Heart Transplant FailureNCT06338306
Tacrolimus and Personalized Therapy to Prevent Acute Rejection Episodes
An observational study of Heart Transplant Failure, run by Fondazione IRCCS Policlinico San Matteo di Pavia at 1 site in Italy.
Trial 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… Read more about this study
- Who is it for?
- Ages 18 to 70 years
- Conditions the study is for
- Heart Transplant Failure
- What is being tested?
- Tacrolimus（FK506）
- How many people
- 25 participants
- Where
- 1 siteItaly
- Study dates
- 7 Jan 2022to 30 Jun 2025
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 70 years
- All sexes
- Adult, Older adult
Study population: 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 (MMF; EC-MPS) or m-TOR inhibitors (Everolimus; Sirolimus).
Who may be able to join
- de novo heart transplant recipient
Who cannot join
- Age < 18 years
- Intolerance to TAC or to some excipient
- Intolerance to glucose
- diabetes mellitus
Trial locations and contacts
1 site in 1 country.
Italy1 site, 1 recruiting
- Recruiting
Fondazione IRCCS Policlinico San Matteo
Pavia, 27100
Ferrari Alessandra, PharmD, +390382503689, alessandra.ferrari@smatteo.pv.it
Simona De Gregori
About this study
Official title: Therapeutic Drug Monitoring of Tacrolimus Personalized Therapy in Heart Transplantation: New Strategies
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.
Read more
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.
Read the 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 3.5% 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:
- study TAC trough concentrations in whole blood (blood [TAC]), PBMC (cells [TAC]), and EMB ([TAC]EMB) simultaneously, across 5 scheduled follow-up visits of 25 HTx recipients
- identify genetic characteristics that influence the metabolism and distribution of tacrolimus in whole blood, cells and EMBs,
- study the relationships between the three concentration profiles ([TAC]blood), [TAC]cells, [TAC]EMB) and clinical outcomes, during the first year after heart transplantation.
- Conditions
- Heart Transplant Failure
- Being tested
- Tacrolimus（FK506）
- Keywords
- Tacrolimus, Whole Blood, PBMCs, Endomyocardial biopsy, Acute rejection, Therapeutic Drug Monitoring (TDM)
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Tacrolimus（FK506）Drug
Prograf
| Study group | Role | What they receive |
|---|---|---|
| De novo heart transplant patients | 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 (MMF; EC-MPS) or m-TOR inhibitors (Everolimus; Sirolimus). Receives: Drug: Tacrolimus（FK506） |
What is being measured
The primary outcome is the main question the study is designed to answer.
Tacrolimus quantification in an unconventional matrix
Each biopsy will be weighed immediately after being taken from the transplanted organ during the 5 scheduled follow up visits.
Tacrolimus will be extraxcted following a validated and published alalytical procedure, consisting of a combined enzymatic-digestion/mass spectrometry assay (online SPE-LC-MS/MS).
Enzymatic tissue digestion followed by a liquid-liquid drug extraction in the same vial of reaction will allow us to avoid both sample loss and contaminations.
TAC concentrations will be expressed as "pg TAC/mg biopsy"
Measured: 0.5, 1, 3, 6 and 12 months after heart transplantation
Tacrolimus quantification in PBMCs
10 mL of peripheral blood will be collected and processed by Fycoll gradient procedure for the PBMCs separation.
PBMCs will be isolated and then counted with an automated cell counter.
TAC concentration in PBMCs (expressed as "ng/1.000.000 cells") will be detected by a validated online SPE- LC-MS/MS method.
Measured: 0.5, 1, 3, 6 and 12 months after heart transplantation
Tacrolimus quantification in whole blood
The TAC concentration will be detected in whole blood using an automatic immunoassay system, used daily for routine monitoring.
TAC concentration will be expressed as "ng/mL" in whole blood.
Therapeutic range: 5-20 ng/mL
Measured: 0.5, 1, 3, 6 and 12 months after heart transplantation
Secondary outcomes (1)
Genetic profile in heart transplant recipients
Variants in the CYP3A4, CYP3A5 and ABC1 will be analyzed:
CYP3A4*22 (SNP rs35599367: 522-191C> T) CYP3A5*3 (rs776746, 6986A> G) CYP3A5*1 The most frequently studied polymorphisms in the ABCB1 gene are C1236T (rs1128503), G2677T/A (rs2032582) and C3435T (rs1045642).
Measured: The pharmacogenetic investigation (PGx) will be carried out at enrollment
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted29 Mar 2024
- Study start7 Jan 2022
- Primary completion30 Jun 2022
- Study completion30 Jun 2025 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Heart Transplant FailureStudies of the same condition, open and under way.
- More trials run by Fondazione IRCCS Policlinico San Matteo di PaviaThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Cohort
- Time perspective
- Prospective
- Enrolment
- 25 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Fondazione IRCCS Policlinico San Matteo di Pavia
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06338306
- Sponsor's protocol ID
- 08073421
- Status last verified
- Mar 2024
- First submitted
- 21 Mar 2024
- Last updated
- 9 Apr 2024
- Results posted
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Molinaro M, Pellegrini C, Cattadori B, De Gregori S. Development and validation of a combined enzymatic-digestion/mass spectrometry assay for Tacrolimus quantitation in cardiac biopsies. J Chromatogr B Analyt Technol Biomed Life Sci. 2020 Sep 1;1152:122215. doi: 10.1016/j.jchromb.2020.122215. Epub 2020 Jun 21.
PubMed 32615534
Study at a glance
From the registry record, last updated by the sponsor on 9 Apr 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Therapeutic Drug Monitoring of Tacrolimus Personalized Therapy in Heart Transplantation: New Strategies
- ClinicalTrials.gov ID
- NCT06338306
- Acronym / sponsor ID
- 08073421
- Conditions
- Heart Transplant Failure
- Keywords
- Tacrolimus, Whole Blood, PBMCs, Endomyocardial biopsy, Acute rejection, Therapeutic Drug Monitoring (TDM)
- Study type
- Observational
- Recruitment status
- Unknown status
- Enrolment
- 25 participants (estimated)
- Lead sponsor
- Fondazione IRCCS Policlinico San Matteo di PaviaUniversity, hospital or other
- Study start
- 7 Jan 2022 (actual)
- Primary completion
- 30 Jun 2022 (actual)
- Study completion
- 30 Jun 2025 (estimated)
- First posted
- 29 Mar 2024 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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 3.5% 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:
- study TAC trough concentrations in whole blood (blood [TAC]), PBMC (cells [TAC]), and EMB ([TAC]EMB) simultaneously, across 5 scheduled follow-up visits of 25 HTx recipients
- identify genetic characteristics that influence the metabolism and distribution of tacrolimus in whole blood, cells and EMBs,
- study the relationships between the three concentration profiles ([TAC]blood), [TAC]cells, [TAC]EMB) and clinical outcomes, during the first year after heart transplantation.
Study design
- Observational model
- Cohort
- Time perspective
- Prospective
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| De novo heart transplant patients | – | Drug: Tacrolimus（FK506）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 (MMF; EC-MPS) or m-TOR inhibitors (Everolimus; Sirolimus). |
Who may qualify
- Ages
- 18 to 70 years
- Sex
- All
- Age groups
- Adult, Older adult
- Study population
- 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 (MMF; EC-MPS) or m-TOR inhibitors (Everolimus; Sirolimus).
Key inclusion criteria (1 listed)
- de novo heart transplant recipient
Key exclusion criteria (4 listed)
- Age < 18 years
- Intolerance to TAC or to some excipient
- Intolerance to glucose
- diabetes mellitus
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Tacrolimus（FK506）Prograf | Drug | De novo heart transplant patients |
Primary outcome
Tacrolimus quantification in an unconventional matrix
Time frame: 0.5, 1, 3, 6 and 12 months after heart transplantation
Each biopsy will be weighed immediately after being taken from the transplanted organ during the 5 scheduled follow up visits. Tacrolimus will be extraxcted following a validated and published alalytical procedure, consisting of a combined enzymatic-digestion/mass spectrometry assay (online SPE-LC-MS/MS). Enzymatic tissue digestion followed by a liquid-liquid drug extraction in the same vial of reaction will allow us to avoid both sample loss and contaminations. TAC concentrations will be expressed as "pg TAC/mg biopsy"
Tacrolimus quantification in PBMCs
Time frame: 0.5, 1, 3, 6 and 12 months after heart transplantation
10 mL of peripheral blood will be collected and processed by Fycoll gradient procedure for the PBMCs separation. PBMCs will be isolated and then counted with an automated cell counter. TAC concentration in PBMCs (expressed as "ng/1.000.000 cells") will be detected by a validated online SPE- LC-MS/MS method.
Tacrolimus quantification in whole blood
Time frame: 0.5, 1, 3, 6 and 12 months after heart transplantation
The TAC concentration will be detected in whole blood using an automatic immunoassay system, used daily for routine monitoring. TAC concentration will be expressed as "ng/mL" in whole blood. Therapeutic range: 5-20 ng/mL
1 secondary outcome
Genetic profile in heart transplant recipients
Time frame: The pharmacogenetic investigation (PGx) will be carried out at enrollment
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 9 Apr 2024.
- Background: PubMed 32615534Molinaro M, Pellegrini C, Cattadori B, De Gregori S. Development and validation of a combined enzymatic-digestion/mass spectrometry assay for Tacrolimus quantitation in cardiac biopsies. J Chromatogr B Analyt Technol Biomed Life Sci. 2020 Sep 1;1152:122215. doi: 10.1016/j.jchromb.2020.122215. Epub 2020 Jun 21.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Heart Transplant Failure, run by Fondazione IRCCS Policlinico San Matteo di Pavia at 1 site in Italy.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 1 inclusion and 4 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 9 Apr 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Italy. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Alessandra Ferrari (+390382503689, alessandra.ferrari@smatteo.pv.it), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Tacrolimus quantification in an unconventional matrix (time frame: 0.5, 1, 3, 6 and 12 months after heart transplantation). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT06338306, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 9 Apr 2024.