<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT04444817</url>
  </required_header>
  <id_info>
    <org_study_id>S-260/2018</org_study_id>
    <nct_id>NCT04444817</nct_id>
  </id_info>
  <brief_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</brief_title>
  <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</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University Hospital Heidelberg</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University Hospital Heidelberg</source>
  <oversight_info>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Modern immunosuppression is characterized by a combination of different immunosuppressants.&#xD;
      As a result, the dose of the individual substances, and thus also their side effects can be&#xD;
      reduced. Immunosuppression on the basis of low-dose calcineurin inhibitors (CNI) with&#xD;
      comparatively low CNI target levels could therefore prevail. Despite all efforts to optimize&#xD;
      the treatment regimen after liver transplantation from deceased donors, the amount of&#xD;
      medication remains high throughout the postoperative course with CNIs being the main&#xD;
      component of immunosuppressive treatment. The main substance used is Tacrolimus in&#xD;
      combination with steroids and possibly Mycophenolic acid. Tacrolimus is considered a narrow&#xD;
      therapeutic index drug requiring individual dose titration, to achieve a satisfactory balance&#xD;
      between maximizing efficacy and minimizing dose-related toxicity. Furthermore, transplanted&#xD;
      recipients have to remain to a very demanding medication regimen for a long time. The burden&#xD;
      of pills required is associated with decreased adherence, and lack of adherence can lead to&#xD;
      rejection and possibly graft loss. The aim of present study is to assess the tough levels and&#xD;
      need of doses adaptation in de novo liver transplantation with Tacrolimus in the clinical&#xD;
      routine, without any intervention in the treatment regimen.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Tacrolimus is considered a narrow therapeutic index drug requiring individual dose titration,&#xD;
      to achieve a satisfactory balance between maximizing efficacy and minimizing dose-related&#xD;
      toxicity. The pharmacokinetic profile of Tacrolimus is characterized by a high degree of&#xD;
      inter- and intraindividual variability. Although it is rapidly absorbed, the bioavailability&#xD;
      of Tacrolimus in the twice-daily capsule formulation is low and variable, ranging from 17 to&#xD;
      23%. This could be due to poor water solubility, extensive first pass metabolism,&#xD;
      p-glycoprotein-mediated efflux and the ingestion of food. Tacrolimus twice-daily capsules are&#xD;
      also associated with a characteristic high peak following dosing, which may be associated&#xD;
      with increased toxicity.&#xD;
&#xD;
      Furthermore, transplanted recipients have to remain to a very demanding medication regimen&#xD;
      for a long time. The burden of pills required is associated with decreased adherence, and&#xD;
      lack of adherence can lead to rejection and possibly graft loss.&#xD;
&#xD;
      The development of once-daily Tacrolimus forms without any change of the form of dissolving&#xD;
      has already been shown to increase patients' adherence, while little difference has been&#xD;
      demonstrated in the Tacrolimus pharmacokinetic profile. The pharmacokinetic profile of&#xD;
      Tacrolimus is characterized by flatter kinetics (i.e., less fluctuation and swing) compared&#xD;
      to twice-daily Tacrolimus providing for a balanced concentration-time consistency over 24&#xD;
      hours which can also lead to reduced incidence and/or intensity of drug toxicity-related&#xD;
      adverse events. Since the development of LCP-Tacrolimus once-daily tablets, with the use of&#xD;
      MeltDose® technology, clinical data have shown lower peak and reduced peak-to-tough&#xD;
      fluctuations.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">November 22, 2018</start_date>
  <completion_date type="Anticipated">December 30, 2021</completion_date>
  <primary_completion_date type="Anticipated">December 30, 2021</primary_completion_date>
  <study_type>Observational [Patient Registry]</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Cohort</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <target_duration>6 Months</target_duration>
  <primary_outcome>
    <measure>The number of required dose adjustments of Tacrolimus formulations used in clinical routine for achieving the target tough level</measure>
    <time_frame>Six months</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Tacrolimus tough level</measure>
    <time_frame>Six months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Tacrolimus dosing</measure>
    <time_frame>Six months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Concentration/dose ratio</measure>
    <time_frame>Six months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mean cumulative dose for cost analysis</measure>
    <time_frame>Six months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Routine laboratory tests</measure>
    <time_frame>Six months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Survival rate</measure>
    <time_frame>Six months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The incidence of acute rejection</measure>
    <time_frame>Six months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The incidence of re-transplantation</measure>
    <time_frame>Six months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Patients' therapy adherence</measure>
    <time_frame>Six months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The incidence of infection with need to reduce Immunosuppression</measure>
    <time_frame>Six months</time_frame>
  </secondary_outcome>
  <number_of_groups>1</number_of_groups>
  <enrollment type="Anticipated">100</enrollment>
  <condition>Liver Transplantation</condition>
  <arm_group>
    <arm_group_label>Tacrolimus-based immunosuppression</arm_group_label>
    <description>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.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Tacrolimus</intervention_name>
    <description>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.</description>
    <arm_group_label>Tacrolimus-based immunosuppression</arm_group_label>
  </intervention>
  <eligibility>
    <study_pop>
      <textblock>
        One hundred Recipients who underwent de novo liver transplant and treated with various oral&#xD;
        Tacrolimus-based immunosupresions (Prograf®, Advagraf® and Envarsus®)&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  18 &lt; Recipient Age ≤ 60 years old&#xD;
&#xD;
          -  Ability to understand and sign an informed consent form&#xD;
&#xD;
          -  Operation and immediate post-operative therapy within the Department of General,&#xD;
             Visceral and Transplantion Surgery, University Hospital Heidelberg&#xD;
&#xD;
          -  De novo liver transplantation until POD 7&#xD;
&#xD;
          -  Immunosuppression after liver transplantation based on Tacrolimus&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Re-transplantation&#xD;
&#xD;
          -  Acute infection of the biliary tract, pneumonia or CMV infection&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>60 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_contact>
    <last_name>Arianeb Mehrabi, MD</last_name>
    <phone>004962215636223</phone>
    <email>arianeb.mehrabi@med.uni-heidelberg.de</email>
  </overall_contact>
  <location>
    <facility>
      <name>Division of Visceral Transplantation, Department of General, Visceral andTransplantation Surgery, University of Heidelberg</name>
      <address>
        <city>Heidelberg</city>
        <state>Baden-Württemberg</state>
        <zip>69120</zip>
        <country>Germany</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Arianeb Mehrabi, MD</last_name>
      <phone>004962215636223</phone>
      <email>arianeb.mehrabi@med.uni-heidelberg.de</email>
    </contact>
  </location>
  <location_countries>
    <country>Germany</country>
  </location_countries>
  <verification_date>June 2020</verification_date>
  <study_first_submitted>June 21, 2020</study_first_submitted>
  <study_first_submitted_qc>June 21, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 24, 2020</study_first_posted>
  <last_update_submitted>June 21, 2020</last_update_submitted>
  <last_update_submitted_qc>June 21, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">June 24, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University Hospital Heidelberg</investigator_affiliation>
    <investigator_full_name>Dr. A. Mehrabi</investigator_full_name>
    <investigator_title>Professsor, Head of the Division of Liver Surgery and Visceral Transplantation</investigator_title>
  </responsible_party>
  <keyword>Tacrolimus</keyword>
  <keyword>immunosuppression</keyword>
  <keyword>Liver transplantation</keyword>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Tacrolimus</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT04444817
org study id: S-260/2018
nct id: NCT04444817
lead sponsor: 
is fda regulated drug: No
is fda regulated device: No
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.
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.
observational model: Cohort
time perspective: Prospective
measure: The number of required dose adjustments of Tacrolimus formulations used in clinical routine for achieving the target tough level
time frame: Six months
measure: Tacrolimus tough level
time frame: Six months
measure: Tacrolimus dosing
time frame: Six months
measure: Concentration/dose ratio
time frame: Six months
measure: Mean cumulative dose for cost analysis
time frame: Six months
measure: Routine laboratory tests
time frame: Six months
measure: Survival rate
time frame: Six months
measure: The incidence of acute rejection
time frame: Six months
measure: The incidence of re-transplantation
time frame: Six months
measure: Patients' therapy adherence
time frame: Six months
measure: The incidence of infection with need to reduce Immunosuppression
time frame: Six months
arm group label: Tacrolimus-based immunosuppression
description: 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.
intervention type: Drug
intervention name: Tacrolimus
description: 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.
arm group label: Tacrolimus-based immunosuppression
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 18 Years
maximum age: 60 Years
healthy volunteers: No
last name: Arianeb Mehrabi, MD
phone: 004962215636223
email: arianeb.mehrabi@med.uni-heidelberg.de
facility: 
status: Recruiting
contact: 
country: Germany
responsible party type: Principal Investigator
investigator affiliation: University Hospital Heidelberg
investigator full name: Dr. A. Mehrabi
investigator title: Professsor, Head of the Division of Liver Surgery and Visceral Transplantation
mesh term: Tacrolimus
sharing ipd: Undecided