<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/NCT02213068</url>
  </required_header>
  <id_info>
    <org_study_id>STU00085274</org_study_id>
    <nct_id>NCT02213068</nct_id>
  </id_info>
  <brief_title>Belatacept 3 Month Post Transplant Conversion Study</brief_title>
  <official_title>Randomized Conversion Of Epstein-Barr Virus (EBV)+ Kidney Transplant Recipients Of Living Or Standard Criteria Donors At Three Months Post Transplantation To Belatacept With MPA Or Belatacept With Low-Dose Tacrolimus (50% Of Dose) Compared To Patients Remaining On Center Specific Standard Therapy Of Tacrolimus And MPA</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Lorenzo Gallon</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Bristol-Myers Squibb</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Northwestern University</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      This study is being done to investigate the impact of changing immunosuppressive medications&#xD;
      from tacrolimus (Prograf®) to belatacept (Nulojix®) between three (3) and six (6) months&#xD;
      after kidney transplantation. The immune system is the body's defense against infection and&#xD;
      other disease. After transplantation, the body sees the new organ as &quot;foreign&quot; and tries to&#xD;
      destroy or &quot;reject&quot; it. Immunosuppressive medications help to prevent the immune system from&#xD;
      attacking the transplanted organ. The primary purpose of this research study is to evaluate&#xD;
      the effects of three (3) different immunosuppressive treatments on rejection in&#xD;
      post-transplant kidney recipients. This study will test whether switching from tacrolimus to&#xD;
      belatacept will improve long-term kidney function.&#xD;
&#xD;
      Three of the immunosuppressants used in this study- mycophenolic acid (MPA), mycophenolate&#xD;
      mofetil (MMF) and tacrolimus- are medications approved by the United States Food and Drug&#xD;
      Administration (FDA) to be used after transplant. All of these medications have been&#xD;
      routinely used in kidney recipients here at Northwestern University.&#xD;
&#xD;
      Belatacept (the &quot;study drug&quot;) has been approved by the FDA for use at the time of transplant.&#xD;
      However, the use of belatacept in this study is considered investigational as it has not been&#xD;
      FDA approved for use beginning at 3 months after transplant.&#xD;
&#xD;
      This study will involve 51 adult kidney transplant recipients at Northwestern.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Immunosuppressive therapy with the calcineurin inhibitors (CNI) cyclosporine (CsA) and&#xD;
      Tacrolimus (Tac), have radically changed the field of organ transplantation. Ironically,&#xD;
      although extensively and effectively used for kidney transplantation and other solid organ&#xD;
      transplants, CsA and Tac cause important adverse renal side effects: acute and chronic renal&#xD;
      dysfunction, hemolytic-uremic syndrome, hypertension, electrolyte disturbances and tubular&#xD;
      acidosis. Chronic nephrotoxicity from CNI has been implicated as a principal cause of&#xD;
      post-transplant renal dysfunction and it is characterized by an irreversible and progressive&#xD;
      tubular atrophy, interstitial fibrosis, and focal hyalinosis of small renal arteries and&#xD;
      arterioles. Attempts to minimize CNIs and their known toxicities have been marginally&#xD;
      successful due to unacceptable rates of acute rejection and drug toxicity. Patients are&#xD;
      converted to alternative immunosuppressive therapy related to CNI side effects including&#xD;
      neurotoxicity, nephrotoxicity, cardiovascular (HTN, hyperlipidemia), metabolic (NODAT), and&#xD;
      cosmetic side effects. Furthermore, this class of medications is associated also, by blocking&#xD;
      Interleukin 2 (IL2) production, with negative impact on regulatory T cells (Tregs) generation&#xD;
      (an important subpopulation of T helper cells that has been associated with positive&#xD;
      immunomodulation and donor specific hypo-responsiveness).&#xD;
&#xD;
      Until the approval of Belatacept for adult EBV+ renal transplant recipients, there have been&#xD;
      limited alternative immunosuppressive agents available to mitigate drug induced renal&#xD;
      impairment. The phase III drug trials of Belatacept in combination with MMF and&#xD;
      corticosteroids have resulted in significant and sustained improvement in glomerular&#xD;
      filtration rate (GFR) at one year through three years post transplant. The overall safety of&#xD;
      belatacept compared to cyclosporine in de novo transplant recipients was similar. However,&#xD;
      there was an increased rate and severity of early acute rejection and post-transplant&#xD;
      lymphoproliferative disorder (PTLD) of the central nervous system in patients treated with&#xD;
      belatacept.&#xD;
&#xD;
      In a phase II switch study conducted by Bristol Myers Squibb (BMS), the incidence of acute&#xD;
      rejection at 24 months post conversion was similar in patients remaining on CNI (4%) compared&#xD;
      to those converted to belatacept (7%). There were no reported cases of post-transplant&#xD;
      lymphoproliferative disorder (PTLD) in this patient population as of two years post&#xD;
      randomization. However, one belatacept patient from Mexico developed tuberculosis and there&#xD;
      were more non-serious fungal infections in the belatacept treated patients.&#xD;
&#xD;
      Mechanistically, CD28 (Cluster of Differentiation 28) and CTLA-4 (cytotoxic&#xD;
      T-lymphocyte-associated protein 4) are important for the function of regulatory T cells&#xD;
      (Tregs). Belatacept binds to CD80/CD86 (Cluster of Differentiation 80/Cluster of&#xD;
      Differentiation 86) ligands on antigen presenting cells (APCs) preventing CD28 to bind with&#xD;
      these ligands and deliver the costimulatory signal to activate the T Cell. CTLA-4 is a&#xD;
      related receptor expressed on activated T cells that also recognizes CD80/CD86 (Cluster of&#xD;
      Differentiation 80/Cluster of Differentiation 86) and is thus termed co-inhibitory. It&#xD;
      transmits both cell intrinsic and cell extrinsic negative signals that impair activation.&#xD;
&#xD;
      Investigation of the effect of early conversion to Belatacept at month 3 post-transplant on&#xD;
      the subpopulations of T cells and B cells and peripheral blood and allograft biopsy-derived&#xD;
      gene expression subpopulation profiles are planned. Optimization of the Belatacept&#xD;
      immunosuppressive regimen to achieve good long term renal function and improved graft&#xD;
      survival requires understanding the relationships of these cell populations to clinical&#xD;
      outcomes.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>July 2014</start_date>
  <completion_date type="Actual">September 2020</completion_date>
  <primary_completion_date type="Actual">September 2020</primary_completion_date>
  <phase>Phase 4</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change in eGFR (MDRD) at 2 Years Post-transplant Compared to Baseline at Month 3 (Conversion)</measure>
    <time_frame>2 years</time_frame>
    <description>To assess change in renal function by calculated (MDRD) GFR of adult EBV seropositive renal transplant recipients of living or standard criteria donors converted from Tacrolimus to Belatacept or low dose Tacrolimus with Belatacept at three months post-operatively compared to renal transplant recipients randomized to remain on standard dose Tacrolimus and MPA for maintenance therapy at 2 years post-transplantation</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Acute Rejection</measure>
    <time_frame>2 years</time_frame>
    <description>Number of Participants with Acute Rejection (AR). AR is defined as allograft dysfunctions in the setting of recipient immune system engaging an allo-response against the kidney transplant.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Graft Survival</measure>
    <time_frame>2 years</time_frame>
    <description>Number of Subjects with a functioning Graft</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Patient Survival</measure>
    <time_frame>2 years</time_frame>
    <description>Number of Subjects alive at the end of 24 months</description>
  </primary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Actual">28</enrollment>
  <condition>Transplant; Failure, Kidney</condition>
  <condition>EBV</condition>
  <arm_group>
    <arm_group_label>belatacept + MPA</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>subjects continue MPA per SOC, receive bimonthly infusions of belatacept while gradually reducing and then discontinuing tacrolimus:&#xD;
Belatacept: 5 mg/kg IV on Day 1, 15, 29, 43, and 57 post-conversion, then monthly thereafter.&#xD;
Tacrolimus tapered over one month as follows:&#xD;
Days 1- 14: SOC administration Day 15 (~ 2 weeks into study): 40-60% of the previous dose Day 21 (~ 3 weeks into study): 20-30% of the previous dose Day 30 (about 1 month): discontinue&#xD;
MPA: administered according to SOC</description>
  </arm_group>
  <arm_group>
    <arm_group_label>belatacept + Low-Dose Tac</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Belatacept: 5 mg/kg IV on Day 1, 15, 29, 43, and 57 post-conversion, then monthly thereafter.&#xD;
Tacrolimus tapered over one month as follows:&#xD;
Days 1- 14: SOC administration Day 15 (~ 2 weeks into study): 10% of the previous dose Day 21 (~ 3 weeks into study): 20% of the previous dose Day 30 (~ 1 month into study): 20% of the previous dose Target trough level ≤ 5 mg per ml of tacrolimus thereafter.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Tacrolimus + MPA standard treatment regimen</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>Standard of Care treatment regimen:&#xD;
Tacrolimus: administered orally twice daily (BID) The total initial dose of Tacrolimus is given at 0.1 mg/kg in two divided doses to achieve a stable 12-hour trough level of 8 - 12 ng/mL on Days 1 through 30, with dose reduction to achieve a 12-hour trough target of 5 - 10 ng/mL thereafter.&#xD;
MPA: dosed orally per package insert beginning on the day of transplantation. Methylprednisolone as sodium succinate is administered as 500 mg IV, 250 mg IV, 125 mg IV, on Days 0, 1, and 2 without corticosteroid taper.&#xD;
MPA dose adjustments for gastrointestinal side effects or leukopenia will be made at the discretion of the investigator.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>belatacept</intervention_name>
    <description>Please reference Arm description for belatacept + MPA and Arm description for Arm belatacept + Low-Dose Tac for details on this intervention</description>
    <arm_group_label>belatacept + Low-Dose Tac</arm_group_label>
    <arm_group_label>belatacept + MPA</arm_group_label>
    <other_name>Belatacept (Nulojix®)</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Tacrolimus</intervention_name>
    <description>Please see Arm Descriptions for both Standard of Care Arm Tacrolimus + MPA standard treatment regimen and belatacept + Low-Dose Tac for details on this intervention</description>
    <arm_group_label>Tacrolimus + MPA standard treatment regimen</arm_group_label>
    <arm_group_label>belatacept + Low-Dose Tac</arm_group_label>
    <other_name>Tacrolimus (Prograf®)</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>MPA</intervention_name>
    <description>Please see Arm Descriptions for both Standard of Care Arm Tacrolimus + MPA standard treatment regimen and belatacept + MPA for details on this intervention</description>
    <arm_group_label>Tacrolimus + MPA standard treatment regimen</arm_group_label>
    <arm_group_label>belatacept + MPA</arm_group_label>
    <other_name>Mycophenolic Acid (MPA) (Myfortic®)</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria&#xD;
&#xD;
          1. Adult ≥ 18 years of age&#xD;
&#xD;
          2. Male or Female&#xD;
&#xD;
          3. EBV seropositive&#xD;
&#xD;
          4. Recipient of renal transplant from living or deceased donor&#xD;
&#xD;
        Exclusion Criteria&#xD;
&#xD;
          1. Recipients with EBV serostatus negative or unknown&#xD;
&#xD;
          2. History of acute rejection (AR) within 3 months prior to randomization&#xD;
&#xD;
          3. History of positive donor specific antibodies (DSA)&#xD;
&#xD;
          4. History of antibody mediated rejection&#xD;
&#xD;
          5. Positive T-cell lymphocytotoxic cross match&#xD;
&#xD;
          6. Proteinuria &gt;1 g/day or &gt; 0.5 g/day if diabetic&#xD;
&#xD;
          7. Rejection on 3 month post-transplant screening biopsy&#xD;
&#xD;
          8. BK nephropathy at 3 months post-transplant screening biopsy&#xD;
&#xD;
          9. Positive pregnancy test at the time of randomization in female of child bearing&#xD;
             potential&#xD;
&#xD;
         10. History of previous transplant&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Lorenzo Gallon, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Northwestern University</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Northwestern University, The Comprehensive Transplant Center</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>January 2023</verification_date>
  <study_first_submitted>August 7, 2014</study_first_submitted>
  <study_first_submitted_qc>August 8, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 11, 2014</study_first_posted>
  <results_first_submitted>August 11, 2021</results_first_submitted>
  <results_first_submitted_qc>August 11, 2021</results_first_submitted_qc>
  <results_first_posted type="Actual">September 8, 2021</results_first_posted>
  <last_update_submitted>January 11, 2023</last_update_submitted>
  <last_update_submitted_qc>January 11, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">February 8, 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>Associate Professor, Northwestern University, Feinberg School of Medicine</investigator_title>
  </responsible_party>
  <keyword>Kidney</keyword>
  <keyword>Renal</keyword>
  <keyword>Transplant</keyword>
  <keyword>EBV</keyword>
  <keyword>Immunosuppressants</keyword>
  <keyword>Belatacept</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>Abatacept</mesh_term>
    <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>December 20, 2019</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/68/NCT02213068/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>March 3, 2020</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/68/NCT02213068/ICF_001.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Belatacept + MPA</title>
          <description>subjects continue MPA per SOC, receive bimonthly infusions of belatacept while gradually reducing and then discontinuing tacrolimus:&#xD;
Belatacept: 5 mg/kg IV on Day 1, 15, 29, 43, and 57 post-conversion, then monthly thereafter.&#xD;
Tacrolimus tapered over one month as follows:&#xD;
Days 1- 14: SOC administration Day 15 (~ 2 weeks into study): 40-60% of the previous dose Day 21 (~ 3 weeks into study): 20-30% of the previous dose Day 30 (about 1 month): discontinue&#xD;
MPA: administered according to SOC&#xD;
belatacept: Please reference Arm description for belatacept + MPA and Arm description for Arm belatacept + Low-Dose Tac for details on this intervention&#xD;
MPA: Please see Arm Descriptions for both Standard of Care Arm Tacrolimus + MPA standard treatment regimen and belatacept + MPA for details on this intervention</description>
        </group>
        <group group_id="P2">
          <title>Belatacept + Low-Dose Tac</title>
          <description>Belatacept: 5 mg/kg IV on Day 1, 15, 29, 43, and 57 post-conversion, then monthly thereafter.&#xD;
Tacrolimus tapered over one month as follows:&#xD;
Days 1- 14: SOC administration Day 15 (~ 2 weeks into study): 10% of the previous dose Day 21 (~ 3 weeks into study): 20% of the previous dose Day 30 (~ 1 month into study): 20% of the previous dose Target trough level ≤ 5 mg per ml of tacrolimus thereafter.&#xD;
belatacept: Please reference Arm description for belatacept + MPA and Arm description for Arm belatacept + Low-Dose Tac for details on this intervention&#xD;
Tacrolimus: Please see Arm Descriptions for both Standard of Care Arm Tacrolimus + MPA standard treatment regimen and belatacept + Low-Dose Tac for details on this intervention</description>
        </group>
        <group group_id="P3">
          <title>Tacrolimus + MPA Standard Treatment Regimen</title>
          <description>Standard of Care treatment regimen:&#xD;
Tacrolimus: administered orally twice daily (BID) The total initial dose of Tacrolimus is given at 0.1 mg/kg in two divided doses to achieve a stable 12-hour trough level of 8 - 12 ng/mL on Days 1 through 30, with dose reduction to achieve a 12-hour trough target of 5 - 10 ng/mL thereafter.&#xD;
MPA: dosed orally per package insert beginning on the day of transplantation. Methylprednisolone as sodium succinate is administered as 500 mg IV, 250 mg IV, 125 mg IV, on Days 0, 1, and 2 without corticosteroid taper.&#xD;
MPA dose adjustments for gastrointestinal side effects or leukopenia will be made at the discretion of the investigator.&#xD;
Tacrolimus: Please see Arm Descriptions for both Standard of Care Arm Tacrolimus + MPA standard treatment regimen and belatacept + Low-Dose Tac for details on this intervention&#xD;
MPA: Please see Arm Descriptions for both Standard of Care Arm Tacrolimus + MPA standard treatment regimen and belatacept + MPA for details on this intervention</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="9"/>
                <participants group_id="P2" count="8"/>
                <participants group_id="P3" count="10"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="9"/>
                <participants group_id="P2" count="8"/>
                <participants group_id="P3" count="10"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Belatacept + MPA</title>
          <description>subjects continue MPA per SOC, receive bimonthly infusions of belatacept while gradually reducing and then discontinuing tacrolimus:&#xD;
Belatacept: 5 mg/kg IV on Day 1, 15, 29, 43, and 57 post-conversion, then monthly thereafter.&#xD;
Tacrolimus tapered over one month as follows:&#xD;
Days 1- 14: SOC administration Day 15 (~ 2 weeks into study): 40-60% of the previous dose Day 21 (~ 3 weeks into study): 20-30% of the previous dose Day 30 (about 1 month): discontinue&#xD;
MPA: administered according to SOC&#xD;
belatacept: Please reference Arm description for belatacept + MPA and Arm description for Arm belatacept + Low-Dose Tac for details on this intervention&#xD;
MPA: Please see Arm Descriptions for both Standard of Care Arm Tacrolimus + MPA standard treatment regimen and belatacept + MPA for details on this intervention</description>
        </group>
        <group group_id="B2">
          <title>Belatacept + Low-Dose Tac</title>
          <description>Belatacept: 5 mg/kg IV on Day 1, 15, 29, 43, and 57 post-conversion, then monthly thereafter.&#xD;
Tacrolimus tapered over one month as follows:&#xD;
Days 1- 14: SOC administration Day 15 (~ 2 weeks into study): 10% of the previous dose Day 21 (~ 3 weeks into study): 20% of the previous dose Day 30 (~ 1 month into study): 20% of the previous dose Target trough level ≤ 5 mg per ml of tacrolimus thereafter.&#xD;
belatacept: Please reference Arm description for belatacept + MPA and Arm description for Arm belatacept + Low-Dose Tac for details on this intervention&#xD;
Tacrolimus: Please see Arm Descriptions for both Standard of Care Arm Tacrolimus + MPA standard treatment regimen and belatacept + Low-Dose Tac for details on this intervention</description>
        </group>
        <group group_id="B3">
          <title>Tacrolimus + MPA Standard Treatment Regimen</title>
          <description>Standard of Care treatment regimen:&#xD;
Tacrolimus: administered orally twice daily (BID) The total initial dose of Tacrolimus is given at 0.1 mg/kg in two divided doses to achieve a stable 12-hour trough level of 8 - 12 ng/mL on Days 1 through 30, with dose reduction to achieve a 12-hour trough target of 5 - 10 ng/mL thereafter.&#xD;
MPA: dosed orally per package insert beginning on the day of transplantation. Methylprednisolone as sodium succinate is administered as 500 mg IV, 250 mg IV, 125 mg IV, on Days 0, 1, and 2 without corticosteroid taper.&#xD;
MPA dose adjustments for gastrointestinal side effects or leukopenia will be made at the discretion of the investigator.&#xD;
Tacrolimus: Please see Arm Descriptions for both Standard of Care Arm Tacrolimus + MPA standard treatment regimen and belatacept + Low-Dose Tac for details on this intervention&#xD;
MPA: Please see Arm Descriptions for both Standard of Care Arm Tacrolimus + MPA standard treatment regimen and belatacept + MPA for details on this intervention</description>
        </group>
        <group group_id="B4">
          <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="9"/>
            <count group_id="B2" value="8"/>
            <count group_id="B3" value="10"/>
            <count group_id="B4" value="27"/>
          </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="47" spread="16.21"/>
                    <measurement group_id="B2" value="49.75" spread="13.33"/>
                    <measurement group_id="B3" value="49.70" spread="13.53"/>
                    <measurement group_id="B4" value="48.81" spread="13.70"/>
                  </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="2"/>
                    <measurement group_id="B2" value="5"/>
                    <measurement group_id="B3" value="4"/>
                    <measurement group_id="B4" value="11"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="7"/>
                    <measurement group_id="B2" value="3"/>
                    <measurement group_id="B3" value="6"/>
                    <measurement group_id="B4" value="16"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Ethnicity (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="5"/>
                    <measurement group_id="B4" value="9"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="1"/>
                    <measurement group_id="B4" value="3"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="5"/>
                    <measurement group_id="B2" value="6"/>
                    <measurement group_id="B3" value="4"/>
                    <measurement group_id="B4" value="15"/>
                  </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 group_id="B4" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                  </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 group_id="B4" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="3"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="4"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="4"/>
                    <measurement group_id="B2" value="3"/>
                    <measurement group_id="B3" value="4"/>
                    <measurement group_id="B4" value="11"/>
                  </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 group_id="B4" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="4"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="6"/>
                    <measurement group_id="B4" value="12"/>
                  </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="9"/>
                    <measurement group_id="B2" value="8"/>
                    <measurement group_id="B3" value="10"/>
                    <measurement group_id="B4" value="27"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Incidence of Delayed Graft Function</title>
          <description>Delayed graft function is defined as the need for hemodialysis during the first week post-transplant.</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="1"/>
                    <measurement group_id="B4" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Incidence of Diabetes</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="3"/>
                    <measurement group_id="B4" value="5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Incidence of Hypertension</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="8"/>
                    <measurement group_id="B2" value="6"/>
                    <measurement group_id="B3" value="10"/>
                    <measurement group_id="B4" value="24"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Positive Cross-Match</title>
          <description>T and B cell crossmatch is used pre-transplant to measure pre-sensitizing events against the kidney transplant. In other words, a positive cross-match prior to transplantation may indicate worse outcomes for the kidney graft survival.</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Baseline Kidney Function as eGFR</title>
          <description>eGFR = estimated glomerular filtration rate.</description>
          <units>mL/min/1.73m2</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="67.33" spread="17.89"/>
                    <measurement group_id="B2" value="67.75" spread="20.01"/>
                    <measurement group_id="B3" value="70.70" spread="20.70"/>
                    <measurement group_id="B4" value="70.19" spread="20.19"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Change in eGFR (MDRD) at 2 Years Post-transplant Compared to Baseline at Month 3 (Conversion)</title>
        <description>To assess change in renal function by calculated (MDRD) GFR of adult EBV seropositive renal transplant recipients of living or standard criteria donors converted from Tacrolimus to Belatacept or low dose Tacrolimus with Belatacept at three months post-operatively compared to renal transplant recipients randomized to remain on standard dose Tacrolimus and MPA for maintenance therapy at 2 years post-transplantation</description>
        <time_frame>2 years</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Belatacept + MPA</title>
            <description>subjects continue MPA per SOC, receive bimonthly infusions of belatacept while gradually reducing and then discontinuing tacrolimus:&#xD;
Belatacept: 5 mg/kg IV on Day 1, 15, 29, 43, and 57 post-conversion, then monthly thereafter.&#xD;
Tacrolimus tapered over one month as follows:&#xD;
Days 1- 14: SOC administration Day 15 (~ 2 weeks into study): 40-60% of the previous dose Day 21 (~ 3 weeks into study): 20-30% of the previous dose Day 30 (about 1 month): discontinue&#xD;
MPA: administered according to SOC&#xD;
belatacept: Please reference Arm description for belatacept + MPA and Arm description for Arm belatacept + Low-Dose Tac for details on this intervention&#xD;
MPA: Please see Arm Descriptions for both Standard of Care Arm Tacrolimus + MPA standard treatment regimen and belatacept + MPA for details on this intervention</description>
          </group>
          <group group_id="O2">
            <title>Belatacept + Low-Dose Tac</title>
            <description>Belatacept: 5 mg/kg IV on Day 1, 15, 29, 43, and 57 post-conversion, then monthly thereafter.&#xD;
Tacrolimus tapered over one month as follows:&#xD;
Days 1- 14: SOC administration Day 15 (~ 2 weeks into study): 10% of the previous dose Day 21 (~ 3 weeks into study): 20% of the previous dose Day 30 (~ 1 month into study): 20% of the previous dose Target trough level ≤ 5 mg per ml of tacrolimus thereafter.&#xD;
belatacept: Please reference Arm description for belatacept + MPA and Arm description for Arm belatacept + Low-Dose Tac for details on this intervention&#xD;
Tacrolimus: Please see Arm Descriptions for both Standard of Care Arm Tacrolimus + MPA standard treatment regimen and belatacept + Low-Dose Tac for details on this intervention</description>
          </group>
          <group group_id="O3">
            <title>Tacrolimus + MPA Standard Treatment Regimen</title>
            <description>Standard of Care treatment regimen:&#xD;
Tacrolimus: administered orally twice daily (BID) The total initial dose of Tacrolimus is given at 0.1 mg/kg in two divided doses to achieve a stable 12-hour trough level of 8 - 12 ng/mL on Days 1 through 30, with dose reduction to achieve a 12-hour trough target of 5 - 10 ng/mL thereafter.&#xD;
MPA: dosed orally per package insert beginning on the day of transplantation. Methylprednisolone as sodium succinate is administered as 500 mg IV, 250 mg IV, 125 mg IV, on Days 0, 1, and 2 without corticosteroid taper.&#xD;
MPA dose adjustments for gastrointestinal side effects or leukopenia will be made at the discretion of the investigator.&#xD;
Tacrolimus: Please see Arm Descriptions for both Standard of Care Arm Tacrolimus + MPA standard treatment regimen and belatacept + Low-Dose Tac for details on this intervention&#xD;
MPA: Please see Arm Descriptions for both Standard of Care Arm Tacrolimus + MPA standard treatment regimen and belatacept + MPA for details on this intervention</description>
          </group>
        </group_list>
        <measure>
          <title>Change in eGFR (MDRD) at 2 Years Post-transplant Compared to Baseline at Month 3 (Conversion)</title>
          <description>To assess change in renal function by calculated (MDRD) GFR of adult EBV seropositive renal transplant recipients of living or standard criteria donors converted from Tacrolimus to Belatacept or low dose Tacrolimus with Belatacept at three months post-operatively compared to renal transplant recipients randomized to remain on standard dose Tacrolimus and MPA for maintenance therapy at 2 years post-transplantation</description>
          <units>mL/min/1.73m2</units>
          <param>Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="9"/>
                <count group_id="O2" value="8"/>
                <count group_id="O3" value="10"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-5.44" spread="5.43"/>
                    <measurement group_id="O2" value="8.08" spread="5.74"/>
                    <measurement group_id="O3" value="-0.38" spread="3.94"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Acute Rejection</title>
        <description>Number of Participants with Acute Rejection (AR). AR is defined as allograft dysfunctions in the setting of recipient immune system engaging an allo-response against the kidney transplant.</description>
        <time_frame>2 years</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Belatacept + MPA</title>
            <description>subjects continue MPA per SOC, receive bimonthly infusions of belatacept while gradually reducing and then discontinuing tacrolimus:&#xD;
Belatacept: 5 mg/kg IV on Day 1, 15, 29, 43, and 57 post-conversion, then monthly thereafter.&#xD;
Tacrolimus tapered over one month as follows:&#xD;
Days 1- 14: SOC administration Day 15 (~ 2 weeks into study): 40-60% of the previous dose Day 21 (~ 3 weeks into study): 20-30% of the previous dose Day 30 (about 1 month): discontinue&#xD;
MPA: administered according to SOC&#xD;
belatacept: Please reference Arm description for belatacept + MPA and Arm description for Arm belatacept + Low-Dose Tac for details on this intervention&#xD;
MPA: Please see Arm Descriptions for both Standard of Care Arm Tacrolimus + MPA standard treatment regimen and belatacept + MPA for details on this intervention</description>
          </group>
          <group group_id="O2">
            <title>Belatacept + Low-Dose Tac</title>
            <description>Belatacept: 5 mg/kg IV on Day 1, 15, 29, 43, and 57 post-conversion, then monthly thereafter.&#xD;
Tacrolimus tapered over one month as follows:&#xD;
Days 1- 14: SOC administration Day 15 (~ 2 weeks into study): 10% of the previous dose Day 21 (~ 3 weeks into study): 20% of the previous dose Day 30 (~ 1 month into study): 20% of the previous dose Target trough level ≤ 5 mg per ml of tacrolimus thereafter.&#xD;
belatacept: Please reference Arm description for belatacept + MPA and Arm description for Arm belatacept + Low-Dose Tac for details on this intervention&#xD;
Tacrolimus: Please see Arm Descriptions for both Standard of Care Arm Tacrolimus + MPA standard treatment regimen and belatacept + Low-Dose Tac for details on this intervention</description>
          </group>
          <group group_id="O3">
            <title>Tacrolimus + MPA Standard Treatment Regimen</title>
            <description>Standard of Care treatment regimen:&#xD;
Tacrolimus: administered orally twice daily (BID) The total initial dose of Tacrolimus is given at 0.1 mg/kg in two divided doses to achieve a stable 12-hour trough level of 8 - 12 ng/mL on Days 1 through 30, with dose reduction to achieve a 12-hour trough target of 5 - 10 ng/mL thereafter.&#xD;
MPA: dosed orally per package insert beginning on the day of transplantation. Methylprednisolone as sodium succinate is administered as 500 mg IV, 250 mg IV, 125 mg IV, on Days 0, 1, and 2 without corticosteroid taper.&#xD;
MPA dose adjustments for gastrointestinal side effects or leukopenia will be made at the discretion of the investigator.&#xD;
Tacrolimus: Please see Arm Descriptions for both Standard of Care Arm Tacrolimus + MPA standard treatment regimen and belatacept + Low-Dose Tac for details on this intervention&#xD;
MPA: Please see Arm Descriptions for both Standard of Care Arm Tacrolimus + MPA standard treatment regimen and belatacept + MPA for details on this intervention</description>
          </group>
        </group_list>
        <measure>
          <title>Acute Rejection</title>
          <description>Number of Participants with Acute Rejection (AR). AR is defined as allograft dysfunctions in the setting of recipient immune system engaging an allo-response against the kidney transplant.</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="9"/>
                <count group_id="O2" value="8"/>
                <count group_id="O3" value="10"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Graft Survival</title>
        <description>Number of Subjects with a functioning Graft</description>
        <time_frame>2 years</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Belatacept + MPA</title>
            <description>subjects continue MPA per SOC, receive bimonthly infusions of belatacept while gradually reducing and then discontinuing tacrolimus:&#xD;
Belatacept: 5 mg/kg IV on Day 1, 15, 29, 43, and 57 post-conversion, then monthly thereafter.&#xD;
Tacrolimus tapered over one month as follows:&#xD;
Days 1- 14: SOC administration Day 15 (~ 2 weeks into study): 40-60% of the previous dose Day 21 (~ 3 weeks into study): 20-30% of the previous dose Day 30 (about 1 month): discontinue&#xD;
MPA: administered according to SOC&#xD;
belatacept: Please reference Arm description for belatacept + MPA and Arm description for Arm belatacept + Low-Dose Tac for details on this intervention&#xD;
MPA: Please see Arm Descriptions for both Standard of Care Arm Tacrolimus + MPA standard treatment regimen and belatacept + MPA for details on this intervention</description>
          </group>
          <group group_id="O2">
            <title>Belatacept + Low-Dose Tac</title>
            <description>Belatacept: 5 mg/kg IV on Day 1, 15, 29, 43, and 57 post-conversion, then monthly thereafter.&#xD;
Tacrolimus tapered over one month as follows:&#xD;
Days 1- 14: SOC administration Day 15 (~ 2 weeks into study): 10% of the previous dose Day 21 (~ 3 weeks into study): 20% of the previous dose Day 30 (~ 1 month into study): 20% of the previous dose Target trough level ≤ 5 mg per ml of tacrolimus thereafter.&#xD;
belatacept: Please reference Arm description for belatacept + MPA and Arm description for Arm belatacept + Low-Dose Tac for details on this intervention&#xD;
Tacrolimus: Please see Arm Descriptions for both Standard of Care Arm Tacrolimus + MPA standard treatment regimen and belatacept + Low-Dose Tac for details on this intervention</description>
          </group>
          <group group_id="O3">
            <title>Tacrolimus + MPA Standard Treatment Regimen</title>
            <description>Standard of Care treatment regimen:&#xD;
Tacrolimus: administered orally twice daily (BID) The total initial dose of Tacrolimus is given at 0.1 mg/kg in two divided doses to achieve a stable 12-hour trough level of 8 - 12 ng/mL on Days 1 through 30, with dose reduction to achieve a 12-hour trough target of 5 - 10 ng/mL thereafter.&#xD;
MPA: dosed orally per package insert beginning on the day of transplantation. Methylprednisolone as sodium succinate is administered as 500 mg IV, 250 mg IV, 125 mg IV, on Days 0, 1, and 2 without corticosteroid taper.&#xD;
MPA dose adjustments for gastrointestinal side effects or leukopenia will be made at the discretion of the investigator.&#xD;
Tacrolimus: Please see Arm Descriptions for both Standard of Care Arm Tacrolimus + MPA standard treatment regimen and belatacept + Low-Dose Tac for details on this intervention&#xD;
MPA: Please see Arm Descriptions for both Standard of Care Arm Tacrolimus + MPA standard treatment regimen and belatacept + MPA for details on this intervention</description>
          </group>
        </group_list>
        <measure>
          <title>Graft Survival</title>
          <description>Number of Subjects with a functioning Graft</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="9"/>
                <count group_id="O2" value="8"/>
                <count group_id="O3" value="10"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="8"/>
                    <measurement group_id="O2" value="8"/>
                    <measurement group_id="O3" value="10"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Patient Survival</title>
        <description>Number of Subjects alive at the end of 24 months</description>
        <time_frame>2 years</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Belatacept + MPA</title>
            <description>subjects continue MPA per SOC, receive bimonthly infusions of belatacept while gradually reducing and then discontinuing tacrolimus:&#xD;
Belatacept: 5 mg/kg IV on Day 1, 15, 29, 43, and 57 post-conversion, then monthly thereafter.&#xD;
Tacrolimus tapered over one month as follows:&#xD;
Days 1- 14: SOC administration Day 15 (~ 2 weeks into study): 40-60% of the previous dose Day 21 (~ 3 weeks into study): 20-30% of the previous dose Day 30 (about 1 month): discontinue&#xD;
MPA: administered according to SOC&#xD;
belatacept: Please reference Arm description for belatacept + MPA and Arm description for Arm belatacept + Low-Dose Tac for details on this intervention&#xD;
MPA: Please see Arm Descriptions for both Standard of Care Arm Tacrolimus + MPA standard treatment regimen and belatacept + MPA for details on this intervention</description>
          </group>
          <group group_id="O2">
            <title>Belatacept + Low-Dose Tac</title>
            <description>Belatacept: 5 mg/kg IV on Day 1, 15, 29, 43, and 57 post-conversion, then monthly thereafter.&#xD;
Tacrolimus tapered over one month as follows:&#xD;
Days 1- 14: SOC administration Day 15 (~ 2 weeks into study): 10% of the previous dose Day 21 (~ 3 weeks into study): 20% of the previous dose Day 30 (~ 1 month into study): 20% of the previous dose Target trough level ≤ 5 mg per ml of tacrolimus thereafter.&#xD;
belatacept: Please reference Arm description for belatacept + MPA and Arm description for Arm belatacept + Low-Dose Tac for details on this intervention&#xD;
Tacrolimus: Please see Arm Descriptions for both Standard of Care Arm Tacrolimus + MPA standard treatment regimen and belatacept + Low-Dose Tac for details on this intervention</description>
          </group>
          <group group_id="O3">
            <title>Tacrolimus + MPA Standard Treatment Regimen</title>
            <description>Standard of Care treatment regimen:&#xD;
Tacrolimus: administered orally twice daily (BID) The total initial dose of Tacrolimus is given at 0.1 mg/kg in two divided doses to achieve a stable 12-hour trough level of 8 - 12 ng/mL on Days 1 through 30, with dose reduction to achieve a 12-hour trough target of 5 - 10 ng/mL thereafter.&#xD;
MPA: dosed orally per package insert beginning on the day of transplantation. Methylprednisolone as sodium succinate is administered as 500 mg IV, 250 mg IV, 125 mg IV, on Days 0, 1, and 2 without corticosteroid taper.&#xD;
MPA dose adjustments for gastrointestinal side effects or leukopenia will be made at the discretion of the investigator.&#xD;
Tacrolimus: Please see Arm Descriptions for both Standard of Care Arm Tacrolimus + MPA standard treatment regimen and belatacept + Low-Dose Tac for details on this intervention&#xD;
MPA: Please see Arm Descriptions for both Standard of Care Arm Tacrolimus + MPA standard treatment regimen and belatacept + MPA for details on this intervention</description>
          </group>
        </group_list>
        <measure>
          <title>Patient Survival</title>
          <description>Number of Subjects alive at the end of 24 months</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="9"/>
                <count group_id="O2" value="8"/>
                <count group_id="O3" value="10"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="9"/>
                    <measurement group_id="O2" value="7"/>
                    <measurement group_id="O3" value="9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>2 years</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Belatacept + MPA</title>
          <description>subjects continue MPA per SOC, receive bimonthly infusions of belatacept while gradually reducing and then discontinuing tacrolimus:&#xD;
Belatacept: 5 mg/kg IV on Day 1, 15, 29, 43, and 57 post-conversion, then monthly thereafter.&#xD;
Tacrolimus tapered over one month as follows:&#xD;
Days 1- 14: SOC administration Day 15 (~ 2 weeks into study): 40-60% of the previous dose Day 21 (~ 3 weeks into study): 20-30% of the previous dose Day 30 (about 1 month): discontinue&#xD;
MPA: administered according to SOC&#xD;
belatacept: Please reference Arm description for belatacept + MPA and Arm description for Arm belatacept + Low-Dose Tac for details on this intervention&#xD;
MPA: Please see Arm Descriptions for both Standard of Care Arm Tacrolimus + MPA standard treatment regimen and belatacept + MPA for details on this intervention</description>
        </group>
        <group group_id="E2">
          <title>Belatacept + Low-Dose Tac</title>
          <description>Belatacept: 5 mg/kg IV on Day 1, 15, 29, 43, and 57 post-conversion, then monthly thereafter.&#xD;
Tacrolimus tapered over one month as follows:&#xD;
Days 1- 14: SOC administration Day 15 (~ 2 weeks into study): 10% of the previous dose Day 21 (~ 3 weeks into study): 20% of the previous dose Day 30 (~ 1 month into study): 20% of the previous dose Target trough level ≤ 5 mg per ml of tacrolimus thereafter.&#xD;
belatacept: Please reference Arm description for belatacept + MPA and Arm description for Arm belatacept + Low-Dose Tac for details on this intervention&#xD;
Tacrolimus: Please see Arm Descriptions for both Standard of Care Arm Tacrolimus + MPA standard treatment regimen and belatacept + Low-Dose Tac for details on this intervention</description>
        </group>
        <group group_id="E3">
          <title>Tacrolimus + MPA Standard Treatment Regimen</title>
          <description>Standard of Care treatment regimen:&#xD;
Tacrolimus: administered orally twice daily (BID) The total initial dose of Tacrolimus is given at 0.1 mg/kg in two divided doses to achieve a stable 12-hour trough level of 8 - 12 ng/mL on Days 1 through 30, with dose reduction to achieve a 12-hour trough target of 5 - 10 ng/mL thereafter.&#xD;
MPA: dosed orally per package insert beginning on the day of transplantation. Methylprednisolone as sodium succinate is administered as 500 mg IV, 250 mg IV, 125 mg IV, on Days 0, 1, and 2 without corticosteroid taper.&#xD;
MPA dose adjustments for gastrointestinal side effects or leukopenia will be made at the discretion of the investigator.&#xD;
Tacrolimus: Please see Arm Descriptions for both Standard of Care Arm Tacrolimus + MPA standard treatment regimen and belatacept + Low-Dose Tac for details on this intervention&#xD;
MPA: Please see Arm Descriptions for both Standard of Care Arm Tacrolimus + MPA standard treatment regimen and belatacept + MPA for details on this intervention</description>
        </group>
      </group_list>
      <serious_events>
        <default_assessment>Non-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="9"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Endocrine disorders</title>
            <event_list>
              <event>
                <sub_title>Death</sub_title>
                <description>Diabetic ketoacidosis</description>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Death</sub_title>
                <description>Patient developed pneumonia with overwhelming sepsis. Not thought to be related to study intervention.</description>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Neoplasms benign, malignant and unspecified (incl cysts and polyps)</title>
            <event_list>
              <event>
                <sub_title>Squamous Cell Carcinoma</sub_title>
                <description>SCC skin cancer removed from nose</description>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <default_assessment>Non-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="6" subjects_at_risk="9"/>
                <counts group_id="E2" subjects_affected="7" subjects_at_risk="8"/>
                <counts group_id="E3" subjects_affected="7" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Neutropenia</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="9"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="8"/>
                <counts group_id="E3" events="2" subjects_affected="2" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>CMV</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>BK infections</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="9"/>
                <counts group_id="E2" events="4" subjects_affected="4" subjects_at_risk="8"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Hyperlipidemia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" events="3" subjects_affected="3" subjects_at_risk="10"/>
              </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>Lorenzo Gallon, MD</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/NCT02213068
org study id: STU00085274
nct id: NCT02213068
lead sponsor: 
collaborator: 
has dmc: No
This study is being done to investigate the impact of changing immunosuppressive medications
      from tacrolimus (Prograf®) to belatacept (Nulojix®) between three (3) and six (6) months
      after kidney transplantation. The immune system is the body's defense against infection and
      other disease. After transplantation, the body sees the new organ as "foreign" and tries to
      destroy or "reject" it. Immunosuppressive medications help to prevent the immune system from
      attacking the transplanted organ. The primary purpose of this research study is to evaluate
      the effects of three (3) different immunosuppressive treatments on rejection in
      post-transplant kidney recipients. This study will test whether switching from tacrolimus to
      belatacept will improve long-term kidney function.

      Three of the immunosuppressants used in this study- mycophenolic acid (MPA), mycophenolate
      mofetil (MMF) and tacrolimus- are medications approved by the United States Food and Drug
      Administration (FDA) to be used after transplant. All of these medications have been
      routinely used in kidney recipients here at Northwestern University.

      Belatacept (the "study drug") has been approved by the FDA for use at the time of transplant.
      However, the use of belatacept in this study is considered investigational as it has not been
      FDA approved for use beginning at 3 months after transplant.

      This study will involve 51 adult kidney transplant recipients at Northwestern.
Immunosuppressive therapy with the calcineurin inhibitors (CNI) cyclosporine (CsA) and
      Tacrolimus (Tac), have radically changed the field of organ transplantation. Ironically,
      although extensively and effectively used for kidney transplantation and other solid organ
      transplants, CsA and Tac cause important adverse renal side effects: acute and chronic renal
      dysfunction, hemolytic-uremic syndrome, hypertension, electrolyte disturbances and tubular
      acidosis. Chronic nephrotoxicity from CNI has been implicated as a principal cause of
      post-transplant renal dysfunction and it is characterized by an irreversible and progressive
      tubular atrophy, interstitial fibrosis, and focal hyalinosis of small renal arteries and
      arterioles. Attempts to minimize CNIs and their known toxicities have been marginally
      successful due to unacceptable rates of acute rejection and drug toxicity. Patients are
      converted to alternative immunosuppressive therapy related to CNI side effects including
      neurotoxicity, nephrotoxicity, cardiovascular (HTN, hyperlipidemia), metabolic (NODAT), and
      cosmetic side effects. Furthermore, this class of medications is associated also, by blocking
      Interleukin 2 (IL2) production, with negative impact on regulatory T cells (Tregs) generation
      (an important subpopulation of T helper cells that has been associated with positive
      immunomodulation and donor specific hypo-responsiveness).

      Until the approval of Belatacept for adult EBV+ renal transplant recipients, there have been
      limited alternative immunosuppressive agents available to mitigate drug induced renal
      impairment. The phase III drug trials of Belatacept in combination with MMF and
      corticosteroids have resulted in significant and sustained improvement in glomerular
      filtration rate (GFR) at one year through three years post transplant. The overall safety of
      belatacept compared to cyclosporine in de novo transplant recipients was similar. However,
      there was an increased rate and severity of early acute rejection and post-transplant
      lymphoproliferative disorder (PTLD) of the central nervous system in patients treated with
      belatacept.

      In a phase II switch study conducted by Bristol Myers Squibb (BMS), the incidence of acute
      rejection at 24 months post conversion was similar in patients remaining on CNI (4%) compared
      to those converted to belatacept (7%). There were no reported cases of post-transplant
      lymphoproliferative disorder (PTLD) in this patient population as of two years post
      randomization. However, one belatacept patient from Mexico developed tuberculosis and there
      were more non-serious fungal infections in the belatacept treated patients.

      Mechanistically, CD28 (Cluster of Differentiation 28) and CTLA-4 (cytotoxic
      T-lymphocyte-associated protein 4) are important for the function of regulatory T cells
      (Tregs). Belatacept binds to CD80/CD86 (Cluster of Differentiation 80/Cluster of
      Differentiation 86) ligands on antigen presenting cells (APCs) preventing CD28 to bind with
      these ligands and deliver the costimulatory signal to activate the T Cell. CTLA-4 is a
      related receptor expressed on activated T cells that also recognizes CD80/CD86 (Cluster of
      Differentiation 80/Cluster of Differentiation 86) and is thus termed co-inhibitory. It
      transmits both cell intrinsic and cell extrinsic negative signals that impair activation.

      Investigation of the effect of early conversion to Belatacept at month 3 post-transplant on
      the subpopulations of T cells and B cells and peripheral blood and allograft biopsy-derived
      gene expression subpopulation profiles are planned. Optimization of the Belatacept
      immunosuppressive regimen to achieve good long term renal function and improved graft
      survival requires understanding the relationships of these cell populations to clinical
      outcomes.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Change in eGFR (MDRD) at 2 Years Post-transplant Compared to Baseline at Month 3 (Conversion)
time frame: 2 years
description: To assess change in renal function by calculated (MDRD) GFR of adult EBV seropositive renal transplant recipients of living or standard criteria donors converted from Tacrolimus to Belatacept or low dose Tacrolimus with Belatacept at three months post-operatively compared to renal transplant recipients randomized to remain on standard dose Tacrolimus and MPA for maintenance therapy at 2 years post-transplantation
measure: Acute Rejection
time frame: 2 years
description: Number of Participants with Acute Rejection (AR). AR is defined as allograft dysfunctions in the setting of recipient immune system engaging an allo-response against the kidney transplant.
measure: Graft Survival
time frame: 2 years
description: Number of Subjects with a functioning Graft
measure: Patient Survival
time frame: 2 years
description: Number of Subjects alive at the end of 24 months
arm group label: belatacept + MPA
arm group type: Experimental
description: subjects continue MPA per SOC, receive bimonthly infusions of belatacept while gradually reducing and then discontinuing tacrolimus:
Belatacept: 5 mg/kg IV on Day 1, 15, 29, 43, and 57 post-conversion, then monthly thereafter.
Tacrolimus tapered over one month as follows:
Days 1- 14: SOC administration Day 15 (~ 2 weeks into study): 40-60% of the previous dose Day 21 (~ 3 weeks into study): 20-30% of the previous dose Day 30 (about 1 month): discontinue
MPA: administered according to SOC
arm group label: belatacept + Low-Dose Tac
arm group type: Active Comparator
description: Belatacept: 5 mg/kg IV on Day 1, 15, 29, 43, and 57 post-conversion, then monthly thereafter.
Tacrolimus tapered over one month as follows:
Days 1- 14: SOC administration Day 15 (~ 2 weeks into study): 10% of the previous dose Day 21 (~ 3 weeks into study): 20% of the previous dose Day 30 (~ 1 month into study): 20% of the previous dose Target trough level ≤ 5 mg per ml of tacrolimus thereafter.
arm group label: Tacrolimus + MPA standard treatment regimen
arm group type: Other
description: Standard of Care treatment regimen:
Tacrolimus: administered orally twice daily (BID) The total initial dose of Tacrolimus is given at 0.1 mg/kg in two divided doses to achieve a stable 12-hour trough level of 8 - 12 ng/mL on Days 1 through 30, with dose reduction to achieve a 12-hour trough target of 5 - 10 ng/mL thereafter.
MPA: dosed orally per package insert beginning on the day of transplantation. Methylprednisolone as sodium succinate is administered as 500 mg IV, 250 mg IV, 125 mg IV, on Days 0, 1, and 2 without corticosteroid taper.
MPA dose adjustments for gastrointestinal side effects or leukopenia will be made at the discretion of the investigator.
intervention type: Drug
intervention name: belatacept
description: Please reference Arm description for belatacept + MPA and Arm description for Arm belatacept + Low-Dose Tac for details on this intervention
arm group label: belatacept + Low-Dose Tac
arm group label: belatacept + MPA
other name: Belatacept (Nulojix®)
intervention type: Drug
intervention name: Tacrolimus
description: Please see Arm Descriptions for both Standard of Care Arm Tacrolimus + MPA standard treatment regimen and belatacept + Low-Dose Tac for details on this intervention
arm group label: Tacrolimus + MPA standard treatment regimen
arm group label: belatacept + Low-Dose Tac
other name: Tacrolimus (Prograf®)
intervention type: Drug
intervention name: MPA
description: Please see Arm Descriptions for both Standard of Care Arm Tacrolimus + MPA standard treatment regimen and belatacept + MPA for details on this intervention
arm group label: Tacrolimus + MPA standard treatment regimen
arm group label: belatacept + MPA
other name: Mycophenolic Acid (MPA) (Myfortic®)
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Lorenzo Gallon, MD
role: Principal Investigator
affiliation: Northwestern University
facility: 
country: United States
responsible party type: Sponsor-Investigator
investigator affiliation: Northwestern University
investigator full name: Lorenzo Gallon
investigator title: Associate Professor, Northwestern University, Feinberg School of Medicine
mesh term: Renal Insufficiency
mesh term: Mycophenolic Acid
mesh term: Abatacept
mesh term: Tacrolimus
provided document: 
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 