Evaluation of the Impact of Tacrolimus-based Immunosuppression on Heidelberg Liver Transplant Cohort (HDTACRO): Study Protocol for an Investigator Initiated, Non-interventional Prospective Study

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.

Study Overview

• Status: Unknown
• Conditions: Liver Transplantation
• Intervention / Treatment: Drug: Tacrolimus

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.

• Study Type: Observational
• Enrollment (Anticipated): 100

Contacts and Locations

Study Locations

• Germany
  • Baden-Württemberg
    • Heidelberg, Baden-Württemberg, Germany, 69120
      • Recruiting
      • Division of Visceral Transplantation, Department of General, Visceral andTransplantation Surgery, University of Heidelberg
      • Contact: Arianeb Mehrabi, MD; Phone Number: 004962215636223; Email: arianeb.mehrabi@med.uni-heidelberg.de

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• 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®)

Description

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

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort

Intervention / Treatment

Tacrolimus-based immunosuppression; Similar to the clinical routine, as soon as a patient is able to swallow and has a sufficient gastrointestinal activity, Tacrolimus-based immunosuppression using Prograf®, Advagraf® or Envarsus® will be started.

Drug: Tacrolimus; Similar to the clinical routine, as soon as a patient is able to swallow and has a sufficient gastrointestinal activity, Tacrolimus-based immunosuppression using Prograf®, Advagraf® or Envarsus® will be started. Furthermore, calcineurin inhibitors-based immunosuppression will be used (initial dose based on the patients' body weight) with the goal of tough levels of 3-7 ng/mL in the first seven days after liver transplantion, depending on immune status and indication for transplantation. Further tough levels will be determined based on factors such as patients' history and indication for liver transplant.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
The number of required dose adjustments of Tacrolimus formulations used in clinical routine for achieving the target tough level	Six months

Secondary Outcome Measures

Outcome Measure	Time Frame
Tacrolimus tough level	Six months
Tacrolimus dosing	Six months
Concentration/dose ratio	Six months
Mean cumulative dose for cost analysis	Six months
Routine laboratory tests	Six months
Survival rate	Six months
The incidence of acute rejection	Six months
The incidence of re-transplantation	Six months
Patients' therapy adherence	Six months
The incidence of infection with need to reduce Immunosuppression	Six months

Collaborators and Investigators

• Sponsor: University Hospital Heidelberg

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): November 22, 2018
• Primary Completion (Anticipated): December 30, 2021
• Study Completion (Anticipated): December 30, 2021

Study Registration Dates

• First Submitted: June 21, 2020
• First Submitted That Met QC Criteria: June 21, 2020
• First Posted (Actual): June 24, 2020

Study Record Updates

• Last Update Posted (Actual): June 24, 2020
• Last Update Submitted That Met QC Criteria: June 21, 2020
• Last Verified: June 1, 2020

More Information

Terms related to this study

• Keywords: Liver transplantation; immunosuppression; Tacrolimus
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Immunosuppressive Agents; Immunologic Factors; Calcineurin Inhibitors; Tacrolimus
• Other Study ID Numbers: S-260/2018

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No