<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/NCT02970630</url>
  </required_header>
  <id_info>
    <org_study_id>DFIDM-1501</org_study_id>
    <secondary_id>2015-005640-34</secondary_id>
    <nct_id>NCT02970630</nct_id>
  </id_info>
  <brief_title>Envarsus® Once Daily With Everolimus in Elderly Kidney Transplant Recipients: Pharmacokinetic and Clinical Study</brief_title>
  <official_title>Envarsus® Tablets Administered Once Daily in Combination With Everolimus in Elderly De-novo Kidney Transplant Recipients: Open-label, Multicentre, Single-arm, Pharmacokinetic and Clinical Study</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Chiesi Farmaceutici S.p.A.</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Cromsource</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Chiesi Farmaceutici S.p.A.</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Prospective, single-arm, open-label, multicentre study with the principal aim to estimate&#xD;
      tacrolimus pharmacokinetic parameters in elderly de-novo kidney transplant recipients of ECD&#xD;
      (Extended Criteria Donor) kidney grafts treated with Envarsus® prolonged release tablets in&#xD;
      combination with everolimus tablets.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">January 2017</start_date>
  <completion_date type="Actual">February 22, 2018</completion_date>
  <primary_completion_date type="Actual">February 22, 2018</primary_completion_date>
  <phase>Phase 2</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>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Tacrolimus Area Under the curve at 24 hours (AUC24)</measure>
    <time_frame>10 days</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Tacrolimus Minimum whole blood concentration (Cmin)</measure>
    <time_frame>10 days</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Tacrolimus Cmin/daily dose</measure>
    <time_frame>10 days</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Tacrolimus AUC24/daily dose</measure>
    <time_frame>10 days</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Tacrolimus within-patient variability of blood trough level</measure>
    <time_frame>from day 3 to month 6</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to reach therapeutic exposure to tacrolimus</measure>
    <time_frame>from day 3 to month 6</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of dose adjustments</measure>
    <time_frame>from day 3 to month 6</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Total daily dose</measure>
    <time_frame>from day 3 to month 6</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Renal function using estimated glomerular filtration rate</measure>
    <time_frame>from day 1 to month 6</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Treatment failure rate</measure>
    <time_frame>from day 1 to month 6</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Delayed graft function</measure>
    <time_frame>from day 1 to month 6</time_frame>
    <description>Number of days between the first and the last renal replacement session</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Acute rejection requiring treatment</measure>
    <time_frame>from day 1 to month 6</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Biopsy proven acute rejections</measure>
    <time_frame>from day 1 to month 6</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Tacrolimus Maximum whole blood concentration (Cmax)</measure>
    <time_frame>10 days</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Tacrolimus Tmax (time that the drug is present at the maximum concentration in serum)</measure>
    <time_frame>10 days</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Tacrolimus Average whole blood drug concentration (Cave)</measure>
    <time_frame>10 days</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Tacrolimus % fluctuation</measure>
    <time_frame>10 days</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Tacrolimus % swing</measure>
    <time_frame>10 days</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Tacrolimus linear correlation coefficient between Cmin and AUC24</measure>
    <time_frame>10 days</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Adverse Events</measure>
    <time_frame>from screening to month 6</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Serious Adverse Events</measure>
    <time_frame>from screening to month 6</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of opportunistic infections</measure>
    <time_frame>from screening to month 6</time_frame>
    <description>Number of opportunistic infections</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">28</enrollment>
  <condition>Kidney Transplantation</condition>
  <arm_group>
    <arm_group_label>Envarsus once a day, everolimus b.i.d.</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Tacrolimus tablets at starting dose of 0.07 mg/kg/day will be administered once daily in the morning.&#xD;
Everolimus tablets at starting dose of 2 mg/day (1 mg b.i.d.) will be administered twice daily, every 12 hours.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Tacrolimus</intervention_name>
    <description>once a day</description>
    <arm_group_label>Envarsus once a day, everolimus b.i.d.</arm_group_label>
    <other_name>Envarsus</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Everolimus</intervention_name>
    <description>twice daily</description>
    <arm_group_label>Envarsus once a day, everolimus b.i.d.</arm_group_label>
    <other_name>Certican</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Subject's written informed consent obtained prior to transplant intervention and prior&#xD;
             to any study-related procedures;&#xD;
&#xD;
          2. Caucasian male or female subjects aged 60 or older who are receiving a primary or&#xD;
             secondary single or dual renal transplant from a blood group compatible deceased&#xD;
             donor;&#xD;
&#xD;
          3. Patients who are planned to receive a renal allograft by Extended Criteria Donor&#xD;
             (ECD);&#xD;
&#xD;
          4. Patients capable of understanding the purposes and risks of the study, who can give&#xD;
             written informed consent and who are willing to participate in and comply with the&#xD;
             study;&#xD;
&#xD;
          5. Patients with low to standard immunological risk, who had a PRA (Panel Reactive&#xD;
             Antibody) ≤ 20% (PRA testing according to centre's practice);&#xD;
&#xD;
          6. Body Mass Index (BMI) between 15 and 35 kg/m2 extremes inclusive;&#xD;
&#xD;
          7. Women must be postmenopausal (physiologic menopause defined as &quot;12 consecutive months&#xD;
             of amenorrhea&quot;) or permanently sterilized (e.g. tubal occlusion, hysterectomy or&#xD;
             bilateral salpingectomy) to be enrolled in the study.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Recipients of any transplanted organ other than a single or dual kidney;&#xD;
&#xD;
          2. Patients unable or unwilling to provide informed consent;&#xD;
&#xD;
          3. Male subjects with females partner of childbearing potential UNLESS they or their&#xD;
             partner are willing to use a reliable method of contraception (see below for details)&#xD;
             from the time of first dose administration and until 8 weeks after the last dose of&#xD;
             study drugs. Male subjects with partners of non-childbearing potential are not&#xD;
             required to use contraception.&#xD;
&#xD;
             Reliable methods of contraception for male subjects and their partner of childbearing&#xD;
             potential must be one of the following:&#xD;
&#xD;
               1. Placement of an intrauterine device or intrauterine system&#xD;
&#xD;
               2. Hormonal contraception (implantable, patch, oral)&#xD;
&#xD;
               3. Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical&#xD;
                  vaults/caps) with spermicidal foam/gel/film/cream/suppository.&#xD;
&#xD;
               4. Male sterilization (with the appropriate post-vasectomy documentation of the&#xD;
                  absence of sperm in the ejaculate &quot;True abstinence&quot; is acceptable only if it is&#xD;
                  in line with the preferred and usual lifestyle of the subject.&#xD;
&#xD;
          4. Recipients of a bone marrow or stem cell transplant;&#xD;
&#xD;
          5. Recipients of a kidney from a cardiac death donor;&#xD;
&#xD;
          6. Recipients of a kidney from an ABO (0, A and blood cell types) incompatible donor;&#xD;
&#xD;
          7. Recipients having pre-transplant donor specific anti-HLA (Human leukocyte antigen&#xD;
             antibodies) (DSA) or who lost the first kidney transplant because of acute rejection;&#xD;
&#xD;
          8. Recipients of a kidney with an anticipated cold ischemia time ≥ 24 hours;&#xD;
&#xD;
          9. Recipients positive for Hepatitis C virus (HCV-RNA positive) and/or Hepatitis B Virus&#xD;
             (HBV-DNA or HBsAg positive);&#xD;
&#xD;
         10. Recipients positive for Human Immunodeficiency Virus (HIV-Ab positive);&#xD;
&#xD;
         11. Patients with a current malignancy or a history of malignancy (within the past 5&#xD;
             years), except basal or non-metastatic squamous cell carcinoma of the skin that has&#xD;
             been treated successfully;&#xD;
&#xD;
         12. Patients with uncontrolled concomitant infection, a systemic infection requiring&#xD;
             treatment, or any other unstable medical condition that could interfere with the study&#xD;
             objectives;&#xD;
&#xD;
         13. Patients with severe diarrhoea, vomiting, active peptic ulcer or gastrointestinal&#xD;
             disorder that may affect the absorption of study drugs;&#xD;
&#xD;
         14. Patients with a white blood cell count ≤ 2.8x109/L unless the absolute neutrophil&#xD;
             count (ANC) is ≥ 1.0x109/L;&#xD;
&#xD;
         15. Patients with a platelet count ≤ 50.0x109/L;&#xD;
&#xD;
         16. Patients with aspartate aminotransferase (AST) or alanine aminotransferase (ALT)&#xD;
             enzyme levels &gt; 3 times the upper limit of normal during the 30 days prior to the&#xD;
             transplant procedure;&#xD;
&#xD;
         17. Patients who were treated with any other investigational agent in the three months&#xD;
             prior to enrolment;&#xD;
&#xD;
         18. Patients who received any investigational new drug, or participated in clinical study&#xD;
             within the last 8 weeks;&#xD;
&#xD;
         19. Patient planned to receive an induction therapy different from rabbit ATG&#xD;
             (Anti-thymocyte globulin) alone or patients who did not start rabbit ATG induction&#xD;
             therapy after transplant;&#xD;
&#xD;
         20. Patients who are already on immunosuppressive drugs the day before transplantation,&#xD;
             except ATG as per protocol;&#xD;
&#xD;
         21. Patients who are planned to receive therapy with any immunosuppressive agent other&#xD;
             than those prescribed in the study;&#xD;
&#xD;
         22. Patients with a known hypersensitivity to corticosteroids, tacrolimus or everolimus or&#xD;
             sirolimus or any of the excipients present in study drugs formulations;&#xD;
&#xD;
         23. Patients with hypersensitivity to macrolides;&#xD;
&#xD;
         24. Patients with any form of substance abuse, psychiatric disorder or a condition that,&#xD;
             in the opinion of the Investigator, may invalidate communication with the&#xD;
             Investigator;&#xD;
&#xD;
         25. Subjects unlikely to comply with the study protocol or unable to understand the nature&#xD;
             and scope of the study but also the possible benefits or unwanted effects of the study&#xD;
             treatments;&#xD;
&#xD;
         26. Other severe acute or chronic medical or psychiatric condition or laboratory&#xD;
             abnormality that may increase the risk associated with study participation or study&#xD;
             drug administration or may interfere with the interpretation of study results and, in&#xD;
             the judgment of the investigator, would make the subject inappropriate for entry into&#xD;
             this study.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>60 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Paolo Rigotti, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Az Osp Padova, Osp. Civile Padova</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Ospedale Ca' Granda - Niguarda</name>
      <address>
        <city>Milano</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Ospedale Maggiore Policlinico</name>
      <address>
        <city>Milano</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Azienda Ospedaliera di Padova</name>
      <address>
        <city>Padova</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Policlinico &quot;A. Gemelli&quot;</name>
      <address>
        <city>Rome</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Policlinico &quot;Le Scotte&quot;</name>
      <address>
        <city>Siena</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Azienda Ospedaliera S. Giovanni Battista</name>
      <address>
        <city>Torino</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Italy</country>
  </location_countries>
  <link>
    <url>https://www.clinicaltrialsregister.eu/ctr-search/trial/2015-005640-34/results</url>
    <description>Study Record on EU Clinical Trials Register including results</description>
  </link>
  <verification_date>February 2019</verification_date>
  <study_first_submitted>October 28, 2016</study_first_submitted>
  <study_first_submitted_qc>November 21, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">November 22, 2016</study_first_posted>
  <last_update_submitted>February 28, 2019</last_update_submitted>
  <last_update_submitted_qc>February 28, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">March 1, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>prophylaxis</keyword>
  <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>No</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/NCT02970630
org study id: DFIDM-1501
secondary id: 2015-005640-34
nct id: NCT02970630
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated device: No
Prospective, single-arm, open-label, multicentre study with the principal aim to estimate
      tacrolimus pharmacokinetic parameters in elderly de-novo kidney transplant recipients of ECD
      (Extended Criteria Donor) kidney grafts treated with Envarsus® prolonged release tablets in
      combination with everolimus tablets.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Tacrolimus Area Under the curve at 24 hours (AUC24)
time frame: 10 days
measure: Tacrolimus Minimum whole blood concentration (Cmin)
time frame: 10 days
measure: Tacrolimus Cmin/daily dose
time frame: 10 days
measure: Tacrolimus AUC24/daily dose
time frame: 10 days
measure: Tacrolimus within-patient variability of blood trough level
time frame: from day 3 to month 6
measure: Time to reach therapeutic exposure to tacrolimus
time frame: from day 3 to month 6
measure: Number of dose adjustments
time frame: from day 3 to month 6
measure: Total daily dose
time frame: from day 3 to month 6
measure: Renal function using estimated glomerular filtration rate
time frame: from day 1 to month 6
measure: Treatment failure rate
time frame: from day 1 to month 6
measure: Delayed graft function
time frame: from day 1 to month 6
description: Number of days between the first and the last renal replacement session
measure: Acute rejection requiring treatment
time frame: from day 1 to month 6
measure: Biopsy proven acute rejections
time frame: from day 1 to month 6
measure: Tacrolimus Maximum whole blood concentration (Cmax)
time frame: 10 days
measure: Tacrolimus Tmax (time that the drug is present at the maximum concentration in serum)
time frame: 10 days
measure: Tacrolimus Average whole blood drug concentration (Cave)
time frame: 10 days
measure: Tacrolimus % fluctuation
time frame: 10 days
measure: Tacrolimus % swing
time frame: 10 days
measure: Tacrolimus linear correlation coefficient between Cmin and AUC24
time frame: 10 days
measure: Adverse Events
time frame: from screening to month 6
measure: Serious Adverse Events
time frame: from screening to month 6
measure: Number of opportunistic infections
time frame: from screening to month 6
description: Number of opportunistic infections
arm group label: Envarsus once a day, everolimus b.i.d.
arm group type: Experimental
description: Tacrolimus tablets at starting dose of 0.07 mg/kg/day will be administered once daily in the morning.
Everolimus tablets at starting dose of 2 mg/day (1 mg b.i.d.) will be administered twice daily, every 12 hours.
intervention type: Drug
intervention name: Tacrolimus
description: once a day
arm group label: Envarsus once a day, everolimus b.i.d.
other name: Envarsus
intervention type: Drug
intervention name: Everolimus
description: twice daily
arm group label: Envarsus once a day, everolimus b.i.d.
other name: Certican
criteria: 
gender: All
minimum age: 60 Years
maximum age: N/A
healthy volunteers: No
last name: Paolo Rigotti, MD
role: Principal Investigator
affiliation: Az Osp Padova, Osp. Civile Padova
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
country: Italy
url: https://www.clinicaltrialsregister.eu/ctr-search/trial/2015-005640-34/results
description: Study Record on EU Clinical Trials Register including results
responsible party type: Sponsor
mesh term: Everolimus
mesh term: Tacrolimus
sharing ipd: No