<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/NCT03256864</url>
  </required_header>
  <id_info>
    <org_study_id>CRAD001HTW02T</org_study_id>
    <nct_id>NCT03256864</nct_id>
  </id_info>
  <brief_title>Twice-daily Tacrolimus and Everolimus Convert to Once-daily Tacrolimus and Everolimus in Liver Transplant Recipient</brief_title>
  <official_title>A Six-month, Prospective, Single-center, Pilot Study Determining the Pharmacokinetics and Effectiveness of Twice-daily Tacolimus and Everolimus Regimen Convert to Once-daily Tacrolimus and Everolimus Regimen in Liver Transplant Patients</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Chang Gung Memorial Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Chang Gung Memorial Hospital</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      It has been identified that nonadherence to immunosuppressant regimen may cause long-term&#xD;
      graft failure and death in solid organ transplant recipients. Therefore, simplification of&#xD;
      the immunosuppression regimen by reducing daily dosing frequency may improve long-term&#xD;
      outcome. The investigators will examine pharmacokinetics and safety profiles of stable liver&#xD;
      transplant recipients receiving twice-daily TAC with EVR (BID) regimen and then being&#xD;
      converted to once-daily TAC with EVR (QD) regimen over a 6-month study period&#xD;
      post-conversion.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Randomized trial of everolimus (EVR) with reduced tacrolimus (TAC) regimen after liver&#xD;
      transplantation has shown similar incidence of composite efficacy failure rate to a standard&#xD;
      tacrolimus regimen, but with superior renal function for up to three years. Recent studies&#xD;
      have demonstrated comparable efficacy and safety profiles in liver transplant recipients&#xD;
      receiving tacrolimus once-daily (QD) and tacrolimus twice-daily (BID) regimens. In kidney&#xD;
      transplantation, once daily everolimus (QD) regimen has shown its safety and effectiveness.&#xD;
      It has been identified that nonadherence to immunosuppressant regimen may cause long-term&#xD;
      graft failure and death in solid organ transplant recipients. Therefore, simplification of&#xD;
      the immunosuppression regimen (e.g. TAC with EVR) by reducing daily dosing frequency may&#xD;
      improve long-term outcome. However, little is known about the effectiveness and safety of&#xD;
      combined TAC and EVR once-daily (QD) regimen in liver transplant recipients. The investigator&#xD;
      will examine pharmacokinetics and safety profiles of stable liver transplant recipients&#xD;
      receiving twice-daily TAC with EVR (BID) regimen and then being converted to once-daily TAC&#xD;
      with EVR (QD) regimen over a 6-month study period post-conversion.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>January 2016</start_date>
  <completion_date type="Actual">May 30, 2020</completion_date>
  <primary_completion_date type="Actual">June 30, 2019</primary_completion_date>
  <phase>Phase 4</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Other</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>To evaluate pharmacokinetic profile of everolimus and tacrolimus in liver transplant recipients on AUC (area under the curve)</measure>
    <time_frame>6 month</time_frame>
    <description>Area under the plasma concentration versus time curve (AUC)</description>
  </primary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">10</enrollment>
  <condition>Liver Transplantation</condition>
  <arm_group>
    <arm_group_label>Tacrolimus and Everolimus BID</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>TAC BID (C0 2.5-5 ng/mL) EVR BID (1.0 mg BID targeted to C0 3-8 ng/mL)&#xD;
Other Names:&#xD;
Prograf&#xD;
Advagraf&#xD;
Zortress&#xD;
Certican</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Tacrolimus and Everolimus QD</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>TAC QD (C0 2.5-5 ng/mL) EVR QD (2.0 mg QD targeted to C0 3-8 ng/mL)&#xD;
Other Names:&#xD;
Prograf&#xD;
Advagraf&#xD;
Zortress&#xD;
Certican</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Tacrolimus and Everolimus</intervention_name>
    <description>In the TAC and EVR BID arm, everolimus will be initiated at a dose of 1.0 mg BID within 24 h of randomization with the dose adjusted from day 5 onward to maintain trough (C0) concentration in the range 3-8 ng/mL. Tacrolimus will be initiated at a dose of 0.15 mg/kg BID and then taper to 0.10 mg/kg BID to maintain trough (C0) concentration in the range 2.5-5 ng/mL.&#xD;
In the TAC and EVR QD arm, everolimus will be initiated at a dose of 2.0 mg QD within 24 h of randomization with the dose adjusted from day 5 onward to maintain trough (C0) concentration in the range 3-8 ng/mL. Tacrolimus will be initiated at a dose of 0.1-0.2 mg/kg/day QD to maintain trough (C0) concentration in the range 2.5-5 ng/mL.</description>
    <arm_group_label>Tacrolimus and Everolimus BID</arm_group_label>
    <arm_group_label>Tacrolimus and Everolimus QD</arm_group_label>
    <other_name>Prograf</other_name>
    <other_name>Advagraf</other_name>
    <other_name>Zortress</other_name>
    <other_name>Certican</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Key inclusion criteria&#xD;
&#xD;
        Stable liver transplant recipients are eligible for inclusion in this study and have to&#xD;
        fulfill all of the following criteria:&#xD;
&#xD;
          1. Liver Transplant Recipients have received liver transplantations for at least 6+1&#xD;
             months prior to enrollment&#xD;
&#xD;
          2. Liver Transplant Recipients have no acute rejection episodes within 3 months prior to&#xD;
             the enrollment and are clinically stable&#xD;
&#xD;
          3. Liver Transplant Recipients have been treated with twice-daily regimen of&#xD;
             tacrolimus(TAC) plus everolimus(EVR) and TAC and EVR trough levels have stayed within&#xD;
             targeted ranges for at least 6 weeks prior to enrollment&#xD;
&#xD;
          4. Provide written informed consent prior to inclusion.&#xD;
&#xD;
          5. Liver transplant recipients who are 18-65 years of age of a primary liver transplant&#xD;
&#xD;
          6. Allograft functioning at an acceptable level as defined by the AST, ALT, Total&#xD;
             Bilirubin levels ≤3 times ULN prior to enrollment.&#xD;
&#xD;
          7. Abbreviated MDRD eGFR ≥ 30 mL/min/1.73m2. Key exclusion criteria&#xD;
&#xD;
        Patients fulfilling any of the following criteria are not eligible for inclusion in this&#xD;
        study:&#xD;
&#xD;
          1. Patients who are recipients of multiple solid organ or islet cell tissue transplants,&#xD;
             or have previously received an organ or tissue transplant. Patients who have a&#xD;
             combined liver-kidney transplant.&#xD;
&#xD;
          2. History of malignancy of any organ system (other than localized basal cell carcinoma&#xD;
             of the skin), treated or untreated, within the past 5 years, regardless of whether&#xD;
             there is evidence of local recurrence or metastases.&#xD;
&#xD;
          3. Existence of any surgical, medical or mental conditions, other than the current&#xD;
             transplantation, which, in the opinion of the investigator, might interfere with the&#xD;
             objectives of the study.&#xD;
&#xD;
          4. Pregnant or nursing (lactating) women.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>65 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>WeiChen Lee, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Chang Gung Memorial Hospital</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Chang Gung Memorial Hospital</name>
      <address>
        <city>Taoyuan</city>
        <country>Taiwan</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Taiwan</country>
  </location_countries>
  <verification_date>June 2020</verification_date>
  <study_first_submitted>February 1, 2016</study_first_submitted>
  <study_first_submitted_qc>August 21, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 22, 2017</study_first_posted>
  <last_update_submitted>June 4, 2020</last_update_submitted>
  <last_update_submitted_qc>June 4, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">June 5, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Chang Gung Memorial Hospital</investigator_affiliation>
    <investigator_full_name>Wei-Chen Lee</investigator_full_name>
    <investigator_title>Chief of transplanet center</investigator_title>
  </responsible_party>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Everolimus</mesh_term>
    <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/NCT03256864
org study id: CRAD001HTW02T
nct id: NCT03256864
lead sponsor: 
has dmc: No
It has been identified that nonadherence to immunosuppressant regimen may cause long-term
      graft failure and death in solid organ transplant recipients. Therefore, simplification of
      the immunosuppression regimen by reducing daily dosing frequency may improve long-term
      outcome. The investigators will examine pharmacokinetics and safety profiles of stable liver
      transplant recipients receiving twice-daily TAC with EVR (BID) regimen and then being
      converted to once-daily TAC with EVR (QD) regimen over a 6-month study period
      post-conversion.
Randomized trial of everolimus (EVR) with reduced tacrolimus (TAC) regimen after liver
      transplantation has shown similar incidence of composite efficacy failure rate to a standard
      tacrolimus regimen, but with superior renal function for up to three years. Recent studies
      have demonstrated comparable efficacy and safety profiles in liver transplant recipients
      receiving tacrolimus once-daily (QD) and tacrolimus twice-daily (BID) regimens. In kidney
      transplantation, once daily everolimus (QD) regimen has shown its safety and effectiveness.
      It has been identified that nonadherence to immunosuppressant regimen may cause long-term
      graft failure and death in solid organ transplant recipients. Therefore, simplification of
      the immunosuppression regimen (e.g. TAC with EVR) by reducing daily dosing frequency may
      improve long-term outcome. However, little is known about the effectiveness and safety of
      combined TAC and EVR once-daily (QD) regimen in liver transplant recipients. The investigator
      will examine pharmacokinetics and safety profiles of stable liver transplant recipients
      receiving twice-daily TAC with EVR (BID) regimen and then being converted to once-daily TAC
      with EVR (QD) regimen over a 6-month study period post-conversion.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Other
masking: None (Open Label)
measure: To evaluate pharmacokinetic profile of everolimus and tacrolimus in liver transplant recipients on AUC (area under the curve)
time frame: 6 month
description: Area under the plasma concentration versus time curve (AUC)
arm group label: Tacrolimus and Everolimus BID
arm group type: Experimental
description: TAC BID (C0 2.5-5 ng/mL) EVR BID (1.0 mg BID targeted to C0 3-8 ng/mL)
Other Names:
Prograf
Advagraf
Zortress
Certican
arm group label: Tacrolimus and Everolimus QD
arm group type: Experimental
description: TAC QD (C0 2.5-5 ng/mL) EVR QD (2.0 mg QD targeted to C0 3-8 ng/mL)
Other Names:
Prograf
Advagraf
Zortress
Certican
intervention type: Drug
intervention name: Tacrolimus and Everolimus
description: In the TAC and EVR BID arm, everolimus will be initiated at a dose of 1.0 mg BID within 24 h of randomization with the dose adjusted from day 5 onward to maintain trough (C0) concentration in the range 3-8 ng/mL. Tacrolimus will be initiated at a dose of 0.15 mg/kg BID and then taper to 0.10 mg/kg BID to maintain trough (C0) concentration in the range 2.5-5 ng/mL.
In the TAC and EVR QD arm, everolimus will be initiated at a dose of 2.0 mg QD within 24 h of randomization with the dose adjusted from day 5 onward to maintain trough (C0) concentration in the range 3-8 ng/mL. Tacrolimus will be initiated at a dose of 0.1-0.2 mg/kg/day QD to maintain trough (C0) concentration in the range 2.5-5 ng/mL.
arm group label: Tacrolimus and Everolimus BID
arm group label: Tacrolimus and Everolimus QD
other name: Prograf
other name: Advagraf
other name: Zortress
other name: Certican
criteria: 
gender: All
minimum age: 18 Years
maximum age: 65 Years
healthy volunteers: No
last name: WeiChen Lee, MD
role: Principal Investigator
affiliation: Chang Gung Memorial Hospital
facility: 
country: Taiwan
responsible party type: Principal Investigator
investigator affiliation: Chang Gung Memorial Hospital
investigator full name: Wei-Chen Lee
investigator title: Chief of transplanet center
mesh term: Everolimus
mesh term: Tacrolimus
sharing ipd: Undecided