Clinical trial NCT04444817: Evaluation of the Impact of Tacrolimus-based Immunosuppression on Heidelberg Liver Transplant Cohort (HDTACRO): Study Protocol for an Investigator Initiated, Non-interventional Prospective Study
Official title: Evaluation of the Impact of Tacrolimus-based Immunosuppression on Heidelberg Liver Transplant Cohort (HDTACRO): Study Protocol for an Investigator Initiated, Non-interventional Prospective Study
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: Liver Transplantation
Keywords: Tacrolimus
immunosuppression
Liver transplantation
Lead sponsor: University Hospital Heidelberg
Sponsor class: OTHER
First posted: 2020-06-24
Enrollment: 100
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: One hundred Recipients who underwent de novo liver transplant and treated with various oral Tacrolimus-based immunosupresions (Prograf®, Advagraf® and Envarsus®)

Brief summary: Modern immunosuppression is characterized by a combination of different immunosuppressants. As a result, the dose of the individual substances, and thus also their side effects can be reduced. Immunosuppression on the basis of low-dose calcineurin inhibitors (CNI) with comparatively low CNI target levels could therefore prevail. Despite all efforts to optimize the treatment regimen after liver transplantation from deceased donors, the amount of medication remains high throughout the postoperative course with CNIs being the main component of immunosuppressive treatment. The main substance used is Tacrolimus in combination with steroids and possibly Mycophenolic acid. Tacrolimus is considered a narrow therapeutic index drug requiring individual dose titration, to achieve a satisfactory balance between maximizing efficacy and minimizing dose-related toxicity. Furthermore, transplanted recipients have to remain to a very demanding medication regimen for a long time. The burden of pills required is associated with decreased adherence, and lack of adherence can lead to rejection and possibly graft loss. The aim of present study is to assess the tough levels and need of doses adaptation in de novo liver transplantation with Tacrolimus in the clinical routine, without any intervention in the treatment regimen.

Detailed description: Tacrolimus is considered a narrow therapeutic index drug requiring individual dose titration, to achieve a satisfactory balance between maximizing efficacy and minimizing dose-related toxicity. The pharmacokinetic profile of Tacrolimus is characterized by a high degree of inter- and intraindividual variability. Although it is rapidly absorbed, the bioavailability of Tacrolimus in the twice-daily capsule formulation is low and variable, ranging from 17 to 23%. This could be due to poor water solubility, extensive first pass metabolism, p-glycoprotein-mediated efflux and the ingestion of food. Tacrolimus twice-daily capsules are also associated with a characteristic high peak following dosing, which may be associated with increased toxicity.

Furthermore, transplanted recipients have to remain to a very demanding medication regimen for a long time. The burden of pills required is associated with decreased adherence, and lack of adherence can lead to rejection and possibly graft loss.

The development of once-daily Tacrolimus forms without any change of the form of dissolving has already been shown to increase patients' adherence, while little difference has been demonstrated in the Tacrolimus pharmacokinetic profile. The pharmacokinetic profile of Tacrolimus is characterized by flatter kinetics (i.e., less fluctuation and swing) compared to twice-daily Tacrolimus providing for a balanced concentration-time consistency over 24 hours which can also lead to reduced incidence and/or intensity of drug toxicity-related adverse events. Since the development of LCP-Tacrolimus once-daily tablets, with the use of MeltDose® technology, clinical data have shown lower peak and reduced peak-to-tough fluctuations.

Eligibility criteria: Inclusion Criteria:

* 18 \< Recipient Age ≤ 60 years old
* Ability to understand and sign an informed consent form
* Operation and immediate post-operative therapy within the Department of General, Visceral and Transplantion Surgery, University Hospital Heidelberg
* De novo liver transplantation until POD 7
* Immunosuppression after liver transplantation based on Tacrolimus

Exclusion Criteria:

* Re-transplantation
* Acute infection of the biliary tract, pneumonia or CMV infection

Primary outcomes:
measure: The number of required dose adjustments of Tacrolimus formulations used in clinical routine for achieving the target tough level
timeFrame: Six months
Secondary outcomes:
measure: Tacrolimus tough level
timeFrame: Six months
measure: Tacrolimus dosing
timeFrame: Six months
measure: Concentration/dose ratio
timeFrame: Six months
measure: Mean cumulative dose for cost analysis
timeFrame: Six months
measure: Routine laboratory tests
timeFrame: Six months
measure: Survival rate
timeFrame: Six months
measure: The incidence of acute rejection
timeFrame: Six months
measure: The incidence of re-transplantation
timeFrame: Six months
measure: Patients' therapy adherence
timeFrame: Six months
measure: The incidence of infection with need to reduce Immunosuppression
timeFrame: Six months
Other outcomes:
Locations:
city: Heidelberg
country: Germany
facility: Division of Visceral Transplantation, Department of General, Visceral andTransplantation Surgery, University of Heidelberg
state: Baden-Württemberg
Study officials:
References:
citation: Khajeh E, Polychronidis G, Ramouz A, Alamdari P, Lemekhova A, Saracevic M, Ali-Hasan-Al-Saegh S, Ghamarnejad O, Majlesara A, Abbasi Dezfouli S, Nickkholgh A, Weiss KH, Rupp C, Mehrabi A, Mieth M. Evaluation of the impact of Tacrolimus-based immunosuppression on Heidelberg liver transplant cohort (HDTACRO): Study protocol for an investigator initiated, non-interventional prospective study. Medicine (Baltimore). 2020 Sep 25;99(39):e22180. doi: 10.1097/MD.0000000000022180.