xml: <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/NCT05997810</url>
    </required_header>
    <id_info>
      <org_study_id>202212100</org_study_id>
      <nct_id>NCT05997810</nct_id>
    </id_info>
    <brief_title>Parathyroid Tumor Clonal Status</brief_title>
    <official_title>A Phase 2 Biomarker Study of Parathyroid Tumor Clonal Status in Primary Hyperparathyroidism</official_title>
    <sponsors>
      <lead_sponsor>
        <agency>Washington University School of Medicine</agency>
        <agency_class>Other</agency_class>
      </lead_sponsor>
    </sponsors>
    <source>Washington University School of Medicine</source>
    <oversight_info>
      <has_dmc>No</has_dmc>
      <is_fda_regulated_drug>No</is_fda_regulated_drug>
      <is_fda_regulated_device>No</is_fda_regulated_device>
    </oversight_info>
    <brief_summary>
      <textblock>
        To define the frequency of monoclonal-X and polyclonal-X tumors in PHPT participants having&#xD;
        parathyroidectomy (PTX) and to define the relationship between parathyroid tumor clonal&#xD;
        status and multiple gland neoplasia (MGN), we will compare surgical and pathologic outcomes&#xD;
        to tumor clonal status in a multicenter cohort of patients having bilateral neck exploration&#xD;
        (BNE) and PTX (primary objectives).&#xD;
      </textblock>
    </brief_summary>
    <detailed_description>
      <textblock>
        To define the frequency of monoclonal-X and polyclonal-X tumors in primary&#xD;
        hyperparathyroidism (PHPT) participants having parathyroidectomy (PTX) and to define the&#xD;
        relationship between parathyroid tumor clonal status and multiple gland neoplasia (MGN), the&#xD;
        investigators will compare surgical and pathologic outcomes to tumor clonal status in a&#xD;
        multicenter cohort of participants having bilateral neck exploration (BNE) and PTX.&#xD;
  &#xD;
        Study participants will be recruited from four high-volume centers at Washington University&#xD;
        in St. Louis (WU), University of California San Francisco, University of Alabama-Birmingham,&#xD;
        and the University of Pennsylvania. Eligible participants will receive standard of care&#xD;
        treatment (parathyroidectomy) and de-identified formalin-fixed paraffin-embedded (FFPE) tumor&#xD;
        samples (stained and unstained from each abnormal gland) will be sent to WU for study. DNA&#xD;
        will be extracted from FFPE samples and the HUMARA assay will be performed according to our&#xD;
        established protocol. Our two published studies show &gt;90% concordance between replicate&#xD;
        HUMARA assays of the same tumor. For additional rigor, two regions of each tumor will be&#xD;
        assayed independently to ensure concordance of clonal status. Tumors where the clonality call&#xD;
        from the two within-tumor samples are discordant will be recorded as such, and the&#xD;
        investigators will perform sensitivity analyses, for aims where this is relevant, of&#xD;
        assigning one or the other clonal state to these samples.&#xD;
  &#xD;
        Further, the investigators will employ a secondary assay (Cytoscan HD array, ThermoFisher) to&#xD;
        assess DNA copy number variation (CNV) in a random set of samples from 58 polyclonal-X cases&#xD;
        and 49 monoclonal-X cases (estimated 107 total assays). Published and unpublished data have&#xD;
        shown that CNV occurs with considerable frequency in parathyroid tumors, including adenomas.&#xD;
        CNV assessment can provide independent verification of an X-inactivation-based finding of&#xD;
        polyclonality by identifying heterogeneous CNV within a tumor sample indicating&#xD;
        polyclonality, or more uniform CNV reflecting monoclonality. Cases with discordant results&#xD;
        (estimated &lt;10%) from HUMARA and CNV assays will be comprehensively studied in the&#xD;
        exploratory objectives.&#xD;
  &#xD;
        De-identified pathologic data including the number and weight of abnormal glands removed from&#xD;
        participants will be recorded at local study sites and entered in a REDCap database&#xD;
        maintained at WU. The Investigators then will review operative and pathologic reports for&#xD;
        correlation of tumor clonality and the presence of single gland neoplasia (SGN) or multiple&#xD;
        gland neoplasia (MGN). In cases of MGN the investigators will perform ms-PCR of HUMARA&#xD;
        alleles on all resected tumors to assess for concordance of clonality. The investigators will&#xD;
        also determine the impact of two common surgical approaches on outcomes in tumors of&#xD;
        different clonal status. The frequency of MGN stratified by tumor clonality will be examined&#xD;
        in participants who undergo UNE with ioPTH monitoring and compared BNE. Operative and&#xD;
        pathology reports will be reviewed as well as ioPTH levels drawn before and both 5 and 10&#xD;
        minutes (PTH T1/2 = 5 min.) after tumor removal. Underlying tumor clonality will be&#xD;
        determined as described above and will be compared to pathologic results (MGN versus SGN), as&#xD;
        well as ioPTH kinetics (% decline from pre-op PTH levels at 5 and 10 minutes after final&#xD;
        tumor removal).&#xD;
  &#xD;
        To define the relationship between parathyroid tumor clonal status and biochemical outcomes&#xD;
        following PTX for PHPT, the investigators will compare baseline clinical features,&#xD;
        surgical/pathologic findings and postoperative biochemical outcomes following PTX to tumor&#xD;
        clonal status in a large, multicenter cohort of participants having PTX. A total of 645&#xD;
        participants with known tumor clonal status will have standard clinical and biochemical data&#xD;
        (serum calcium, albumin, intact PTH, 25(OH)D, and creatinine) recorded at baseline (before&#xD;
        PTX), and at 2 weeks, 3 months, and 6 months post-PTX (not all labs are recorded at each&#xD;
        follow-up time point). The investigators will compare the frequency of elevated PTH (ePTH) at&#xD;
        each time point in participants with monoclonal-X and polyclonal-X tumors. The investigators&#xD;
        have previously shown that vitamin D status impacts ePTH following PTX. To investigate&#xD;
        abnormal vitamin D metabolism, the most common mechanism of secondary hyperparathyroidism as&#xD;
        a cause of polyclonal-X disease, the investigators also will perform a comprehensive analysis&#xD;
        of vitamin D status in a subset of 111 WUSM participants with monoclonal-X and polyclonal-X&#xD;
        tumors. Our analysis will include biochemical indices of vitamin D metabolism&#xD;
        (25-hydroxyvitamin D, 1,25-dihydroxyvitamin D and vitamin D binding protein levels).&#xD;
      </textblock>
    </detailed_description>
    <overall_status>Active, not recruiting</overall_status>
    <start_date type="Actual">April 11, 2023</start_date>
    <completion_date type="Anticipated">January 2026</completion_date>
    <primary_completion_date type="Anticipated">January 2025</primary_completion_date>
    <study_type>Observational</study_type>
    <has_expanded_access>No</has_expanded_access>
    <study_design_info>
      <observational_model>Case-Only</observational_model>
      <time_perspective>Prospective</time_perspective>
    </study_design_info>
    <primary_outcome>
      <measure>Primary Endpoint 1</measure>
      <time_frame>24 months</time_frame>
      <description>Frequency of occurrence of monoclonal-X versus polyclonal-X parathyroid tumors in a prospective multi-center cohort of patients having parathyroidectomy for primary hyperparathyroidism.</description>
    </primary_outcome>
    <primary_outcome>
      <measure>Primary Endpoint 2</measure>
      <time_frame>24 months</time_frame>
      <description>Determine clinicopathologic features of monoclonal-X versus polyclonal-X parathyroid tumors in a prospective multi-center cohort of patients with PHPT referred for PTX.</description>
    </primary_outcome>
    <primary_outcome>
      <measure>Primary Endpoint 3</measure>
      <time_frame>24 months</time_frame>
      <description>Perform a prospective study of biochemical outcomes of PTX in PHPT patients with monoclonal-X and polyclonal-X tumors.</description>
    </primary_outcome>
    <secondary_outcome>
      <measure>Secondary Endpoint</measure>
      <time_frame>24 months</time_frame>
      <description>To investigate mechanism(s) of monoclonal-X and polyclonal-X parathyroid tumorigenesis using functional and genomic approaches (e.g. calcium sensing capacity determined by EC50 and single nucleotide variants / copy number variation).</description>
    </secondary_outcome>
    <enrollment type="Anticipated">839</enrollment>
    <condition>Parathyroid Tumor</condition>
    <condition>Primary Hyperparathyroidism</condition>
    <biospec_retention>Samples Without DNA</biospec_retention>
    <biospec_descr>
      <textblock>
        Biospecimen samples will be obtained from FFPE tumor slides, Fresh-frozen tissue, and Blood.&#xD;
  &#xD;
        NOTE: Fresh-frozen tumor, normal gland biopsy and blood samples will be collected at the WUSM&#xD;
        study site only.&#xD;
      </textblock>
    </biospec_descr>
    <eligibility>
      <study_pop>
        <textblock>
          Females scheduled to have surgery for primary hyperparathyroidism.&#xD;
        </textblock>
      </study_pop>
      <sampling_method>Non-Probability Sample</sampling_method>
      <criteria>
        <textblock>
          Inclusion Criteria:&#xD;
  &#xD;
            -  Diagnosed with nonfamilial primary hyperparathyroidism biochemically confirmed by&#xD;
               measurement of serum calcium and intact PTH within 60 days of enrollment.&#xD;
  &#xD;
            -  Female.&#xD;
  &#xD;
            -  Age ≥ 18 years&#xD;
  &#xD;
            -  Ability to understand and willingness to sign an IRB approved written informed consent&#xD;
               document (or that of legally authorized representative, if applicable).&#xD;
  &#xD;
          Exclusion Criteria:&#xD;
  &#xD;
            -  Patients with a history of cervicofacial irradiation.&#xD;
  &#xD;
            -  Patients with recurrent or persistent PHPT after prior PTX.&#xD;
  &#xD;
            -  Patients with secondary hyperparathyroidism due to renal failure on renal replacement&#xD;
               therapy (i.e. hemodialysis or peritoneal dialysis).&#xD;
  &#xD;
            -  Patients with tertiary hyperparathyroidism due to renal failure with or without&#xD;
               history of renal transplantation.&#xD;
  &#xD;
            -  Patients receiving calcimimetic agents (e.g. cinacalcet / Sensipar) within 30 days of&#xD;
               PTX.&#xD;
  &#xD;
            -  Patients currently taking lithium or with a history of lithium use.&#xD;
  &#xD;
            -  Pregnant patients&#xD;
        </textblock>
      </criteria>
      <gender>Female</gender>
      <minimum_age>18 Years</minimum_age>
      <maximum_age>80 Years</maximum_age>
      <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
    </eligibility>
    <location>
      <facility>
        <name>University of Alabama-Birmingham</name>
        <address>
          <city>Birmingham</city>
          <state>Alabama</state>
          <zip>35233</zip>
          <country>United States</country>
        </address>
      </facility>
    </location>
    <location>
      <facility>
        <name>University of California-Department of Surgery</name>
        <address>
          <city>San Francisco</city>
          <state>California</state>
          <zip>94143</zip>
          <country>United States</country>
        </address>
      </facility>
    </location>
    <location>
      <facility>
        <name>Hospital of the University of Pennsylvania</name>
        <address>
          <city>Philadelphia</city>
          <state>Pennsylvania</state>
          <zip>19104</zip>
          <country>United States</country>
        </address>
      </facility>
    </location>
    <location_countries>
      <country>United States</country>
    </location_countries>
    <verification_date>August 2023</verification_date>
    <study_first_submitted>August 4, 2023</study_first_submitted>
    <study_first_submitted_qc>August 11, 2023</study_first_submitted_qc>
    <study_first_posted type="Actual">August 18, 2023</study_first_posted>
    <last_update_submitted>August 11, 2023</last_update_submitted>
    <last_update_submitted_qc>August 11, 2023</last_update_submitted_qc>
    <last_update_posted type="Actual">August 18, 2023</last_update_posted>
    <responsible_party>
      <responsible_party_type>Sponsor</responsible_party_type>
    </responsible_party>
    <condition_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Parathyroid Neoplasms</mesh_term>
      <mesh_term>Hyperparathyroidism</mesh_term>
      <mesh_term>Hyperparathyroidism, Primary</mesh_term>
    </condition_browse>
    <!-- Results have not yet been posted for this study                                          -->
  </clinical_study>
  
  
text: 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/NCT05997810
  org study id: 202212100
  nct id: NCT05997810
  lead sponsor: 
  has dmc: No
  is fda regulated drug: No
  is fda regulated device: No
  To define the frequency of monoclonal-X and polyclonal-X tumors in PHPT participants having
        parathyroidectomy (PTX) and to define the relationship between parathyroid tumor clonal
        status and multiple gland neoplasia (MGN), we will compare surgical and pathologic outcomes
        to tumor clonal status in a multicenter cohort of patients having bilateral neck exploration
        (BNE) and PTX (primary objectives).
  To define the frequency of monoclonal-X and polyclonal-X tumors in primary
        hyperparathyroidism (PHPT) participants having parathyroidectomy (PTX) and to define the
        relationship between parathyroid tumor clonal status and multiple gland neoplasia (MGN), the
        investigators will compare surgical and pathologic outcomes to tumor clonal status in a
        multicenter cohort of participants having bilateral neck exploration (BNE) and PTX.
  
        Study participants will be recruited from four high-volume centers at Washington University
        in St. Louis (WU), University of California San Francisco, University of Alabama-Birmingham,
        and the University of Pennsylvania. Eligible participants will receive standard of care
        treatment (parathyroidectomy) and de-identified formalin-fixed paraffin-embedded (FFPE) tumor
        samples (stained and unstained from each abnormal gland) will be sent to WU for study. DNA
        will be extracted from FFPE samples and the HUMARA assay will be performed according to our
        established protocol. Our two published studies show >90% concordance between replicate
        HUMARA assays of the same tumor. For additional rigor, two regions of each tumor will be
        assayed independently to ensure concordance of clonal status. Tumors where the clonality call
        from the two within-tumor samples are discordant will be recorded as such, and the
        investigators will perform sensitivity analyses, for aims where this is relevant, of
        assigning one or the other clonal state to these samples.
  
        Further, the investigators will employ a secondary assay (Cytoscan HD array, ThermoFisher) to
        assess DNA copy number variation (CNV) in a random set of samples from 58 polyclonal-X cases
        and 49 monoclonal-X cases (estimated 107 total assays). Published and unpublished data have
        shown that CNV occurs with considerable frequency in parathyroid tumors, including adenomas.
        CNV assessment can provide independent verification of an X-inactivation-based finding of
        polyclonality by identifying heterogeneous CNV within a tumor sample indicating
        polyclonality, or more uniform CNV reflecting monoclonality. Cases with discordant results
        (estimated <10%) from HUMARA and CNV assays will be comprehensively studied in the
        exploratory objectives.
  
        De-identified pathologic data including the number and weight of abnormal glands removed from
        participants will be recorded at local study sites and entered in a REDCap database
        maintained at WU. The Investigators then will review operative and pathologic reports for
        correlation of tumor clonality and the presence of single gland neoplasia (SGN) or multiple
        gland neoplasia (MGN). In cases of MGN the investigators will perform ms-PCR of HUMARA
        alleles on all resected tumors to assess for concordance of clonality. The investigators will
        also determine the impact of two common surgical approaches on outcomes in tumors of
        different clonal status. The frequency of MGN stratified by tumor clonality will be examined
        in participants who undergo UNE with ioPTH monitoring and compared BNE. Operative and
        pathology reports will be reviewed as well as ioPTH levels drawn before and both 5 and 10
        minutes (PTH T1/2 = 5 min.) after tumor removal. Underlying tumor clonality will be
        determined as described above and will be compared to pathologic results (MGN versus SGN), as
        well as ioPTH kinetics (% decline from pre-op PTH levels at 5 and 10 minutes after final
        tumor removal).
  
        To define the relationship between parathyroid tumor clonal status and biochemical outcomes
        following PTX for PHPT, the investigators will compare baseline clinical features,
        surgical/pathologic findings and postoperative biochemical outcomes following PTX to tumor
        clonal status in a large, multicenter cohort of participants having PTX. A total of 645
        participants with known tumor clonal status will have standard clinical and biochemical data
        (serum calcium, albumin, intact PTH, 25(OH)D, and creatinine) recorded at baseline (before
        PTX), and at 2 weeks, 3 months, and 6 months post-PTX (not all labs are recorded at each
        follow-up time point). The investigators will compare the frequency of elevated PTH (ePTH) at
        each time point in participants with monoclonal-X and polyclonal-X tumors. The investigators
        have previously shown that vitamin D status impacts ePTH following PTX. To investigate
        abnormal vitamin D metabolism, the most common mechanism of secondary hyperparathyroidism as
        a cause of polyclonal-X disease, the investigators also will perform a comprehensive analysis
        of vitamin D status in a subset of 111 WUSM participants with monoclonal-X and polyclonal-X
        tumors. Our analysis will include biochemical indices of vitamin D metabolism
        (25-hydroxyvitamin D, 1,25-dihydroxyvitamin D and vitamin D binding protein levels).
  observational model: Case-Only
  time perspective: Prospective
  measure: Primary Endpoint 1
  time frame: 24 months
  description: Frequency of occurrence of monoclonal-X versus polyclonal-X parathyroid tumors in a prospective multi-center cohort of patients having parathyroidectomy for primary hyperparathyroidism.
  measure: Primary Endpoint 2
  time frame: 24 months
  description: Determine clinicopathologic features of monoclonal-X versus polyclonal-X parathyroid tumors in a prospective multi-center cohort of patients with PHPT referred for PTX.
  measure: Primary Endpoint 3
  time frame: 24 months
  description: Perform a prospective study of biochemical outcomes of PTX in PHPT patients with monoclonal-X and polyclonal-X tumors.
  measure: Secondary Endpoint
  time frame: 24 months
  description: To investigate mechanism(s) of monoclonal-X and polyclonal-X parathyroid tumorigenesis using functional and genomic approaches (e.g. calcium sensing capacity determined by EC50 and single nucleotide variants / copy number variation).
  Biospecimen samples will be obtained from FFPE tumor slides, Fresh-frozen tissue, and Blood.
  
        NOTE: Fresh-frozen tumor, normal gland biopsy and blood samples will be collected at the WUSM
        study site only.
  study pop: 
  sampling method: Non-Probability Sample
  criteria: 
  gender: Female
  minimum age: 18 Years
  maximum age: 80 Years
  healthy volunteers: Accepts Healthy Volunteers
  facility: 
  facility: 
  facility: 
  country: United States
  responsible party type: Sponsor
  mesh term: Parathyroid Neoplasms
  mesh term: Hyperparathyroidism
  mesh term: Hyperparathyroidism, Primary