<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/NCT04496401</url>
  </required_header>
  <id_info>
    <org_study_id>RC19_0247</org_study_id>
    <nct_id>NCT04496401</nct_id>
  </id_info>
  <brief_title>PK Study in Diabetic Transplant récipients : From Twice-daily Tacrolimus to Once-daily Extended-release Tacrolimus</brief_title>
  <acronym>SPK-PK</acronym>
  <official_title>Comparison of Pharmacokinetic (PK) Levels Before and After Conversion From Twice-daily Tacrolimus to Once-daily Extended-release Tacrolimus (LCPT) in Diabetic Transplant récipients</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Nantes University Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Chiesi Farmaceutici S.p.A.</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Nantes University Hospital</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>
      The investigators believe that the pharmacological properties of Envarsus®, well studied in&#xD;
      kidney transplantation, may be also suitable after simultaneous kidney and pancreas&#xD;
      transplantation than Prograf. Indeed, Envarsus® has demonstrated a clinical efficacy and&#xD;
      safety in a complete clinical development plan.&#xD;
&#xD;
      This study is to establish the pharmacokinetic profile of tacrolimus prolonged-release&#xD;
      (hereafter referred to as 'ENVARSUS®') in diabetics who have undergone kidney and pancreas&#xD;
      transplantation, and compare it to the pharmacokinetic profile of standard twice-daily&#xD;
      tacrolimus. The study will be conducted in 25 patients hospitalized at Nantes University&#xD;
      Hospital.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The study will be conducted in 25 patients hospitalized at Nantes University Hospital.&#xD;
      Tacrolimus will be started on the day of surgery (or on the day after) according to Nantes&#xD;
      local standard doses and practices. After a stable trough level is achieved (on postoperative&#xD;
      day 7-17) the first PK profile will be measured. Subsequently, the switch to ENVARSUS® will&#xD;
      be performed (initial dose of 0.17 mg/kg/day) on a single morning oral dosage regimen. A&#xD;
      second PK profile will be measured, between 7 to 14 days after initiation of ENVARSUS®. All&#xD;
      these PK measurements will take place during the post-operative recovery in the hospital&#xD;
      (typically 2-3 weeks). All patients will receive Thymoglobulin or Alemtuzumab induction,&#xD;
      Myfortic or Cellcept (or generics), with or without prednisone according to local practices.&#xD;
      Anti-infectious prophylaxis will be given according to Nantes local practices.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">September 28, 2020</start_date>
  <completion_date type="Anticipated">March 15, 2024</completion_date>
  <primary_completion_date type="Anticipated">March 15, 2024</primary_completion_date>
  <phase>Phase 4</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Other</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>To characterise the bioavailability of Envarsus® and compare it to the bioavailability of tacrolimus</measure>
    <time_frame>Initial tacrolimus PK profile measurement: day 7-17 post SPK transplantation. Second ENVARSUS® PK profile measurement: day 15-32 post SPK transplantation</time_frame>
    <description>To characterise the PK profile of extended release tacrolimus (Envarsus®) in diabetic transplant recipients, and compare it to the PK profile of tacrolimus : bioavailability AUC0-24</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Further quantification of the PK profile of extended release tacrolimus and Myfortic in patients with both functional grafts: Cmin</measure>
    <time_frame>Initial tacrolimus and myfortic PK profile measurement: day 7-17 post SPK transplantation. Second ENVARSUS® and Myfortic PK profile measurement: day 15-32 post SPK transplantation</time_frame>
    <description>Cmin</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Further quantification of the PK profile of extended release tacrolimus and Myfortic in patients only with a functional kidney graft in case of early pancreas thrombosis.: Cmin</measure>
    <time_frame>Initial tacrolimus and myfortic PK profile measurement: day 7-17 post SPK transplantation. Second ENVARSUS® and Myfortic PK profile measurement: day 15-32 post SPK transplantation</time_frame>
    <description>Cmin</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Further quantification of the PK profile of extended release tacrolimus and Myfortic in patients with both functional grafts : Cmax</measure>
    <time_frame>Initial tacrolimus and Myfortic PK profile measurement: day 7-17 post SPK transplantation. Second ENVARSUS® and Myfortic PK profile measurement: day 15-32 post SPK transplantation</time_frame>
    <description>Cmax</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Further quantification of the PK profile of extended release tacrolimus and Myfortic in patients only with a functional kidney graft in case of early pancreas thrombosis.: Cmax</measure>
    <time_frame>Initial tacrolimus and Myfortic PK profile measurement: day 7-17 post SPK transplantation. Second ENVARSUS® and Myfortic PK profile measurement: day 15-32 post SPK transplantation</time_frame>
    <description>Cmax</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Further quantification of the PK profile of extended release tacrolimus and Myfortic in patients with both functional grafts: Cavg</measure>
    <time_frame>Initial tacrolimus and Myfortic PK profile measurement: day 7-17 post SPK transplantation. Second ENVARSUS® and Myfortic PK profile measurement: day 15-32 post SPK transplantation</time_frame>
    <description>Cavg</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Further quantification of the PK profile of extended release tacrolimus and Myforticin patients only with a functional kidney graft in case of early pancreas thrombosis.: Cavg</measure>
    <time_frame>Initial tacrolimus and Myfortic PK profile measurement: day 7-17 post SPK transplantation. Second ENVARSUS® and Myfortic PK profile measurement: day 15-32 post SPK transplantation</time_frame>
    <description>Cavg</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Further quantification of the PK profile of extended release tacrolimus and Myfortic in patients with both functional grafts: Tmax</measure>
    <time_frame>Initial tacrolimus and Myfortic PK profile measurement: day 7-17 post SPK transplantation. Second ENVARSUS® and Myfortic PK profile measurement: day 15-32 post SPK transplantation</time_frame>
    <description>Tmax</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Further quantification of the PK profile of extended release tacrolimus and Myfortic in patients only with a functional kidney graft in case of early pancreas thrombosis..: Tmax</measure>
    <time_frame>Initial tacrolimus and Myfortic PK profile measurement: day 7-17 post SPK transplantation. Second ENVARSUS® and Myfortic PK profile measurement: day 15-32 post SPK transplantation</time_frame>
    <description>Tmax</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Further quantification of the PK profile of extended release tacrolimus and Myfortic in patients with both functional grafts : Ke</measure>
    <time_frame>Initial tacrolimus and Myfortic PK profile measurement: day 7-17 post SPK transplantation. Second ENVARSUS® and Myfortic PK profile measurement: day 15-32 post SPK transplantation</time_frame>
    <description>Ke</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Further quantification of the PK profile of extended release tacrolimus and Myfortic in patients only with a functional kidney graft in case of early pancreas thrombosis.: Ke</measure>
    <time_frame>Initial tacrolimus and Myfortic PK profile measurement: day 7-17 post SPK transplantation. Second ENVARSUS® and Myfortic PK profile measurement: day 15-32 post SPK transplantation</time_frame>
    <description>Ke</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Further quantification of the PK profile of extended release tacrolimus and Myfortic in patients with both functional grafts : t1/2</measure>
    <time_frame>Initial tacrolimus and Myfortic PK profile measurement: day 7-17 post SPK transplantation. Second ENVARSUS® and Myfortic PK profile measurement: day 15-32 post SPK transplantation</time_frame>
    <description>t1/2</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Further quantification of the PK profile of extended release tacrolimus and Myfortic in patients only with a functional kidney graft in case of early pancreas thrombosis.: t1/2</measure>
    <time_frame>Initial tacrolimus and Myfortic PK profile measurement: day 7-17 post SPK transplantation. Second ENVARSUS® and Myfortic PK profile measurement: day 15-32 post SPK transplantation</time_frame>
    <description>t1/2</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Further quantification of the PK profile of extended release tacrolimus and Myfortic in patients with both functional grafts: % fluctuation</measure>
    <time_frame>Initial tacrolimus and Myfortic PK profile measurement: day 7-17 post SPK transplantation. Second ENVARSUS® and Myfortic PK profile measurement: day 15-32 post SPK transplantation</time_frame>
    <description>% fluctuation</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Further quantification of the PK profile of extended release tacrolimus and Myfortic in patients only with a functional kidney graft in case of early pancreas thrombosis: % fluctuation</measure>
    <time_frame>Initial tacrolimus and Myfortic PK profile measurement: day 7-17 post SPK transplantation. Second ENVARSUS® and Myfortic PK profile measurement: day 15-32 post SPK transplantation</time_frame>
    <description>% fluctuation</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Assessment of biological and clinical tolerance/ safety: Incidence of serious adverse events</measure>
    <time_frame>Months 6, or on leaving hospital if after 6 months (maximum one year after the inclusion)</time_frame>
    <description>Incidence of serious adverse events</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">25</enrollment>
  <condition>Kidney Transplantation</condition>
  <condition>Pancreas Transplantation</condition>
  <condition>Diabetes</condition>
  <arm_group>
    <arm_group_label>Tacrolimus then Envarsus</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Tacrolimus will be started on the day of surgery. After a stable trough level is achieved (on postoperative day 7-17) the first PK profile will be measured. Subsequently, the switch to ENVARSUS® will be performed</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Tacrolimus and Tacrolimus Extended Release Oral Tablet [Envarsus]</intervention_name>
    <description>Phase 1: standard dose and frequency tacrolimus, used in accordance with licensing and local protocols. Suitable target trough level should be between 7-14 ng/ml.&#xD;
Phase 2: ENVARSUS® (LCP Tacro - extended release tacrolimus), used once-daily at an initial dose of 0.17mg/kg, dose adjusted to maintain an appropriate therapeutic blood concentration (measured by trough level). Suitable target trough level should be between 7-14 ng/ml.</description>
    <arm_group_label>Tacrolimus then Envarsus</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patient is willing and able to give informed consent for participation in the trial.&#xD;
&#xD;
          -  Male or Female, aged 18 years or above.&#xD;
&#xD;
          -  Type I Diabetics patients with end stage chronic renal failure&#xD;
&#xD;
          -  Recipient of kidney and pancreas-transplant&#xD;
&#xD;
          -  At least one of the two transplants are functioning at time of PK profile measurements&#xD;
             : a patient with early pancreatic graft failure due to thrombosis may be included if&#xD;
             the kidney is well functioning&#xD;
&#xD;
          -  Standard immunosuppressive therapy has been started post-operatively, in accordance&#xD;
             with local policy, including tacrolimus.&#xD;
&#xD;
          -  In the Investigator's opinion, is able and willing to comply with all trial&#xD;
             requirements.&#xD;
&#xD;
          -  Patients with social security.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        The participant may not enter the trial if ANY of the following apply:&#xD;
&#xD;
          -  Patient is inappropriate for standard immunosuppressive therapy.&#xD;
&#xD;
          -  Any other significant disease or disorder which, in the opinion of the Investigator,&#xD;
             may either put the patients at risk because of participation in the trial, or may&#xD;
             influence the result of the trial, or the patient's ability to participate in the&#xD;
             trial.&#xD;
&#xD;
          -  Concomitant therapy with drugs potentially interfering with tacrolimus&#xD;
             pharmacokinetics, especially those interfering with CYP3A4 (see 4.4 section in&#xD;
             tacrolimus / ENVARSUS® summary of product characteristics).&#xD;
&#xD;
          -  Loss of the pancreatic graft due to immunological causes&#xD;
&#xD;
          -  Pregnant or breast-feeding women and female patient with potential childbearing&#xD;
             refusing contraception.&#xD;
&#xD;
          -  Vulnerable people: persons deprived of liberty; under trusteeship or under&#xD;
             curatorship.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>DIEGO CANTAROVICH</last_name>
    <role>Principal Investigator</role>
    <affiliation>Nantes University Hospital</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Nantes University Hospital</name>
      <address>
        <city>Nantes</city>
        <zip>44093</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>France</country>
  </location_countries>
  <verification_date>May 2023</verification_date>
  <study_first_submitted>July 23, 2020</study_first_submitted>
  <study_first_submitted_qc>July 29, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">August 3, 2020</study_first_posted>
  <last_update_submitted>May 17, 2023</last_update_submitted>
  <last_update_submitted_qc>May 17, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">May 18, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Tacrolimus</keyword>
  <keyword>kidney transplant</keyword>
  <keyword>pancreas transplant</keyword>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Tacrolimus</mesh_term>
  </intervention_browse>
  <!-- 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/NCT04496401
org study id: RC19_0247
nct id: NCT04496401
lead sponsor: 
collaborator: 
is fda regulated drug: No
is fda regulated device: No
The investigators believe that the pharmacological properties of Envarsus®, well studied in
      kidney transplantation, may be also suitable after simultaneous kidney and pancreas
      transplantation than Prograf. Indeed, Envarsus® has demonstrated a clinical efficacy and
      safety in a complete clinical development plan.

      This study is to establish the pharmacokinetic profile of tacrolimus prolonged-release
      (hereafter referred to as 'ENVARSUS®') in diabetics who have undergone kidney and pancreas
      transplantation, and compare it to the pharmacokinetic profile of standard twice-daily
      tacrolimus. The study will be conducted in 25 patients hospitalized at Nantes University
      Hospital.
The study will be conducted in 25 patients hospitalized at Nantes University Hospital.
      Tacrolimus will be started on the day of surgery (or on the day after) according to Nantes
      local standard doses and practices. After a stable trough level is achieved (on postoperative
      day 7-17) the first PK profile will be measured. Subsequently, the switch to ENVARSUS® will
      be performed (initial dose of 0.17 mg/kg/day) on a single morning oral dosage regimen. A
      second PK profile will be measured, between 7 to 14 days after initiation of ENVARSUS®. All
      these PK measurements will take place during the post-operative recovery in the hospital
      (typically 2-3 weeks). All patients will receive Thymoglobulin or Alemtuzumab induction,
      Myfortic or Cellcept (or generics), with or without prednisone according to local practices.
      Anti-infectious prophylaxis will be given according to Nantes local practices.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Other
masking: None (Open Label)
measure: To characterise the bioavailability of Envarsus® and compare it to the bioavailability of tacrolimus
time frame: Initial tacrolimus PK profile measurement: day 7-17 post SPK transplantation. Second ENVARSUS® PK profile measurement: day 15-32 post SPK transplantation
description: To characterise the PK profile of extended release tacrolimus (Envarsus®) in diabetic transplant recipients, and compare it to the PK profile of tacrolimus : bioavailability AUC0-24
measure: Further quantification of the PK profile of extended release tacrolimus and Myfortic in patients with both functional grafts: Cmin
time frame: Initial tacrolimus and myfortic PK profile measurement: day 7-17 post SPK transplantation. Second ENVARSUS® and Myfortic PK profile measurement: day 15-32 post SPK transplantation
description: Cmin
measure: Further quantification of the PK profile of extended release tacrolimus and Myfortic in patients only with a functional kidney graft in case of early pancreas thrombosis.: Cmin
time frame: Initial tacrolimus and myfortic PK profile measurement: day 7-17 post SPK transplantation. Second ENVARSUS® and Myfortic PK profile measurement: day 15-32 post SPK transplantation
description: Cmin
measure: Further quantification of the PK profile of extended release tacrolimus and Myfortic in patients with both functional grafts : Cmax
time frame: Initial tacrolimus and Myfortic PK profile measurement: day 7-17 post SPK transplantation. Second ENVARSUS® and Myfortic PK profile measurement: day 15-32 post SPK transplantation
description: Cmax
measure: Further quantification of the PK profile of extended release tacrolimus and Myfortic in patients only with a functional kidney graft in case of early pancreas thrombosis.: Cmax
time frame: Initial tacrolimus and Myfortic PK profile measurement: day 7-17 post SPK transplantation. Second ENVARSUS® and Myfortic PK profile measurement: day 15-32 post SPK transplantation
description: Cmax
measure: Further quantification of the PK profile of extended release tacrolimus and Myfortic in patients with both functional grafts: Cavg
time frame: Initial tacrolimus and Myfortic PK profile measurement: day 7-17 post SPK transplantation. Second ENVARSUS® and Myfortic PK profile measurement: day 15-32 post SPK transplantation
description: Cavg
measure: Further quantification of the PK profile of extended release tacrolimus and Myforticin patients only with a functional kidney graft in case of early pancreas thrombosis.: Cavg
time frame: Initial tacrolimus and Myfortic PK profile measurement: day 7-17 post SPK transplantation. Second ENVARSUS® and Myfortic PK profile measurement: day 15-32 post SPK transplantation
description: Cavg
measure: Further quantification of the PK profile of extended release tacrolimus and Myfortic in patients with both functional grafts: Tmax
time frame: Initial tacrolimus and Myfortic PK profile measurement: day 7-17 post SPK transplantation. Second ENVARSUS® and Myfortic PK profile measurement: day 15-32 post SPK transplantation
description: Tmax
measure: Further quantification of the PK profile of extended release tacrolimus and Myfortic in patients only with a functional kidney graft in case of early pancreas thrombosis..: Tmax
time frame: Initial tacrolimus and Myfortic PK profile measurement: day 7-17 post SPK transplantation. Second ENVARSUS® and Myfortic PK profile measurement: day 15-32 post SPK transplantation
description: Tmax
measure: Further quantification of the PK profile of extended release tacrolimus and Myfortic in patients with both functional grafts : Ke
time frame: Initial tacrolimus and Myfortic PK profile measurement: day 7-17 post SPK transplantation. Second ENVARSUS® and Myfortic PK profile measurement: day 15-32 post SPK transplantation
description: Ke
measure: Further quantification of the PK profile of extended release tacrolimus and Myfortic in patients only with a functional kidney graft in case of early pancreas thrombosis.: Ke
time frame: Initial tacrolimus and Myfortic PK profile measurement: day 7-17 post SPK transplantation. Second ENVARSUS® and Myfortic PK profile measurement: day 15-32 post SPK transplantation
description: Ke
measure: Further quantification of the PK profile of extended release tacrolimus and Myfortic in patients with both functional grafts : t1/2
time frame: Initial tacrolimus and Myfortic PK profile measurement: day 7-17 post SPK transplantation. Second ENVARSUS® and Myfortic PK profile measurement: day 15-32 post SPK transplantation
description: t1/2
measure: Further quantification of the PK profile of extended release tacrolimus and Myfortic in patients only with a functional kidney graft in case of early pancreas thrombosis.: t1/2
time frame: Initial tacrolimus and Myfortic PK profile measurement: day 7-17 post SPK transplantation. Second ENVARSUS® and Myfortic PK profile measurement: day 15-32 post SPK transplantation
description: t1/2
measure: Further quantification of the PK profile of extended release tacrolimus and Myfortic in patients with both functional grafts: % fluctuation
time frame: Initial tacrolimus and Myfortic PK profile measurement: day 7-17 post SPK transplantation. Second ENVARSUS® and Myfortic PK profile measurement: day 15-32 post SPK transplantation
description: % fluctuation
measure: Further quantification of the PK profile of extended release tacrolimus and Myfortic in patients only with a functional kidney graft in case of early pancreas thrombosis: % fluctuation
time frame: Initial tacrolimus and Myfortic PK profile measurement: day 7-17 post SPK transplantation. Second ENVARSUS® and Myfortic PK profile measurement: day 15-32 post SPK transplantation
description: % fluctuation
measure: Assessment of biological and clinical tolerance/ safety: Incidence of serious adverse events
time frame: Months 6, or on leaving hospital if after 6 months (maximum one year after the inclusion)
description: Incidence of serious adverse events
arm group label: Tacrolimus then Envarsus
arm group type: Experimental
description: Tacrolimus will be started on the day of surgery. After a stable trough level is achieved (on postoperative day 7-17) the first PK profile will be measured. Subsequently, the switch to ENVARSUS® will be performed
intervention type: Drug
intervention name: Tacrolimus and Tacrolimus Extended Release Oral Tablet [Envarsus]
description: Phase 1: standard dose and frequency tacrolimus, used in accordance with licensing and local protocols. Suitable target trough level should be between 7-14 ng/ml.
Phase 2: ENVARSUS® (LCP Tacro - extended release tacrolimus), used once-daily at an initial dose of 0.17mg/kg, dose adjusted to maintain an appropriate therapeutic blood concentration (measured by trough level). Suitable target trough level should be between 7-14 ng/ml.
arm group label: Tacrolimus then Envarsus
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: DIEGO CANTAROVICH
role: Principal Investigator
affiliation: Nantes University Hospital
facility: 
country: France
responsible party type: Sponsor
mesh term: Tacrolimus