis
timeFrame: 2 years
Other outcomes:
Locations:
city: Pavia
country: Italy
facility: Clinical and Experimental Pharmacokinetics Unit
city: Pavia
country: Italy
facility: Clinical Epidemiology and Biometry Unit
city: Pavia
country: Italy
facility: Department of Cardiac Surgery
city: Pavia
country: Italy
facility: Department of Respiratory Diseases - Biochemical and Genetics Lab.
Study officials:
affiliation: IRCCS Policlinico San Matteo
name: Mariadelfina Molinaro, MScBiol
role: PRINCIPAL_INVESTIGATOR
References: