Improving Immunosuppressive Therapy in Heart Transplantation

NCT ID: NCT03932539

Last Updated: 2019-08-19

Basic Information

• Recruitment Status: UNKNOWN
• Total Enrollment: 25 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2019-05-14
• Study Completion Date: 2021-12-31

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

Conditions

Rejection Heart Transplant; Immunosuppression

Study Design

• Observational Model Type: COHORT
• Study Time Perspective: PROSPECTIVE

Study Groups

Twenty-five de-novo heart transplant recipients

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.

No interventions assigned to this group

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 70 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Fondazione IRCCS Policlinico San Matteo di Pavia

OTHER

Sponsor Role: lead

Responsible Party

Mariadelfina Molinaro

Principal Investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Mariadelfina Molinaro, MScBiol

Role: PRINCIPAL_INVESTIGATOR

IRCCS Policlinico San Matteo

Locations

Clinical and Experimental Pharmacokinetics Unit

Pavia, , Italy

Clinical Epidemiology and Biometry Unit

Pavia, , Italy

Department of Cardiac Surgery

Pavia, , Italy

Department of Respiratory Diseases - Biochemical and Genetics Lab.

Pavia, , Italy

Countries

Italy

Other Identifiers

15547/2019

Identifier Type: -

Identifier Source: org_study_id