<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/NCT01680861</url>
  </required_header>
  <id_info>
    <org_study_id>20110126</org_study_id>
    <nct_id>NCT01680861</nct_id>
  </id_info>
  <brief_title>Tacrolimus/Everolimus Versus Tacrolimus/Enteric-Coated Mycophenolate Sodium</brief_title>
  <official_title>Randomized, Open-Label Trial of Tacrolimus/Everolimus vs. Tacrolimus/Enteric-Coated Mycophenolate Sodium to Prevent Biopsy-Proven Acute Rejection and Chronic Allograft Injury in Adult, Primary Kidney Transplantation</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Gaetano Ciancio</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of Miami</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      A recent therapeutic strategy following renal transplantation includes simultaneous use of&#xD;
      reduced calcineurin inhibitor (CNI) dosing and maximized use of a non-nephrotoxic,&#xD;
      antiproliferative drug (inosine monophosphate dehydrogenase (IMPDH) or TOR inhibitor), with&#xD;
      the goals of reducing/avoiding CNI nephrotoxicity, the incidence of acute rejection, and&#xD;
      chronic allograft injury (CAI) (i.e., interstitial fibrosis/tubular atrophy), leading to more&#xD;
      favorable longer-term patient and graft survival.1-7 Early corticosteroid withdrawal has also&#xD;
      been used in the attempt to avoid well-known side effects while maintaining favorable patient&#xD;
      and graft survival.8-10 While the investigators center and numerous other centers have also&#xD;
      included single agent, antibody induction utilizing the lymphodepleting polyclonal antibody&#xD;
      rabbit anti-human thymocyte globulin (ATG), nondepleting human anti-interleukin-2 receptor&#xD;
      (CD25) monoclonal antibody daclizumab (Dac) or basiliximab, or lymphodepleting humanized&#xD;
      anti-CD52 monoclonal antibody alemtuzumab,11-17 evidence now suggests that an even more&#xD;
      effective induction strategy may include the combined use of more than one induction agent&#xD;
      (each with fewer doses than if used alone), with the goal of bringing the kidney transplant&#xD;
      recipient even closer (through more effectively timed lymphodepletion) to an optimally&#xD;
      immunosuppressed state, allowing further reduction in long-term maintenance drug dosing.18-25&#xD;
      The investigators have now successfully used dual ATG/Dac induction therapy in both&#xD;
      kidney-alone23-24 and simultaneous kidney-pancreas (SPK) transplantation,18-20 and a recent&#xD;
      report from the investigators center of kidney-alone and SPK recipients shows that the&#xD;
      addition of anti-CD25 to ATG for induction therapy more effectively delays the return of&#xD;
      peripheral blood CD25+ cells.25 In the kidney-alone recipient study 3 doses of ATG were&#xD;
      combined with 2 doses of Dac for induction,23-24 vs. the investigators previous studies&#xD;
      utilizing single agent induction with 7 doses of ATG or 5 doses of Dac.4,16,17 Successful&#xD;
      combination of ATG/basiliximab as dual induction in kidney transplantation has also been&#xD;
      reported elsewhere,21-22 along with equivalency in clinical outcomes using daclizumab vs.&#xD;
      basiliximab.13&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      A. Primary Objectives:&#xD;
&#xD;
        1. The percentage of patients who develop chronic allograft injury (CAI) progression during&#xD;
           the first 12 months post-transplant protocol biopsy (i.e., higher grade of IF/TA at&#xD;
           either the 6 or 12 month protocol biopsy in comparison with the baseline biopsy).&#xD;
&#xD;
        2. The incidence rate of biopsy-proven acute rejection (BPAR) during the first 12 months&#xD;
           post-transplant.&#xD;
&#xD;
      B. Secondary Objectives:&#xD;
&#xD;
        1. Adverse events including graft loss (death-censored and death-uncensored), and death at&#xD;
           12 months post-transplant.&#xD;
&#xD;
        2. Incidence rate and severity (severity of CAI at 12 months as well), based upon careful&#xD;
           review of all clinically indicated and protocol biopsies.&#xD;
&#xD;
        3. Renal function as determined by serum creatinine and estimated glomerular filtration&#xD;
           rate (eGFR) (calculated using the abbreviated MDRD formula) at 12, months&#xD;
           post-transplant. Use of multivariable analysis to compare renal function as well as BPAR&#xD;
           and CAI progression will also be performed (particularly, after adjusting for the&#xD;
           significant effects of donor age, recipient age, race/ethnicity, and any other&#xD;
           predictors).&#xD;
&#xD;
      5. Adverse events including withholding (for ≥ 28 days) or discontinuance of study&#xD;
      medications (and reasons why), new onset diabetes mellitus after transplantation (NODAT),&#xD;
      infections requiring hospitalization, and requirement of anti-lipid medication at 12 months&#xD;
      post-transplant.&#xD;
&#xD;
      6. Avoidance of the requirement for maintenance corticosteroid therapy after renal&#xD;
      transplantation.&#xD;
&#xD;
      7. Allowance of reduced maintenance tacrolimus dosing (rTd).&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>November 2012</start_date>
  <completion_date type="Actual">December 2014</completion_date>
  <primary_completion_date type="Actual">December 2014</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>BPAR (Biopsy-proven Acute Rejection) Incidence During the First 12 Months Post-transplant</measure>
    <time_frame>1 year</time_frame>
    <description>BPAR (biopsy-proven acute rejection) incidence during the first 12 months post-transplant. Grading is determined using standard Banff criteria.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Incidence of Chronic Allograft Nephropathy (CAI) at 12 Months Post-transplant</measure>
    <time_frame>1 year</time_frame>
    <description>Incidence of (biopsy-proven) chronic allograft nephropathy (CAI) [interstitial fibrosis and tubular atrophy, using standard Banff criteria] at 12 months post-transplant.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Graft Loss (Return to Permanent Dialysis or Death)</measure>
    <time_frame>during the first 12 months post-transplant</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>eGFR (Calculated Glomerular Filtration Rate), i.e., Renal Function, at 1 Month Post-transplant.</measure>
    <time_frame>at 1 month post-transplant</time_frame>
    <description>using the abbreviated MDRD formula.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>eGFR (Renal Function) at Month 3 Post-transplant</measure>
    <time_frame>at 3 months post-transplant</time_frame>
    <description>Renal function as determined by the estimated glomerular filtration rate (eGFR) at 3 months post-transplant, using the abbreviated MDRD formula.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>eGFR (Renal Function) at 6 Months Post-transplant</measure>
    <time_frame>at 6 months post-transplant</time_frame>
    <description>using the abbreviated MDRD formula.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Discontinuance of Any Study Medication (Tacrolimus, Everolimus, or EC-MPS)</measure>
    <time_frame>during the first 12 months post-transplant</time_frame>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">32</enrollment>
  <condition>Transplant; Failure, Kidney</condition>
  <arm_group>
    <arm_group_label>Tacrolimus and Everolimus</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients in both arms will receive reduced tacrolimus dosing (rTd), 0.1 mg/kg PO divided in two daily doses - beginning when serum Cr decreases to a level of &lt;4 mg/dl (i.e., acceptable renal transplant function) postoperatively. Target tacrolimus trough levels during the first year post-transplant and thereafter will be 5-8 ng/ml.&#xD;
Everolimus initiated within 24 hours post-transplant (i.e., immediately following randomization) at 0.75mg PO BID and will be adjusted in order to achieve target everolimus trough levels of 3-8 ng/ml.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Tacrolimus and Enteric-Coated Mycophenolate Sodium (EC-MPS)</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Patients in both arms will receive reduced tacrolimus dosing (rTd), 0.1 mg/kg PO divided in two daily doses - beginning when serum Cr decreases to a level of &lt;4 mg/dl (i.e., acceptable renal transplant function) postoperatively. Target tacrolimus trough levels during the first year post-transplant and thereafter will be 5-8 ng/ml.&#xD;
EC-MPS will be initiated at 720 mg PO BID starting on the first post-operative day.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Tacrolimus</intervention_name>
    <description>Tacrolimus dosing (rTd) is planned, 0.1 mg/kg PO BID - beginning when serum Cr decreases to a level of &lt;4 mg/dl (i.e., acceptable renal transplant function) postoperatively. Target tacrolimus trough levels during the first year post-transplant and thereafter will be 5-8 ng/ml.</description>
    <arm_group_label>Tacrolimus and Enteric-Coated Mycophenolate Sodium (EC-MPS)</arm_group_label>
    <arm_group_label>Tacrolimus and Everolimus</arm_group_label>
    <other_name>Prograf (brand name)</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Everolimus</intervention_name>
    <description>Everolimus initiated at 0.75 PO BID and will be adjusted in order to achieve target everolimus trough levels of 3-8 ng/ml.</description>
    <arm_group_label>Tacrolimus and Everolimus</arm_group_label>
    <other_name>Zortress (brand name)</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Enteric Coated Mycophenolate Sodium (EC-MPS)</intervention_name>
    <description>EC-MPS 720 mg PO BID - beginning on 1st postoperative day.</description>
    <arm_group_label>Tacrolimus and Enteric-Coated Mycophenolate Sodium (EC-MPS)</arm_group_label>
    <other_name>Myfortic (brand name)</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Corticosteroids</intervention_name>
    <description>Corticosteroids will be given as per our center protocol, i.e., a bolus of 500 mg of Methylprednisolone intravenously at surgery and daily x2, followed by 1.0 mg/kg, then 0.5 mg/kg orally until weaned off completely by 7-10 days postoperatively - the plan is for corticosteroids to be discontinued by 7-10 days postoperatively in both groups.</description>
    <arm_group_label>Tacrolimus and Enteric-Coated Mycophenolate Sodium (EC-MPS)</arm_group_label>
    <arm_group_label>Tacrolimus and Everolimus</arm_group_label>
    <other_name>Methylprednisolone</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Weight &gt; 40 kg.&#xD;
&#xD;
          -  Deceased donor (SCD) or LD.&#xD;
&#xD;
          -  Donor-recipient 1 haplotype matched pairs with a minimum matching of 1 HLA DR antigen.&#xD;
&#xD;
          -  Negative standard cross match for T cells.&#xD;
&#xD;
          -  Pretransplant panel reactive antibodies of &lt; 30%.&#xD;
&#xD;
          -  Graft required to be functional, producing at least 100ml of urine within 24hr after&#xD;
             transplantation.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Previously received or is receiving an organ transplant other than a kidney.&#xD;
&#xD;
          -  Donor organ with a cold ischemic time &gt; 48 hours.&#xD;
&#xD;
          -  ABO incompatible donor kidney.&#xD;
&#xD;
          -  Recipients of T cell, or B cell crossmatch positive transplant.&#xD;
&#xD;
          -  Panel reactive antibody (PRA) &gt;30%&#xD;
&#xD;
          -  HIV or Hepatitis C virus, or Hepatitis B virus antigenemia.&#xD;
&#xD;
          -  Current malignancy or a history of malignancy&#xD;
&#xD;
          -  Liver disease&#xD;
&#xD;
          -  Uncontrolled concomitant infections and/or severe diarrhea, vomiting, active upper&#xD;
             gastro-intestinal tract malabsorption or an active peptic ulcer&#xD;
&#xD;
          -  Use of warfarin, fluvastatin, or herbal supplements during the study.&#xD;
&#xD;
          -  Use of astemizole, pimozide, cisapride, terfenadine, or ketoconazole.&#xD;
&#xD;
          -  Hypersensitivity to thymoglobulin, IL-2 receptor inhibitor monoclonal antibodies,&#xD;
             tacrolimus, everolimus, MPA, or corticosteroids.&#xD;
&#xD;
          -  Pregnant or lactating.&#xD;
&#xD;
          -  Abnormal screening/baseline labs WBC, platelet count, triglycerides, and cholesterol&#xD;
             Double kidneys,ECD, pediatric en-block, and donation after cardiac death (DCD)&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>75 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Gaetano Ciancio, M.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Miami</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of Miami</name>
      <address>
        <city>Miami</city>
        <state>Florida</state>
        <zip>33136</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>October 2016</verification_date>
  <study_first_submitted>March 6, 2012</study_first_submitted>
  <study_first_submitted_qc>September 4, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 7, 2012</study_first_posted>
  <results_first_submitted>June 20, 2016</results_first_submitted>
  <results_first_submitted_qc>October 21, 2016</results_first_submitted_qc>
  <results_first_posted type="Estimate">December 15, 2016</results_first_posted>
  <last_update_submitted>October 21, 2016</last_update_submitted>
  <last_update_submitted_qc>October 21, 2016</last_update_submitted_qc>
  <last_update_posted type="Estimate">December 15, 2016</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>University of Miami</investigator_affiliation>
    <investigator_full_name>Gaetano Ciancio</investigator_full_name>
    <investigator_title>Professor of Surgery</investigator_title>
  </responsible_party>
  <keyword>Kidney transplant patients</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Renal Insufficiency</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Mycophenolic Acid</mesh_term>
    <mesh_term>Methylprednisolone</mesh_term>
    <mesh_term>Everolimus</mesh_term>
    <mesh_term>Tacrolimus</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Tacrolimus/Everolimus</title>
          <description>our experimental maintenance arm: Target 12-hr Tacrolimus trough level: 5-8 ng/mL Target 12-hr Everolimus trough level: 3-8 ng/mL.</description>
        </group>
        <group group_id="P2">
          <title>Tacrolimus/EC-MPS</title>
          <description>our standard maintenance arm: Target 12-hr Tacrolimus trough level: 5-8 ng/mL Target EC-MPS dose: 720 mg PO BID (as tolerated).</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Early Post-transplant Period</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="16">One patient didn't produce sufficient urine during first 24hr post-transplant (ineligible).</participants>
                <participants group_id="P2" count="16">One patient developed immediate DGF (delayed graft function) and was therefore ineligible.</participants>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="15"/>
                <participants group_id="P2" count="15"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="1"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Protocol Violation</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
        <period>
          <title>First 12 Months Post-transplant</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="15"/>
                <participants group_id="P2" count="15"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="15"/>
                <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>Tacrolimus/Everolimus</title>
          <description>our experimental maintenance arm.</description>
        </group>
        <group group_id="B2">
          <title>Tacrolimus/EC-MPS</title>
          <description>our standard maintenance arm.</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="15"/>
            <count group_id="B2" value="15"/>
            <count group_id="B3" value="30"/>
          </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="49.9" spread="10.5"/>
                    <measurement group_id="B2" value="48.5" spread="11.2"/>
                    <measurement group_id="B3" value="49.2" spread="10.8"/>
                  </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="4"/>
                    <measurement group_id="B3" value="7"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="12"/>
                    <measurement group_id="B2" value="11"/>
                    <measurement group_id="B3" value="23"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race/Ethnicity, Customized</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>African-American</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="5"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Hispanic</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="7"/>
                    <measurement group_id="B2" value="10"/>
                    <measurement group_id="B3" value="17"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>White/Asian</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                    <measurement group_id="B2" value="3"/>
                    <measurement group_id="B3" value="6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="15"/>
                    <measurement group_id="B2" value="15"/>
                    <measurement group_id="B3" value="30"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>BPAR (Biopsy-proven Acute Rejection) Incidence During the First 12 Months Post-transplant</title>
        <description>BPAR (biopsy-proven acute rejection) incidence during the first 12 months post-transplant. Grading is determined using standard Banff criteria.</description>
        <time_frame>1 year</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Tacrolimus/Everolimus</title>
            <description>our experimental maintenance arm.</description>
          </group>
          <group group_id="O2">
            <title>Tacrolimus/EC-MPS</title>
            <description>our standard maintenance arm.</description>
          </group>
        </group_list>
        <measure>
          <title>BPAR (Biopsy-proven Acute Rejection) Incidence During the First 12 Months Post-transplant</title>
          <description>BPAR (biopsy-proven acute rejection) incidence during the first 12 months post-transplant. Grading is determined using standard Banff criteria.</description>
          <units>participants</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="15"/>
                <count group_id="O2" value="15"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority or Other</non_inferiority_type>
            <p_value>0.32</p_value>
            <method>Log Rank</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Incidence of Chronic Allograft Nephropathy (CAI) at 12 Months Post-transplant</title>
        <description>Incidence of (biopsy-proven) chronic allograft nephropathy (CAI) [interstitial fibrosis and tubular atrophy, using standard Banff criteria] at 12 months post-transplant.</description>
        <time_frame>1 year</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Tacrolimus/Everolimus</title>
            <description>our experimental maintenance arm.</description>
          </group>
          <group group_id="O2">
            <title>Tacrolimus/EC-MPS</title>
            <description>our standard maintenance arm.</description>
          </group>
        </group_list>
        <measure>
          <title>Incidence of Chronic Allograft Nephropathy (CAI) at 12 Months Post-transplant</title>
          <description>Incidence of (biopsy-proven) chronic allograft nephropathy (CAI) [interstitial fibrosis and tubular atrophy, using standard Banff criteria] at 12 months post-transplant.</description>
          <units>participants</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="15"/>
                <count group_id="O2" value="15"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3"/>
                    <measurement group_id="O2" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority or Other</non_inferiority_type>
            <p_value>0.99</p_value>
            <method>Log Rank</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Graft Loss (Return to Permanent Dialysis or Death)</title>
        <time_frame>during the first 12 months post-transplant</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Tacrolimus/Everolimus</title>
            <description>our experimental maintenance arm</description>
          </group>
          <group group_id="O2">
            <title>Tacrolimus/EC-MPS</title>
            <description>our standard maintenance arm</description>
          </group>
        </group_list>
        <measure>
          <title>Graft Loss (Return to Permanent Dialysis or Death)</title>
          <units>participants</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="15"/>
                <count group_id="O2" value="15"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <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>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority or Other</non_inferiority_type>
            <p_value>1.0</p_value>
            <method>Log Rank</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>eGFR (Calculated Glomerular Filtration Rate), i.e., Renal Function, at 1 Month Post-transplant.</title>
        <description>using the abbreviated MDRD formula.</description>
        <time_frame>at 1 month post-transplant</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Tacrolimus/Everolimus</title>
            <description>our experimental maintenance arm</description>
          </group>
          <group group_id="O2">
            <title>Tacrolimus/EC-MPS</title>
            <description>our standard maintenance arm</description>
          </group>
        </group_list>
        <measure>
          <title>eGFR (Calculated Glomerular Filtration Rate), i.e., Renal Function, at 1 Month Post-transplant.</title>
          <description>using the abbreviated MDRD formula.</description>
          <units>ml/min per 1.73 m2</units>
          <param>Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="15"/>
                <count group_id="O2" value="15"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="82.1" spread="8.2"/>
                    <measurement group_id="O2" value="62.1" spread="6.2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority or Other</non_inferiority_type>
            <p_value>0.06</p_value>
            <method>t-test, 2 sided</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>eGFR (Renal Function) at Month 3 Post-transplant</title>
        <description>Renal function as determined by the estimated glomerular filtration rate (eGFR) at 3 months post-transplant, using the abbreviated MDRD formula.</description>
        <time_frame>at 3 months post-transplant</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Tacrolimus/Everolimus</title>
            <description>our experimental maintenance arm</description>
          </group>
          <group group_id="O2">
            <title>Tacrolimus/EC-MPS</title>
            <description>our standard maintenance arm</description>
          </group>
        </group_list>
        <measure>
          <title>eGFR (Renal Function) at Month 3 Post-transplant</title>
          <description>Renal function as determined by the estimated glomerular filtration rate (eGFR) at 3 months post-transplant, using the abbreviated MDRD formula.</description>
          <units>ml/min per 1.73 m^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="15"/>
                <count group_id="O2" value="15"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="75.7" spread="6.0"/>
                    <measurement group_id="O2" value="65.6" spread="4.2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority or Other</non_inferiority_type>
            <p_value>0.18</p_value>
            <method>t-test, 2 sided</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>eGFR (Renal Function) at 6 Months Post-transplant</title>
        <description>using the abbreviated MDRD formula.</description>
        <time_frame>at 6 months post-transplant</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Tacrolimus/Everolimus</title>
            <description>our experimental maintenance arm</description>
          </group>
          <group group_id="O2">
            <title>Tacrolimus/EC-MPS</title>
            <description>our standard maintenance arm</description>
          </group>
        </group_list>
        <measure>
          <title>eGFR (Renal Function) at 6 Months Post-transplant</title>
          <description>using the abbreviated MDRD formula.</description>
          <units>ml/min per 1.73 m2</units>
          <param>Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="13"/>
                <count group_id="O2" value="14"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="66.7" spread="5.0"/>
                    <measurement group_id="O2" value="63.7" spread="3.9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority or Other</non_inferiority_type>
            <p_value>0.65</p_value>
            <method>t-test, 2 sided</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Discontinuance of Any Study Medication (Tacrolimus, Everolimus, or EC-MPS)</title>
        <time_frame>during the first 12 months post-transplant</time_frame>
        <population>Note: one patient in the Tacrolimus/EC-MPS arm discontinued EC-MPS at 12 months post-transplant following a colon cancer diagnosis and the necessity to receive chemotherapy.</population>
        <group_list>
          <group group_id="O1">
            <title>Tacrolimus/Everolimus</title>
            <description>our experimental maintenance arm</description>
          </group>
          <group group_id="O2">
            <title>Tacrolimus/EC-MPS</title>
            <description>our standard maintenance arm</description>
          </group>
        </group_list>
        <measure>
          <title>Discontinuance of Any Study Medication (Tacrolimus, Everolimus, or EC-MPS)</title>
          <population>Note: one patient in the Tacrolimus/EC-MPS arm discontinued EC-MPS at 12 months post-transplant following a colon cancer diagnosis and the necessity to receive chemotherapy.</population>
          <units>participants</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="15"/>
                <count group_id="O2" value="15"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>during the first 12 months post-transplant,</time_frame>
      <desc>Here, we are reporting the numbers of patients who 1) developed an infection requiring hospitalization (or had an opportunistic viral infection not requiring hospitalization) and 2) developed NODAT (new onset diabetes after transplant) (among patients not having pretransplant diabetes mellitus) during the first 12 months post-transplant. Please note that adverse events specified to be studied as secondary outcomes were the only AEs collected in our randomized trial.</desc>
      <group_list>
        <group group_id="E1">
          <title>Tacrolimus/Everolimus</title>
          <description>our experimental maintenance arm</description>
        </group>
        <group group_id="E2">
          <title>Tacrolimus/EC-MPS</title>
          <description>our standard maintenance arm</description>
        </group>
      </group_list>
      <serious_events>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="15"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="15"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Endocrine disorders</title>
            <event_list>
              <event>
                <sub_title>NODAT</sub_title>
                <description>Occurrence of New Onset Diabetes after Transplant among patients not having pretransplant diabetes.</description>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="15"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="15"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Urinary Tract Infection Requiring Hospitalization</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="15"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Ear Infection Requiring Hospitalization</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Pneumonia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Sepsis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="15"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>CMV Viremia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Polyoma Viral Infection (Viremia)</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="15"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Herpes Zoster Infection</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="15"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="15"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>1</frequency_threshold>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E2" 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>
    <point_of_contact>
      <name_or_title>Jeffrey Gaynor, Ph.D. biostatistician</name_or_title>
      <organization>Miami Transplant Institute</organization>
      <email>jgaynor@med.miami.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/NCT01680861
org study id: 20110126
nct id: NCT01680861
lead sponsor: 
has dmc: Yes
A recent therapeutic strategy following renal transplantation includes simultaneous use of
      reduced calcineurin inhibitor (CNI) dosing and maximized use of a non-nephrotoxic,
      antiproliferative drug (inosine monophosphate dehydrogenase (IMPDH) or TOR inhibitor), with
      the goals of reducing/avoiding CNI nephrotoxicity, the incidence of acute rejection, and
      chronic allograft injury (CAI) (i.e., interstitial fibrosis/tubular atrophy), leading to more
      favorable longer-term patient and graft survival.1-7 Early corticosteroid withdrawal has also
      been used in the attempt to avoid well-known side effects while maintaining favorable patient
      and graft survival.8-10 While the investigators center and numerous other centers have also
      included single agent, antibody induction utilizing the lymphodepleting polyclonal antibody
      rabbit anti-human thymocyte globulin (ATG), nondepleting human anti-interleukin-2 receptor
      (CD25) monoclonal antibody daclizumab (Dac) or basiliximab, or lymphodepleting humanized
      anti-CD52 monoclonal antibody alemtuzumab,11-17 evidence now suggests that an even more
      effective induction strategy may include the combined use of more than one induction agent
      (each with fewer doses than if used alone), with the goal of bringing the kidney transplant
      recipient even closer (through more effectively timed lymphodepletion) to an optimally
      immunosuppressed state, allowing further reduction in long-term maintenance drug dosing.18-25
      The investigators have now successfully used dual ATG/Dac induction therapy in both
      kidney-alone23-24 and simultaneous kidney-pancreas (SPK) transplantation,18-20 and a recent
      report from the investigators center of kidney-alone and SPK recipients shows that the
      addition of anti-CD25 to ATG for induction therapy more effectively delays the return of
      peripheral blood CD25+ cells.25 In the kidney-alone recipient study 3 doses of ATG were
      combined with 2 doses of Dac for induction,23-24 vs. the investigators previous studies
      utilizing single agent induction with 7 doses of ATG or 5 doses of Dac.4,16,17 Successful
      combination of ATG/basiliximab as dual induction in kidney transplantation has also been
      reported elsewhere,21-22 along with equivalency in clinical outcomes using daclizumab vs.
      basiliximab.13
A. Primary Objectives:

        1. The percentage of patients who develop chronic allograft injury (CAI) progression during
           the first 12 months post-transplant protocol biopsy (i.e., higher grade of IF/TA at
           either the 6 or 12 month protocol biopsy in comparison with the baseline biopsy).

        2. The incidence rate of biopsy-proven acute rejection (BPAR) during the first 12 months
           post-transplant.

      B. Secondary Objectives:

        1. Adverse events including graft loss (death-censored and death-uncensored), and death at
           12 months post-transplant.

        2. Incidence rate and severity (severity of CAI at 12 months as well), based upon careful
           review of all clinically indicated and protocol biopsies.

        3. Renal function as determined by serum creatinine and estimated glomerular filtration
           rate (eGFR) (calculated using the abbreviated MDRD formula) at 12, months
           post-transplant. Use of multivariable analysis to compare renal function as well as BPAR
           and CAI progression will also be performed (particularly, after adjusting for the
           significant effects of donor age, recipient age, race/ethnicity, and any other
           predictors).

      5. Adverse events including withholding (for ≥ 28 days) or discontinuance of study
      medications (and reasons why), new onset diabetes mellitus after transplantation (NODAT),
      infections requiring hospitalization, and requirement of anti-lipid medication at 12 months
      post-transplant.

      6. Avoidance of the requirement for maintenance corticosteroid therapy after renal
      transplantation.

      7. Allowance of reduced maintenance tacrolimus dosing (rTd).
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: BPAR (Biopsy-proven Acute Rejection) Incidence During the First 12 Months Post-transplant
time frame: 1 year
description: BPAR (biopsy-proven acute rejection) incidence during the first 12 months post-transplant. Grading is determined using standard Banff criteria.
measure: Incidence of Chronic Allograft Nephropathy (CAI) at 12 Months Post-transplant
time frame: 1 year
description: Incidence of (biopsy-proven) chronic allograft nephropathy (CAI) [interstitial fibrosis and tubular atrophy, using standard Banff criteria] at 12 months post-transplant.
measure: Graft Loss (Return to Permanent Dialysis or Death)
time frame: during the first 12 months post-transplant
measure: eGFR (Calculated Glomerular Filtration Rate), i.e., Renal Function, at 1 Month Post-transplant.
time frame: at 1 month post-transplant
description: using the abbreviated MDRD formula.
measure: eGFR (Renal Function) at Month 3 Post-transplant
time frame: at 3 months post-transplant
description: Renal function as determined by the estimated glomerular filtration rate (eGFR) at 3 months post-transplant, using the abbreviated MDRD formula.
measure: eGFR (Renal Function) at 6 Months Post-transplant
time frame: at 6 months post-transplant
description: using the abbreviated MDRD formula.
measure: Discontinuance of Any Study Medication (Tacrolimus, Everolimus, or EC-MPS)
time frame: during the first 12 months post-transplant
arm group label: Tacrolimus and Everolimus
arm group type: Experimental
description: Patients in both arms will receive reduced tacrolimus dosing (rTd), 0.1 mg/kg PO divided in two daily doses - beginning when serum Cr decreases to a level of <4 mg/dl (i.e., acceptable renal transplant function) postoperatively. Target tacrolimus trough levels during the first year post-transplant and thereafter will be 5-8 ng/ml.
Everolimus initiated within 24 hours post-transplant (i.e., immediately following randomization) at 0.75mg PO BID and will be adjusted in order to achieve target everolimus trough levels of 3-8 ng/ml.
arm group label: Tacrolimus and Enteric-Coated Mycophenolate Sodium (EC-MPS)
arm group type: Active Comparator
description: Patients in both arms will receive reduced tacrolimus dosing (rTd), 0.1 mg/kg PO divided in two daily doses - beginning when serum Cr decreases to a level of <4 mg/dl (i.e., acceptable renal transplant function) postoperatively. Target tacrolimus trough levels during the first year post-transplant and thereafter will be 5-8 ng/ml.
EC-MPS will be initiated at 720 mg PO BID starting on the first post-operative day.
intervention type: Drug
intervention name: Tacrolimus
description: Tacrolimus dosing (rTd) is planned, 0.1 mg/kg PO BID - beginning when serum Cr decreases to a level of <4 mg/dl (i.e., acceptable renal transplant function) postoperatively. Target tacrolimus trough levels during the first year post-transplant and thereafter will be 5-8 ng/ml.
arm group label: Tacrolimus and Enteric-Coated Mycophenolate Sodium (EC-MPS)
arm group label: Tacrolimus and Everolimus
other name: Prograf (brand name)
intervention type: Drug
intervention name: Everolimus
description: Everolimus initiated at 0.75 PO BID and will be adjusted in order to achieve target everolimus trough levels of 3-8 ng/ml.
arm group label: Tacrolimus and Everolimus
other name: Zortress (brand name)
intervention type: Drug
intervention name: Enteric Coated Mycophenolate Sodium (EC-MPS)
description: EC-MPS 720 mg PO BID - beginning on 1st postoperative day.
arm group label: Tacrolimus and Enteric-Coated Mycophenolate Sodium (EC-MPS)
other name: Myfortic (brand name)
intervention type: Drug
intervention name: Corticosteroids
description: Corticosteroids will be given as per our center protocol, i.e., a bolus of 500 mg of Methylprednisolone intravenously at surgery and daily x2, followed by 1.0 mg/kg, then 0.5 mg/kg orally until weaned off completely by 7-10 days postoperatively - the plan is for corticosteroids to be discontinued by 7-10 days postoperatively in both groups.
arm group label: Tacrolimus and Enteric-Coated Mycophenolate Sodium (EC-MPS)
arm group label: Tacrolimus and Everolimus
other name: Methylprednisolone
criteria: 
gender: All
minimum age: 18 Years
maximum age: 75 Years
healthy volunteers: No
last name: Gaetano Ciancio, M.D.
role: Principal Investigator
affiliation: University of Miami
facility: 
country: United States
responsible party type: Sponsor-Investigator
investigator affiliation: University of Miami
investigator full name: Gaetano Ciancio
investigator title: Professor of Surgery
mesh term: Renal Insufficiency
mesh term: Mycophenolic Acid
mesh term: Methylprednisolone
mesh term: Everolimus
mesh term: Tacrolimus
sharing ipd: No
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 