<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/NCT03020589</url>
  </required_header>
  <id_info>
    <org_study_id>16-2073</org_study_id>
    <nct_id>NCT03020589</nct_id>
  </id_info>
  <brief_title>Study of Pharmacogenomic-Guided Tacrolimus Dosing and Monitoring in Kidney Transplant Recipients</brief_title>
  <acronym>TAC3A5</acronym>
  <official_title>Study of Pharmacogenomic-Guided Tacrolimus Dosing and Monitoring in Kidney Transplant Recipients</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of North Carolina, Chapel Hill</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of North Carolina, Chapel Hill</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Objective: Investigate the direct correlation of CYP3A5 genotype with tacrolimus trough&#xD;
      levels and clinical outcomes. The primary endpoint of this study is to evaluate the&#xD;
      proportion of patients reaching target levels (8-10 ng/mL) on Day 3 and Day 7 after kidney&#xD;
      transplantation.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Participants: All new kidney transplant recipients aged 18 to 65 years who are admitted at&#xD;
      UNC-CH and provided informed consent will be included in this study (Unless they meet the&#xD;
      exclusion criteria specified). A total of an anticipated 260 subjects will be included in the&#xD;
      study, 130 of which will be included in the pharmacogenomic group and the remaining 130 will&#xD;
      be in the control group.&#xD;
&#xD;
      Procedures (methods): The pharmacogenomic group will partake in a 12-month study comprising&#xD;
      of two periods, Genotype-Guided Initial Dosing Intervention and Follow-up.&#xD;
&#xD;
      Briefly, patients on transplant waitlist will be screened for eligibility. At the&#xD;
      pre-intervention assessment (Study Day 0), buccal swab samples for genotyping will be&#xD;
      collected on all eligible patients who provided informed consent (performed in real time).&#xD;
      Results of the genotyping test will be incorporated into electronic medical record (EMR). The&#xD;
      initial tacrolimus dose will be based on genotype: 0.1 mg/kg/day (non- expressers) or 0.2&#xD;
      mg/kg/day, with maximum of 20 mg/day (expressers) given in 2 divided doses. Eligible patients&#xD;
      who consented to receive genotype-guided tacrolimus dose will enter the pharmacogenomic group&#xD;
      and will receive the initial tacrolimus dosing based on genotype results following kidney&#xD;
      transplantation (Study Day 1). Subsequent tacrolimus dosing will then be adjusted according&#xD;
      to trough concentrations (C0) and therapeutic target concentrations. The genotype-guided&#xD;
      dosing recommendation for tacrolimus only refers to the initial tacrolimus dose. All patients&#xD;
      in the pharmacogenomic group will be followed from Study Day 2 and up to 12 months to assess&#xD;
      long-term outcome.&#xD;
&#xD;
      Age-, race-, and disease-matched patients who had previously received kidney transplantation&#xD;
      with standard tacrolimus dosing from 2010 to present will also be asked to give consent for&#xD;
      genotyping (historical controls). These patients will be included in the control group and&#xD;
      their safety and efficacy data will be collected retrospectively for up to 12 months from the&#xD;
      initiation of first tacrolimus dose.&#xD;
&#xD;
      As there are confounding variables, including age, race and disease state that may impact the&#xD;
      results of the study, our study design incorporates an overall matching strategy, so that we&#xD;
      can identify a well-matched control group. First, to control for differences in care over&#xD;
      time, patients in the pharmacogenomic group will be matched to controls enrolled from 2010 to&#xD;
      present. This time period was selected as there had been no major changes in standard of care&#xD;
      or treatment regimen since 2010. After eligibility is met, control patients will be selected&#xD;
      to match the pharmacogenomic group using a computerized matching algorithm that has been&#xD;
      optimized to match baseline demographic and disease characteristics that have been identified&#xD;
      a priori as likely to influence the treatment response to tacrolimus. To balance the&#xD;
      trade-off between minimizing bias and maximizing matched sample size, a systematic approach&#xD;
      will be conducted to identify the number of matched control patients for each patient in the&#xD;
      pharmacogenomic group. This approach will include the following steps: 1) run the desired&#xD;
      matching algorithm, starting with 1:1 (one control to one patient in the pharmacogenomic&#xD;
      group) matching and iterating until the maximum desired number of potential controls per&#xD;
      treated subject is reached; 2) for each iteration, test for covariate balance; and (3)&#xD;
      generate numeric summaries and graphical plots of the balance statistics across all&#xD;
      iterations in order to determine the optimal number.&#xD;
&#xD;
      The selection of patients for the control group using a matching algorithm will be conducted&#xD;
      by an independent statistician in a blinded and unbiased manner. The statistician will have&#xD;
      no knowledge of survival outcome, other outcome data, and genotype. The algorithm will not be&#xD;
      used to guide treatment in any way.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">February 6, 2017</start_date>
  <completion_date type="Actual">June 28, 2022</completion_date>
  <primary_completion_date type="Actual">July 31, 2021</primary_completion_date>
  <phase>Phase 4</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Proportion of Patients Reaching Target Tacrolimus Levels (8-10 ng/mL) on Day 3 After Kidney Transplantation</measure>
    <time_frame>Day 3 after transplantation</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Proportion of Patients Reaching Target Tacrolimus Levels (8-10 ng/mL) on Day 7 After Kidney Transplantation</measure>
    <time_frame>Day 7 after transplantation</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Number of Events of Biopsy Proven Acute Rejection (BPAR)</measure>
    <time_frame>first 3 months (Days 0 through 90), 91-180, and 181-365 days after transplantation</time_frame>
    <description>The number of events of BPAR within the first 3 months (Days 0 through 90), 91-180, and 181-365 days after transplantation</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Tacrolimus Level</measure>
    <time_frame>4 months</time_frame>
    <description>Time to achieve tacrolimus therapeutic range at 0 to 4 months (8-10 ng/mL)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mean Number of Dose Adjustments and/or Drug Alterations</measure>
    <time_frame>12 months</time_frame>
    <description>Mean number of dose adjustments and/or drug alteration or addition due to insufficient immunosuppression.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percent of Participants With Chronic Renal Impairment by eGFR Category</measure>
    <time_frame>12 months</time_frame>
    <description>Renal function will be assessed using estimated Glomerular Filtration Rate (eGFR). Creatinine clearance (CrCl) may also be calculated as a reference. Patients will be categorized as having either mild (eGFR of 60 mL/min/1.73m^2 to 89 mL/min/1.73m^2), moderate (eGFR of 30 mL/min/1.73m^2 to 59 mL/min/1.73m^2), or severe renal impairment (eGFR &lt;30 mL/min/1.73m^2).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Adverse Outcomes</measure>
    <time_frame>12 months</time_frame>
    <description>Number of adverse outcomes (i.e., graft loss, infection, and death)</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Direct and Indirect Costs</measure>
    <time_frame>12 months</time_frame>
    <description>Direct and indirect cost related to treatment and management kidney transplant recipients</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">97</enrollment>
  <condition>Renal Transplant</condition>
  <arm_group>
    <arm_group_label>CYP3A5 based tacrolimus dosing</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Subjects in this treatment arm will receive initial tacrolimus based on their genotype i.e., CYP3A5*1/*1 and CYP3A5*1/*3 (Expressers) will receive the initial tacrolimus dose of 0.2 mg/kg/day, with maximum of 20 mg/day in 2 divided doses. For CYP3A5*3/*3 (Non-Expressers), the subjects will receive initial tacrolimus dose of 0.1 mg/kg/day in 2 divided doses.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Control</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>Subjects in the prospective control group will receive standard tacrolimus dosing as recommended per package insert and will not be dosed based on their genotype. Similarly, subjects that underwent renal transplant after 2010 and received standard tacrolimus dosing (per package insert) will serve as historical controls.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Tacrolimus</intervention_name>
    <description>See description in arm/group sections</description>
    <arm_group_label>CYP3A5 based tacrolimus dosing</arm_group_label>
    <other_name>Prograf, Advagraf</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  All new kidney transplant recipients aged 18 to 65 years who are admitted at UNC-CH&#xD;
             and provided informed consent will be included in this study.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        - Patients will be excluded from participating in the study to receive genotype-guided&#xD;
        tacrolimus dosing if he/she meets any of the exclusion criteria described below.&#xD;
&#xD;
          -  Recipients who did not consent to participate in the study.&#xD;
&#xD;
          -  Highly sensitized patients (ie, pretransplant T or B cell flow crossmatch positive)&#xD;
&#xD;
          -  Recipients of ABO incompatible kidney transplant&#xD;
&#xD;
          -  Recipients with preformed donor-specific antibodies (DSA)&#xD;
&#xD;
          -  Human Leukocyte Antigen (HLA) identical kidney transplant&#xD;
&#xD;
          -  Recipients of non-kidney transplant&#xD;
&#xD;
          -  Recipients of repeat transplant if they are on immunosuppression at the time of&#xD;
             transplant&#xD;
&#xD;
          -  Patients using medications that have known pharmacokinetic (PK) drug interaction with&#xD;
             tacrolimus&#xD;
&#xD;
          -  Patients in whom tacrolimus therapy is contraindicated&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>65 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Alexander Toledo, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of North Carolina, Chapel Hill</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Univeristy of North Carolina</name>
      <address>
        <city>Chapel Hill</city>
        <state>North Carolina</state>
        <zip>27514</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>July 2022</verification_date>
  <study_first_submitted>January 11, 2017</study_first_submitted>
  <study_first_submitted_qc>January 11, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 13, 2017</study_first_posted>
  <results_first_submitted>June 9, 2022</results_first_submitted>
  <results_first_submitted_qc>July 18, 2022</results_first_submitted_qc>
  <results_first_posted type="Actual">July 21, 2022</results_first_posted>
  <last_update_submitted>June 20, 2023</last_update_submitted>
  <last_update_submitted_qc>June 20, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">June 26, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Renal Transplant</keyword>
  <keyword>Tacrolimus</keyword>
  <keyword>UNC</keyword>
  <keyword>Phase IV</keyword>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Tacrolimus</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
    <ipd_description>No participant data will be shared outside the research team.</ipd_description>
  </patient_data>
  <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>July 9, 2018</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/89/NCT03020589/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>CYP3A5 Based Tacrolimus Dosing</title>
          <description>Subjects in this treatment arm will receive initial tacrolimus based on their genotype i.e., CYP3A5*1/*1 and CYP3A5*1/*3 (Expressers) will receive the initial tacrolimus dose of 0.2 mg/kg/day, with maximum of 20 mg/day in 2 divided doses. For CYP3A5*3/*3 (Non-Expressers), the subjects will receive initial tacrolimus dose of 0.1 mg/kg/day in 2 divided doses.&#xD;
Tacrolimus: See description in arm/group sections</description>
        </group>
        <group group_id="P2">
          <title>Control</title>
          <description>Subjects in the prospective control group will receive standard tacrolimus dosing as recommended per package insert and will not be dosed based on their genotype. Similarly, subjects that underwent renal transplant after 2010 and received standard tacrolimus dosing (per package insert) will serve as historical controls.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="40"/>
                <participants group_id="P2" count="57"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="40"/>
                <participants group_id="P2" count="57"/>
              </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>CYP3A5 Based Tacrolimus Dosing</title>
          <description>Subjects in this treatment arm will receive initial tacrolimus based on their genotype i.e., CYP3A5*1/*1 and CYP3A5*1/*3 (Expressers) will receive the initial tacrolimus dose of 0.2 mg/kg/day, with maximum of 20 mg/day in 2 divided doses. For CYP3A5*3/*3 (Non-Expressers), the subjects will receive initial tacrolimus dose of 0.1 mg/kg/day in 2 divided doses.&#xD;
Tacrolimus: See description in arm/group sections</description>
        </group>
        <group group_id="B2">
          <title>Control</title>
          <description>Subjects in the prospective control group will receive standard tacrolimus dosing as recommended per package insert and will not be dosed based on their genotype. Similarly, subjects that underwent renal transplant after 2010 and received standard tacrolimus dosing (per package insert) will serve as historical controls.</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="40"/>
            <count group_id="B2" value="57"/>
            <count group_id="B3" value="97"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="49" lower_limit="18" upper_limit="64"/>
                    <measurement group_id="B2" value="51" lower_limit="18" upper_limit="64"/>
                    <measurement group_id="B3" value="51" lower_limit="18" upper_limit="64"/>
                  </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="23"/>
                    <measurement group_id="B2" value="25"/>
                    <measurement group_id="B3" value="48"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="17"/>
                    <measurement group_id="B2" value="32"/>
                    <measurement group_id="B3" value="49"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race/Ethnicity, Customized</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>Black or African American</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="21"/>
                    <measurement group_id="B2" value="31"/>
                    <measurement group_id="B3" value="52"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>White</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="14"/>
                    <measurement group_id="B2" value="21"/>
                    <measurement group_id="B3" value="35"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Asian</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="3"/>
                    <measurement group_id="B3" value="5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Hispanic</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>American Indian or Alaska Native</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="40"/>
                    <measurement group_id="B2" value="57"/>
                    <measurement group_id="B3" value="97"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Proportion of Patients Reaching Target Tacrolimus Levels (8-10 ng/mL) on Day 3 After Kidney Transplantation</title>
        <time_frame>Day 3 after transplantation</time_frame>
        <group_list>
          <group group_id="O1">
            <title>CYP3A5 Based Tacrolimus Dosing</title>
            <description>Subjects in this treatment arm will receive initial tacrolimus based on their genotype i.e., CYP3A5*1/*1 and CYP3A5*1/*3 (Expressers) will receive the initial tacrolimus dose of 0.2 mg/kg/day, with maximum of 20 mg/day in 2 divided doses. For CYP3A5*3/*3 (Non-Expressers), the subjects will receive initial tacrolimus dose of 0.1 mg/kg/day in 2 divided doses.&#xD;
Tacrolimus: See description in arm/group sections</description>
          </group>
          <group group_id="O2">
            <title>Control</title>
            <description>Subjects in the prospective control group will receive standard tacrolimus dosing as recommended per package insert and will not be dosed based on their genotype. Similarly, subjects that underwent renal transplant after 2010 and received standard tacrolimus dosing (per package insert) will serve as historical controls.</description>
          </group>
        </group_list>
        <measure>
          <title>Proportion of Patients Reaching Target Tacrolimus Levels (8-10 ng/mL) on Day 3 After Kidney Transplantation</title>
          <units>proportion of participants</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="40"/>
                <count group_id="O2" value="57"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.2"/>
                    <measurement group_id="O2" value="0.14"/>
                  </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</non_inferiority_type>
            <p_value>0.58</p_value>
            <method>Fisher Exact</method>
            <param_type>Risk Ratio (RR)</param_type>
            <param_value>1.27</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.67</ci_lower_limit>
            <ci_upper_limit>2.05</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Proportion of Patients Reaching Target Tacrolimus Levels (8-10 ng/mL) on Day 7 After Kidney Transplantation</title>
        <time_frame>Day 7 after transplantation</time_frame>
        <group_list>
          <group group_id="O1">
            <title>CYP3A5 Based Tacrolimus Dosing</title>
            <description>Subjects in this treatment arm will receive initial tacrolimus based on their genotype i.e., CYP3A5*1/*1 and CYP3A5*1/*3 (Expressers) will receive the initial tacrolimus dose of 0.2 mg/kg/day, with maximum of 20 mg/day in 2 divided doses. For CYP3A5*3/*3 (Non-Expressers), the subjects will receive initial tacrolimus dose of 0.1 mg/kg/day in 2 divided doses.&#xD;
Tacrolimus: See description in arm/group sections</description>
          </group>
          <group group_id="O2">
            <title>Control</title>
            <description>Subjects in the prospective control group will receive standard tacrolimus dosing as recommended per package insert and will not be dosed based on their genotype. Similarly, subjects that underwent renal transplant after 2010 and received standard tacrolimus dosing (per package insert) will serve as historical controls.</description>
          </group>
        </group_list>
        <measure>
          <title>Proportion of Patients Reaching Target Tacrolimus Levels (8-10 ng/mL) on Day 7 After Kidney Transplantation</title>
          <units>Proportion of participants</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="40"/>
                <count group_id="O2" value="57"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.29"/>
                    <measurement group_id="O2" value="0.21"/>
                  </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</non_inferiority_type>
            <p_value>0.46</p_value>
            <method>Fisher Exact</method>
            <param_type>Risk Ratio (RR)</param_type>
            <param_value>1.26</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.72</ci_lower_limit>
            <ci_upper_limit>2.02</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Events of Biopsy Proven Acute Rejection (BPAR)</title>
        <description>The number of events of BPAR within the first 3 months (Days 0 through 90), 91-180, and 181-365 days after transplantation</description>
        <time_frame>first 3 months (Days 0 through 90), 91-180, and 181-365 days after transplantation</time_frame>
        <group_list>
          <group group_id="O1">
            <title>CYP3A5 Based Tacrolimus Dosing</title>
            <description>Subjects in this treatment arm will receive initial tacrolimus based on their genotype i.e., CYP3A5*1/*1 and CYP3A5*1/*3 (Expressers) will receive the initial tacrolimus dose of 0.2 mg/kg/day, with maximum of 20 mg/day in 2 divided doses. For CYP3A5*3/*3 (Non-Expressers), the subjects will receive initial tacrolimus dose of 0.1 mg/kg/day in 2 divided doses.&#xD;
Tacrolimus: See description in arm/group sections</description>
          </group>
          <group group_id="O2">
            <title>Control</title>
            <description>Subjects in the prospective control group will receive standard tacrolimus dosing as recommended per package insert and will not be dosed based on their genotype. Similarly, subjects that underwent renal transplant after 2010 and received standard tacrolimus dosing (per package insert) will serve as historical controls.</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Events of Biopsy Proven Acute Rejection (BPAR)</title>
          <description>The number of events of BPAR within the first 3 months (Days 0 through 90), 91-180, and 181-365 days after transplantation</description>
          <units>BPAR events</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="40"/>
                <count group_id="O2" value="57"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Days 0 through 90</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3"/>
                    <measurement group_id="O2" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Days 91-180</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Days 181-365</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Tacrolimus Level</title>
        <description>Time to achieve tacrolimus therapeutic range at 0 to 4 months (8-10 ng/mL)</description>
        <time_frame>4 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>CYP3A5 Based Tacrolimus Dosing</title>
            <description>Subjects in this treatment arm will receive initial tacrolimus based on their genotype i.e., CYP3A5*1/*1 and CYP3A5*1/*3 (Expressers) will receive the initial tacrolimus dose of 0.2 mg/kg/day, with maximum of 20 mg/day in 2 divided doses. For CYP3A5*3/*3 (Non-Expressers), the subjects will receive initial tacrolimus dose of 0.1 mg/kg/day in 2 divided doses.&#xD;
Tacrolimus: See description in arm/group sections</description>
          </group>
          <group group_id="O2">
            <title>Control</title>
            <description>Subjects in the prospective control group will receive standard tacrolimus dosing as recommended per package insert and will not be dosed based on their genotype. Similarly, subjects that underwent renal transplant after 2010 and received standard tacrolimus dosing (per package insert) will serve as historical controls.</description>
          </group>
        </group_list>
        <measure>
          <title>Tacrolimus Level</title>
          <description>Time to achieve tacrolimus therapeutic range at 0 to 4 months (8-10 ng/mL)</description>
          <units>Days</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="40"/>
                <count group_id="O2" value="57"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="6.4" spread="5.96"/>
                    <measurement group_id="O2" value="7.87" spread="5.35"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Mean Number of Dose Adjustments and/or Drug Alterations</title>
        <description>Mean number of dose adjustments and/or drug alteration or addition due to insufficient immunosuppression.</description>
        <time_frame>12 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>CYP3A5 Based Tacrolimus Dosing</title>
            <description>Subjects in this treatment arm will receive initial tacrolimus based on their genotype i.e., CYP3A5*1/*1 and CYP3A5*1/*3 (Expressers) will receive the initial tacrolimus dose of 0.2 mg/kg/day, with maximum of 20 mg/day in 2 divided doses. For CYP3A5*3/*3 (Non-Expressers), the subjects will receive initial tacrolimus dose of 0.1 mg/kg/day in 2 divided doses.&#xD;
Tacrolimus: See description in arm/group sections</description>
          </group>
          <group group_id="O2">
            <title>Control</title>
            <description>Subjects in the prospective control group will receive standard tacrolimus dosing as recommended per package insert and will not be dosed based on their genotype. Similarly, subjects that underwent renal transplant after 2010 and received standard tacrolimus dosing (per package insert) will serve as historical controls.</description>
          </group>
        </group_list>
        <measure>
          <title>Mean Number of Dose Adjustments and/or Drug Alterations</title>
          <description>Mean number of dose adjustments and/or drug alteration or addition due to insufficient immunosuppression.</description>
          <units>Adjustments</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="40"/>
                <count group_id="O2" value="57"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="7.86" spread="2.5"/>
                    <measurement group_id="O2" value="7.37" spread="2.7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Percent of Participants With Chronic Renal Impairment by eGFR Category</title>
        <description>Renal function will be assessed using estimated Glomerular Filtration Rate (eGFR). Creatinine clearance (CrCl) may also be calculated as a reference. Patients will be categorized as having either mild (eGFR of 60 mL/min/1.73m^2 to 89 mL/min/1.73m^2), moderate (eGFR of 30 mL/min/1.73m^2 to 59 mL/min/1.73m^2), or severe renal impairment (eGFR &lt;30 mL/min/1.73m^2).</description>
        <time_frame>12 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>CYP3A5 Based Tacrolimus Dosing</title>
            <description>Subjects in this treatment arm will receive initial tacrolimus based on their genotype i.e., CYP3A5*1/*1 and CYP3A5*1/*3 (Expressers) will receive the initial tacrolimus dose of 0.2 mg/kg/day, with maximum of 20 mg/day in 2 divided doses. For CYP3A5*3/*3 (Non-Expressers), the subjects will receive initial tacrolimus dose of 0.1 mg/kg/day in 2 divided doses.&#xD;
Tacrolimus: See description in arm/group sections</description>
          </group>
          <group group_id="O2">
            <title>Control</title>
            <description>Subjects in the prospective control group will receive standard tacrolimus dosing as recommended per package insert and will not be dosed based on their genotype. Similarly, subjects that underwent renal transplant after 2010 and received standard tacrolimus dosing (per package insert) will serve as historical controls.</description>
          </group>
        </group_list>
        <measure>
          <title>Percent of Participants With Chronic Renal Impairment by eGFR Category</title>
          <description>Renal function will be assessed using estimated Glomerular Filtration Rate (eGFR). Creatinine clearance (CrCl) may also be calculated as a reference. Patients will be categorized as having either mild (eGFR of 60 mL/min/1.73m^2 to 89 mL/min/1.73m^2), moderate (eGFR of 30 mL/min/1.73m^2 to 59 mL/min/1.73m^2), or severe renal impairment (eGFR &lt;30 mL/min/1.73m^2).</description>
          <units>percentage of participants</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="40"/>
                <count group_id="O2" value="57"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Mild : Week 1</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="23"/>
                    <measurement group_id="O2" value="24"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Mild : Month12</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="53"/>
                    <measurement group_id="O2" value="46"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Moderate : Week 1</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="35"/>
                    <measurement group_id="O2" value="42"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Moderate : Month12</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="33"/>
                    <measurement group_id="O2" value="51"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Severe : Week 1</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="43"/>
                    <measurement group_id="O2" value="35"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Severe : Month12</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="13"/>
                    <measurement group_id="O2" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Adverse Outcomes</title>
        <description>Number of adverse outcomes (i.e., graft loss, infection, and death)</description>
        <time_frame>12 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>CYP3A5 Based Tacrolimus Dosing</title>
            <description>Subjects in this treatment arm will receive initial tacrolimus based on their genotype i.e., CYP3A5*1/*1 and CYP3A5*1/*3 (Expressers) will receive the initial tacrolimus dose of 0.2 mg/kg/day, with maximum of 20 mg/day in 2 divided doses. For CYP3A5*3/*3 (Non-Expressers), the subjects will receive initial tacrolimus dose of 0.1 mg/kg/day in 2 divided doses.&#xD;
Tacrolimus: See description in arm/group sections</description>
          </group>
          <group group_id="O2">
            <title>Control</title>
            <description>Subjects in the prospective control group will receive standard tacrolimus dosing as recommended per package insert and will not be dosed based on their genotype. Similarly, subjects that underwent renal transplant after 2010 and received standard tacrolimus dosing (per package insert) will serve as historical controls.</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Adverse Outcomes</title>
          <description>Number of adverse outcomes (i.e., graft loss, infection, and death)</description>
          <units>adverse outcomes</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="40"/>
                <count group_id="O2" value="57"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Graft loss</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Infection</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="12"/>
                    <measurement group_id="O2" value="17"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Death</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>Direct and Indirect Costs</title>
        <description>Direct and indirect cost related to treatment and management kidney transplant recipients</description>
        <time_frame>12 months</time_frame>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Adverse events are reported from the study start through Study Day 365.</time_frame>
      <group_list>
        <group group_id="E1">
          <title>CYP3A5 Based Tacrolimus Dosing</title>
          <description>Subjects in this treatment arm will receive initial tacrolimus based on their genotype i.e., CYP3A5*1/*1 and CYP3A5*1/*3 (Expressers) will receive the initial tacrolimus dose of 0.2 mg/kg/day, with maximum of 20 mg/day in 2 divided doses. For CYP3A5*3/*3 (Non-Expressers), the subjects will receive initial tacrolimus dose of 0.1 mg/kg/day in 2 divided doses.&#xD;
Tacrolimus: See description in arm/group sections</description>
        </group>
        <group group_id="E2">
          <title>Control</title>
          <description>Subjects in the prospective control group will receive standard tacrolimus dosing as recommended per package insert and will not be dosed based on their genotype. Similarly, subjects that underwent renal transplant after 2010 and received standard tacrolimus dosing (per package insert) will serve as historical controls.</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="1" subjects_at_risk="40"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="40"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="57"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Biopsy Proven Acute Rejection</sub_title>
                <counts group_id="E1" events="6" subjects_affected="4" subjects_at_risk="40"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="57"/>
              </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="40" subjects_at_risk="40"/>
                <counts group_id="E2" subjects_affected="57" subjects_at_risk="57"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Leukopenia</sub_title>
                <counts group_id="E1" events="86" subjects_affected="30" subjects_at_risk="40"/>
                <counts group_id="E2" events="101" subjects_affected="37" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Anemia</sub_title>
                <counts group_id="E1" events="115" subjects_affected="39" subjects_at_risk="40"/>
                <counts group_id="E2" events="96" subjects_affected="56" subjects_at_risk="57"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Hypertension</sub_title>
                <counts group_id="E1" events="24" subjects_affected="11" subjects_at_risk="40"/>
                <counts group_id="E2" events="40" subjects_affected="25" subjects_at_risk="57"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Diarrhea</sub_title>
                <counts group_id="E1" events="16" subjects_affected="12" subjects_at_risk="40"/>
                <counts group_id="E2" events="37" subjects_affected="22" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" events="26" subjects_affected="12" subjects_at_risk="40"/>
                <counts group_id="E2" events="28" subjects_affected="21" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Constipation</sub_title>
                <counts group_id="E1" events="18" subjects_affected="9" subjects_at_risk="40"/>
                <counts group_id="E2" events="12" subjects_affected="9" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" events="14" subjects_affected="8" subjects_at_risk="40"/>
                <counts group_id="E2" events="15" subjects_affected="10" subjects_at_risk="57"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Infection</sub_title>
                <counts group_id="E1" events="12" subjects_affected="10" subjects_at_risk="40"/>
                <counts group_id="E2" events="17" subjects_affected="12" subjects_at_risk="57"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Hyperkalemia</sub_title>
                <counts group_id="E1" events="65" subjects_affected="28" subjects_at_risk="40"/>
                <counts group_id="E2" events="90" subjects_affected="44" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Hyperglycemia</sub_title>
                <counts group_id="E1" events="89" subjects_affected="18" subjects_at_risk="40"/>
                <counts group_id="E2" events="53" subjects_affected="23" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Hypomagnesemia</sub_title>
                <counts group_id="E1" events="94" subjects_affected="33" subjects_at_risk="40"/>
                <counts group_id="E2" events="145" subjects_affected="53" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Hypophosphatemia</sub_title>
                <counts group_id="E1" events="34" subjects_affected="20" subjects_at_risk="40"/>
                <counts group_id="E2" events="48" subjects_affected="27" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Hyperlipidemia</sub_title>
                <counts group_id="E1" events="7" subjects_affected="7" subjects_at_risk="40"/>
                <counts group_id="E2" events="16" subjects_affected="14" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Edema</sub_title>
                <counts group_id="E1" events="20" subjects_affected="9" subjects_at_risk="40"/>
                <counts group_id="E2" events="22" subjects_affected="12" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Hypokalemia</sub_title>
                <counts group_id="E1" events="9" subjects_affected="7" subjects_at_risk="40"/>
                <counts group_id="E2" events="9" subjects_affected="8" subjects_at_risk="57"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Neurotoxicity</sub_title>
                <counts group_id="E1" events="5" subjects_affected="3" subjects_at_risk="40"/>
                <counts group_id="E2" events="5" subjects_affected="5" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Tremor</sub_title>
                <counts group_id="E1" events="12" subjects_affected="10" subjects_at_risk="40"/>
                <counts group_id="E2" events="25" subjects_affected="22" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" events="16" subjects_affected="11" subjects_at_risk="40"/>
                <counts group_id="E2" events="26" subjects_affected="21" subjects_at_risk="57"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Abnormal renal function</sub_title>
                <counts group_id="E1" events="56" subjects_affected="23" subjects_at_risk="40"/>
                <counts group_id="E2" events="73" subjects_affected="39" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Increase creatinine</sub_title>
                <counts group_id="E1" events="36" subjects_affected="20" subjects_at_risk="40"/>
                <counts group_id="E2" events="29" subjects_affected="21" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Delayed Graft Function Requiring Dialysis</sub_title>
                <counts group_id="E1" events="13" subjects_affected="13" subjects_at_risk="40"/>
                <counts group_id="E2" events="12" subjects_affected="12" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Graft loss</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="40"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="57"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>All Principal Investigators ARE 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>Robert Dupuis, PharmD</name_or_title>
      <organization>University of North Carolina at Chapel Hill</organization>
      <phone>919-966-6194</phone>
      <email>re_dupuis@unc.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/NCT03020589
org study id: 16-2073
nct id: NCT03020589
lead sponsor: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
is us export: No
Objective: Investigate the direct correlation of CYP3A5 genotype with tacrolimus trough
      levels and clinical outcomes. The primary endpoint of this study is to evaluate the
      proportion of patients reaching target levels (8-10 ng/mL) on Day 3 and Day 7 after kidney
      transplantation.
Participants: All new kidney transplant recipients aged 18 to 65 years who are admitted at
      UNC-CH and provided informed consent will be included in this study (Unless they meet the
      exclusion criteria specified). A total of an anticipated 260 subjects will be included in the
      study, 130 of which will be included in the pharmacogenomic group and the remaining 130 will
      be in the control group.

      Procedures (methods): The pharmacogenomic group will partake in a 12-month study comprising
      of two periods, Genotype-Guided Initial Dosing Intervention and Follow-up.

      Briefly, patients on transplant waitlist will be screened for eligibility. At the
      pre-intervention assessment (Study Day 0), buccal swab samples for genotyping will be
      collected on all eligible patients who provided informed consent (performed in real time).
      Results of the genotyping test will be incorporated into electronic medical record (EMR). The
      initial tacrolimus dose will be based on genotype: 0.1 mg/kg/day (non- expressers) or 0.2
      mg/kg/day, with maximum of 20 mg/day (expressers) given in 2 divided doses. Eligible patients
      who consented to receive genotype-guided tacrolimus dose will enter the pharmacogenomic group
      and will receive the initial tacrolimus dosing based on genotype results following kidney
      transplantation (Study Day 1). Subsequent tacrolimus dosing will then be adjusted according
      to trough concentrations (C0) and therapeutic target concentrations. The genotype-guided
      dosing recommendation for tacrolimus only refers to the initial tacrolimus dose. All patients
      in the pharmacogenomic group will be followed from Study Day 2 and up to 12 months to assess
      long-term outcome.

      Age-, race-, and disease-matched patients who had previously received kidney transplantation
      with standard tacrolimus dosing from 2010 to present will also be asked to give consent for
      genotyping (historical controls). These patients will be included in the control group and
      their safety and efficacy data will be collected retrospectively for up to 12 months from the
      initiation of first tacrolimus dose.

      As there are confounding variables, including age, race and disease state that may impact the
      results of the study, our study design incorporates an overall matching strategy, so that we
      can identify a well-matched control group. First, to control for differences in care over
      time, patients in the pharmacogenomic group will be matched to controls enrolled from 2010 to
      present. This time period was selected as there had been no major changes in standard of care
      or treatment regimen since 2010. After eligibility is met, control patients will be selected
      to match the pharmacogenomic group using a computerized matching algorithm that has been
      optimized to match baseline demographic and disease characteristics that have been identified
      a priori as likely to influence the treatment response to tacrolimus. To balance the
      trade-off between minimizing bias and maximizing matched sample size, a systematic approach
      will be conducted to identify the number of matched control patients for each patient in the
      pharmacogenomic group. This approach will include the following steps: 1) run the desired
      matching algorithm, starting with 1:1 (one control to one patient in the pharmacogenomic
      group) matching and iterating until the maximum desired number of potential controls per
      treated subject is reached; 2) for each iteration, test for covariate balance; and (3)
      generate numeric summaries and graphical plots of the balance statistics across all
      iterations in order to determine the optimal number.

      The selection of patients for the control group using a matching algorithm will be conducted
      by an independent statistician in a blinded and unbiased manner. The statistician will have
      no knowledge of survival outcome, other outcome data, and genotype. The algorithm will not be
      used to guide treatment in any way.
allocation: Non-Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Proportion of Patients Reaching Target Tacrolimus Levels (8-10 ng/mL) on Day 3 After Kidney Transplantation
time frame: Day 3 after transplantation
measure: Proportion of Patients Reaching Target Tacrolimus Levels (8-10 ng/mL) on Day 7 After Kidney Transplantation
time frame: Day 7 after transplantation
measure: Number of Events of Biopsy Proven Acute Rejection (BPAR)
time frame: first 3 months (Days 0 through 90), 91-180, and 181-365 days after transplantation
description: The number of events of BPAR within the first 3 months (Days 0 through 90), 91-180, and 181-365 days after transplantation
measure: Tacrolimus Level
time frame: 4 months
description: Time to achieve tacrolimus therapeutic range at 0 to 4 months (8-10 ng/mL)
measure: Mean Number of Dose Adjustments and/or Drug Alterations
time frame: 12 months
description: Mean number of dose adjustments and/or drug alteration or addition due to insufficient immunosuppression.
measure: Percent of Participants With Chronic Renal Impairment by eGFR Category
time frame: 12 months
description: Renal function will be assessed using estimated Glomerular Filtration Rate (eGFR). Creatinine clearance (CrCl) may also be calculated as a reference. Patients will be categorized as having either mild (eGFR of 60 mL/min/1.73m^2 to 89 mL/min/1.73m^2), moderate (eGFR of 30 mL/min/1.73m^2 to 59 mL/min/1.73m^2), or severe renal impairment (eGFR <30 mL/min/1.73m^2).
measure: Number of Adverse Outcomes
time frame: 12 months
description: Number of adverse outcomes (i.e., graft loss, infection, and death)
measure: Direct and Indirect Costs
time frame: 12 months
description: Direct and indirect cost related to treatment and management kidney transplant recipients
arm group label: CYP3A5 based tacrolimus dosing
arm group type: Experimental
description: Subjects in this treatment arm will receive initial tacrolimus based on their genotype i.e., CYP3A5*1/*1 and CYP3A5*1/*3 (Expressers) will receive the initial tacrolimus dose of 0.2 mg/kg/day, with maximum of 20 mg/day in 2 divided doses. For CYP3A5*3/*3 (Non-Expressers), the subjects will receive initial tacrolimus dose of 0.1 mg/kg/day in 2 divided doses.
arm group label: Control
arm group type: No Intervention
description: Subjects in the prospective control group will receive standard tacrolimus dosing as recommended per package insert and will not be dosed based on their genotype. Similarly, subjects that underwent renal transplant after 2010 and received standard tacrolimus dosing (per package insert) will serve as historical controls.
intervention type: Drug
intervention name: Tacrolimus
description: See description in arm/group sections
arm group label: CYP3A5 based tacrolimus dosing
other name: Prograf, Advagraf
criteria: 
gender: All
minimum age: 18 Years
maximum age: 65 Years
healthy volunteers: No
last name: Alexander Toledo, MD
role: Principal Investigator
affiliation: University of North Carolina, Chapel Hill
facility: 
country: United States
responsible party type: Sponsor
mesh term: Tacrolimus
sharing ipd: No
ipd description: No participant data will be shared outside the research team.
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 