<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/NCT03289650</url>
  </required_header>
  <id_info>
    <org_study_id>STU00205327</org_study_id>
    <nct_id>NCT03289650</nct_id>
  </id_info>
  <brief_title>Extended Release Tacrolimus vs. Twice-Daily Tacrolimus</brief_title>
  <official_title>Once-Daily Extended-Release Tacrolimus vs. Twice-Daily Tacrolimus: Impact on T-Cell Subpopulations and Markers of Renal Tubule-toxicity in Kidney Transplant Patients</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Lorenzo Gallon</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Northwestern University</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>Yes</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      The overall aim of the study is to prospectively investigate the impact of two maintenance&#xD;
      calcineurin inhibitor immunosuppressive regimens: once-daily extended release tacrolimus and&#xD;
      twice-daily tacrolimus on subpopulations of T and B cells and alloreactive T cells as well as&#xD;
      on renal allograft function.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Kidney transplantation is the treatment of choice for most patients with end-stage renal&#xD;
      disease. Lifelong immunosuppressive therapies are required to prevent organ rejection.&#xD;
      However, long term exposure to immunosuppressive therapy after kidney transplantation can&#xD;
      place patients at risk for multiple adverse events. The optimal immunosuppressive therapy is&#xD;
      not well established. Tacrolimus, a calcineurin inhibitor (CNI) is highly effective in&#xD;
      preventing acute rejection after organ transplantation (2). It is used as part of the&#xD;
      immunosuppression regimen for the majority of kidney and liver transplant recipients (3).&#xD;
      However, treatment with current formulation of Tacrolimus generates high peaks and low&#xD;
      troughs in drug concentrations in the blood. It is known that high exposure to CNI is&#xD;
      associated with renal toxicities and adverse events (4). New once-daily dosage formulations&#xD;
      are now developed with the hope of minimizing side effects while maintaining excellent&#xD;
      outcomes (5-8).&#xD;
&#xD;
      LCP-Tacro (Envarsus® XR, Veloxis Pharmaceuticals), a new once-daily formulation of&#xD;
      tacrolimus, was approved by the FDA in 2015 for conversion from twice-daily tacrolimus in&#xD;
      kidney transplant recipients. It is a prolonged-release tacrolimus formulation, utilizing a&#xD;
      MeltDose drug delivery technology designed to improve the bioavailability of drugs with low&#xD;
      water solubility (1). Recent clinical data demonstrated that once-daily LCP-Tacro has&#xD;
      improved pharmacokinetic bioavailability, rapid achievement of therapeutic trough levels,&#xD;
      less fluctuation and swing in whole blood concentration, non-inferior efficacy and similar&#xD;
      safety, with lower tacrolimus dose than other tacrolimus formulations.&#xD;
&#xD;
      The target population is adult recipients of immediately functioning living and deceased&#xD;
      donor renal allografts. Immediate function will be defined as the absence of the need for&#xD;
      hemodialysis in the first week following renal transplantation.&#xD;
&#xD;
      Prospective randomized single center open label study of 2 groups of kidney transplant&#xD;
      patients&#xD;
&#xD;
        -  Group 1 : standard of care (SOC) control group will receive tacrolimus twice-daily&#xD;
           (n=25)&#xD;
&#xD;
        -  Group 2 : LCP-Tacro (Envarsus® XR) group will receive LCPT tablets once daily (n=25)&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">September 5, 2017</start_date>
  <completion_date type="Actual">February 23, 2021</completion_date>
  <primary_completion_date type="Actual">February 23, 2021</primary_completion_date>
  <phase>Phase 3</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>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change in Kidney Transplant Function From 2 Weeks Post Transplant Through 12 Months Post Transplant</measure>
    <time_frame>2 weeks post transplant through 12 months post transplant</time_frame>
    <description>change in the mean eGFR from the baseline (2 weeks post transplant), 3 months (post transplant) , and 12 months (post transplant).</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change in Subpopulations of T Cells From 2 Weeks Post Transplant Through 12 Months Post Transplant</measure>
    <time_frame>Measured at 2 weeks post transplant, 3 months post transplant, 12 months post transplant</time_frame>
    <description>Blood, urine and kidney tissue analysis via serial flow cytometric immunophenotyping (includes regulatory T and B cell populations as well as immune functions).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Participants With Acute Rejection at 3 Months and 12 Months Post-Transplant</measure>
    <time_frame>Measured at 3 months post transplant, 12 months post transplant</time_frame>
    <description>Acute rejection of kidney transplant is determined via biopsy.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Participants With Graft Loss at 3 Months and 12 Months Post-Transplant</measure>
    <time_frame>Measured at 3 months post transplant, 12 months post transplant</time_frame>
    <description>Graft loss is determined via biopsy.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Subjects Deceased at at 3 Months and 12 Months Post-Transplant</measure>
    <time_frame>Through 12 months post transplant</time_frame>
    <description>Subject survival status is continually monitored via routine follow-up visits.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Participants With Change in Allograft Immunohistopathology Profile</measure>
    <time_frame>Measured at 3 months post transplant, 12 months post transplant</time_frame>
    <description>Tissue analysis via immunohistopathological staining and microscopic examination Moderate acute tubular necrosis =&gt; presence of focal coagulative necrosis or infarction on histopathologic examination&#xD;
Arteriolar hyalinosis grade 2 means: Replacement of degenerated smooth muscle cells by hyaline deposits in more than 1 arteriole, without circumferential involvement&#xD;
Global glomerulosclerosis &gt;grade 2, means glomerulosclerosis affecting more than 50% of glomeruli in the biopsy sample&#xD;
IFTA : Interstitial fibrosis and tubular atrophy: Inflammation in 26% to 50% of scarred cortical parenchyma</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">29</enrollment>
  <condition>End Stage Renal Disease</condition>
  <condition>Rejection of Renal Transplant</condition>
  <arm_group>
    <arm_group_label>Standard of care tacrolimus twice-daily</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
  </arm_group>
  <arm_group>
    <arm_group_label>Extended-release tacrolimus once-daily</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Tacrolimus</intervention_name>
    <description>immunosuppressive agent tacrolimus, given twice-daily</description>
    <arm_group_label>Standard of care tacrolimus twice-daily</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Tacrolimus Extended Release Oral Tablet [Envarsus]</intervention_name>
    <description>immunosuppressive agent extended-release tacrolimus, given once daily</description>
    <arm_group_label>Extended-release tacrolimus once-daily</arm_group_label>
    <other_name>LCP-tacro</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
        1. Patients who are males or females aged 18-65 years. 2. Use of the following induction&#xD;
        medications: basiliximab and rituximab. 2. Donors aged 18-65 years. 3. No prior organ&#xD;
        transplant 4. Patients who are single-organ recipients (kidney only). 5. Women who are of&#xD;
        childbearing potential must have a negative serum pregnancy test before transplantation and&#xD;
        agree to use a medically acceptable method of contraception throughout the treatment&#xD;
        period.&#xD;
&#xD;
        6. Subject (recipient) is able to understand the consent form and give written informed&#xD;
        consent&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Delayed graft function (please see above).&#xD;
&#xD;
          2. Known sensitivity or contraindication to alemtuzumab, Envarsus® XR, tacrolimus or MMF.&#xD;
&#xD;
          3. Use of the following induction medications: basiliximab and rituximab&#xD;
&#xD;
          4. Patient with significant or active infection.&#xD;
&#xD;
          5. Patients with a positive flow cytometric crossmatch using donor lymphocytes and&#xD;
             recipient serum.&#xD;
&#xD;
          6. Patients with PRA &gt; 40%&#xD;
&#xD;
          7. Patients with current or historic donor specific antibodies&#xD;
&#xD;
          8. Body Mass Index (BMI) of &lt; 18 or &gt; 35&#xD;
&#xD;
          9. Patients who are pregnant or nursing mothers.&#xD;
&#xD;
         10. Patients whose life expectancy is severely limited by diseases other than renal&#xD;
             disease.&#xD;
&#xD;
         11. Ongoing active substance abuse, drug or alcohol.&#xD;
&#xD;
         12. Major ongoing psychiatric illness or recent history of noncompliance.&#xD;
&#xD;
         13. Significant cardiovascular disease (e.g.):&#xD;
&#xD;
               -  Significant non-correctable coronary artery disease;&#xD;
&#xD;
               -  Ejection fraction below 30%;&#xD;
&#xD;
               -  History of recent myocardial infarction.&#xD;
&#xD;
         14. Malignancy within 3 years, excluding non-melanoma skin cancers.&#xD;
&#xD;
         15. Serologic evidence of infection with HIV or HBVs-Ag positive.&#xD;
&#xD;
         16. Patients with a screening/baseline total white blood cell count &lt; 4,000/mm3; platelet&#xD;
             count &lt; 100,000/mm3; triglyceride &gt; 400 mg/dl; total cholesterol &gt; 300 mg/dl.&#xD;
&#xD;
         17. Investigational drug within 30 days prior to transplant surgery.&#xD;
&#xD;
         18. Anti-T cell therapy within 30 days prior to transplant surgery.&#xD;
&#xD;
         19. Diagnosis of atypical-Hemolytic Uremic Syndrome (aHUS).&#xD;
&#xD;
         20. Subjects transplanted with a Hepatitis C NAT-positive kidney.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>65 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Northwestern University</name>
      <address>
        <city>Chicago</city>
        <state>Illinois</state>
        <zip>60611</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>March 2023</verification_date>
  <study_first_submitted>September 12, 2017</study_first_submitted>
  <study_first_submitted_qc>September 18, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 21, 2017</study_first_posted>
  <results_first_submitted>February 1, 2023</results_first_submitted>
  <results_first_submitted_qc>March 15, 2023</results_first_submitted_qc>
  <results_first_posted type="Actual">April 10, 2023</results_first_posted>
  <last_update_submitted>March 15, 2023</last_update_submitted>
  <last_update_submitted_qc>March 15, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">April 10, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>Northwestern University</investigator_affiliation>
    <investigator_full_name>Lorenzo Gallon</investigator_full_name>
    <investigator_title>Professor of Medicine</investigator_title>
  </responsible_party>
  <keyword>immunosuppression</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Kidney Failure, Chronic</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Tacrolimus</mesh_term>
  </intervention_browse>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>October 3, 2019</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/50/NCT03289650/Prot_SAP_000.pdf</document_url>
    </provided_document>
    <provided_document>
      <document_type>Informed Consent Form</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>Yes</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>September 17, 2019</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/50/NCT03289650/ICF_001.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Group 1: Control Arm: Standard of Care (SOC) Tacrolimus</title>
          <description>1-2 mg 2x daily (BID), per SOC. The dose will be modified to achieve 12 hours trough concentrations of 8-12 ng/ml</description>
        </group>
        <group group_id="P2">
          <title>Group 2: Interventional Arm: Study Related Drug: LCP-Tacrolimus/Envarsus XR (LCP-Tacro/Envarsus XR)</title>
          <description>One 5mg extended-release tablet taken once daily (QD) to achieve a 24-hour trough concentrations of 8-12 ng/ml</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="14"/>
                <participants group_id="P2" count="15"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="14"/>
                <participants group_id="P2" count="15"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Standard of Care Tacrolimus Twice-daily</title>
          <description>Tacrolimus: immunosuppressive agent tacrolimus, given twice-daily</description>
        </group>
        <group group_id="B2">
          <title>Extended-release Tacrolimus Once-daily</title>
          <description>Tacrolimus Extended Release Oral Tablet [Envarsus]: immunosuppressive agent extended-release tacrolimus, given once daily</description>
        </group>
        <group group_id="B3">
          <title>Total</title>
          <description>Total of all reporting groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="14"/>
            <count group_id="B2" value="15"/>
            <count group_id="B3" value="29"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="43.14" spread="12.7"/>
                    <measurement group_id="B2" value="47.53" spread="16.04"/>
                    <measurement group_id="B3" value="45.4" spread="14.4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                    <measurement group_id="B2" value="3"/>
                    <measurement group_id="B3" value="6"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="11"/>
                    <measurement group_id="B2" value="12"/>
                    <measurement group_id="B3" value="23"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="2"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="4"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="10"/>
                    <measurement group_id="B2" value="13"/>
                    <measurement group_id="B3" value="23"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Cause of Kidney Disease</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>Diabetes</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                    <measurement group_id="B2" value="4"/>
                    <measurement group_id="B3" value="7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Glomerulonephritis</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                    <measurement group_id="B2" value="4"/>
                    <measurement group_id="B3" value="7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Obstructive Nephropathy</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Congenital</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Others</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="5"/>
                    <measurement group_id="B2" value="5"/>
                    <measurement group_id="B3" value="10"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Type of Donor</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>Cadaveric</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Living</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="14"/>
                    <measurement group_id="B2" value="14"/>
                    <measurement group_id="B3" value="28"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Panel reactive antibodies (PRA)</title>
          <units>percentage</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <title>Major histocompatibility complex class I (MHC-I) antibodies</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="1.93" spread="2.79"/>
                    <measurement group_id="B2" value="4.20" spread="8.44"/>
                    <measurement group_id="B3" value="3.1" spread="6.4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Major histocompatibility complex class II (MHC-II) antibodies</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="3.07" spread="5.18"/>
                    <measurement group_id="B2" value="4.07" spread="9.01"/>
                    <measurement group_id="B3" value="3.6" spread="7.3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Estimated glomerular filtration rate (eGFR)</title>
          <description>measured in mL/min/1.73m^2. MDRD equation was used to calculate GFR, using age, sex, race and serum creatinine</description>
          <units>ml/min/1.73m2</units>
          <param>Median</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="52.43" spread="9.26"/>
                    <measurement group_id="B2" value="51.77" spread="9.69"/>
                    <measurement group_id="B3" value="52.1" spread="10.6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Change in Kidney Transplant Function From 2 Weeks Post Transplant Through 12 Months Post Transplant</title>
        <description>change in the mean eGFR from the baseline (2 weeks post transplant), 3 months (post transplant) , and 12 months (post transplant).</description>
        <time_frame>2 weeks post transplant through 12 months post transplant</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Group 1: Control Arm: Standard of Care (SOC) Tacrolimus</title>
            <description>Tacrolimus: immunosuppressive agent tacrolimus, 1-2 mg 2x daily (BID), per SOC. The dose will be modified to achieve 12 hours trough concentrations of 8-12 ng/ml</description>
          </group>
          <group group_id="O2">
            <title>Group 2: Interventional Arm: Study Related Drug: LCP-Tacrolimus/Envarsus XR (LCP-Tacro/Envarsus XR)</title>
            <description>Tacrolimus Extended Release Oral Tablet [Envarsus]: immunosuppressive agent extended-release tacrolimus, One 5mg extended-release tablet taken once daily (QD) to achieve a 24-hour trough concentrations of 8-12 ng/ml</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Kidney Transplant Function From 2 Weeks Post Transplant Through 12 Months Post Transplant</title>
          <description>change in the mean eGFR from the baseline (2 weeks post transplant), 3 months (post transplant) , and 12 months (post transplant).</description>
          <units>mL/min/1.73m^2</units>
          <param>Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="14"/>
                <count group_id="O2" value="15"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2.03" spread="1.71"/>
                    <measurement group_id="O2" value="-2.19" spread="1.77"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change in Subpopulations of T Cells From 2 Weeks Post Transplant Through 12 Months Post Transplant</title>
        <description>Blood, urine and kidney tissue analysis via serial flow cytometric immunophenotyping (includes regulatory T and B cell populations as well as immune functions).</description>
        <time_frame>Measured at 2 weeks post transplant, 3 months post transplant, 12 months post transplant</time_frame>
        <population>Secondary outcome data will not be reported because support to collect secondary data was not present</population>
        <group_list>
          <group group_id="O1">
            <title>Group 1: Control Arm: Standard of Care (SOC) Tacrolimus</title>
            <description>1-2 mg 2x daily (BID), per SOC. The dose will be modified to achieve 12 hours trough concentrations of 8-12 ng/ml</description>
          </group>
          <group group_id="O2">
            <title>Group 2: Interventional Arm: Study Related Drug: LCP-Tacrolimus/Envarsus XR (LCP-Tacro/Envarsus XR)</title>
            <description>One 5mg extended-release tablet taken once daily (QD) to achieve a 24-hour trough concentrations of 8-12 ng/ml</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Subpopulations of T Cells From 2 Weeks Post Transplant Through 12 Months Post Transplant</title>
          <description>Blood, urine and kidney tissue analysis via serial flow cytometric immunophenotyping (includes regulatory T and B cell populations as well as immune functions).</description>
          <population>Secondary outcome data will not be reported because support to collect secondary data was not present</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
                <count group_id="O2" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Participants With Acute Rejection at 3 Months and 12 Months Post-Transplant</title>
        <description>Acute rejection of kidney transplant is determined via biopsy.</description>
        <time_frame>Measured at 3 months post transplant, 12 months post transplant</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Group 1: Control Arm: Standard of Care (SOC) Tacrolimus</title>
            <description>1-2 mg 2x daily (BID), per SOC. The dose will be modified to achieve 12 hours trough concentrations of 8-12 ng/ml</description>
          </group>
          <group group_id="O2">
            <title>Group 2: Interventional Arm: Study Related Drug: LCP-Tacrolimus/Envarsus® XR (LCP-Tacro/Envarsus XR)</title>
            <description>One 5mg extended-release tablet taken once daily (QD) to achieve a 24-hour trough concentrations of 8-12 ng/ml</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With Acute Rejection at 3 Months and 12 Months Post-Transplant</title>
          <description>Acute rejection of kidney transplant is determined via biopsy.</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="14"/>
                <count group_id="O2" value="15"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Acute rejection at 3 months</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Acute rejection at 12 months</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Participants With Graft Loss at 3 Months and 12 Months Post-Transplant</title>
        <description>Graft loss is determined via biopsy.</description>
        <time_frame>Measured at 3 months post transplant, 12 months post transplant</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Group 1: Control Arm: Standard of Care (SOC) Tacrolimus</title>
            <description>Tacrolimus: immunosuppressive agent Tacrolimus 1-2 mg 2x daily (BID), per SOC. The dose will be modified to achieve 12 hours trough concentrations of 8-12 ng/ml-daily</description>
          </group>
          <group group_id="O2">
            <title>Group 2: Interventional Arm: Study Related Drug: LCP-Tacrolimus/Envarsus XR (LCP-Tacro/Envarsus XR)</title>
            <description>One 5mg extended-release tablet taken once daily (QD) to achieve a 24-hour trough concentrations of 8-12 ng/ml</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With Graft Loss at 3 Months and 12 Months Post-Transplant</title>
          <description>Graft loss is determined via biopsy.</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="14"/>
                <count group_id="O2" value="15"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Graft Loss at 3 months</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Graft loss at 12 months</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Subjects Deceased at at 3 Months and 12 Months Post-Transplant</title>
        <description>Subject survival status is continually monitored via routine follow-up visits.</description>
        <time_frame>Through 12 months post transplant</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Group 1: Control Arm: Standard of Care (SOC) Tacrolimus</title>
            <description>Tacrolimus: immunosuppressive agent Tacrolimus 1-2 mg 2x daily (BID), per SOC. The dose will be modified to achieve 12 hours trough concentrations of 8-12 ng/ml</description>
          </group>
          <group group_id="O2">
            <title>Group 2: Interventional Arm: Study Related Drug: LCP-Tacrolimus/Envarsus® XR (LCP-Tacro/Envarsus XR)</title>
            <description>Tacrolimus Extended Release Oral Tablet [Envarsus]: immunosuppressive agent extended-release One 5mg extended-release tablet taken once daily (QD) to achieve a 24-hour trough concentrations of 8-12 ng/ml</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Subjects Deceased at at 3 Months and 12 Months Post-Transplant</title>
          <description>Subject survival status is continually monitored via routine follow-up visits.</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="14"/>
                <count group_id="O2" value="15"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Subject Death at 3 months</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Subject Death at 12 months</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Participants With Change in Allograft Immunohistopathology Profile</title>
        <description>Tissue analysis via immunohistopathological staining and microscopic examination Moderate acute tubular necrosis =&gt; presence of focal coagulative necrosis or infarction on histopathologic examination&#xD;
Arteriolar hyalinosis grade 2 means: Replacement of degenerated smooth muscle cells by hyaline deposits in more than 1 arteriole, without circumferential involvement&#xD;
Global glomerulosclerosis &gt;grade 2, means glomerulosclerosis affecting more than 50% of glomeruli in the biopsy sample&#xD;
IFTA : Interstitial fibrosis and tubular atrophy: Inflammation in 26% to 50% of scarred cortical parenchyma</description>
        <time_frame>Measured at 3 months post transplant, 12 months post transplant</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Group 1: Control Arm: Standard of Care (SOC) Tacrolimus</title>
            <description>1-2 mg 2x daily (BID), per SOC. The dose will be modified to achieve 12 hours trough concentrations of 8-12 ng/ml</description>
          </group>
          <group group_id="O2">
            <title>Group 2: Interventional Arm: Study Related Drug: LCP-Tacrolimus/Envarsus XR (LCP-Tacro/Envarsus XR)</title>
            <description>One 5mg extended-release tablet taken once daily (QD) to achieve a 24-hour trough concentrations of 8-12 ng/ml</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With Change in Allograft Immunohistopathology Profile</title>
          <description>Tissue analysis via immunohistopathological staining and microscopic examination Moderate acute tubular necrosis =&gt; presence of focal coagulative necrosis or infarction on histopathologic examination&#xD;
Arteriolar hyalinosis grade 2 means: Replacement of degenerated smooth muscle cells by hyaline deposits in more than 1 arteriole, without circumferential involvement&#xD;
Global glomerulosclerosis &gt;grade 2, means glomerulosclerosis affecting more than 50% of glomeruli in the biopsy sample&#xD;
IFTA : Interstitial fibrosis and tubular atrophy: Inflammation in 26% to 50% of scarred cortical parenchyma</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="14"/>
                <count group_id="O2" value="15"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Acute tubular necrosis &gt; moderate &gt;=2</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2"/>
                    <measurement group_id="O2" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Arteriolar Hyalinosis &gt;= grade 2</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2"/>
                    <measurement group_id="O2" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>isometric vacuolization of tubules</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Arteriolar myocyte vacuolization</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Thrombotic microangiopathy</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Global glomerulosclerosis &gt;grade 2</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>IFTA &gt; grade 2</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Adverse events were reviewed at 1 year after tranplant</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Standard of Care Tacrolimus Twice-daily</title>
          <description>Tacrolimus: immunosuppressive agent tacrolimus, given twice-daily</description>
        </group>
        <group group_id="E2">
          <title>Extended-release Tacrolimus Once-daily</title>
          <description>Tacrolimus Extended Release Oral Tablet [Envarsus]: immunosuppressive agent extended-release tacrolimus, given once daily</description>
        </group>
      </group_list>
      <serious_events>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="14"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="14"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="15"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Hospitalizations</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="14"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="15"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="7" subjects_at_risk="14"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="15"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Immune system disorders</title>
            <event_list>
              <event>
                <sub_title>Infections</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="14"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Malignancy</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="14"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Leukopenia</sub_title>
                <counts group_id="E1" events="4" subjects_affected="4" subjects_at_risk="14"/>
                <counts group_id="E2" events="4" subjects_affected="4" subjects_at_risk="15"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>BK Viremia</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="14"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="15"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <limitations_and_caveats>The study ran out of funding and as a result the outcome (Change in Subpopulations of T Cells) has not been analyzed. The PI will look for additional funding to complete the analysis</limitations_and_caveats>
    <point_of_contact>
      <name_or_title>Lorenzo Gallon</name_or_title>
      <organization>Northwestern University</organization>
      <phone>312 695 4457</phone>
      <email>l-gallon@northwestern.edu</email>
    </point_of_contact>
  </clinical_results>
</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/NCT03289650
org study id: STU00205327
nct id: NCT03289650
lead sponsor: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
is us export: Yes
The overall aim of the study is to prospectively investigate the impact of two maintenance
      calcineurin inhibitor immunosuppressive regimens: once-daily extended release tacrolimus and
      twice-daily tacrolimus on subpopulations of T and B cells and alloreactive T cells as well as
      on renal allograft function.
Kidney transplantation is the treatment of choice for most patients with end-stage renal
      disease. Lifelong immunosuppressive therapies are required to prevent organ rejection.
      However, long term exposure to immunosuppressive therapy after kidney transplantation can
      place patients at risk for multiple adverse events. The optimal immunosuppressive therapy is
      not well established. Tacrolimus, a calcineurin inhibitor (CNI) is highly effective in
      preventing acute rejection after organ transplantation (2). It is used as part of the
      immunosuppression regimen for the majority of kidney and liver transplant recipients (3).
      However, treatment with current formulation of Tacrolimus generates high peaks and low
      troughs in drug concentrations in the blood. It is known that high exposure to CNI is
      associated with renal toxicities and adverse events (4). New once-daily dosage formulations
      are now developed with the hope of minimizing side effects while maintaining excellent
      outcomes (5-8).

      LCP-Tacro (Envarsus® XR, Veloxis Pharmaceuticals), a new once-daily formulation of
      tacrolimus, was approved by the FDA in 2015 for conversion from twice-daily tacrolimus in
      kidney transplant recipients. It is a prolonged-release tacrolimus formulation, utilizing a
      MeltDose drug delivery technology designed to improve the bioavailability of drugs with low
      water solubility (1). Recent clinical data demonstrated that once-daily LCP-Tacro has
      improved pharmacokinetic bioavailability, rapid achievement of therapeutic trough levels,
      less fluctuation and swing in whole blood concentration, non-inferior efficacy and similar
      safety, with lower tacrolimus dose than other tacrolimus formulations.

      The target population is adult recipients of immediately functioning living and deceased
      donor renal allografts. Immediate function will be defined as the absence of the need for
      hemodialysis in the first week following renal transplantation.

      Prospective randomized single center open label study of 2 groups of kidney transplant
      patients

        -  Group 1 : standard of care (SOC) control group will receive tacrolimus twice-daily
           (n=25)

        -  Group 2 : LCP-Tacro (Envarsus® XR) group will receive LCPT tablets once daily (n=25)
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Change in Kidney Transplant Function From 2 Weeks Post Transplant Through 12 Months Post Transplant
time frame: 2 weeks post transplant through 12 months post transplant
description: change in the mean eGFR from the baseline (2 weeks post transplant), 3 months (post transplant) , and 12 months (post transplant).
measure: Change in Subpopulations of T Cells From 2 Weeks Post Transplant Through 12 Months Post Transplant
time frame: Measured at 2 weeks post transplant, 3 months post transplant, 12 months post transplant
description: Blood, urine and kidney tissue analysis via serial flow cytometric immunophenotyping (includes regulatory T and B cell populations as well as immune functions).
measure: Number of Participants With Acute Rejection at 3 Months and 12 Months Post-Transplant
time frame: Measured at 3 months post transplant, 12 months post transplant
description: Acute rejection of kidney transplant is determined via biopsy.
measure: Number of Participants With Graft Loss at 3 Months and 12 Months Post-Transplant
time frame: Measured at 3 months post transplant, 12 months post transplant
description: Graft loss is determined via biopsy.
measure: Number of Subjects Deceased at at 3 Months and 12 Months Post-Transplant
time frame: Through 12 months post transplant
description: Subject survival status is continually monitored via routine follow-up visits.
measure: Number of Participants With Change in Allograft Immunohistopathology Profile
time frame: Measured at 3 months post transplant, 12 months post transplant
description: Tissue analysis via immunohistopathological staining and microscopic examination Moderate acute tubular necrosis => presence of focal coagulative necrosis or infarction on histopathologic examination
Arteriolar hyalinosis grade 2 means: Replacement of degenerated smooth muscle cells by hyaline deposits in more than 1 arteriole, without circumferential involvement
Global glomerulosclerosis >grade 2, means glomerulosclerosis affecting more than 50% of glomeruli in the biopsy sample
IFTA : Interstitial fibrosis and tubular atrophy: Inflammation in 26% to 50% of scarred cortical parenchyma
arm group label: Standard of care tacrolimus twice-daily
arm group type: Active Comparator
arm group label: Extended-release tacrolimus once-daily
arm group type: Active Comparator
intervention type: Drug
intervention name: Tacrolimus
description: immunosuppressive agent tacrolimus, given twice-daily
arm group label: Standard of care tacrolimus twice-daily
intervention type: Drug
intervention name: Tacrolimus Extended Release Oral Tablet [Envarsus]
description: immunosuppressive agent extended-release tacrolimus, given once daily
arm group label: Extended-release tacrolimus once-daily
other name: LCP-tacro
criteria: 
gender: All
minimum age: 18 Years
maximum age: 65 Years
healthy volunteers: No
facility: 
country: United States
responsible party type: Sponsor-Investigator
investigator affiliation: Northwestern University
investigator full name: Lorenzo Gallon
investigator title: Professor of Medicine
mesh term: Kidney Failure, Chronic
mesh term: Tacrolimus
provided document: 
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
limitations and caveats: The study ran out of funding and as a result the outcome (Change in Subpopulations of T Cells) has not been analyzed. The PI will look for additional funding to complete the analysis
point of contact: 